Genetic Aspects of

Autoimmunity:
Concept, and Molecular approach for
Therapy

Marsetyawan HNE Soesatyo

Dept of Histology & Cell Biology
Div.Immunology, Faculty of Medicine UGM
 Autoimmunity
 General properties:
• Adaptive immune reactions against ‘self’
molecules/proteins/antigens
• Occurs spontaneously or inducible
• Caused by multiple interacting factors:
 Immunologic, genetic, infections, anatomic
sequestration (immunological privilege
sites), drugs, toxins
• Systemic or organ-specific
 Figure 13-1
Table. Some common autoimmune diseases
 Figure 13-4
Table. Some autoimmune diseases that can be transferred
by pathogenic IgG
 Genetic factors
 Genetic predispositions
• Single gene mutation
• Multigenic predisposition
• Induced mutation
 MHC genes
• Control susceptibility to the disease
 Figure 13-18

Fig. Different types of genetic predispositions in autoimmune diseases

 Major histocompatibility (MHC) genes

 H-2 (mouse): model of studies

• Chromosome 17
 HLA (human leukocyte antigen: human)
• Chromosome 6, 4x106 base pairs, contains >
200 genes
• (highly) Polymorphic genes
 Class I: A, B, and C

 Class II: DP, DQ, and DR

 Class III: C2, C4a, C4b, BF and TNF 

genes
Fig. Maps of human and mouse MHC loci
 The Human Leukocyte Antigen Complex (6p21.31)
Class III
Class II (1.1 Mb) (0.7Mb) Class I (2.2Mb)

DP DQ DR B C A

Centromere Telomere

Frequent Class I-like genes

Recombination and pseudogenes
Complement
and Cytokines

Recombination Recombination
is rare is rare
 Figure 5-13

Human MHC genes are highly polymorphic (WHO

Nomenclature Committee, 2004)
 Association of MHC genotype and
Autoimmunity
 Involving T cells  susceptibility to
autoimmune diseases
• Different ability of different allelic
variants of MHC molecules to present
autoantigenic peptides to autoreactive T
cells
• MHC restriction:
 MHC molecules restrict the ability of T cells
to recognize antigens
Table. Associations of HLA serotype and sex

Figure 13-20
with susceptibility to autoimmune disease
Figure 13-23
IDDM
Fig. Amino acid changes in
Fig
the sequence of an MHC
class II protein correlate
with susceptibility to and
protection from diabetes

salt bridge
cha
in
Arg
Asp Ala
 Figure 5-17

TCR and self MHC molecule

Therapeutic strategies for autoimmunity:
In animal models, and human (?)
 Blockade of co-stimulatory molecule
signals
 Induce the regulatory T cells (T reg:
CD4+CD25+, Tr1, Th3)  suppress auto
reactive T cells
 Using monoclonal Abs
 Cytokine treatment
 Antigen clearance
 B7.1 (CD80),
B7.2 (CD86)

CD28+, CD152+

Tregs inhibit
CD4CD25 autoreactive T cells

Monoclonal Abs
Cytokines: IL-10
TGF-
 Concept of regulatory T cells
 Dates back to 1970s: ‘T suppressor’
 Maintain peripheral tolerance; limit
effector responses  prevent excessive
immune-mediated tissue damage
 Gene expression: FoxP3
 CD4+CD25+
 CD4+CD25-
• Tr1
• Th3
 Prominent cytokine production
• IL-10, TGF-, IL-4
 FoxP3 gene
• Encodes transcription factor 
differentiation into CD4CD25 T cells
• Absent in human IPEX
(immunodysregulation-
polyendorinopathy- enteropathy- X-
linked), and in mutant scurvy mice
 “Policing pregnancy: T regs help keep the
peace”
(Trends Immunol. 2004, 25:563-65)

 T regs (regulatory T cells): CD4+CD25+

• Suppressing autoimmunity
• Suppression of allograft rejection
• Inhibition of anti-tumor immunity
• Control persistence of some infectious agents

• Pregnancy  increased enormously

 T regs…help keep the peace
(cont’d)
 Human pregnancy
• Facts
 Increased number in peripheral blood &
decidua since 1st trimester; post-natal
period: decreased
 Increased functional regulatory activity
inhibition
• Pregnancy ----- autoimmune syndrome (RA)
remission?
• Adoptive T cell transfer, depleted T regs 
rejection allogeneic fetus (mice)
 T regs…help keep the peace
(cont’d)
 Possible mechanism(s) underlying:
the inhibition of effector T cells by T
regs
• Induction of tryptophan-degrading
enzyme: indoleamine 2,3 dioxygenase
(IDO) on APCs (DC) through CTLA-4
expression
• Secretion of inhibitory cytokines: IL-10,
TGF-
 Concluding Remarks
 Fail to maintain self tolerance
• Centrally- (bone marrow, thymus) or
peripherally (anergy, cytokine deviation, T reg)
• Immune regulatory mechanisms breakdown
 Genetic factors (predispose genes,
MHC/HLA genes) are primarily crucial, plus
environmental factors (infections, toxins,
drugs)