Rheumatology 2006;45:1461–1465 doi:10.

1093/rheumatology/kel329
Advance Access publication 23 September 2006

Review

Autoimmunity vs autoinflammation in Behcet’s disease:

do we oversimplify a complex disorder?
H. Direskeneli
KEY WORDS: Behcet’s disease, Innate, Adaptive, Pathogenesis.

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Behcet’s disease (BD) is a systemic inflammatory disorder such as Staphylococcus aureus, Propionibacterium acnes and
with a diverse spectrum of clinical manifestations including coagulase negative staphylococcia are cultured from BD lesions,
mucocutaneous, ocular, vascular, gastrointestinal, musculoskele- gram-negative microorganisms such as E. coli and Prevotella
tal and central nervous system involvement [1]. A complex species were also, suprisingly, present when compared with
genetic background leading to a pro-inflammatory, innate- acne vulgaris.
immune-system-derived activation perpetuated by adaptive Various immunological studies show an immune
immune responses against enviromental and auto-antigens is hyperreactivity to streptococcia in BD. KTH-1 (a crude extract
accepted to be the hallmark of BD [2]. This review aims to of Streptococcus sanguis SSH-83) causes increased IL-6 and
make an in-depth critical analysis of current data for interferon- (IFN- ) secretion by peripheral blood (PB) T-cells
recent controversies on the role of innate immune system vs of BD patients [13]. KTH-1 also up-regulates -T-cells in short-
autoimmunity in BD [3–5]. term T-cell cultures and KTH-1-specific -T-cell lines secrete
pro-inflammatory mediators IL-6, CXCL-8 and tumor necrosis
factor- (TNF- ) [14]. Lipoteichoic acid, a streptococcal cell
membrane antigen, is also demonstrated to cause increased
Recent epidemiological data
CXCL-8 production from PB mononuclear cells of BD patients
Although epidemiological data is scarse in BD, some recent [15]. However, in addition to streptococcal antigens, E. coli and
observations from Japan suggest that the prevalence of BD is S. aureus also activate BD lymphocytes to release increased
reducing among uveitis patients (23.2% in 1981–1983 vs 5.8% in amounts of IFN- and IL-6 [16]. Comparison of PB lymphocyte
1999–2001) and the disease is becoming milder (ocular attacks changes after stimulation with streptococcal and E. coli extracts
and vision loss getting less frequent) [6, 7]. Since the genetic also gave similar proliferative responses [17]. As microbial
background of the Japanese population at risk is accepted to be antigens common to different species seem to drive a similar
fairly stable, enviromental factors are implicated in this change. immune activation in BD, not the specific microorganism itself
Male patients from Turkey who presented in the 1990s are also but its presence and persistence might determine its role in BD
reported to have a lower risk of losing vision compared with pathogenesis [2].
patients presented in the 1980s. However, the authors preferred Recent reports of benefical anti-bacterial therapy also support
to explain this trend by a more aggressive treatment approach [8]. the role of streptococcia in BD [18, 19]. However, studies,
In another recent study from Turkey, BD patients were observed especially of longitudinal nature, that might show the association
to have a lower monthly family income, lower wealth score and of oral colonization with oral ulcer development and whether
lower education with higher unemployment compared with anti-bacterial treatments effect oral bacterial colonization are
those with ankylosing spondylitis and inflammatory bowel lacking. Another crucial weakness of ‘infection’ theory is the
disease patients, suggesting again the role of enviromental factors effective role of TNF- -antagonists in BD treatment, which
in disease pathogenesis [9]. are contraindicated in active infection.

Infectious aetiology Autoimmunity and BD

As BD starts mostly from the oral mucosal surface (oral apthae A seminal paper from Rose et al. [20] define as the direct proof
as the first manifestation in 70% of the patients), oral microbial of autoimmunity the transfer of autoimmune disease to normal
flora has long been implicated in BD pathogenesis. Oral recipients or animals, such as fetal heart block induction by
manifestations are increased after dental manipulations, anti-Ro antibodies. Indirect evidence is the transfer of disease by
and hypersensitivity to streptococcal skin tests are shown [10]. T-cells to severe combined immunodeficiency (SCID) mice as
Oral health parameters such as dental and periodental indices are demonstrated for Grave’s disease, thyroiditis, systemic lupus
impaired in BD and are associated with a more severe disease erythematosus (SLE) or induction of disease in animals by
course [11]. Oral streptococcal colonization is increased in BD autoantigens such as myastenia gravis or uveoretinitis models.
patients with a dominance of atypical streptococcal species Identification of possibly pathogenic self-reactive T or B cells in
in BD patients’ oral flora. Pustular skin lesions are also shown tissues (such as insulin-dependent diabetes) is the weakest of
to be non-sterile in BD [12]. Although a wide variety of organisms evidences for autoimmunity. Some circumstantial evidence for

Division of Rheumatology, Faculty of Medicine, Marmara University, Istanbul, Turkey.

Submitted 20 June 2006; revised version accepted 15 August 2006.

Correspondence to: H. Direskeneli, Division of Rheumatology, Marmara University Hospital, Tophanelioglu Cad. 13/15, Altunizade, Istanbul, Turkey.
E-mail: [email protected]
1461

The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
1462 H. Direskeneli

autoimmunity are also described. These are lymphocytic Autoinflammation and BD

infiltration of target organs, especially if there is a restriction
in V-gene usage, associations with major histocompatibility A recently introduced concept to BD is ‘autoinflammation’.
complex (MHC) molecules and favourable responses to Autoinflammatory diseases are described as a group of inherited
immunosuppression. disorders characterized by episodes of seemingly unprovoked
Behcet’s disease does not have the classical clinical features recurrent inflammatory attacks of innate nature, mainly by
of autoimmunity such as anti-nuclear antibody (ANA) positivity, neutrophils [39]. In contrast to classical autoimmune disorders,
female dominance and association with other autoimmune no significant high-titre autoantibodies or antigen-specific T-cells
diseases such as Sjogren’s syndrome [3]. A multi-sytemic animal are present. The prototype disorder in Middle Eastern popula-
model of BD is also non-existent. However, BD has various tions is familial Mediterranean fever (FMF), a disease caused
aspects that deserve to be evaluated as ‘autoimmune’. by mutations of MEFV gene, encoding the newly described
Some effective treatments in BD such as azathioprine and pyrin/marenostrin protein. MEFV and pyrin are expressed at high
cylophosphamide are classical immunosuppressives, and levels in neutrophils, monocytes and dendritic cells but not in

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cyclosporine A is a T-cell inhibitor. However, TNF- -antagonists lymphocytes. The N-terminal of pyrin binds to another pyrin-
are also an exception in this concept, as they act mainly as anti- domain-containing protein called apoptosis speck like protein
inflammatory agents and are accepted to be contraindicated in containing a caspase-recruitment domain (CARD)(ASC), and
through this interaction might regulate IL-1 processing, NF-
autoimmune diseases such as SLE and multiple sclerosis.
From an immunological perspective, a possibly antigen-driven activation and apoptosis. However, both inhibitory
and enhancing effects have been observed depending on the
change in peripheral blood CD4þ and CD8þ T-cell repertoire
experimental system [40].
with oligoclonal T-cell receptor V subset increases are observed
Behcet’s disease, with some of its clinical features such as
in BD [21]. For an autoimmune aetiology, a general B-cell
recurrent non-scarring mucocutaneous lesions and non-deforming
activation and autoantibodies against cell surface antigens such as
arthritis, and enhanced inflammatory response with the over-
anti-endothelial cell (AECA) and anti-lymphocyte antibodies are
expression of pro-inflammatory cytokines, is described to be in
demonstrated [22, 23]. Later on, antibodies against specific
this spectrum [4]. MEFV mutations are also observed more
antigens such as -tropomyosin, -enolase and, recently, kinectin
frequently in BD and associate with a more severe disease [41].
were shown [24–26]. Among the candidate autoantigens, human
However, various clinical aspects differ between the two diseases,
heat-shock protein 60 (HSP60) is the most extensively investigated
which is discussed in further detail previously [5]. Among these,
[27]. Four immunodominant epitopes of HSP60 are shown to pediatric onset and paroxysmal attacks of serosal inflammation
cause T- and B-cell responses in studies from UK, Japan and and fever typical of autoinflammatory disorders are not char-
Turkey [28–30]. A T-helper 1 (Th1) type, pro-inflammatory acteristic of BD, whereas panuveitis, extensive vasculitis, hyper-
cytokine response to HSP60-derived peptide 336-51 with IFN- , coagulability and a disease course getting milder in late ages are
IL-12 and TNF- production is demonstrated [31]. Txk, a tyrosine common [5]. Another crucial difference between FMF and BD is
kinase expressed in Th1 cells up-regulating IFN- gene transcrip- the prolonged inflammatory skin response. Pathergy test, a non-
tion, also responds to peptide 336-51. However, when long-term specific response to skin trauma, is typically described in BD and
T-cell lines were produced from PB mononuclear cells with some neutrophilic dermatoses such as pyoderma gangrenosum
repetitive stimulation, 336-51-responsive T-cell lines were present and Sweet’s syndrome [1, 42]. Pathergy reactions are shown to be
also in healthy controls, suggesting that healthy immune associated with skin flora, as extensive skin cleasing decreases the
repertoire also responds to human HSP60 as an immunodominant positivity of the test [43]. In a chronological study of pathergy,
antigen [32]. mixed neutrophil and T-cell infiltrations are observed as early as
In terms of animal models for autoimmunity, HSP60 peptide 4 h, with a peak density in 24 h in BD patients’ skin biopsies [42].
336-51 and -tropomyosin are both shown to cause uveitis in No pathergy skin response is reported in FMF [44], although
rats, but without any other clinical features of BD [24, 33]. An oral erizipel-like skin lesions or rarely cutaneous vasculitis with
conjugate of peptide 336-51 and cholera toxin-B is shown to neutrophil infiltrations are observed. Similar to pathergy test,
ameliorate uveitis in the animal model; a preliminary study is also skin responses to urate crystals are described in BD, which is again
reported in BD patients with uveitis [34]. a highly specific response not observed in FMF [45, 46]. When
Another crucial element of autoimmunity is MHC relationship. innate responses to urate crystals are investigated, urate-derived
Most classical autoimmune disorders are shown to have an MHC superoxide production in neutrophils was found to be dose-
class II association, leading to a disease-associated peptide dependent and very similar in magnitude in both BD and FMF,
hypothesis (MHC-class-II-associated presentation of pathogenic and was even higher in FMF monocytes [46]. Urate crystals
epitope to CD4þ T-helper cells) such as shared-epitope in are recently shown to activate NALP3 inflammasome, a protein
rheumatoid arthritis. However, BD is associated with a class I complex of cryopyrin, ASC and a protein called CARDINAL
antigen, HLA-B*51 [1, 2]. Although this association is similar to (CARD-inhibitor of NF- -activating ligand), causing the
spondyloarthropathies, possible immune mechanisms associated activation of caspase-1 complex and leading to the release of
with HLA-B*27 are not studied sufficiently in BD. Recently, a IL-1 [40, 47].
HLA-B*51-restricted peptide from an MHC class I chain-related
gene (MICA) antigen is shown to activate CD8þ T-cells with an
up-regulated IFN- response in BD patients [35]. Another study
has previously shown that an HLA-B*51-related peptide Pathways from innate to adaptive responses
(also present in HLA-B*27) causes the proliferation of PB Although there are clinical and inflammatory response similarities
mononuclear cells only in HLA-B*51-positive BD patients with between autoinflammatory disorders and BD, presence of a
posterior uveitis [36]. As a genetic susceptibility associated with prolonged inflammation such as non-specific (pathergy) or urate-
B*2702 has also been implicated in BD, interactions of natural induced skin responses suggests that innate and adaptive
killer (NK) and T cells through the NK receptors may also be pathways are more integrated in BD. A unifying hypothesis
important in the pathogenesis of BD with an interaction between for BD requires the explanation of these links between the two
NK receptor KIR3DL1 and HLA-Bw4 motif [37, 38]. Other main arms of immune system. One explanation might be an
recently described HLA-B27-related immune mechanisms such unprovoked, uncontrolled innate-related inflammation causing an
as heavy-chain association or bacterial persistance are not adaptive system activation only as a secondary response, as in
studied in BD yet. autoinflammatory disorders [4]. An overactivated cytokine
 Autoimmunity vs autoinflammation in BD 1463

cascade through IL-1, IL-6, IL-18, TNF- and chemokines TABLE 1. Mechanisms of responses from innate to adaptive immunity in
such as CXCL-8 might activate non-specific and non-pathogenic Behcet’s disease
T- and B-cell responses in BD. As an example, increased
CD3þHLA-DRþ, CD4þCD69þ, CD8þCD25þ and
A persistant bacterial stimuli (oral or skin infections) activating
CD8þCD69þ T-cells are observed in the peripheral blood adaptive immune responses through PRRs [2, 17]
during FMF attacks; however, these adaptive responses are
Uncontrolled innate-related inflammation (caspase pathway IL-1,
IL-18) [4]
possibly not pathogenetic [48].

Neutrophil activation with T-cell derived chemokines (CXCL-8) [61]
However, the situation can be more complex in BD.
Defective neutrophil apoptotic clearance and bacterial defence with
Neutrophils, although accepted as primary effector cells of MBL deficiency [58]
inflammation, are usually neglected in their role in later stages
Bacterial -T-cell activation and antigen-presentation [28]
of immune activation and response [49]. They have the capability
HLA-B*51-associated responses
to present antigen under inflammatory conditions with MHC
Presentation of a Behcet-related peptide to CD8þ cytotoxic T-cells [35]
class II and costimulatory molecule expressions. They generate
HLA-B common peptide activation of CD4þ T-cells [36]

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chemotactic signals such as TNF- that attract monocytes
Bw4-associated NK receptor activation [38]
and dendritic cells (DC), and influence whether macrophages
differentiate to a predominantly pro- or anti-inflammatory state.
IFN- and B-lymphocyte stimulator (BLyS) are also released subset as they differ from both Th1 as well as Th2 and are
by neutrophils and cause proliferation and maturation of T and B associated with a unique, neutrophil-rich sterile inflammation [61].
cells, respectively [49]. In this context, neutrophil activation, Auto- (HSP60, retinal-S antigen) or microbial-derived antigen-
cytokine release and antigen presentation may link innate immune stimulated T-cell lines mainly of Th1 phenotype were also
system to adaptive responses and by definition gives a broader demonstrated in other studies in BD [2].
role to neutrophils than ‘autoinflammation’, which is accepted to Another important cell subset that links innate and adaptive
be a limited inflammatory response without an effective adaptive responses is -T-cells. Although they possess a T-cell receptor, this
component. Behcet’s disease in this respect require a more critical T-cell subset is activated mainly by bacteria-originated molecules.
analysis of neutrophil activation, and BD neutrophils may have a -T-cells are shown to activate dendritic cells recently and can
different profile compared with autoinflammatory disorders [50]. make antigen presentation. They are also activated under stress
An intruguing hypothesis might be the role of a ‘persistant conditions recognizing damaged cells [62]. Various studies demon-
infection’ in BD. Cryopyrin-associated inflammasomes in strated elevated -T-cell presence in BD patients [17, 63]. They are
neutrophils can be activated by bacterial peptidoglycans (PGN), increased in skin biopsies together with HSP60 expression in BD
bacterial RNA and various gram-positive bacterial toxins [49, 51]. [64]. These cells respond to both streptococcia and HSP60-derived
Pathways of inflammasome and recently described pattern- peptides [17, 28] and might participate in tissue destruction and
recognition receptors (PRRs) such as toll-like receptors (TLRs) presentation of self and foreign antigens to adaptive immune cells.
intersect as both are sensors of bacterial products. The augmented As all activated cells require antigen-presentation first, DC
adaptive responses in BD compared with autoinflammatory maturation is now accepted to be the critical step for the induction
disorders can be the result of persistant oral and skin infections of adaptive responses and BD is possibly no exception. Both
discussed above. In addition to adaptive responses to bacterial pathogen and autoantigen-driven T-cell polarization are con-
and mammalian ‘cross-reactive’ epitopes of human HSP60, a trolled by DCs through DC-priming receptors including PRRs
direct activation of innate immunity through TLRs by HSP60 and tissue factors such as cytokine and chemokines [65].
is also shown [27, 52]. HSPs released from necrotic (but not Interactions between DCs and neutrophils, T, B, NK and -T-
apoptotic) cells are observed to activate DCs [53]. Recently, cells determine the nature of immune responses that characterize
HSP60 is also shown to induce DC maturation with increased the unique clinical syndrome complex of BD (Table 1).
MHC class II, CD40, CD54 and CD86 expressions and allogeneic
T-cell proliferation with a Th1 bias [54]. We have also recently
shown that both human HSP60 and streptococcal extracts
activate TLR-6 on BD neutrophils [55]. As another link between Future pathways to explore
oral diseases, TLRs and HSPs, human T-cell proliferative As an effective adaptive response seems to be required for the
responses to human HSP60 is increased in patients with prolonged immune activation in BD, mechanisms supported by
periodontal disease and this proliferation can be inhibited with the literature above are possibly not mutually exclusive. APCs
anti-TLR2 antibodies [56]. such as dendritic cells and keratinocytes, neutrophils, CD4,
As neutrophils arrive very early to initiate inflammation in CD8 and -T-cells are present in BD lesions with confusing
tissues and live too briefly [49], clearance of apopototic material histopathological data according to the age (24–72 h) and type
by complement system proteins such mannose-binding lectin (folliculitis vs erythema nodosum) of the lesions. As dissecting
(MBL), surfactant protein-A and SP-D are critical in suppressing each mechanism separately (single cytokine or chemokine
inflammation. An adaptive response related to neutrophils in measurements) seems insufficient to view the whole picture in
BD may be promoted by aberrant phagocytosis of apoptotic BD, immune mediators and pathways such as apoptosis, NF-
neutrophils by dendritic cells, as shown in ANCA-associated or TLR signalling should be investigated with new techniques
vasculitis [57]. In this context, serum MBL levels are shown to be such as multiplex bead immunoassays, mRNA oligoarrays or
decreased in BD patients, and MBL deficiency may prolong whole-genome microarrays [66, 67].
the exposure of neutrophil-related antigens to adaptive immune
system [58]. A lower bacterial clearence due to low MBL levels
may also predispose to bacterial infections and a higher
Conclusions
prevelance of S. mutans colonization is observed in patients with
low MBL levels in BD [59]. An immune response is possibly triggered by two main
Another model points to a possible role of T-cells for mechanisms. According to the ‘danger theory’ by Matzinger
neutrophil activation in BD. A principal source of CXCL-8, [68], the immune system responds to the alarm signals of injured
the major neutrophil chemoattractant in BD peripheral blood, is host-cells, which activate antigen-presenting cells. ‘The pattern-
lymphocytes [60]. Recently, skin-derived T-cell clones from BD recognition theory’ places the role of microbial ‘non-self’ as the
patients were shown to produce CXCL-8 and GM-CSF, but failed dominant stimuli for innate immune system, which in turn triggers
to secrete IFN- or IL-5. These cells might represent a particular an adaptive response [69]. Human HSP60 can be an example of
1464 H. Direskeneli

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