Immunoregulation,Immunodysregulation and Autoimmune Disorders

1
???????????????
Immunoregulation,Immunodysregulation and
Autoimmune Disorders
? ? ?
??????? ????
2008?9?18?
2
Contents
Part I Concept of Immunohomeostasis Part II
Immunological Tolerance Part III
Immunoregulation and Immunodysregulation Part IV
Mechanisms of Autoimmune Diseases
3
Part I Concept of Immunohomeostasis
???????
4
Complexity of the Immune System

• Two systems (innate and adaptive)
• Organs and connecting network
• Different lineage of cells
• Numerous T and B cell clones with unique Ag
  specificity
• Has to be able to distinguish self from non-self

5
A properly coordinated (regulated) immune
system will
1 Defend against infectious microorganisms

1. Stay in harmony with self-antigens and tissues of
   the host
2. Maintain appropriate magnitude when responding to
   foreign Ags challenge

6
??????? ????????? ??????? ??????? ???????
7
Hypersensitivity Overreaction to foreign
substances
Immuno-imbalance
Athma Hayfever Contact hypersensitivity
8
Immuno-imbalance
Immunodeficiency unable to control infection
Frequent infection with various pathogens
9
Autoimmunity Attack of self-antigens
Immuno-imbalance
SLE Rheumatoid Arthritis Diabetes AS
10
Part II Immunological tolerance
????
11
2-1 ??????

• ??????????????????????????,???????????????
  ??????????????????????????????????????????????????
  ?????
• ?????????
• B???????????

12

• ?????????????????????
• ?????????????????
• ????,
• ???????,
• ??????

13
2-2 ??????

• T ??????
• B ??????
• ????????

14
T ????????
???APC???? T ??????????
15
T-B ?????????
????
BCR
B
Th
TCR
MHC II
? ?
T-B ? ? ? ? ? ? ? ?
16
???????B???????????
????
BCR
B
???? T ??
TCR
MHC II
T-B ? ? ? ? ? ?
17
Part III Immunoregulation and dysregulation
?????????
18

• ???T??????????????????
• Th1/Th2/Th17?????????
• ???????????(IL-2, IL-10, TGF-b)
• ????(??)????????? (ITIM, LAIRE, AICD)
• ?????????????????

19
?????????????? T ??
???? - 1
20
(No Transcript)
21
???? - 2
Normal mouse
CD4 T cells eliminated CD25 cells
Autoimmune diseases thyroid stomach
salivary gland Langerhans islets adrenal
glands ovaries testes
T cell-deficient mouse
22
(No Transcript)
23

• CD4CD25 Tregs
• A naturally occurring unique lineage of
  regulatory T cells
• Comprise 5-10 of peripheral CD4 T cells in
  human and mice
• Capable of maintaining self tolerance in vivo
• Characterized by expression of CD4 and CD25 on
  surface, FOXP3 in the nucleus
• Require activation and cell contact to repress
  proliferation of
• CD4CD25- T cells in vitro

24
The miracle CD4CD25 Tregs
??????????? ???????? ?????? ???????????(HIV??) ???
????????(RA,MS?)
25
?CD25 Treg ??????????
Peripheral Lymphocyte Repertoire
B
Abs
B, 1010
CD4
Th1, Th2, Th3
CD4, 1010
CD8
CTL
CD8, 1010
Immunization
26
Peripheral Lymphocyte Repertoire
????
B
B, 1010
CD4
CD4, 1010

CD8
CD8, 1010
Immunization
CD25 Treg
CD25, 109
27
IPEX

• Immune deficiency/dysregulation
• Polyendocrinopathy
• Enteropathy (Often have Ab against gut
  epithelium)
• X-linked inheritance

28
(No Transcript)
29
FOXP3 Mutations
30
Immuno-dysregulation
31
Part IV
Mechanisms of autoimmune disorders
??????????
32
?????
??????????????????????????????????????????
???????????????
33
??????????

• ????????????T?????
• ??????
• ???????????????????
• ???
• ??????????????T????
• ????

34
(No Transcript)
35
??????????????
36
?????????

• 1 ???????????
• ???????????????????
• ?????????????????
• Naive T and B lymphocytes
• Anergic cells

37
2 ????????????? --????
38
3 ??????????????????? (1) ??????? (2)
?????????????? (3) T-B ??????? (4) ????????
39
(1)???????
LCMV
( LCMV ??????? b ??)
TCR
(90 T???????TCR)
25
25
25
25
LCMV
LCMV / TCR
TCR
Non
?? ??
? ? ?
40
??????????????
41
(2)??????????????
? ? ????????????? (Fas?CD5 ?
CTLA-4??????) ?????????
??????(CD22,CD5,CD72,PD-1,FcgRIIB)?? ? ?
IL-2???????? LPS ???????
42
T-B ???????????????
BCR
Th -- a
B
Th -- b
MHC II
Th -- c
? ?
??????
???
T-B ? ? ? ?
MHC?????
43
Immune Dysregulation and Autoimmunity

• Mechanisms
• auto-antibody formation
• auto-aggressive infiltrating lymphocytes
• Examples
• CVID IgA deficiency relatives of CVID
• DiGeorge Syndrome Omenn Syndrome
• Wiskott Aldrich Syndrome
• IPEX (FOXP3)
• APECED (AIRE)
• ALPS (FAS Ia, FASL Ib, Caspase 10 IIa, Cas 8 Iib)

44
?????????????
45
??? ?? ??? ??? ??? 38 ? ???? ??? ???? ??
100083 Tel[phone] E-Mailxmgao_at_bjmu.edu.c
n