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Advances in Experimental Medicine and Biology 1060
Benjamin M.J Owens

Matthew A. Lakins Editors
Stromal
Immunology
Advances in Experimental Medicine and Biology
Editorial Board:
IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel

ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy
NIMA REZAEI, Tehran University of Medical Sciences, Tehran, Iran
More information about this series at http://www.springer.com/series/5584

Benjamin M.J Owens • Matthew A. Lakins
Editors
Stromal Immunology
Editors
Benjamin M.J Owens Matthew A. Lakins
Somerville College F-star Biotechnology Ltd.,
University of Oxford Babraham Research Campus
Oxford, UK Cambridge, UK
EUSA Pharma
Hemel Hempstead
Hertfordshire, UK
ISSN 0065-2598 ISSN 2214-8019 (electronic)

Advances in Experimental Medicine and Biology
ISBN 978-3-319-78125-9 ISBN 978-3-319-78127-3 (eBook)
https://doi.org/10.1007/978-3-319-78127-3
Library of Congress Control Number: 2018948663
© Springer International Publishing AG, part of Springer Nature 2018

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
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Preface
The concept for this book arose as a result of growing interest in the investigation of
non-hematopoietic stromal cells and their impact on immune responses. Through
interactions during diverse doctoral and postdoctoral research programmes spanning
several years at the University of York, the University of Cambridge and the
University of Oxford, we recognised a need for a cohesive group to bring together
scientists interested in the concepts underlying stromal immunology, and the
Stromal Immunology Group (StIG) was born.
Having organised several successful international StIG conferences, we felt that
a missing part of the picture was an advanced book comprising a collection of writ-
ings from leaders in stromal immunology that could act as a primer for professional
researchers new to this specialist field. This book would also provide support for the
teaching of graduate and undergraduate students in science and medicine.
What follows is the collected work of scientists and physicians from across the
world, all of whom share a belief in the huge potential for research into stromal
immunology to contribute to medical research. Topics covered range from the inter-
action between leukocytes and lymph node stromal cells, inflammatory responses of
mesenchymal stem cells and fibroblasts to the key roles of stromal cells in response
to infection, the tumour microenvironment and the healthy and inflamed intestine.
Important avenues for future research are addressed, as are the uses of advanced cell
culture systems for the investigation of human tissue stromal cell function and stro-
mal cell targeting for therapeutic benefit.
Numerous studies have addressed the significant therapeutic potential of exploit-
ing stromal cells in combating disease. Pancreatic cancer, for example, and specifi-
cally pancreatic ductal adenocarcinoma (PDAC), is a stromal-rich, lethal malignancy
fundamentally resistant to standard of care therapies. Much work has been carried
out targeting the desmoplasmic nature of PDAC, particularly the cancer-associated
fibroblast and endothelial cell containing component. Whilst strategies aimed at
depleting these cell types to aid drug perfusion and immune cell infiltration work
well in murine models, the translatability of such approaches remains in question.
This approach is not limited to pancreatic cancer. Many other stromal-rich
tumours which employ a highly desmoplastic stroma as a physical barrier to immune
v
vi Preface
cell infiltration could be treated in such a way. Breast, prostate, and colon cancer all
recruit and influence their tumour microenvironment in order to regulate immune
escape, promote metastasis and aid progression. These cancers, and more recently
others such as non-small cell lung carcinoma, are put through a prognostic test
evaluating their tumour:stroma ratio and the outcome is used to successfully predict
prognosis and the chances of relapse. Soon, tools such as the tumour:stroma ratio
measurement could serve as an influencing factor on suggested treatment and
whether targeting the stroma is a valid approach for those specific diseases.
Similarly, gaining a deeper understanding of specific mediators of stromal cell
activation in chronically inflamed tissue – such as the recent discovery of Oncostatin
M as a driver of intestinal stromal cell activation during inflammatory bowel dis-
ease – may lead to the identification of novel therapeutic axes that can be targeted
to revolutionise therapy for patients with these debilitating inflammatory
conditions.
We hope that this introduction to advanced concepts in stromal immunology
serves as a useful, stimulating and enjoyable tool for those with an interest in
learning more about this exciting area of immunology, and we look forward to
seeing the field expand and grow over the coming years.
And remember, ‘It’s all about the Stroma’
Oxford, UK Benjamin M.J Owens

Hertfordshire, UK
Cambridge, UK Matthew A. Lakins
Acknowledgements
This textbook was produced as a collaboration between the British Society for
Immunology, the BSI Stromal Immunology Group and Springer Publishing,
USA. We are indebted to all the authors for their valuable contributions.
vii
Contents
1 Leukocyte-Stromal Interactions Within Lymph Nodes�� 1

Joshua D’Rozario, David Roberts, Muath Suliman,
Konstantin Knoblich, and Anne Fletcher
2 Stromal Cell Responses in Infection�� 23
Paul M. Kaye
3 Fibroblasts and Osteoblasts in Inflammation and Bone Damage �� 37
Jason D. Turner, Amy J. Naylor, Christopher Buckley,
Andrew Filer, and Paul-Peter Tak
4 Molecular and Cellular Requirements for the Assembly
of Tertiary Lymphoid Structures�� 55
C. G. Mueller, S. Nayar, J. Campos, and F. Barone
5 Mesenchymal Stem Cells as Endogenous Regulators
of Inflammation�� 73
Hafsa Munir, Lewis S. C. Ward, and Helen M. McGettrick
6 Stromal Cells in the Tumor Microenvironment�� 99
Alice E. Denton, Edward W. Roberts, and Douglas T. Fearon
7 Immunosuppression by Intestinal Stromal Cells�� 115
Iryna V. Pinchuk and Don W. Powell
8 Novel Models to Study Stromal Cell-Leukocyte
Interactions in Health and Disease�� 131
Mattias Svensson and Puran Chen
Index�� 147
ix
Contributors
F. Barone Rheumatology Research Group, Institute of Inflammation and Ageing

(IIA), University of Birmingham, Birmingham, UK
Christopher Buckley Rheumatology Research Group, Institute for Inflammation
and Ageing, College of Medical and Dental Sciences, University of Birmingham,
Queen Elizabeth Hospital, Birmingham, UK
The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
J. Campos Rheumatology Research Group, Institute of Inflammation and Ageing
Puran Chen Center for Infectious Medicine, F59, Department of Medicine,
Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm,
Sweden
Joshua D’Rozario Department of Biochemistry and Molecular Biology, Monash
University, Clayton, VIC, Australia
Institute of Immunology and Immunotherapy, University of Birmingham,
Birmingham, UK
Alice E. Denton Lymphocyte Signalling and Development, Babraham Institute,
Cambridge, UK
Douglas T. Fearon Cold Spring Harbor Laboratory, Weill Cornell Medical
College, New York, NY, USA
Andrew Filer Rheumatology Research Group, Institute for Inflammation and
Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen
Elizabeth Hospital, Birmingham, UK
Anne Fletcher Department of Biochemistry and Molecular Biology, Monash
University, Clayton, VIC, Australia
Birmingham, UK
xi
xii Contributors
Paul M. Kaye Centre for Immunology and Infection, Department of Biology and
Hull York Medical School, University of York, York, UK
Konstantin Knoblich Department of Biochemistry and Molecular Biology,
Monash University, Clayton, VIC, Australia
Birmingham, UK
Helen M. McGettrick Rheumatology Research Group, Institute of Inflammation
and Ageing, University of Birmingham, Birmingham, UK
C. G. Mueller CNRS UPR 3572, Laboratory of Immunopathology and Therapeutic
Chemistry/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et
Cellulaire, Université de Strasbourg, Strasbourg, France
Hafsa Munir MRC Cancer Unit/Hutchison, University of Cambridge, Cambridge,
UK
S. Nayar Rheumatology Research Group, Institute of Inflammation and Ageing
Amy J. Naylor Rheumatology Research Group, Institute for Inflammation and
Iryna V. Pinchuk Departments of Internal Medicine, University of Texas Medical
Branch, Galveston, TX, USA
Microbiology and Immunology, University of Texas Medical Branch, Galveston,
TX, USA
Don W. Powell Departments of Internal Medicine, University of Texas Medical
Branch, Galveston, TX, USA
Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch,
Galveston, TX, USA
David Roberts Institute of Immunology and Immunotherapy, University of
Birmingham, Birmingham, UK
Edward W. Roberts Department of Pathology, University of California San
Francisco, San Francisco, CA, USA
Muath Suliman Institute of Immunology and Immunotherapy, University of
Birmingham, Birmingham, UK
Mattias Svensson Center for Infectious Medicine, F59, Department of Medicine,
Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm,
Sweden
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Contributors xiii
Paul-Peter Tak Division of Clinical Immunology & Rheumatology, Academic

Medical Center/University of Amsterdam, Amsterdam, The Netherlands
Jason D. Turner Rheumatology Research Group, Institute for Inflammation and
Lewis S. C. Ward Discovery Sciences, AstraZeneca, Cambridge, UK
Chapter 1
Leukocyte-Stromal Interactions Within
Lymph Nodes
Joshua D’Rozario, David Roberts, Muath Suliman,

Konstantin Knoblich, and Anne Fletcher
Abstract Lymph nodes play a crucial role in the formation and initiation of immune
responses, allowing lymphocytes to efficiently scan for foreign antigens and serving
as rendezvous points for leukocyte-antigen interactions. Here we describe the major
stromal subsets found in lymph nodes, including fibroblastic reticular cells, lym-
phatic endothelial cells, blood endothelial cells, marginal reticular cells, follicular
dendritic cells and other poorly defined subsets such as integrin alpha-7+ pericytes.
We focus on biomedically relevant interactions with T cells, B cells and dendritic
cells, describing pro-survival mechanisms of support for these cells, promotion of
their migration and tolerance-inducing mechanisms that help keep the body free of
autoimmune-mediated damage.
Keywords Stromal cells · Lymph nodes · Fibroblasts · FRCs · Lymphoid fibro-

blasts · Lymphatic endothelium · Endothelial cells · LECs · Stromal Immunology ·
Podoplanin · Non-haematopoietic
1.1 Introduction
Lymph nodes are the most prevalent secondary lymphoid organ (SLO), contained in
the neck, armpits, lungs, abdomen, collarbone, knee and groin regions [1]. They
range in size from a few millimetres to over 2 cm and enlarge significantly under
certain conditions involving immune activation, such as infection or cancer [1, 2].
J. D’Rozario · K. Knoblich (*) · A. Fletcher (*)

Department of Biochemistry and Molecular Biology, Monash University,
Clayton, VIC, Australia
Birmingham B15 2TT, United Kingdom
e-mail: [email protected]; [email protected]
D. Roberts · M. Suliman
Birmingham B15 2TT, United Kingdom
© Springer International Publishing AG, part of Springer Nature 2018 1

B. M.J Owens, M. A. Lakins (eds.), Stromal Immunology, Advances in Experimental
Medicine and Biology 1060, https://doi.org/10.1007/978-3-319-78127-3_1
2 J. D’Rozario et al.
Lymph nodes are structurally organised and contain a cortex, paracortex and
medulla, which are separated into different regions to allow the movement of lymph
through the organ [3]. The cortex is situated beneath the capsule and subcapsular
sinus with B lymphocytes and follicular dendritic cells contained within follicles
present in the cortical region [4]. The paracortex lies deeper within the lymph node
structure with T lymphocytes homing to these regions to interact with antigen-
presenting cells [4]. The medulla consists of B lymphocytes and macrophages dis-
persed within medullary cords which allow for the movement of lymph from the
cortex into efferent lymphatic vessels [4]. This structure allows for antigen-bearing
antigen-presenting cells (APCs) and lymphocytes to efficiently interact within the
lymph node, enabling an appropriate immune response against an invading patho-
gen [5]. The microenvironment of the lymph node is crucial for immune function
and consists of endothelial cells lining lymphatics and blood vessels and fibroblastic
reticular cells which create the internal reticular structure of lymphoid organs [6].
Lymph, which may bear soluble antigen, enters the lymph node through afferent
lymphatic vessels, where it empties into the subcapsular sinus and then traverses
through the medullary sinuses surrounding the medullary cords to interact with B
cells [4]. The lymph filters though the cortex where it exits via the efferent lym-
phatic vessels contained in the hilus [4]. Dendritic cells (DCs) actively migrate into
the lymph node via afferent lymphatics [7]. Dendritic cells then migrate to paracor-
tical T cell zone using stromal cells as a scaffold for migration [8]. B and T cells also
use the stroma to migrate, entering lymph nodes from the bloodstream through spe-
cialised high endothelial venules [9]. Following entry, B cells move to the B cell
follicles in the cortex, while T cells move to the paracortical T cell zone where they
can begin scanning arriving APCs for their cognate antigen [8, 10, 11].
Structural components of the lymph node are now broadly appreciated as pri-
mary regulators of the adaptive immune response [10, 12–26]. These lymphatic
structural components, termed lymph node stromal cells (LNSCs), comprise of non-
haematopoietic cells that can be divided into functionally and phenotypically dis-
tinct subsets based on surface expression of glycoproteins CD31 and podoplanin
(gp38) with an absence of haematopoietic marker CD45 [14]. These include blood
endothelial cells (BECs), lymphatic endothelial cells (LECs), integrin α7+ pericytes
(IAPs), follicular dendritic cells (FDCs) and fibroblastic reticular cells (FRCs) [14,
22, 27]. These stromal cells play a variety of roles in lymph node homeostasis and
function, as they interact with lymphocytes to create an optimal microenvironment
for cell activation and migration.
1.2 Fibroblastic Reticular Cells (FRCs)
Selectable markers: Gp38+, CD31-, ER-TR7+, LTβR+, desmin+, aSMA+

FRCs are myofibroblasts that have evolved to create a specialised microenviron-
ment within lymph nodes. FRCs are heterogeneous and exist in different niches
within the lymph node, fulfilling unique immunoregulatory roles [27] (Table 1.1,
Fig. 1.1a–f).
1 Leukocyte-Stromal Interactions Within Lymph Nodes 3
Table 1.1 Lymph node FRC subsets

FRC
subtype Characteristics Phenotype Function References
T cell zone Secretion of CCL19,CCL21 PDPN+, Maintaining T cell [8, 11, 14,
reticular and IL-7 within paracortex desmin+, homeostasis 22, 30, 33,
cells MAdCAM-, Forming conduit 36]
(TRCs) CCL19+, network
CCL21+ Allowing
lymphocytes to
migrate and
interact efficiently
on the 3D
meshwork
B cell zone Located in (resident) or near Resident cells: Supporting B cell [24, 25, 37,
reticular (inducible) B cell follicles. PDPN+, survival and 38]
cells They secrete BAFF and are CCL19+, BAFF+ follicle boundary
(BRCs) induced during inflammation Inducible cells: integrity
to produce CXCL13 PDPN+,
CXCL13+
Marginal Located in subcapsular PDPN+, desmin, Produce very high [39–41]
reticular region MADCAM1, levels of IL-7.
cells Not found in tertiary IL-7Hi, Precursor cell type
(MRCs) lymphoid organs CXCL13+, for FDCs within
RANKLHi lymph nodes
Follicular Within lymph nodes, FDCs CD21+, CD35+, Maintains [41, 42]
dendritic develop from MRCs but are MFGE8+, germinal centre
cells nonetheless highly distinct CXCL13+, integrity.
(FDCs) from other FRC types. ICAM1+, Facilitates the
Located within primary and VCAM1, BAFF+ production of
secondary B cell follicles. high-affinity
Secretion of CXCL13 antibodies
Pericytic Surrounds HEVs PDPN+ Prevents bleeding [34]
FRCs PDPN signals to CLEC-2 on from HEVs into
platelets to maintain lymph nodes
endothelial integrity
Medullary Associated with plasma PDPN+ Poorly studied [4]
FRCs cells and macrophages
1.2.1 Structural Roles
FRCs play crucial roles in secreting extracellular matrix components and forming a
cellular meshwork to give the lymph node strength, flexibility and structure [8, 14,
22, 28–30].
While not a focus of this review, as a general characteristic, FRCs secrete a broad
array of extracellular matrix components, including collagens and laminins,
decorin, biglycan, fibromodulin and vitronectin, to maintain the lymph node struc-
ture [8, 14, 22] (Fig. 1.1d).
T zone resident FRCs facilitate leukocyte migration and priming by supporting
and secreting a 3D conduit network to maintain the lymph node microenvironment
[8, 14, 30–32]. Conduits are microtubules created by FRCs, which secrete constituent
D’Rozario et al. A. B. C.
IL-7
CXCL13
Subcapsular & CCL19 BAFF
CCL21
perifollicular zone (C)
II Y II Y
T cell zone T CCR7+
B T B CXCR5+
ILC3
(A, B, D, E) BAFF-R+ IL-7-R+
O
O
T cell and DC B cell and ILC3
O
aracon B and T cell survival aracon
O
O
Medulla D. E.
O
O
Perivascular Pdpn+
Zone (F)
O
O
Conduit and ECM network DC migraon
FRC Platelet HEV

F.
S1P SIP1R1
SYK
P
PDPN CLEC2 VE Cadherin
juncons
Primary B cell follicle (B)
HEV integrity
Fig. 1.1 FRC subsets reside in different lymph node niches and fulfil distinct functions. (a) T zone
FRCs produce CCR7 ligands CCL19 and CCL21, which promote migration of naïve T cells and
dendritic cells [8, 11]. (b) Within primary B cell follicles, B zone FRCs produce BAFF to promote
the survival of naïve B cells [24], while within the paracortex, T zone FRCs produce IL-7 to pro-
mote the survival of naïve T cells [14]. (c) Within the subcapsular zone, marginal reticular cells
produce CXCL13 to interact with innate lymphoid-like cells [39]. In the perifollicular zone close
to primary B cell follicles, during inflammation some FRCs inducibly express CXCL13 to facili-
tate B cell follicle expansion [37]. (d) FRCs within the T zone create the conduit network through
secretion of basement membrane and other extracellular matrix components [8, 14, 22, 33]. (e) T
zone FRCs drive DC migration via signalling through DC-expressed CLEC-2, which binds podo-
planin expressed by FRCs [56]. (f) In the perivascular zone, FRCs maintain the blood-lymph bar-
rier by responding to infiltrating platelets. Platelets express CLEC-2, which binds podoplanin on
FRCs, delivering a SYK-mediated signalling cascade that results in release of sphingosine-1-
phosphate-1 from platelet surfaces, which binds S1P1-receptor on high endothelial venules, stimu-
lating upregulation of VE-cadherin, which tightens endothelial cell junctions and prevents further
nontargeted cell and liquid influx from the bloodstream [34]
basement membrane components and ensheath them. They permit low-molecular-

weight molecules arriving via lymphatics to permeate quickly into the T cell zone
to access resident dendritic cells (DCs) [30, 32, 33]. This allows DCs to rapidly
process and present antigen to scanning T cells, permitting speedy initiation of an
adaptive immune response. FRCs also surround high endothelial venules (HEVs)
where they maintain the blood-lymph barrier by signalling to CLEC2 expressed by
infiltrating blood-borne platelets, via the FRC-expressed glycoprotein ligand podo-
planin [34]. CLEC-2 signalling induces the release of sphingosine-1-phosphate
from the platelet surface, which regulates the binding strength of endothelial cells
through VE-cadherin junctions [34].
In response to infection or inflammation, FRCs dynamically regulate lymph

node expansion and contraction through expression of podoplanin, which maintains
actomyosin contractility under homeostatic conditions and permits relaxation when
it binds its ligand CLEC-2, expressed by DCs during inflammation [28, 29]. FRCs
also proliferate during inflammation [28, 29, 35]. These dual mechanisms allow the
lymph node to dynamically respond to and accommodate changing numbers of
lymphocytes during activation and contraction phases of the immune response [28,
29, 35].
These important structural roles for FRCs are briefly discussed here but have
been reviewed in detail elsewhere [22, 27].
1.2.2 Interactions with T Cells
1.2.2.1 Provision of Migration and Survival Factors
FRCs exist throughout the paracortical T cell zone; accordingly, interactions with T
cells have been most closely studied. Chemotactic factors secreted from paracorti-
cal FRCs create the T cell zone by attracting naïve T cells and antigen-presenting
cells (APCs) allowing them to initiate an immune response [10, 11, 14, 43]. This
occurs through secretion of CCL19 and CCL21, which signal to CCR7 expressed
by naïve T cells, leading to their migration through the lymph node [8, 10, 43, 44]
(Fig. 1.1a).
T zone FRCs have also been shown to promote the survival and turnover of naïve
lymphocytes via the secretion of T cell survival and growth factor IL-7 [14]
(Fig. 1.1b). The secretion of this factor regulates and maintains the naïve CD4+ and
CD8+ T lymphocyte pool within the lymph node ready for cell priming [14].
These effects of FRCs are particularly relevant to naïve T cells, since activated T
lymphocytes within the lymph node are retained and can continue to function when
FRCs are depleted [25].
1.2.2.2 Suppressive Tolerance
FRCs are capable of robustly suppressing CD8+ T cell proliferation early after their
activation [19–21] (Fig. 1.2a).
Early after activation, T cells secrete inflammatory cytokines interferon gamma
(IFN-γ) and tumour necrosis factor alpha (TNF-α), which stimulate FRCs to secrete
nitric oxide (NO). NO acts in a paracrine manner on T lymphocytes curbing their
proliferation [19–21]. NO is a highly pleiotropic molecule which facilitates many
metabolic and immunologic pathways within the body [45]. Activated T cell-derived
factors increase NO-producing enzyme nitric oxide synthase 2 (NOS2) mRNA and
protein levels in FRCs leading to the release of NO [19–21]. Accordingly, NOS2−/−
FRCs are unable to mediate T cell suppression [19–21]. Cyclooxygenases 1 and 2
D’Rozario et al.
A CD8 Fibroblastic
CD4
reticular cell
CD4 CD8
2. Nitric oxide release

1. IFN-γ, Dendritic cell
curbs T cell
TNF-α
proliferation
Lymphatic
endothelial cell
NOS2
T cell
B expression
CD8 T cell receptor specificity for peptide/MHC = deletion
CD8 Low/no T cell receptor specificity for peptide/MHC = survival
CD8 T cell receptor specificity for peptide/MHC = deletion
CD8 Low/no T cell receptor specificity for peptide/MHC = survival
Fig. 1.2 Lymph node stromal cells impose suppressive and deletional tolerance. (a) Newly acti-
vated CD8+ T cells produce IFN-γ, TNF-α and an unidentified signal, which induce FRCs to
increase expression of enzyme nitric oxide synthase 2 (NOS2) and produce nitric oxide (NO).
FRC-derived NO acts on the T cell population to curb proliferation [19–21]. LECs are similarly
capable of releasing NO to curb T cell proliferation [20]. (b) LECs and FRCs present endoge-
nously expressed tissue-restricted antigens on MHC class I molecules to CD8+ T cells and delete
T cells that respond with sufficient affinity [17, 18]. Similar mechanisms involving MHC class
II-dependent antigen presentation are likely to operate for CD4 T cells [23, 26]
(COX1 and 2) in conjunction with NO2 expression have been hypothesised to play
a potential role in T cell suppression, though further study is required [21].
This mechanism functions in vivo [20], though the immunological reach is still
poorly understood.
Lymph node stromal cells may also induce tolerance in CD4+ T cells types
through expression of MHC class II and associated antigen presentation pathway
molecules under steady state and inflammatory conditions [22, 23, 26]. This theory
has been reinforced by the ability of lymph node stromal cells to tolerise CD4+ T
cells through the presentation of self-antigens via peptide-MHC class II expression
[23, 26] and to induce homeostatic Treg proliferation [23]. In vitro data suggest that
FRCs, LECs and BECs may acquire MHC II molecules from dendritic cells through
cell-to-cell contact [26].
1.2.2.3 Deletional Tolerance
T cell tolerance induction by lymphoid stromal cells was first noted by Lee et al.
[13], who showed that CD8+ T cells expressing a TCR reactive to ovalbumin (OVA)
were specifically tolerised following interactions with lymph node stromal cells
expressing OVA and that this prevented mice that expressed OVA in the gut (iFABP-
tOVA) from developing autoimmunity. It was then shown that this response was due
to FRCs and that FRCs could directly present self-antigen to T cells via MHC class
I [18] (Fig. 1.2b), demonstrating that FRCs were capable of deleting autoreactive T
cells and preventing autoimmunity. PD-1−/− T cells or PD-L1-blocking antibodies
have been used to interfere with tolerance mechanisms in the iFABP-tOVA model,
causing autoimmune enteritis [46].
FRCs were shown to express an array of organ-specific and tissue-restricted anti-
gens [17, 18]. Tissue-restricted antigens (TRAs) are self-antigens native to periph-
eral tissues and organs and expressed at low levels within lymphoid organs for the
purpose of educating the immune system for tolerance induction [47]. A major
regulator of TRA expression in the thymus is the autoimmune regulator gene (Aire)
[47]. However, in non-haematopoietic lymph node stromal subsets, Aire is not
expressed [18]. It has been shown in human and murine tissues that increased
expression of the Aire-like protein DEAF-1 correlates with peripheral tissue antigen
(PTA) expression [48]. While other factors may simultaneously exist, these results
suggest a role of the DEAF-1 gene in regulating lymphatic PTA expression, which
requires further elucidation.
1.2.2.4 Systemic Effects of Interactions with T Cells
The depletion of FRCs has been shown to significantly attenuate cell-mediated

immunity, as FRCs are required for the initiation of antiviral immune responses [25,
49]. In conditional FRC knockout models (DM2 BAC transgenic/FAP-DTR mice),
naïve T and B lymphocytes were significantly depleted resulting in poor T and B
cell-mediated immune responses during influenza A virus infection [25].
Similarly, the CCL19-Cre × Ltbr−/− mouse, which has an abnormal FRC network
low in podoplanin, CCL19, CCL21 and IL-7, was unable to clear systemic lympho-
cytic choriomeningitis virus (LCMV) or mouse hepatitis virus showing a requirement
for full FRC maturity [49]. These mice showed a 60–70% depletion of T cells and
were unable to clear the viral infections by day 10 compared to control mice [49].
CCL19-Cre × iDTR mice, which are susceptible to inducible depletion of FRCs
upon administration of diphtheria toxin, exhibited the loss of naïve CD4+ and CD8+
T cells within the lymph node during FRC ablation, as immunisation of mice with
inactive influenza A virus led to an impairment of T cell priming and proliferation,
with deterioration of antiviral T cell responses [24].
Furthermore, transplantation of IL-7Cre × R26-EYFP mice lymph nodes into
C57BL/6 mice have shown that FRCs play a crucial role in providing IL-7 to ini-
tialise successful reformation of lymph node structure after avascular transplanta-
tion [50]. IL-7 derived from FRCs was also shown to promote T cell
immunocompetence leading to structural adaptation of the lymph node microenvi-
ronment following systemic viral infection [50]. Damage to FRCs in clinical set-
tings, in particular HIV infection, causes profound T cell immunodeficiency
independent of viral load [51, 52].
1.2.3 Interactions with B Cells
FRCs in primary B cell follicles produce B cell-activating factor (BAFF) [24], a

cytokine which drives the proliferation and maturation of B cells [53]. The produc-
tion of this cytokine within primary follicles provides a favourable niche for B lym-
phocytes to develop [24] (Fig. 1.1b). Accordingly, FRC depletion has been shown
to reduce the pool of naive B cells within lymph nodes [24, 25].
FRCs in the perifollicular zone have been shown to produce CXCL13 during
infection, enabling the B cell follicle to expand and provide a favourable microen-
vironment for B cell activation and maturation [37, 54] (Fig. 1.1c). Inflammation
was initiated by the injection of complete Freund’s adjuvant into the ears of mice,
and interactions with B cell zone reticular cells were analysed in ear-draining lymph
nodes [37]. During systemic inflammation, B cells entered T zone areas of the
lymph node in response to CXCL13 expressing B cell zone reticular cells, to expand
the B follicle region [37].
1.2.3.1 Systemic Effects of Interactions with B Cells
Cremasco et al. [24] portray the loss of FRCs as detrimental to humoral immunity
with immunisation with an inactivated influenza A virus leading to a reduction in
influenza-specific immunoglobulin M in conditional FRC knockouts (CCL19-
Cre × iDTRfl/fl mice) compared to control mice. In addition, these mice also exhib-
ited impaired B cell viability and poor B cell follicle organisation, suggesting a
systemic FRC importance in humoral immune responses.
In mouse graft-versus-host disease (GVHD) models, CD157+ FRC damage has
been shown to impair IgG and IgA humoral immune responses to subcutaneous and
oral antigens as B cell follicles are disrupted following FRC reduction [55].
1.2.4 Interactions with Dendritic Cells
Lymph node stroma has been shown in vivo to promote DC motility into and within
the lymph node via the interactions between FRCs or LECs bearing podoplanin and
activated DCs expressing Clec-2 [56]. Using Clec1b (CLEC-2) −/−foetal liver chi-
meras compared to wild type, it was shown that CLEC-2+ DCs navigate from
parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that
display the glycoprotein podoplanin [56]. Activation of CLEC-2 by podoplanin

downregulates RhoA activity and phosphorylation of myosin light chains, causing
cell spreading, and induces formation of protrusions through Vav signalling and
activation of Rac1 [56]. Together these mechanisms promote DC motility across
LEC and FRC stromal surfaces to allow antigen-bearing DCs to reach the lymph
node and migrate within it in search of antigen-specific T cells.
Recent work highlights an important role for DCs in maintaining FRC survival
and proliferation. DCs directly maintain FRC survival through provision of lym-
photoxin ligands, which bind lymphotoxin beta receptor (LTbR) on FRCs, which
upregulates podoplanin, in turn providing survival stimulus through maintenance of
integrin-mediated adhesions [57]. Chyou et al. [58] showed that the initiation of
FRC proliferation early in infection does not require DCs but that DCs induce FRCs
to upregulate VEGF, which drives expansion of BECs and LECs. Yang et al. [35]
revealed that DCs play an important indirect role in initiating FRC proliferation, by
inducing naïve lymphocyte trapping within the lymph node early after infection is
sensed. Moreover, various chains of MHC class II molecules were shown to become
upregulated under inflammation on LECs, FRCs and BECs [22, 23, 26]. This sug-
gests that subsets of LNSCs may be transcribing MHC class II molecules and/or
receiving peptides from antigen-presenting cells, demonstrating a further encom-
passing role of LNSCs in innate immune responses.
1.2.5 irect Detection of Inflammatory Stimuli

D
and Interactions with Other Immune Cells
FRCs may be involved in the detection of lymph-borne infection or inflammatory

signals via the expression of genes associated with pattern recognition toll-
like receptors (TLRs) 3 and 4 [18, 22]. As TLRs respond to foreign pathogens by
alerting the immune system, this data suggests that FRCs may directly detect viruses
and bacteria. This idea has been reinforced by various studies which have docu-
mented the (direct or indirect) activation of LECs and FRCs via the usage of viral
and bacterial immunostimulants or analogues which interact with TLR 3 and TLR
4 [18, 22, 28, 29, 35, 59].
The upregulation of chemoattractants and regulatory factors associated with the
innate immune response has also been identified by transcriptional analysis of
LNSCs [22]. FRCs express CXCL1, CXCL10, CCL2, CCL7, IL-33, IL-34, CSF1,
CCL5 and CXCL9 and also express receptors for type I and II interferons [22].
1.3 Marginal Reticular Cells
Marginal reticular cells (MRCs) populate the outer regions of the cortex of lymph
nodes [39]. They are located deep to the floor of the subcapsular sinus (SCS) and are
phenotypically distinct from T zone fibroblastic reticular cells (FRCs) and follicular
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dendritic cells (FDCs). MRCs strongly express MAdCAM-1, CXCL13 and RANKL
[39, 40]. The latter is an essential cytokine for lymph node development [60, 61].
However, the markers CCL21 expressed by T zone FRCs and CR1/CD35 expressed
by FDCs are, respectively, absent or only trace expressed [39], indicating that MRCs
are indeed a distinct stromal subset to these populations. Phenotypically similar
groups of reticular cells have been found in other secondary lymphoid organs
(SLOs), including the spleen and mucosa-associated lymphoid tissues [39, 62].
Contrastingly no similar groups of cells have been found in the tertiary lymphoid
organs (TLOs) [5] associated with chronic inflammation.
During organogenesis, lymph nodes develop from accumulations of mesenchyme
and haematopoietic cells associated with epithelium or vasculature, known as anla-
gen [63]. The haematopoietic cells are known as lymphoid tissue inducer (LTi) cells
which bear the phenotype CD45+ CD4+ CD3−. LTi cells interact with the mesen-
chymal cells known as lymphoid tissue organiser (LTo) cells. LTo cells express adhe-
sion molecule (ICAM-1, VCAM-1, MAdCAM-1) and chemokine (CXCL13,
CCL19, CCL21) profiles upon stimulation by LTi through their secretion of lympho-
toxin (LT)-α1β2 [63, 64]. Subsequently CXCL13 attracts LTi through binding cells
at its CXCR5 receptor, propagating a positive feedback loop of development [63,
65–67]. MRCs are thought to be a direct descendent of LTo cells [40]. While yet to
be proven, supportive evidence includes their similar molecular phenotypes and the
high concentration of LTo cells and RANKL expression in the outer areas of embry-
onic LNs, which in adult lymph nodes becomes a niche for MRCs [39, 68].
In addition to their embryonic developmental role, the ability of MRCs to give
rise to FDCs in the adult lymph node has also been demonstrated. The MRCs exhibit
maturation into a transitional phenotype before evolving into phenotypically mature
FDCs through a two-step process [41]. FDCs in the spleen arise through other
mechanisms, developing from perivascular precursors [69].
Immune-stromal interactions of MRCs are still poorly understood. MRCs are
located in various SLOs adjacent to the primary route of antigenic entry, suggesting
that they may play a role in the regulation of antigen transportation pathways [39,
68]. In adult mice, MRCs produce CXCL13 to attract CXCR5+ innate lymphoid-
like cells type 3 (ILC3), which drive lymph node repair and regeneration after dam-
age [50, 70]. CXCL13 is also a B cell chemoattractant, and it has been hypothesised
that MRCs may be involved in the transport of antigens from the SCS into the B
follicle or to facilitate the motility of B cells in the outer follicle through their
expression of adhesion molecules [39].
The cytokines IL-7 and RANKL are both expressed to high levels by MRCs [39,
68] and are thought to be crucial for lymphoid homeostasis. IL-7 is a naïve T cell
survival factor suggesting that it is also involved in regulation of T cell survival. In
an in vitro murine model, the inoculation of mice with LTβR-Fc resulted in disor-
ganisation of the follicular assembly of the white splenic pulp, and the disappear-
ance of MRC layers, demonstrated by a loss of CXCL13 and RANKL staining [68].
In lymph nodes, LTβR-Fc downregulated CXCL13 but did not alter RANKL stain-
ing. This indicates that either RANKL expression in lymph nodes is independent of
LTβR-NIK signalling or that another RANKL-expressing cell type is able to com-
pensate for loss of LTβR ligands within the lymph node [68].
Their anatomical placement proximal to the inflow tract of antigens in SLOs,

along with cytokine and chemokine expression, suggests that MRCs have an impor-
tant role in regulating lymphoid function and SLO homeostasis.
1.4 Lymphatic Endothelial Cells (LECs)
Selectable markers: Gp38+, CD31+, Lyve-1
1.4.1 Structural and Chemoattractive Role
LECs create afferent and efferent lymphatic vessels, primarily to allow for the entry
of antigen-presenting dendritic cells and soluble antigens into the paracortex of the
lymph node [71, 72] and the egress of lymphocytes from the medulla [73]. LECs are
also contained within medullary sinuses and line the ceiling (cLECs) and the floor
(fLECs) of the subcapsular sinus [72]. It is thought that because of their prime posi-
tion close to lymph, LECs might also be an early cell type to encounter and present
antigens by environmental sampling [74]. LECs from different areas of the lymph
node show differing expression of key surface markers: subcapsular LECs are
PD-L1hi, ICAM-1hi, MAdCAM-1+ and LTbRlo; medullary LECs are PD-L1hi,
ICAM-1hi, MAdCAM-1neg and LTbR+; and cortical LECs are PD-L1int, ICAM-
1int, MAdCAM-1neg and LTbR+ [75].
Under inflammatory conditions, LECs direct macrophages and antigen-bearing
dendritic cells along lymphatics, between LECs lining the subcapsular sinus, into
the lymph node structure. LECs express podoplanin and similar to FRCs are capable
of driving DC migration towards and within lymph nodes through signalling to
CLEC-2 [56] (see Sect. 1.2.4). They produce CCL21 [22] and are thought to regu-
late availability of chemokines such as CCL21 and CCL19 in the subcapsular sinus
and local parenchymal tissue through expression of scavenging receptors ACKR2
and ACKR4 [76] (Fig. 1.3a). ACKR2 is a scavenging receptor tasked with removing
inflammatory cytokines from the cell surface of LECs during inflammation [76].
This allows for suppression of immature DCs and other inflammatory cells and
keeps leukocytes from adhering to LECs. ACKR4 is thought to control the distribu-
tion of CCL19 and CCL21 to assist DC migration through cognate receptor CCR7,
by maintaining optimal availability of these chemokines [76].
While mouse LECs are able to adhere to plastic like FRCs, human LECs are
unable to do so indicating a difference in adhesion factors or requirements that is not
yet understood [77]. This might be a case of gene downregulation, as many as 50%
of LEC-defining genes were found to be silenced under culture conditions com-
pared to freshly isolated cells [78].
D’Rozario et al.
A LEC interactions C BEC interactions

CCL21 IL-7 IL-7R
CCL19 FRC
T cell
CC chemokines
VEGF
Leukocyte PD1
PD-L1
ACKR2
proliferation DC
MHC I
Self antigen
IL-1β
ACKR4 TCD8+
cell
TCR IL-1R
B BEC interactions
T cell T cell T cell X CD99-CD99

X CD31-CD31
L-selectin CCR7 LFA-1
PNAd CCL21
ICAM-1
CCL19
HEV
VE-Cadherin
unzipped
Rolling Acvaon Adhesion Intraluminal
crawling
Fig. 1.3 Crosstalk between endothelial cell subsets and leukocytes. (a) Lymphatic endothelial
cells (LECs) produce IL-7 to promote survival of naïve T cells, binding to the IL-7 receptor (IL-
7R) [79]. They express programmed death ligand 1 (PD-L1) which binds PD-1 on T cells. When
this interaction occurs after T cells recognise self-antigen presented by LECs via MHC class I,
deletional tolerance is induced [17, 74]. LECs also control leukocyte migration and adhesion
through expression of atypical cytokine receptor ACKR2, which sequesters inflammatory CC che-
mokines, and ACKR4, which binds CCL19 and CCL21 [107]. (b) High endothelial venules are
constructed from blood endothelial cells (BECs) expressing peripheral node addressin (PNAd)
[58]. Naïve leukocytes enter the lymph node through interactions with HEVs. First, they roll and
loosely tether to the HEV when L-selectin binds PNAd on the HEV. Next, the T cell undergoes
chemokine-mediated activation when CCL21 and CCL19 secreted into the lumen of the vessel
bind CCR7. This induces conformational changes to LFA-1, allowing it to undergo tight adhesion
by binding ICAM-1. Lastly, homeotypic interactions between CD31 and CD99, each expressed by
both the leukocyte and endothelial cell, position the leukocyte between two endothelial cells,
where VE-cadherin junctions unzip allowing the leukocyte to move through [84]. (c) BECs
undergo homeostatic proliferation through signals with FRCs, which produce VEGF, and dendritic
cells, through mechanisms that may include secretion of IL-1b [58, 93]
1.4.2 Interactions with T Cells and DCs
1.4.2.1 Provision of Survival Factors
LECs are a robust source of IL-7 and together with FRCs, which also produce IL-7,
likely to be important regulators of T cell homeostasis [79] (Fig. 1.3a). IL-7 has
proliferative and anti-apoptotic signalling abilities and is important for T cell
survival in SLOs. In vitro experiments of co-cultures of LECs with T cells or T cells

with conditioned media from LECs show an improved ability to promote T cell
survival compared to a similar setup with the addition of anti-IL7 neutralising anti-
body [50].
1.4.2.2 Suppressive Tolerance
LECs are capable of suppressing the proliferation of newly activated CD4 and
CD8+ T cells through the production of nitric oxide, similar to FRCs [20] (Fig. 1.2a).
Under inflammatory conditions, but in the absence of infection, LECs suppress
maturation of DCs, reducing expression of CD86 and their ability to prime CD8+ T
cells [80]. This occurred through binding between ICAM-1 on LECs and Mac-1 on
DCs and is hypothesised to reduce the risk of immune priming under inflammatory
conditions in the absence of infection [80].
LECs show upregulation of surface MHC class II 18 h after initiation of an
inflammatory response [22]. This may contribute to CD4 T cell tolerance through
increased antigen presentation. This upregulation is IFNg dependent [26]. LECs are
capable of transiently acquiring peptide-MHC class II from DCs in vivo and in vitro,
directly proportional to the number of DCs present [26]. In the same study, LECs
were shown to promote apoptosis of CD4+ T cells in an antigen-specific fashion
[26].
Recently, Hirosue et al. [74] demonstrated that LECs can absorb exogenous OVA
and will process and cross-present the OVA-derived SIINFEKL peptide fragment to
CD8+ T cells in vitro [74] (Fig. 1.3a). LECs also upregulated PD-L1, which signals
to PD-1 expressed by T cells and is a well-known cause of T cell exhaustion under
conditions of prolonged inflammation (Fig. 1.3a). OVA-specific CD8+ T cell
activation was impaired; T cells stimulated by LECs made less IL-2 and upregulated
CTLA-4 earlier than those activated by DCs [74].
1.4.2.3 Deletional Tolerance
Similar to FRCs, LECs within lymph nodes express a variety of peripheral tissue-
restricted antigens (PTAs), including Deaf-1 controlled Ins2 and Ppy [48, 81],
though FRCs and LECs do not express identical arrays of PTAs [17, 18]. PTA
expression by tolerance-inducing cells, such as LECs, is pivotal to delete T cells
reactive to endogenous antigens expressed in relatively few tissues. Cohen et al.
[17] showed using an endogenous melanocyte-specific self-antigen derived from
tyrosinase that LECs directly presented self-antigen to Tyr-specific CD8+ T cells,
deleting those that respond and purging the repertoire of autoimmune clones
(Figs. 1.2b and 1.3a). In contrast, LECs indirectly induce CD4+ T cell anergy by
presentation of PTAs to DCs [82], showing that LECs utilise different mechanisms
of tolerance induction for CD4+ and CD8+ T cells.
In the thymus, Aire controls the expression of PTAs, but in lymph node stromal
cells, Aire is not expressed [18]. However, studies in NOD mice demonstrate that
PTA genes that are Aire-controlled in the thymus, such as Ambp, Fgb and Ppy, are
regulated by the transcription factor Deaf-1 in the lymph node [48], which is
expressed by LECs as well as FRCs [18]. During the progression of diabetes, alter-
native splicing of Deaf-1 occurs reducing PTA expression in mice and humans, but
the effect of alternative splicing and PTA expression with respect to development of
diabetes and other diseases is yet to be determined [48].
LECs do not express CD80, CD86, OX40L, 4-1BBL or CD70. These are essen-
tial molecules to drive accumulation of activated T cells, and their lack of costimu-
latory molecule expression may help account for their ability to delete naïve
autoantigen expressing T cells. However, LECs express high levels of PD-L1, a
molecule associated with deletion of tolerance-specific CD8+ T cells [17, 75].
Lymph node LECs were unique in their high expression of PTAs and PD-L1,
compared with LECs in peripheral tissues such as the diaphragm and colon, show-
ing that the lymph node microenvironment is uniquely specialised for tolerance
induction [75].
1.5 Blood Endothelial Cells (BECs)
Selectable markers: Gp38-, CD31+, ICAM-1+
1.5.1 Transendothelial Migration
BECs facilitate the migration of naïve lymphocytes into lymph nodes by forming
specialised postcapillary venules known as high endothelial venules (HEVs) [3].
BECs comprising HEVs show a distinctive cuboidal morphology supported by a
basement membrane and have been shown to play a specialised role in allowing
lymphocyte entry to SLOs through the process known as diapedesis, transendothe-
lial migration or leukocyte extravasation (Fig. 1.3b). Migration into lymph nodes
does not require inflammation, but bears similarities with migration of leukocytes to
inflamed sites [83]. HEVs act as gatekeepers for lymph nodes by creating pockets
holding newly arrived lymphocytes until space in the parenchyma becomes avail-
able, granting entry at a rate proportionate to egress from the lymph node [9].
During cell circulation, naïve T and B cells enter the medulla by squeezing
between tightly adherent endothelial cells forming high endothelial venules (HEVs).
The process of slowing down and breaching the endothelial barrier involves well-
characterised interactions including leukocyte rolling, activation, adhesion and
intraluminal crawling [84], which involve targeted interactions between endothe-
lium and T cells [85] (Fig. 1.3b).
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couldn’t even if he were up. They are stealing my spoons,
Wunderlich, and I am going into the river!’
“Well, I kept holding her, and I said what one would in such cases:
‘Courage, dear lady. It will be all right. Control yourself, I beg of you.
We will go and speak with them. Let us go.’ And I got her to go back
up the street to her house. The soldiery were up in the dining-room,
where Madame had left them, some twenty of them, at the great
silver-chest.
“‘Gentlemen,’ I say politely, ‘with which one of you may I have the
pleasure of a little conversation?’ ‘They begin to laugh, and they say:
‘With all of us, Papa.’ But one of them steps out and presents
himself, a fellow as tall as a tree, with a black waxed moustache and
big red hands sticking out of his braided cuffs. ‘Lenoir,’ he said, and
saluted with his left hand, for he had five or six spoons in his right.
‘Sergeant Lenoir. What can I do for you?’
“‘Herr Officer,’ I say, appealing to his sense of honour, ‘after your
magnificent charge, how can you stoop to this sort of thing? The
town has not closed its gates to the Emperor.’
“‘What do you expect?’ he answered. ‘War is war. The people need
these things....’
“‘But you ought to be careful,’ I interrupted him, for an idea had
come into my head. ‘This lady,’ I said—one will say anything at a
time like that—‘the lady of the house, she isn’t a German. She is
almost a compatriot of yours—she is a Frenchwoman....’ ‘Oh, a
Frenchwoman,’ he repeated. And then what do you suppose he said,
this big swashbuckler? ‘Oh, an emigrée? Then she is an enemy of
philosophy!’
“I was quite taken aback, but I managed not to laugh. ‘You are a
man of intellect, I see,’ said I. ‘I repeat that I consider your conduct
unworthy.’ He was silent for a moment. Then he got red, tossed his
half-dozen spoons back into the chest, and exclaimed, ‘Who told you
I was going to do anything with these things but look at them? It’s
fine silver. If one or two of my men take a piece as a souvenir....’
“Well, in the end, they took plenty of souvenirs, of course. No use
appealing to justice, either human or divine. I suppose they knew no
other god than that terrible little Corsican....”
CHAPTER V
“Did you ever see him, Herr Pastor?”
The plates were being changed again. An enormous brick-red boiled
ham appeared, strewn with crumbs and served with a sour brown
onion sauce, and so many vegetables that the company could have
satisfied their appetites from that one vegetable-dish. Lebrecht
Kröger undertook the carving, and skilfully cut the succulent slices,
with his elbows slightly elevated and his two long forefingers laid out
along the back of the knife and fork. With the ham went the Frau
Consul’s celebrated “Russian jam,” a pungent fruit conserve
flavoured with spirits.
No, Pastor Wunderlich regretted to say that he had never set eyes
on Bonaparte. Old Buddenbrook and Jean Jacques Hoffstede had
both seen him face to face, one in Paris just before the Russian
campaign, reviewing the troops at the Tuileries; the other in Dantzig.
“I must say, he wasn’t a very cheerful person to look at,” said the
poet, raising his brows, as he disposed of a forkful of ham, potato,
and sprouts. “But they say he was in a lively mood, at Dantzig.
There was a story they used to tell, about how he would gamble all
day with the Germans, and make them pay up too, and then spend
the evening playing with his generals. Once he swept a handful of
gold off the table, and said: ‘Les Allemands aiment beaucoup ces
petits Napoléons, n’est-ce pas, Rapp?’ ‘Oui, Sire, plus que le Grand!’
Rapp answered.”
There was general laughter—Hoffstede had told the story very
prettily, even mimicking the Emperor’s manner. Old Buddenbrook
said: “Well, joking aside, one can’t help having respect for his
personal greatness.... What a nature!”
The Consul shook his head gravely.
“No, no—we of the younger generation do not see why we should
revere the man who murdered the Duc d’Engien, and butchered
eight hundred prisoners in Egypt....”
“All that is probably exaggerated and overdrawn,” said Pastor
Wunderlich. “The Duke was very likely a feather-brained and
seditious person, and as for the prisoners, their execution was
probably the deliberate and necessary policy of a council of war.”
And he went on to speak of a book at which he had been looking, by
one of the Emperor’s secretaries, which had appeared some years
before and was well worth reading.
“All the same,” persisted the Consul, snuffing a flickering candle in
the sconce in front of him, “I cannot understand it—I cannot
understand the admiration people have for this monster. As a
Christian, as a religious man, I can find no room in my heart for such
a feeling.”
He had, as he spoke, the slightly inclined head and the rapt look of a
man in a vision. His father and Pastor Wunderlich could be seen to
exchange the smallest of smiles.
“Well, anyhow,” grinned the old man, “the little napoleons aren’t so
bad, eh? My son has more enthusiasm for Louis Philippe,” he said to
the company in general.
“Enthusiasm?” repeated Jean Jacques Hoffstede, rather
sarcastically.... “That is a curious juxtaposition, Philippe Égalité and
enthusiasm....”
“God knows, I feel we have much to learn from the July Monarchy,”
the Consul said, with serious zeal. “The friendly and helpful attitude
of French constitutionalism toward the new, practical ideals and
interests of our time ... is something we should be deeply thankful
for....”
“Practical ideals—well, ye-es—” The elder Buddenbrook gave his
jaws a moment’s rest and played with his gold snuff-box. “Practical
ideals—well—h’m—they don’t appeal to me in the least.” He dropped
into dialect, out of sheer vexation. “We have trade schools and
technical schools and commercial schools springing up on every
corner; the high schools and the classical education suddenly turn
out to be all foolishness, and the whole world thinks of nothing but
mines and factories and making money.... That’s all very fine, of
course. But in the long run, pretty stupid, isn’t it?... I don’t know
why, but it irritates me like the deuce.... I don’t mean, Jean, that the
July Monarchy is not an admirable régime....”
Senator Langhals, as well as Gratjens and Köppen, stood by the
Consul.... They felt that high praise was due to the French
government, and to similar efforts that were being made in
Germany. It was worthy of all respect—Herr Köppen called it
“respeck.” He had grown more and more crimson from eating, and
puffed audibly as he spoke. Pastor Wunderlich had not changed
colour; he looked as pale, refined, and alert as ever, while drinking
down glass after glass of wine.
The candles burned down slowly in their sockets. Now and then they
flickered in a draught and dispersed a faint smell of wax over the
table.
There they all sat, on heavy, high-backed chairs, consuming good
heavy food from good heavy silver plate, drinking full-bodied wines
and expressing their views freely on all subjects. When they began
to talk shop, they slipped unconsciously more and more into dialect,
and used the clumsy but comfortable idioms that seemed to embody
to them the business efficiency and the easy well-being of their
community. Sometimes they even used an overdrawn pronunciation
by way of making fun of themselves and each other, and relished
their clipped phrases and exaggerated vowels with the same
heartiness as they did their food.
The ladies had not long followed the discussion. Madame Kröger
gave them the cue by setting forth a tempting method of boiling
carp in red wine. “You cut it into nice pieces, my dear, and put it in
the saucepan, add some cloves, and onions, and a few rusks, a little
sugar, and a spoonful of butter, and set it on the fire.... But don’t
wash it, on any account. All the blood must remain in it.”
The elder Kröger was telling the most delightful stories; and his son
Justus, who sat with Dr. Grabow down at the bottom of the table,
near the children, was chaffing Mamsell Jungmann. She screwed up
her brown eyes and stood her knife and fork upright on the table
and moved them back and forth. Even the Överdiecks were very
lively. Old Frau Överdieck had a new pet name for her husband:
“You good old bell-wether,” she said, and laughed so hard that her
cap bobbed up and down.
But all the various conversations around the table flowed together in
one stream when Jean Jacques Hoffstede embarked upon his
favourite theme, and began to describe the Italian journey which he
had taken fifteen years before with a rich Hamburg relative. He told
of Venice, Rome, and Vesuvius, of the Villa Borghese, where Goethe
had written part of his Faust; he waxed enthusiastic over the
beautiful Renaissance fountains that wafted coolness upon the warm
Italian air, and the formal gardens through the avenues of which it
was so enchanting to stroll. Some one mentioned the big wilderness
of a garden outside the Castle Gate, that belonged to the
Buddenbrooks.
“Upon my word,” the old man said, “I still feel angry with myself that
I have never put it into some kind of order. I was out there the other
day—and it is really a disgrace, a perfect primeval forest. It would be
a pretty bit of property, if the grass were cut and the trees trimmed
into formal shapes.”
The Consul protested strenuously. “Oh, no, Papa! I love to go out
there in the summer and walk in the undergrowth; it would quite
spoil the place to trim and prune its free natural beauty.”
“But, deuce take it, the free natural beauty belongs to me—haven’t I
the right to put it in order if I like?”
“Ah, Father, when I go out there and lie in the long grass among the
undergrowth, I have a feeling that I belong to nature and not she to
me....”
“Krishan, don’t eat too much,” the old man suddenly called out, in
dialect. “Never mind about Tilda—it doesn’t hurt her. She can put it
away like a dozen harvest hands, that child!”
And truly it was amazing, the prowess of this scraggy child with the
long, old-maidish face. Asked if she wanted more soup, she
answered in a meek drawling voice: “Ye-es, ple-ase.” She had two
large helpings both of fish and ham, with piles of vegetables; and
she bent short-sightedly over her plate, completely absorbed in the
food, which she chewed ruminantly, in large mouthfuls. “Oh, Un-cle,”
she replied, with amiable simplicity, to the old man’s gibe, which did
not in the least disconcert her. She ate: whether it tasted good or
not, whether they teased her or not, she smiled and kept on,
heaping her plate with good things, with the instinctive, insensitive
voracity of a poor relation—patient, persevering, hungry, and lean.
CHAPTER VI
And now came, in two great cut-glass dishes, the “Plettenpudding.”
It was made of layers of macaroons, raspberries, lady-fingers, and
custard. At the same time, at the other end of the table, appeared
the blazing plum-pudding which was the children’s favourite sweet.
“Thomas, my son, come here a minute,” said Johann Buddenbrook,
taking his great bunch of keys from his trousers pocket. “In the
second cellar to the right, the second bin, behind the red Bordeaux,
two bottles—you understand?” Thomas, to whom such orders were
familiar, ran off and soon came back with the two bottles, covered
with dust and cobwebs; and the little dessert-glasses were filled with
sweet, golden-yellow malmsey from these unsightly receptacles.
Now the moment came when Pastor Wunderlich rose, glass in hand,
to propose a toast; and the company fell silent to listen. He spoke in
the pleasant, conversational tone which he liked to use in the pulpit;
his head a little on one side, a subtle, humorous smile on his pale
face, gesturing easily with his free hand. “Come, my honest friends,
let us honour ourselves by drinking a glass of this excellent liquor to
the health of our host and hostess in their beautiful new home.
Come, then—to the health of the Buddenbrook family, present and
absent! May they live long and prosper!”
“Absent?” thought the Consul to himself, bowing as the company
lifted their glasses. “Is he referring to the Frankfort Buddenbrooks,
or perhaps the Duchamps in Hamburg—or did old Wunderlich really
mean something by that?” He stood up and clinked glasses with his
father, looking him affectionately in the eye.
Broker Gratjens got up next, and his speech was rather long-winded;
he ended by proposing in his high-pitched voice a health to the firm
of Johann Buddenbrook, that it might continue to grow and prosper
and do honour to the town.
Johann Buddenbrook thanked them all for their kindness, first as
head of the family and then as senior partner of the firm—and sent
Thomas for another bottle of Malmsey. It had been a mistake to
suppose that two would be enough.
Lebrecht Kröger spoke too. He took the liberty of remaining seated,
because it looked less formal, and gestured with his head and hands
most charmingly as he proposed a toast to the two ladies of the
family, Madame Antoinette and the Frau Consul. As he finished, the
Plettenpudding was nearly consumed, and the Malmsey nearing its
end; and then, to a universal, long-drawn “Ah-h!” Jean Jacques
Hoffstede rose up slowly, clearing his throat. The children clapped
their hands with delight.
“Excusez! I really couldn’t help it,” he began. He put his finger to his
long sharp nose and drew a paper from his coat pocket.... A
profound silence reigned throughout the room.
His paper was gaily parti-coloured. On the outside of it was written,
in an oval border surrounded by red flowers and a profusion of gilt
flourishes:
“On the occasion of my friendly participation in a delightful
house-warming party given by the Buddenbrook family.
October 1835.”
He read this aloud first; then turning the paper over, he began, in a
voice that was already somewhat tremulous:
Honoured friends, my modest lay

Hastes to greet you in these walls:
May kind Heaven grant to-day
Blessing on their spacious halls.
Thee, my friend with silver hair,

And thy faithful, loving spouse,
And your children young and fair—
I salute you, and your house.
Industry and beauty chaste
See we linked in marriage band:
Venus Anadyomene
And cunning Vulcan’s busy hand.
May no future storms dismay

With unkind blast the joyful hour;
May each new returning day
Blessings on your pathway shower.
Ceaselessly shall I rejoice

O’er the fortune that is yours:
As to-day I lift my voice,
May I still, while life endures.
In your splendid walls live well,

And cherish with affection true
Him who in his humble cell
Penned to-day these lines for you
He bowed to a unanimous outburst of applause.

“Charming, Hoffstede,” cried old Buddenbrook. “It was too charming
for words. I drink your health.”
But when the Frau Consul touched glasses with the poet, a delicate
blush mantled her cheek; for she had seen the courtly bow he made
in her direction when he came to the part about the Venus
Anadyomene.
CHAPTER VII
The general merriment had now reached its height. Herr Köppen felt
a great need to unfasten a few buttons of his waistcoat; but it
obviously wouldn’t do, for not even the elderly gentlemen were
permitting themselves the liberty. Lebrecht Kröger sat up as straight
as he did at the beginning; Pastor Wunderlich’s face was as pale as
ever, his manner as correct. The elder Buddenbrook had indeed sat
back a little in his chair, but he maintained perfect decorum. There
was only Justus Kröger—he was plainly a little overtaken.
But where was Dr. Grabow? The butter, cheese and fruit had just
been handed round; and the Frau Consul rose from her chair and
unobtrusively followed the waitress from the room; for the Doctor,
Mamsell Jungmann, and Christian were no longer in their places, and
a smothered wail was proceeding from the hall. There in the dim
light, little Christian was half-lying, half-crouching on the round
settee that encircled the central pillar. He was uttering heart-
breaking groans. Ida and the Doctor stood beside him.
“Oh dear, oh dear,” said she, “the poor child is very bad!”
“I’m ill, Mamma, damned ill,” whimpered Christian, his little deep-set
eyes darting back and forth, and his big nose looking bigger than
ever. The “damned” came out in a tone of utter despair; but the
Frau Consul said: “If we use such words, God will punish us by
making us suffer still more!”
Doctor Grabow felt the lad’s pulse. His kindly face grew longer and
gentler.
“It’s nothing much, Frau Consul,” he reassured her. “A touch of
indigestion.” He prescribed in his best bed-side manner: “Better put
him to bed and give him a Dover powder—perhaps a cup of
camomile tea, to bring out the perspiration.... And a rigorous diet,
you know, Frau Consul. A little pigeon, a little French bread....”
“I don’t want any pigeon,” bellowed Christian angrily. “I don’t want
to eat anything, ever any more. I’m ill, I tell you, damned ill!” The
fervour with which he uttered the bad word seemed to bring him
relief.
Doctor Grabow smiled to himself—a thoughtful, almost a melancholy
smile. He would soon eat again, this young man. He would do as the
rest of the world did—his father, and all their relatives and friends:
he would lead a sedentary life and eat four good, rich, satisfying
meals a day. Well, God bless us all! He, Friedrich Grabow, was not
the man to upset the habits of these prosperous, comfortable
tradesmen and their families. He would come when he was sent for,
prescribe a few days’ diet—a little pigeon, a slice of French bread—
yes, yes, and assure the family that it was nothing serious this time.
Young as he was, he had held the head of many an honest burgher
who had eaten his last joint of smoked meat, his last stuffed turkey,
and, whether overtaken unaware in his counting-house or after a
brief illness in his solid old four-poster, had commended his soul to
God. Then it was called paralysis, a “stroke,” a sudden death. And
he, Friedrich Grabow, could have predicted it, on all of these
occasions when it was “nothing serious this time”—or perhaps at the
times when he had not even been summoned, when there had only
been a slight giddiness after luncheon. Well, God bless us all! He,
Friedrich Grabow, was not the man to despise a roast turkey himself.
That ham with onion sauce had been delicious, hang it! And the
Plettenpudding, when they were already stuffed full—macaroons,
raspberries, custard.... “A rigorous diet, Frau Consul, as I say. A little
pigeon, a little French bread....”
CHAPTER VIII
They were rising from table.
“Well, ladies and gentlemen, gesegnete Mahlzeit! Cigars and coffee
in the next room, and a liqueur if Madame feels generous.... Billiards
for whoever chooses. Jean, you will show them the way back to the
billiard-room? Madame Köppen, may I have the honour?”
Full of well-being, laughing and chattering, the company trooped
back through the folding doors into the landscape-room. The Consul
remained behind, and collected about him the gentlemen who
wanted to play billiards.
“You won’t try a game, Father?”
No, Lebrecht Kröger would stop with the ladies, but Justus might go
if he liked.... Senator Langhals, Köppen, Gratjens, and Doctor
Grabow went with the Consul, and Jean Jacques Hoffstede said he
would join them later. “Johann Buddenbrook is going to play the
flute,” he said. “I must stop for that. Au revoir, messieurs.”
As the gentlemen passed through the hall, they could hear from the
landscape-room the first notes of the flute, accompanied by the Frau
Consul on the harmonium: an airy, charming little melody that
floated sweetly through the lofty rooms. The Consul listened as long
as he could. He would have liked to stop behind in an easy-chair in
the landscape-room and indulge the reveries that the music conjured
up; but his duties as host....
“Bring some coffee and cigars into the billiard-room,” he said to the
maid whom he met in the entry.
“Yes, Line, coffee!” Herr Köppen echoed, in a rich, well-fed voice,
trying to pinch the girl’s red arm. The c came from far back in his
throat, as if he were already swallowing the coffee.
“I’m sure Madame Köppen saw you through the glass,” Consul
Kröger remarked.
“So you live up there, Buddenbrook?” asked Senator Langhals. To
the right a broad white staircase with a carved baluster led up to the
sleeping-chambers of the Consul’s family in the second storey; to the
left came another row of rooms. The party descended the stairs,
smoking, and the Consul halted at the landing.
“The entresol has three rooms,” he explained—“the breakfast-room,
my parents’ sleeping-chamber, and a third room which is seldom
used. A corridor runs along all three.... This way, please. The
wagons drive through the entry; they can go all the way out to
Bakers’ Alley at the back.”
The broad echoing passageway below was paved with great square
flagstones. At either end of it were several offices. The odour of the
onion sauce still floated out from the kitchen, which, with the
entrance to the cellars, lay on the left of the steps. On the right, at
the height of a storey above the passageway, a scaffolding of
ungainly but neatly varnished rafters thrust out from the wall,
supporting the servants’ quarters above. A sort of ladder which led
up to them from the passage was their only means of ingress or
egress. Below the scaffolding were some enormous old cupboards
and a carved chest.
Two low, worn steps led through a glass door out to the courtyard
and the small wash-house. From here you could look into the pretty
little garden, which was well laid out, though just now brown and
sodden with the autumn rains, its beds protected with straw mats
against the cold. At the other end of the garden rose the “portal,”
the rococo façade of the summer house. From the courtyard,
however, the party took the path to the left, leading between two
walls through another courtyard to the annexe.
They entered by slippery steps into a cellar-like vault with an
earthen floor, which was used as a granary and provided with a rope
for hauling up the sacks. A pair of stairs led up to the first storey,
where the Consul opened a white door and admitted his guests to
the billiard-room.
It was a bare, severe-looking room, with stiff chairs ranged round
the sides. Herr Köppen flung himself exhausted into one of them.
“I’ll look on for a while,” said he, brushing the wet from his coat.
“It’s the devil of a Sabbath day’s journey through your house,
Buddenbrook!”
Here too the stove was burning merrily, behind a brass lattice.
Through the three high, narrow windows one looked out over red
roofs gleaming with the wet, grey gables and courtyards.
The Consul took the cues out of the rack. “Shall we play a
carambolage, Senator?” he asked. He went around and closed the
pockets on both tables. “Who is playing with us? Gratjens? The
Doctor? All right. Then will you take the other table, Gratjens and
Justus? Köppen, you’ll have to play.”
The wine-merchant stood up and listened, with his mouth full of
smoke. A violent gust of wind whistled between the houses, lashed
the window-panes with rain, and howled down the chimney.
“Good Lord!” he said, blowing out the smoke. “Do you think the
Wullenwewer will get into port, Buddenbrook? What abominable
weather!”
Yes, and the news from Travemünde was not of the best, Consul
Kröger agreed, chalking his cue. Storms everywhere on the coast.
Nearly as bad as in 1824, the year of the great flood in St.
Petersburg. Well, here was the coffee.
They poured it out and drank a little and began their game. The talk
turned upon the Customs Union, and Consul Buddenbrook waxed
enthusiastic.
“An inspiration, gentlemen,” he said. He finished a shot and turned
to the other table, where the topic had begun. “We ought to join at
the earliest opportunity.”
Herr Köppen disagreed. He fairly snorted in opposition. “How about
our independence?” he asked incensed, supporting himself
belligerently on his cue. “How about our self-determination? Would
Hamburg consent to be a party to this Prussian scheme? We might
as well be annexed at once! Heaven save us, what do we want of a
customs union? Aren’t we well enough as we are?”
“Yes, you and your red wine, Köppen. And the Russian products are
all right. But there is little or nothing else imported. As for exports,
well, we send a little corn to Holland and England, it is true. But I
think we are far from being well enough as we are. In days gone by
a very different business went on. Now, with the Customs Union, the
Mecklenburgs and Schleswig-Holstein would be opened up—and
private business would increase beyond all reckoning....”
“But look here, Buddenbrook,” Gratjens broke in, leaning far over the
table and shifting his cue in his bony hand as he took careful aim, “I
don’t get the idea. Certainly our own system is perfectly simple and
practical. Clearing on the security of a civic oath—”
“A fine old institution,” the Consul admitted.
“Do you call it fine, Herr Consul?” Senator Langhals spoke with some
heat. “I am not a merchant; but to speak frankly—well, I think this
civic oath business has become little short of a farce: everybody
makes light of it, and the State pockets the loss. One hears things
that are simply scandalous. I am convinced that our entry into the
Customs Union, so far as the Senate is concerned—”
Herr Köppen flung down his cue. “Then there will be a conflick,” he
said heatedly, forgetting to be careful with his pronunciation. “I
know what I’m sayin’—God help you, but you don’t know what
you’re talkin’ about, beggin’ your pardon.”
Well, thank goodness! thought the rest of the company, as Jean
Jacques entered at this point. He and Pastor Wunderlich came
together, arm in arm, two cheerful, unaffected old men from another
and less troubled age.
“Here, my friends,” he began. “I have something for you: a little
rhymed epigram from the French.”
He sat down comfortably opposite the billiard-players, who leaned
upon their cues across the tables. Drawing a paper from his pocket
and laying his long finger with the signet ring to the side of his
pointed nose, he read aloud, with a mock-heroic intonation:
“When the Maréchal Saxe and the proud Pompadour
Were driving out gaily in gilt coach and four,
Frelon spied the pair: ‘Oh, see them,’ he cried:
‘The sword of our king—and his sheath, side by side.’”
Herr Köppen looked disconcerted for a minute. Then he dropped the
“conflick” where it was and joined in the hearty laughter that echoed
to the ceiling of the billiard-room. Pastor Wunderlich withdrew to the
window, but the movement of his shoulders betrayed that he was
chuckling to himself.
Herr Hoffstede had more ammunition of the same sort in his pocket,
and the gentlemen remained for some time in the billiard-room. Herr
Köppen unbuttoned his waistcoat all the way down, and felt much
more at ease here than in the dining-room. He gave vent to droll
low-German expressions at every turn, and at frequent intervals
began reciting to himself with enormous relish:
“When the Maréchal Saxe....”
It sounded quite different in his harsh bass.
CHAPTER IX
It was rather late, nearly eleven, when the party began to break up.
They had reassembled in the landscape-room, and they all made
their adieux at the same time. The Frau Consul, as soon as her hand
had been kissed in farewell, went upstairs to see how Christian was
doing. To Mamsell Jungmann was left the supervision of the maids
as they set things to rights and put away the silver. Madame
Antoinette retired to the entresol. But the Consul accompanied his
guests downstairs, across the entry, and outside the house.
A high wind was driving the rain slantwise through the streets as the
old Krögers, wrapped in heavy fur mantles, slipped as fast as they
could into their carriage. It had been waiting for hours before the
door. The street was lighted by the flickering yellow rays from oil
lamps hanging on posts before the houses or suspended on heavy
chains across the streets. The projecting fronts of some of the
houses jutted out into the roadway; others had porticos or raised
benches added on. The street ran steeply down to the River Trave; it
was badly paved, and sodden grass sprang up between the cracks.
The church of St. Mary’s was entirely shrouded in rain and darkness.
“Merci,” said Lebrecht Kröger, shaking the Consul’s hand as he stood
by the carriage door. “Merci, Jean; it was too charming!” The door
slammed, and the carriage drove off. Pastor Wunderlich and Broker
Gratjens expressed their thanks and went their way. Herr Köppen, in
a mantle with a five-fold cape and a broad grey hat, took his plump
wife on his arm and said in his gruff bass: “G’night, Buddenbrook.
Go in, go in; don’t catch cold. Best thanks for everything—don’t
know when I’ve fed so well! So you like my red wine at four marks?
Well, g’night, again.”
The Köppens went in the same direction as the Krögers, down
toward the river; Senator Langhals, Doctor Grabow, and Jean
Jacques Hoffstede turned the other way. Consul Buddenbrook stood
with his hands in his trousers pockets and listened to their footsteps
as they died away down the empty, damp, dimly-lighted street. He
shivered a little in his light clothes as he stood there a few paces
from his own house, and turned to look up at its grey gabled façade.
His eyes lingered upon the motto carved in the stone over the
entrance, in antique lettering: Dominus providebit—“The Lord will
provide.” He bowed his head a little and went in, bolting the door
carefully behind him. Then he locked the vestibule door and walked
slowly across the echoing floor of the great entry. The cook was
coming down the stairs with a tray of glasses in her hands, and he
asked her, “Where’s the master, Trina?”
“In the dining-room, Herr Consul,” said she, and her face went as
red as her arms, for she came from the country and was very
bashful.
As he passed through the dark hall, he felt in his pocket for the
letter. Then he went quickly into the dining-room, where a few small
candle-ends in one of the candelabra cast a dim light over the empty
table. The sour smell of the onion sauce still hung on the air.
Over by the windows Johann Buddenbrook was pacing comfortably
up and down, with his hands behind his back.
CHAPTER X
“Well, Johann, my son, where are you going?” He stood still and put
his hand out to his son—his white Buddenbrook hand, a little too
short, though finely modelled. His active figure showed indistinctly
against the dark-red curtains, the only gleams of white being from
his powdered hair and the lace frill at his throat.
“Aren’t you sleepy? I’ve been here listening to the wind; the weather
is something fearful. Captain Kloot is on his way from Riga....”
“Oh, Father, with God’s help all will be well.”
“Well, do you think I can depend on that? I know you are on
intimate terms with the Almighty—”
The Consul felt his courage rise at this display of good humour.
“Well, to get to the point,” he began, “I came in here not to bid you
good night, but to—you won’t be angry, will you, Papa?... I didn’t
want to disturb you with this letter on such a festive occasion ... it
came this afternoon....”
“Monsieur Gotthold, voilà!” The old man affected to be quite
unmoved as he took the sealed blue paper. “Herr Johann
Buddenbrook, Senior. Personal. A careful man, your step-brother,
Jean! Have I answered his second letter, that came the other day?
And so now he writes me a third.” The old man’s rosy face grew
sterner as he opened the seal with one finger, unfolded the thin
paper, and gave it a smart rap with the back of his hand as he
turned about to catch the light from the candles. The very
handwriting of this letter seemed to express revolt and disloyalty. All
the Buddenbrooks wrote a fine, flowing hand; but these tall straight
letters were full of heavy strokes, and many of the words were
hastily underlined.
The Consul had drawn back a little to where the row of chairs stood
against the wall; he did not sit down, as his father did not; but he
grasped one of the high chair-backs nervously and watched the old
man while he read, his lips moving rapidly, his brows drawn together,
and his head on one side.
Father,
I am probably mistaken in entertaining any further hope
of your sense of justice or any appreciation of my feelings
at receiving no reply from my second pressing letter
concerning the matter in question. I do not comment
again on the character of the reply I received to my first
one. I feel compelled to say, however, that the way in
which you, by your lamentable obstinacy, are widening the
rift between us, is a sin for which you will one day have to
answer grievously before the judgment seat of God. It is
sad enough that when I followed the dictates of my heart
and married against your wishes, and further wounded
your insensate pride by taking over a shop, you should
have repulsed me so cruelly and remorselessly; but the
way in which you now treat me cries out to Heaven, and
you are utterly mistaken if you imagine that I intend to
accept your silence without a struggle. The purchase price
of your newly acquired house in the Mengstrasse was a
hundred thousand marks; and I am aware that Johann,
your business partner and your son by your second
marriage, is living with you as your tenant, and after your
death will become the sole proprietor of both house and
business. With my step-sister in Frankfort, you have
entered into agreements which are no concern of mine.
But what does concern me, your eldest son, is that you
carry your un-Christian spirit so far as to refuse me a
penny of compensation for my share in the house. When
you gave me a hundred thousand marks on my marriage
and to set me up in business, and told me that a similar
sum and no more should be bequeathed me by will, I said
nothing, for I was not at the time sufficiently informed as
to the amount of your fortune. Now I know more: and not
regarding myself as disinherited in principle, I claim as my
right the sum of thirty-three thousand and three hundred
and thirty-three marks current, or a third of the purchase
price. I make no comment on the damnable influences
which are responsible for the treatment I have received.
But I protest against them with my whole sense of justice
as a Christian and a business man. Let me tell you for the
last time that, if you cannot bring yourself to recognize
the justice of my claims, I shall no longer be able to
respect you as a Christian, a parent, or a man of business.
Gotthold Buddenbrook.
“You will excuse me for saying that I don’t get much pleasure out of
reading that rigmarole all over again.—Voilà!” And Johann
Buddenbrook tossed the letter to his son, with a contemptuous
gesture. The Consul picked it up as it fluttered to his feet, and
looked at his father with troubled eyes, while the old man took the
long candle-snuffers from their place by the window and with angry
strides crossed the room to the candelabrum in the corner.
“Assez, I say. N’en parlons plus! To bed with you—en avant!” He
quenched one flame after another under the little metal cap. There
were only two candles left when the elder turned again to his son,
whom he could hardly see at the far end of the room.
“Eh bien—what are you standing there for? Why don’t you say
something?”
“What shall I say, Father? I am thoroughly taken aback.”
“You are pretty easily taken aback, then,” Johann Buddenbrook
rapped out irritably, though he knew that the reproach was far from
being a just one. His son was in fact often his superior when it came
to a quick decision upon the advantageous course.
“‘Damnable influences,’” the Consul quoted. “That is the first line I
can make out. Do you know how it makes me feel, Father? And he
reproaches us with ‘unchristian behaviour!’”
“You’ll let yourself be bluffed by this miserable scribble, will you?”
Johann Buddenbrook strode across to his son, dragging the
extinguisher on its long stick behind him. “‘Unchristian behaviour!’
Ha! He shows good taste, doesn’t he, this canting money-grabber? I
don’t know what to make of you young people! Your heads are full
of fantastic religious humbug—practical idealism, the July Monarchy,
and what not: and we old folk are supposed to be wretched cynics.
And then you abuse your poor old Father in the coarsest way rather
than give up a few thousand thaler.... So he deigns to look down
upon me as a business man, does he? Well, as a business man, I
know what faux-frais are!—Faux-frais,” he repeated, rolling the r in
his throat. “I sha’n’t make this high-falutin scamp of a son any
fonder of me by giving him what he asks for, it seems to me.”
“What can I say, Father? I don’t care to feel that he has any
justification when he talks of ‘influences.’ As an interested party I
don’t like to tell you to stick out, but— It seems to me I’m as good a
Christian as Gotthold ... but still....”
“‘Still’—that is exactly it, Jean, you are right to say ‘still.’ What is the
real state of the case? He got infatuated with his Mademoiselle
Stüwing and wouldn’t listen to reason; he made scene after scene,
and finally he married her, after I had absolutely refused to give my
consent. Then I wrote to him: ‘Mon très cher fils: you are marrying
our shop—very well, that’s an end of it. We cease to be on friendly
terms from now on. I won’t cut you off, or do anything
melodramatic. I am sending you a hundred thousand marks as a
wedding present, and I’ll leave you another hundred thousand in my
will. But that is absolutely all you’ll get, not another shilling!’ That
shut his mouth.—What have our arrangements got to do with him?
Suppose you and your sister do get a bit more, and the house has
been bought out of your share?”
“Father, surely you can understand how painful my position is! I
ought to advise you in the interest of family harmony—but....” The
Consul sighed. Johann Buddenbrook peered at him, in the dim light,
to see what his expression was. One of the two candles had gone
out of itself; the other was flickering. Every now and then a tall,
smiling white figure seemed to step momentarily out of the tapestry
and then back again.
“Father,” said the Consul softly. “This affair with Gotthold depresses
me.”
“What’s all this sentimentality, Jean? How does it depress you?”
“We were all so happy here to-day, Father; we had a glorious
celebration, and we felt proud and glad of what we have
accomplished, and of having raised the family and firm to a position
of honour and respect.... But this bitter feud with my own brother,
with your eldest son, is like a hidden crack in the building we have
erected. A family should be united, Father. It must keep together. ‘A
house divided against itself will fall.’”
“There you are with your milk-and-water stuff, Jean! All I say is, he’s
an insolent young puppy.”
A pause ensued. The last candle burned lower and lower.
“What are you doing, Jean?” asked Johann Buddenbrook. “I can’t
see you.”
The Consul said shortly, “I’m calculating.” He was standing erect,
and the expression in his eyes had changed. They had looked
dreamy all the evening; but now they stared into the candle-flame
with a cold sharp gaze. “Either you give thirty-three thousand, three
hundred and thirty-three marks to Gotthold, and fifteen thousand to
the family in Frankfort—that makes forty-eight thousand, three
hundred and thirty-five in all—or, you give nothing to Gotthold, and
twenty-five thousand to the family in Frankfort. That means a gain
of twenty-three thousand, three hundred and thirty-five for the firm.
But there is more to it than that. If you give Gotthold a
compensation for the house, you’ve started the ball rolling. He is
likely to demand equal shares with my sister and me after your
death, which would mean a loss of hundreds of thousands to the
firm. The firm could not face it, and I, as sole head, could not face it
either.” He made a vigorous gesture and drew himself more erect
than before. “No, Papa,” he said, and his tone bespoke finality, “I
must advise you not to give in.”
“Bravo!” cried the old man. “There’s an end of it! N’en parlons plus!
En avant! Let’s get to bed.”
And he extinguished the last candle. They groped through the pitch-
dark hall, and at the foot of the stairs they stopped and shook
hands.
“Good night, Jean. And cheer up. These little worries aren’t
anything. See you at breakfast!”
The Consul went up to his rooms, and the old man felt his way along
the baluster and down to the entresol. Soon the rambling old house
lay wrapped in darkness and silence. Hopes, fears, and ambitions all
slumbered, while the rain fell and the autumn wind whistled around
gables and street corners.
PART TWO
CHAPTER I
It was mid-April, two and a half years later. The spring was more
advanced than usual, and with the spring had come to the
Buddenbrook family a joy that made old Johann sing about the
house and moved his son to the depths of his heart.
The Consul sat at the big roll-top writing-desk in the window of the
breakfast-room, at nine o’clock one Sunday morning. He had before
him a stout leather portfolio stuffed with papers, from among which
he had drawn a gilt-edged notebook with an embossed cover, and
was busily writing in it in his small, thin, flowing script. His hand
hurried over the paper, never pausing except to dip his quill in the
ink.
Both the windows were open, and the spring breeze wafted delicate
odours into the room, lifting the curtains gently. The garden was full
of young buds and bathed in tender sunshine; a pair of birds called
and answered each other pertly. The sunshine was strong, too, on
the white linen of the breakfast-table and the gilt-borders of the old
china.
The folding doors into the bedroom were open, and the voice of old
Johann could be heard inside, singing softly to a quaint and ancient
tune:
A kind papa, a worthy man,
He rocks the baby in the cradle,
He feeds the children sugar-plums
And stirs the porridge with a ladle.
He sat beside the little green-curtained cradle, close to the Frau
Consul’s lofty bed, and rocked it softly with one hand. Madame
Antoinette, in a white lace cap and an apron over her striped frock,
was busy with flannel and linen at the table. The old couple had
given up their bedroom to the Frau Consul for the time being, to
make things easier for the servants, and were sleeping in the unused
room in the entresol.
Consul Buddenbrook gave scarcely a glance at the adjoining room,
so absorbed was he in his work. His face wore an expression of
earnest, almost suffering piety, his mouth slightly open, the chin a
little dropped; his eyes filled from time to time. He wrote:
“To-day, April 14, 1838, at six o’clock in the morning, my dear wife,
Elizabeth Buddenbrook, born Kröger, was, by God’s gracious help,
happily delivered of a daughter, who will receive the name of Clara in
Holy Baptism. Yea, the Lord hath holpen mightily; for according to
Doctor Grabow, the birth was somewhat premature, and her
condition not of the best. She suffered great pain. Oh, Lord God of
Sabaoth, where is there any other God save Thee? who helpest us in
all our times of need and danger, and teachest us to know Thy will
aright, that we may fear Thee and obey Thy commandments! O
Lord, lead us and guide us all, so long as we live upon this earth....”
The pen hurried glibly over the paper, with here and there a
commercial flourish, talking with God in every line. Two pages
further on: “I have taken out,” it said, “an insurance policy for my
youngest daughter, of one hundred and fifty thaler current. Lead her,
O Lord, in Thy ways, give her a pure heart, O God, that she may one
day enter into the mansions of eternal peace. For inasmuch as our
weak human hearts are prone to forget Thy priceless gift of the
sweet, blessed Jesus....” And so on for three pages. Then he wrote
“Amen.” But still the faint scratching sound of the pen went on, over
several more pages. It wrote of the precious spring that refreshes
the tired wanderer, of the Saviour’s holy wounds gushing blood, of
the broad way and the narrow way, and the glory of the Eternal
God. It is true that after a while the Consul began to feel that he
had written enough; that he might let well enough alone, and go in
to see his wife, or out to the counting-house. Oh, fie, fie! Did one so
soon weary of communion with his Lord and Saviour? Was it not
robbing his God to scant Him of this service? No, he would go on, as
a chastisement for these unholy impulses. He cited whole pages of
Scripture, he prayed for his parents, his wife, his children, and
himself, he prayed even for his brother Gotthold. And then, with a
last quotation and three final “Amens,” he strewed sand on the
paper and leaned back with a sigh of relief.
He crossed one leg over the other and slowly turned the pages of
the notebook, reading dates and entries here and there, written in
his own hand, and thanking the Lord afresh as he saw how in every
time of need and danger He had stretched out His hand to aid. Once
he had lain so ill of small-pox that his life had been despaired of—yet
it had been saved. And once, when he was a boy, a beer-vat had
fallen on him. A large quantity of beer was being brewed for a
wedding, in the old days when the brewing was done at home; and
a vat had fallen over, pinning the boy beneath it. It had taken six
people to lift it up again, and his head had been crushed so that the
blood ran down in streams. He was carried into a shop, and, as he
still breathed, the doctor and the surgeon were sent for. They told
the father to prepare for the worst and to bow to the will of God.
But the Almighty had blessed the work of healing, and the boy was
saved and restored to health. The Consul dwelt a while upon this
account, re-living the accident in his mind. Then he took his pen
again and wrote after his last “Amen”: “Yea, O God, I will eternally
praise Thee!”
Another time, his life had been saved from danger by water, when
he had gone to Bergen, as a young man. The account read:
“At high water, when the freight boats of the Northern Line are in,
we have great difficulty getting through the press to our landing. I
was standing on the edge of the scow, with my feet on the thole-
pins, leaning my back against the sailboat, trying to get the scow
nearer in, when, as luck would have it, the oak thole-pins broke, and
I went head over heels into the water. The first time I came up,
nobody was near enough to get hold of me; the second time, the
scow went over my head. There were plenty of people there anxious
to save me, but they had to keep the sailboat and the scow off, so
that I should not come up under them; and all their shoving would
probably have been in vain if a rope had not suddenly broken on one
of the sailboats belonging to the Line, so that she swung further out;
and this, by the grace of God, gave me room enough to come up in
free water. It was only the top of my head, with the hair, that they
saw; but it was enough, for they were all lying on their stomachs
with their heads sticking out over the scow, and the man at the bow
grabbed me by the hair, and I got hold of his arm. He was in an
unsafe position himself and could not hold me, but he gave a yell,
and they all took hold of him around the waist and pulled. I hung
on, though he bit me to make me let go. So they got me in at last.”
There followed a long prayer of thanksgiving, which the Consul re-
read with tear-wet eyes.
On another page he had said: “I could write much more, were I
minded to reveal the passions of my youth....” The Consul passed
over this, and began to read here and there from the period of his
marriage and the birth of his first child. The union, to be frank, could
hardly be called a love-match. His father had tapped him on the
shoulder and pointed out to him the daughter of the wealthy Kröger,
who could bring the firm a splendid marriage portion. He had
accepted the situation with alacrity; and from the first moment had
honoured his wife as the mate entrusted to him by God.
After all, his father’s second marriage had been of much the same
kind.
“‘A kind Papa, a worthy man.’”
He could still hear old Johann softly humming in the bedroom. What
a pity he had so little taste for those old records! He stood with both
feet firmly planted in the present, and concerned himself seldom
with the past of his family. Yet in times gone by he too had made a
few entries in the gilt-edged book. The Consul turned to those
pages, written in a florid hand on rather coarse paper that was
already yellowing with age. They were chiefly about his first
marriage. Ah, Johann Buddenbrook must have adored his first wife,
the daughter of a Bremen merchant! The one brief year it had been
granted him to live with her was the happiest of his life—“l’année la
plus heureuse de ma vie,” he had written there. The words were

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1 Leukocyte-Stromal Interactions Within Lymph Nodes������������������������ 1

F. Barone Rheumatology Research Group, Institute of Inflammation and Ageing

Paul-Peter Tak Division of Clinical Immunology & Rheumatology, Academic

Joshua D’Rozario, David Roberts, Muath Suliman,

Keywords Stromal cells · Lymph nodes · Fibroblasts · FRCs · Lymphoid fibro-

J. D’Rozario · K. Knoblich (*) · A. Fletcher (*)

© Springer International Publishing AG, part of Springer Nature 2018 1

1.2 Fibroblastic Reticular Cells (FRCs)

Selectable markers: Gp38+, CD31-, ER-TR7+, LTβR+, desmin+, aSMA+

Table 1.1 Lymph node FRC subsets

1.2.1 Structural Roles

aracon B and T cell survival aracon

Conduit and ECM network DC migraon

FRC Platelet HEV

basement membrane components and ensheath them. They permit low-­molecular-­

In response to infection or inflammation, FRCs dynamically regulate lymph

1.2.2 Interactions with T Cells

1.2.2.1 Provision of Migration and Survival Factors

1.2.2.2 Suppressive Tolerance

2. Nitric oxide release

CD8 T cell receptor specificity for peptide/MHC = deletion

CD8 Low/no T cell receptor specificity for peptide/MHC = survival

CD8 T cell receptor specificity for peptide/MHC = deletion

CD8 Low/no T cell receptor specificity for peptide/MHC = survival

1.2.2.3 Deletional Tolerance

1.2.2.4 Systemic Effects of Interactions with T Cells

The depletion of FRCs has been shown to significantly attenuate cell-mediated

1.2.3 Interactions with B Cells

FRCs in primary B cell follicles produce B cell-activating factor (BAFF) [24], a

1.2.3.1 Systemic Effects of Interactions with B Cells

1.2.4 Interactions with Dendritic Cells

display the glycoprotein podoplanin [56]. Activation of CLEC-2 by podoplanin

1.2.5  irect Detection of Inflammatory Stimuli

FRCs may be involved in the detection of lymph-borne infection or inflammatory

1.3 Marginal Reticular Cells

Their anatomical placement proximal to the inflow tract of antigens in SLOs,

1.4 Lymphatic Endothelial Cells (LECs)

Selectable markers: Gp38+, CD31+, Lyve-1

1.4.1 Structural and Chemoattractive Role

A LEC interactions C BEC interactions

Oxford, UK Benjamin M.J Owens

1 Leukocyte-Stromal Interactions Within Lymph Nodes�� 1

J. D’Rozario · K. Knoblich () · A. Fletcher ()

1.2 Fibroblastic Reticular Cells (FRCs)

1.2.1 Structural Roles

aracon B and T cell survival aracon

Conduit and ECM network DC migraon

basement membrane components and ensheath them. They permit low-molecular-

1.2.2 Interactions with T Cells

1.2.2.1 Provision of Migration and Survival Factors

1.2.2.2 Suppressive Tolerance

1.2.2.3 Deletional Tolerance

1.2.2.4 Systemic Effects of Interactions with T Cells

1.2.3 Interactions with B Cells

1.2.3.1 Systemic Effects of Interactions with B Cells

1.2.4 Interactions with Dendritic Cells

1.2.5 irect Detection of Inflammatory Stimuli

1.3 Marginal Reticular Cells

1.4 Lymphatic Endothelial Cells (LECs)

1.4.1 Structural and Chemoattractive Role

1.4.2 Interactions with T Cells and DCs

1.4.2.1 Provision of Survival Factors

1.4.2.2 Suppressive Tolerance

1.4.2.3 Deletional Tolerance

1.5 Blood Endothelial Cells (BECs)

1.5.1 Transendothelial Migration