Chapter 10

The Humoral Immune

Response
Outlines:
1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. How and where are B cells activated?
3. What is class switch? Functions of AID?
4. The functions of Ig isotypes: neutralization, opsonization,
and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors:
ADCC and resistant to parasite infection.
1
 3華航機師未確診卻抗體陽性
加驗家人釐清傳播鏈
2021-0427
指揮中心疫情監測組組長周志浩說，這3名未確診但抗體陽性為本國籍40
多歲男性（2名）及本國籍40多歲女性（1名），3人分別於4月22日、4月24
日及4月25日接受專案採檢，檢驗結果核酸檢測皆為陰性，血清抗體皆呈IgM
陰性、IgG陽性。
記者會中媒體提問，這3名未確診、但檢出血清抗體陽性機師是否會納入
國內確診者名單中，陳時中表示，依照過去習慣，血清抗體陽性、核酸檢
驗陰性者不會列入確診名單及執行近期接觸者疫調，但會串連長時間資料，
了解同住家人血清抗體情形，畢竟已經感染已久。
2021-0504
指揮中心今天宣布國內新增新冠肺炎確診個案。其中案1153為華航機師，
並證實該機師於4月22日施打第一劑新冠肺炎疫苗，確定為首例國內接種武漢
肺炎疫苗後確診。指揮中心發言人莊人祥表示，案1153機師在5月1日發病，
與接種疫苗中間間隔9天。
據最新國際研究，牛津AZ的新冠肺炎疫苗接種12天起可降低感染風險，約
減少6成感染機率，第一劑2到4週後保護力就會逐漸形成，完整接種2劑保護
力可望達70%，且接種後即便感染病毒量也較低，大幅降低傳染力。

2
 【新冠肺炎／不斷更新】上週本土＋93、死
亡＋13！新變異株「大角星」境外移入14例
2023-0420
指揮中心指出，上週每日平均新增93例本土確定病例，較前一週每日平
均新增86例有小幅度增加，此外，上週平均每日新增13例死亡，當中有99%
具慢性病史、63%未打滿3劑疫苗、95%為60歲以上。綜合通報趨勢、醫療資
源使用情形、口服抗病毒藥物開立數及住宿式機構陽性率研判，疫情持續處
於低點。
而指揮中心發言人羅一鈞在記者會上也針對近期傳出的新變異株Arcturus
「大角星」說明，據統計台灣目前已累積14例Arcturus「大角星」個案，皆
為境外移入病例，來源國主要是日本、泰國，全球的主流病毒株依然是XBB
株，雖然Arcturus「大角星」的占比有增加，但疫苗仍有保護效果，重症及
住院率並無上升，仍是待觀察變異株。
新的Omicron亞型變異株「XBB.1.16」，俗稱「大角星（Arcturus）」是印度
最近疫情再起的主要原因，造成當地確診數破萬例。目前，國內本土雖然未
檢驗出XBB.1.16確定病例，不過境外檢出已累積14例。

為何對舊病毒株的疫苗、或是感染的後天性免疫記憶，仍然對
新變異株病毒仍有一定的保護效果？
 為何對舊病毒株的疫苗、或是感染的後天性免疫
記憶，仍然對新變異株病毒仍有一定的保護效果？

一般來說，疫苗或感染後天性免疫系統產生的保護效果，是通過識別病原
體表面上的一些特定結構（例如蛋白質、糖等）來實現的。當病原體入侵體內
時，這些特定結構會激活免疫系統，並促使其產生特定的抗體和T細胞，以攻
擊和清除病原體。
當出現新變異的病原體時，它們的表面結構可能會發生變化，從而導致免
疫系統難以識別和攻擊。但是，儘管新變異株的表面結構與原有的病原體不同，
它們的基本結構和生物學特性仍然相似，因此原有的疫苗或感染後天性免疫系
統可能仍然具有一定的保護效果。
此外，一些疫苗設計時就考慮到了可能發生的變異情況，並選擇了具有更
廣泛覆蓋範圍的病原體表面結構作為疫苗的目標。這些疫苗可能會對新變異株
提供更好的保護效果。
總的來說，對於新變異株，原有的疫苗或感染後天性免疫系統可能會失去
一定的保護效果，但仍然可能提供一定的保護作用，尤其是對於那些基本結構
相似的變異株。同時，科學家和製藥公司也在不斷努力研發新的疫苗和藥物，
以應對不斷變化的病原體。
by ChapGPT
The humoral immune
response is mediated by
Ab molecules that are
secreted by plasma cells

Opsonization: coating the

surface of a pathogen to
enhance phagocytosis

5
but naive

6
 The Humoral Immune
Response
Outlines:
1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. How and where are B cells activated?
3. What is class switch? Functions of AID?
4. The functions of Ig isotypes: neutralization, opsonization,
and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors:
ADCC and resistant to parasite infection.
7
Tind 引發之反應則像 innate R
8
 (TI-1) (TI-2)

(cytokines)

9
(polyclonal mitogen, 裂殖素) (pA31)
Properties of
different classes
of Ags that elicit
Ab responses

10
(p427-430)
B-cell activation by TI-2
Ags requires, or is greatly
enhanced by, cytokines

TI-1 Ags: activate both immature and

mature B cells
DC
TI-2 Ags: activate only mature B cells
Mostly bacterial capsular polysaccharides
Mainly by B-1 (CD5) cells (young children)
or marginal zone B cells (adults)

(p428-429)

11
A second signal is required for B-cell activation by
either thymus-dependent or thymus-independent Ags

TFH: T follicular helper cells NIK: (NF-B inducing kinase)

12
B-cell responses to Ag are enhanced by co-ligation of the B-cell co-receptor (p408)

TAPA: target of an
anti-proliferative Ab
(Immunoreceptor
tyrosine inhibitory motifs)
ITAM

With co-receptor,
require 102 instead
of 104 mIgM for B-
cell activation. (↑ CD40 expression) 13
 The Humoral Immune
Response
Outlines:
1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. How and where are B cells activated?
3. What is class switch? Functions of AID?
4. The functions of Ig isotypes: neutralization, opsonization,
and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors:
ADCC and resistant to parasite infection.
14
TFH cells provide several signals that activate B cells
and control their subsequent differentiation

15
T cells and B cells must recognize Ags contained
within the same molecular complex in order to interact

B-cell activation by
armed T cells

16
B cells and helper
T cells must
recognize
epitopes of the
same molecular
complex in order
to interact
Linked recognition
- same molecule
- not the same epitope

Hapten + carrier
Cognate T cells:
T cells that see same Ag
and provide help to B
cells.
Ensure tolerance
to self antigens

17
(p408-409)
Protein Ags attached
to polysaccharide
Ags allow T cells to
help polysaccharide-
specific B cells
Vaccine against Haemophilus
influenzae type b is a conjugate
of bacterial polysaccharide and
the tetanus toxoid protein.

Isotype switching requires

the expression of CD40L by
the helper T cells → hyper-
IgM immunodeficiency (HIM-1
syndrome)

18
 The Humoral Immune
Response
Outlines:
1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. How and where are B cells activated?
3. What is class switch? Functions of AID?
4. The functions of Ig isotypes: neutralization, opsonization,
and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors:
ADCC and resistant to parasite infection.
19
Meeting of Ag-binding B and T cells
at the border between the T-cell and
B-cell zones in the spleen
T cells - CCR7 ↔ CCL19 or CCL21
B cells - CXCR5 ↔ CXCL13
EBI2 ↔ 7,25-dihydrooxycholesterol

20
When an armed helper T cell
encounters an Ag-binding B cell,
it becomes polarized and
secretes IL-4 and other
cytokines as well as the cell-
associated TNF family member
CD40 ligand at the point of cell- MTOC: microtubule-
organizing center
cell contact

(cytoskeleton)

B T
CD40 and CD40L
CD30L and CD30
41BBL and 41BB
ICAM-1 and LFA-1
ICOSL and ICOS

21
Induction of SAP in TFH
cells allows SLAM
family receptor to
mediate sustained
contact with B cells

幫助 TFH ↔ B cell interaction 一開始 SAP 濃度低，細胞之間無法靠緊

SLAM ↔ SAP
CD84 ↔ Ly108

SLAM: signaling lymphocyte

activation molecule
SAP: SLAM-associated
SLAM: protein
signaling lymphocyte
activation molecule
SAP: SLAM-associated protein

活化之TFH表現高 SAP，讓細胞緊黏 22
BAFF and APRIL promote
B-cell survival and regulate
differentiation

On FDCs, stroma, epithelia

APRIL: a proliferation inducing ligand
BAFF : B-cell-activating factor of the
TNF family) on macrophages and DCs

On B cells
TACI: TNF-like receptor transmembrane
TRAF3
activator and calcium modulator and
cyclophilin interactor
BCMA: B-cell maturation antigen

23
Opsonized Ags are captured and preserved by
subcapsular sinus (SCS) macrophages

(FDC)

24
Armed helper T cells stimulate the proliferation and
then the differentiation of Ag-binding B cells

IL-4: B-cell stimulating factor 1 (BSF-1) or B-cell growth factor 1 (BCGF-1)

IL-5: B-cell growth factor 2 (BCGF-2)
IL-6: B-cell stimulating factor 2 (BSF-2) or B-cell differentiation factor 1 (BCDF)
25
Different cytokines induce switching to different isotypes

Isotype switching requires the expression of CD40L by the helper T cells

TI-2 responsesimmunodeficiency
→ hyper-IgM might induce IgG,(HIM-1
when use signals through BAFF (B-cell-
syndrome)
activating factor of the TNF family) on M and DCs.

26
 Plasma cells secrete Ab at a high rate but can no
longer respond to Ag or helper T cells

(condensed chromatin
prominent perinuclear
Golgi apparatus)

27
Second phase of the primary B-cell immune response -
activated B cells form germinal centers in lymphoid follicles

CCL19 and CCL21

to CCR7 on B cells
Germinal centers are sites of intense cell proliferation and cell death

Green: Ki67 stained proliferating cells Red: FDC staining

29
The primary Ab repertoire is diversified by three
processes that modify the rearranged Ig gene

Somatic hypermutation 是增進抗體結合力重要的先導步驟

30
 apical

IL-1 + CD 23

(immune-complex coating)

(secrete CXCL13 to CXCR5 on B cells)

basal
*

no CXCR4

small size
non-dividing
* with surface Ig

large size
expanded cytoplasm 31
CXCR4+ or diffuse chromatin
CXCR5+ * no surface Ig
The structure of germinal centers

Affinity Proliferation
maturation (6-8 hrs each time, 3-4
times/day)
 mutation (1/103)
 selection

Cyclic reentry model (p4016-417)

and CXCR5+

32
Somatic hypermutation introduces variation into the rearranged Ig variable region that is
subject to negative and positive selection to yield improved Ag binding (affinity maturation)

33
Selection for high-affinity mutants in the GC relies on help
provided by TFH cells

對抗原結合力高之B
cell，可以再和 TFH 作
用，得到活化之訊號；
部分如此之 B cell，
也可再回 dark zone。

34
Activated B cells undergo
rounds of mutation and
selection for higher-affinity
mutants in the germinal center,
resulting in high-affinity Ab-
secreting plasma cells and
high-affinity memory B cells

BLIMP-1 (B-lymphocyte-induced maturation

protein 1): an important regulatory protein that
switches off genes required for B-cell
proliferation and class switch in the GC. It also
induces the formation of plasma cells, including
 CXCR5 and ↑CXCR4 and 4:1 integrins.

35
Immune complexes bind to the surface of follicular dendritic cells

iccosomes:
Immune complex-coated bodies

36
 Immune complexes bound
to follicular dendritic cells
form iccosomes, which are
released and can be taken
up by B cells in the germinal
center

iccosomes:
Immune complex-coated bodies
taken up
Source:
live pathogens
or vaccine Ags + adjuvant bind

37
 The Humoral Immune
Response
Outlines:
1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. How and where are B cells activated?
3. What is class switch? Functions of AID?
4. The functions of Ig isotypes: neutralization, opsonization,
and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors:
ADCC and resistant to parasite infection.
38
Immunoglobulin isotype (class) switch

IgM IgG

39
Isotype switching involves recombination
between specific switch signals

150 X (GAGCT)n(GGGGGT), n=3-7

Enzyme: unknown
AID (activation-induced cytidine deaminase)
UNG, APE1, Ku70:Ku80 40
AID (activation-induced cytidine deaminase) in
class switching and somatic hypermutation

Normal IgM, little IgG in AID-/- mice. AID基因發現：

AID基因缺損相關疾病；hyper-IgM syndrome (type II) by Dr. Honjo in 2002
41
AID (activation-induced cytidine deaminase) in
class switching and somatic hypermutation

No somatic hypermutation in AID-/- mice.

42
Activation-induced cytidine
deaminase (AID) is the initiator
of mutations in somatic
hypermutation gene conversion,
and class switching

The sequence of AID is related to

that of a protein known as APOBEC1
(apolipoprotein B mRNA editing
catalytic polypeptide 1), which
convert cytosine to uracil by
deamination in apolipoprotein B
mRNA.

43
Generation of single –
strand nicks in DNA by
sequential action of AID,
UNG, and APE1

UNG: uracil-DNA-glycosylase
(to form abasic site in the DNA)

APE1: apurinic/apyrimidinic
endonuclease 1
(to generate a single-strand nick)

44
 AID initiates processes that lead to
somatic hypermutation, gene conversion
and class switch recombination

(synthesize DNA over the abasic

sites and have a random
nucleotide insertion )

(through homologous
recombination with pseudogenes)

(因為有許多 DNA nick)

45
Class switching involves
recombination between
specific switch signals

S : 150 repeats of
(GAGCT)3-7(GGGGGT)
- form R-loop

如何調控？
S 前亦有 promoter

46
Isotype switching is preceded by transcriptional
activation of heavy-chain C-region genes

調控：S 前有 promoter

47
 The Humoral Immune
Response
Outlines:
1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. How and where are B cells activated?
3. What is class switch? Functions of AID?
4. The functions of Ig isotypes: neutralization, opsonization,
and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors:
ADCC and resistant to parasite infection.
48
 The distribution and
functions of Ig isotypes

49
Each human Ig isotope has specialized functions and a unique distribution

50
Transcytosis of IgA Ab across epithelia is mediated
by the poly-Ig receptor

pIgR被裁剪，稱為
secretory component
(由epithelial cell 所表現)

(ploy-Ig receptor)

51
FcRn binds to the Fc portion of IgG

FcRn: similar to MHC I

an IgG transport protein
in placenta
binds to IgG at C2/C3
2 FcRn for 1 IgG
- also maintain the IgG
level in plasma

2 : 1

52
Ig isotypes are selectively
distributed in the body

No Ig in the brain

53
Neutralization of toxin by IgG Abs protects cells from their damaging action

binding toxin

Toxoids: modified toxins, lack of toxic activity but retain the receptor–binding site
Passive immunization: anti snake venom (antivenins)
IVIG (intravenous immune globulin)
1018 molecules (107 different specificities)
200-400 mg/Kg
54
Viral infection of cells can be blocked by neutralizing Abs

Anti-hemagglutinin of
influenza virus

55
Abs can prevent the attachment of bacteria to cell surface

56
The classical
pathway of C’
activation is
initiated by the Ag bound

binding of C1q to
Ab on a surface
such as a bacterial
surface

57
Erythrocyte CR1 helps to clear immune complexes from the circulation.

C3b – CR1

58
 The Humoral Immune
Response
Outlines:
1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. How and where are B cells activated?
3. What is class switch? Functions of AID?
4. The functions of Ig isotypes: neutralization, opsonization,
and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors:
ADCC and resistant to parasite infection.
59
The destruction of Ab-coated pathogens via Fc receptors
Distinct receptors for the Fc region of the different Ig isotypes are
expressed on different accessory cells

60
Bound Ab is distinguishable
from free Ig by its state of
aggregation

61
Fc and C’ receptors on phagocytes trigger the uptake
and degradation of Ag-coated bacteria

62
Ab-coated target cells can be killed by NK cells in Ab-
dependent cell-mediated cyotoxicity (ADCC)

63
IgE Ab-cross-linking on
mast-cell surface leads
to a rapid release of
inflammatory mediators

Mast cells: important for the

resistance to parasite infection.
The accumulation of mast cells
In the intestine, known as
mastocytosis with helminth
infection.

64
複習重點：
1. T-ind 與 T-dep 活化的情況

2. 除了 linked recognition 之外，其他有關B細胞活化時所需之分

子或是細胞？

3. 1) AID 的功能; 2)缺損時的影響

4. affinity maturation 的重要性、與發生的機制

5. 各抗體的重要功能？

6. Ab-Ag 複合體的清除

7. ADCC

65