Autoimmunitás/Autoimmunitás kialakulásának okai
Populáció ~5% szenved
autoimmun betegségben
TÚLÉRZÉKENYSÉGI REAKCIÓK ÁTTEKINTÉSE/Autoimmunitás?
I. típusú
II. típusú
III. típusú
IV. típusú
„azonnali”
„késői”
Ellenanyag mediált
T sejt mediált
specifikus IgE
sejtfelszíni antigénnel
specifikusan reagáló
ellenanyag, IgG
aspecifikusan
MHC függő T sejt
lerakódó, szolubilis aktiváció
immunkomplex
hízósejtekből
felszabaduló
mediátor
anyagok
FcR mediált, gyuladás,
sejtfunkció gátlás
FcR mediált,
komplement
aktiváció,
gyulladás
citokinek,
citotoxicitás
„Klasszikus
allergia”
újszülöttkori hemolitikus
anémia, (penicillin?)
érzékenység, M. gravis
szérumbetegség,
SLE
kontakt drematitisz
Igen gyakran autoimmun betegségek együttjárói
Tolerancia
Molecular Mechanisms of Autoimmunity
How is autoimmunity
induced?
What could go wrong
here?
1-immunologic factor
2-genetic f.
3-enviroment f.
7
Genetikai tényezők
Much recent attention has focused on the role of T cells in autoimmunity, for two main
reasons. First, helper T cells are the key regulators of all immune responses to proteins,
and most self antigens implicated in autoimmune diseases are proteins. Second, several
autoimmune diseases are genetically linked to the MHC (the HLA complex in humans), and
the function of MHC molecules is to present peptide antigens to T cells.
Chromosomal Region
Gene of Interest
Function
Diseases
Genes Involved in Immune Regulation
1p13
PTPN22
Protein tyrosine phosphatase; role in T and B cell receptors signaling
RA, T1D, IBD
1p12
CD2/CD58
Costimulation of T cells
RA, MS
1p31
IL23R
Component
of IL-23
receptor;
role with
in generation
and maintenance
Table 14-4.
Selected Non-HLA
Genetic
Associations
Autoimmune Diseases
of
IBD, PS, AS
TH17 cells
1q32
IL10
Downregulates expression of costimulators, MHC molecules, IL-12
in dendritic cells; inhibits TH1 responses
IBD, SLE, T1D
2q33
CTLA4
Inhibitory receptor of T cells, effector molecule of regulatory T cells
T1D, RA
4q26
IL2/IL21
Growth and differentiation factors for T cells; IL-2 is involved in
maintenance of functional Tregs
IBD, CeD, RA,
T1D, MS
5q33
IL12B
p40 subunit of IL-12 (TH1-inducing cytokine) and IL-23 (TH17inducing cytokine)
IBD, PS
8p23
BLK
B lymphocyte tyrosine kinase, involved in B cell activation
SLE, RA
10p15
IL2RA
IL-2 receptor α chain (CD25); role in T cell activation and
maintenance of regulatory T cells
MS, T1D
Genes Involved in Responses to Microbes
16q12
NOD2
Cytoplasmic sensor of bacteria
IBD
2q37
ATG16
Autophagy (destruction of microbes, maintenance of epithelial cell
integrity)
IBD
7q32, 2q24
IRF5, IFIH1
Type I interferon responses to viruses
SLE
AS, ankylosing spondylitis; CeD, celiac diseases; IBD, inflammatory bowel disease; MS, multiple sclerosis; PS, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1D, type 1 diabetes.
Data from Zenewicz L, C Abraham, RA Flavell, and J Cho. Unraveling the genetics of autoimmunity. Cell 140:791-797, 2010, with permission of the publisher.
Table 14-5. Examples of Single-Gene Mutations That Cause Autoimmune Diseases
Phenotype of Mutant or
Knockout Mouse
Mechanism of Failure of
Tolerance
AIRE
Destruction of endocrine
organs by antibodies,
lymphocytes
Failure of central tolerance
Autoimmune polyendocrine
syndrome (APS)
C4
SLE
Defective clearance of immune
complexes; failure of B cell
tolerance?
SLE
CTLA-4
Lymphoproliferation; T cell
infiltrates in multiple organs,
especially heart; lethal by 3-4
weeks
Failure of anergy in CD4+ T cells;
defective function of regulatory T
cells
CTLA-4 polymorphisms
associated with several
autoimmune diseases
Fas/FasL
Anti-DNA and other
autoantibodies; immune
complex nephritis; arthritis;
lymphoproliferation
Defective deletion of anergic selfreactive B cells; reduced deletion of
mature CD4+ T cells
Autoimmune
lymphoproliferative
syndrome (ALPS)
FoxP3
Multiorgan lymphocytic
infiltrates, wasting
Deficiency of functional regulatory T
cells
IPEX
IL-2,
IL-2Rα/β
Inflammatory bowel disease;
anti-erythrocyte and anti-DNA
autoantibodies
Defective development, survival, or
function of regulatory T cells
None known
SHP-1
Multiple autoantibodies
Failure of negative regulation of B
cells
None known
Gene
Human Disease?
AIRE, autoimmune regulator gene; IL-2, interleukin-2; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; SHP-1, SH2-containing phosphatase 1; SLE, systemic lupus
erythematosus.
Immunológiai tényezők
Defects in deletion (negative selection) of T or B cells or receptor editing in
B cells during the maturation of these cells in the generative lymphoid
organs
Defective numbers and functions of regulatory T lymphocytes
Defective apoptosis of mature self-reactive lymphocytes
Inadequate function of inhibitory receptors
Activation of APCs, which overcomes regulatory mechanisms and results in
excessive T cell activation
Several ways in which infectious agents
could break self tolerance
Foszfatáz
Ubiquitináció-degradáció
+Citokin környezet
CTLA-4 nagyobb affinitású, mint a CD28
mice lacking CTLA-4 develop uncontrolled lymphocyte activation with massively enlarged lymph nodes and
spleen and fatal multiorgan lymphocytic infiltrates suggestive of systemic autoimmunity. The autoimmune
disorders in PD-1 knockout mice are less severe than in CTLA-4 knockouts. It has been postulated that CTLA4 functions mainly to control initial T cell activation in lymphoid organs whereas PD-1 is more important for
limiting responses of differentiated effector cells in peripheral tissues.
Peripheral B-cell anergy
Patogén specifikus– kereszt reaktivitás
Cross-Reactivity
22
Patogén független
Pl. fokozott MHC expresszió
epitóp terjedés
Intramolekuláris epitóp terjedés
Szuperantigének (pl. bakteriális toxinok) az MHC II molekulákhoz és a T-sejt
receptorokhoz kívülről ( nem a specifikus antigén-kötő helyen) kapcsolódnak,
így egyszerre nagy számú nem specikus T-sejt proliferációját idézhetik elő.
4. Polyclonal Activation Hypothesis
•
•
B-cell mitogens, e.g. LPS, EBV
Bact. Superag.  TCR (V)  -self or
Th
BUT
 Limited specificity, e.g. thyroiditis
 Clonally restricted e.g. -DNA in SLE
27
Danger Theory
• Anti-self B & T-cells always present.
• AIR is due to release of “danger signals.”
• Response to tissue damage, necrosis or cell
distress, e.g. infection or injury.
• BUT AIR can occur without tissue damage, e.g.
immunisn. with self-ag; Tx; genetic defects.
28
Summary
• Self reactive B-cells & T-cells are normally
present but anergic.
• Several factors can induce an AIR: Genetic
 Tissue damage & release of cryptic ag.
 Somatic mutation in Ig V-genes
 Ag mimicry
 Tr defects
 Danger signals
29
BAFF– B cell activating faktor (B-sejtek fitnesz faktora)
.A BAFF konstitutív expressziója kell az érett B-sejtek hosszútávú túléléséhez. Nincs BAFF nincs
érett B-sejt, overexpressszió megnövekedett B-sejt szám.
A BAFF normál körülmények között limitáltan termelődik. BAFFR van szerepe BCMA, TACI-nak
nincs.
BAFF
A B-sejtek versenyeznek
limitált szabad BAFF-ért
a
Több BAFF jelenléte esetén több
B-sejt maradhat életben
Michael P., 2009, Nat. Rev. Immunol.