immune tolerance and autoimmunity ------

1. IMMUNE TOLERANCE AND
AUTOIMMUNITY
Asep Harirohman
Department of Internal Medicine
Medical Faculty of Airlangga Univ. – Dr Soetomo Teaching Hospital
Surabaya
2020

2. • Immune system of the human body acts as a ‘double edged sword’ that
can either heal or harm
• In a healthy person, the immune system can differentiate between the
‘self’’ and the ‘non-self’’
• Immune responses can cause damage if they are directed against the
individual’s own components, which are often referred to as self-antigens
or autoantigens by autoreactive lymphocyte
• Immune tolerance refers to unresponsiveness of the immune system
toward certain substances or tissues that are normally capable of
stimulating an immune response
INTRODUCTION

3. DIVERSITY OF B AND T
LYMPHOCYTE REPERTOIRE

4. • Generation of antibodies and T cell receptors by V(D)J
recombination
• Lymphocyte development: generation of cells with
functional and useful antigen receptors
• Selection of B cells and T cells based on their specificity to
decrease self-reactivity
• Diseases resulting from defects or errors in lymphocyte
development: immunodeficiencies and cancers

5. Rearrangement B Cell Gen Receptor (Immunoglobulin)
Murphy et al., 2017

6. • Numerous V region genes are preceded by Leader or signal sequences
(60-90 bp) exons interspersed with introns
• Heavy chain contains V (Variable), D (Diversity), J (Joining) and C
(Constant) region gene segments
• V - D - J – C
• Light chain contains V, J, and C region gene segments
• V - J - C
• Constant region genes are sub-divided into exons encoding domains
(CH1,CH2, CH3, CH4)

7. Multiple gene segments increase Ig
diversity
Combinatorial diversity:
Heavy chains
40 x 25 x 6 = 6000
Light chains
40 x 5 = 200 k
30 x 4 = 120 l
Total possible:
320 x 6000 = 1.9x106

8. The beta chain gene is
formed from different
V, D, J, and C gene
recombination.
During T cell development
alpha chain V, J and C
genes recombine to
form the T cell alpha gene
that characterizes
that T cell.
Rearrangement T Cell Receptor
Murphy et al., 2017

9. Summary: Ig vs TCR

10. TOLERANSI IMUN
T
olerance
Central
(Bone marrow ,
Thymus)
Peripheral
(Spleen , Lymph
node etc)
Thymic
tolerance to
self antigen
(In Thymus)
B-cell tolerance
to self antigen
(In Bone Marrow)

11. T CeLL central tOLERANCE
Storey M and Jordan S, 2008

12. Early thymocyte development :
1. Commitment of hematopoietic precursors to the T-cell lineage
2. Initiation of antigen receptor gene rearrangements
3. Expansion of cells that have successfully rearranged one of their T-cell receptor genes
The second phase :
1. Positive selection
2. Negative selection
3. Lineage commitment
T CeLL
central tOLERANCE

13. • NEGATIVE SELECTION: results from strong interaction of a self peptide/MHC
complex with the TCR of a thymocyte. (Foreign antigens are not brought to the
thymus by APC, so typically antigen in thymus is self)
• POSITIVE SELECTION: results from weak interaction of a self peptide/MHC
complex with the TCR of a thymocyte. (Links the MHC specificity of the TCR to the
functional potential of each T cell)
• Resulting T cells are more likely to be useful
• In the thymus, some self-reactive T cells become “regulatory T cells” rather than
dying. Regulatory T cells can suppress T cell immune responses in the periphery

14. T CeLL
pheripheral tOLERANCE
T-cell-intrinsic mechanisms
of peripheral tolerance
• Ignorance
• Anergy
• Phenotypic skewing
• Apoptosis
T-cell-extrinsic mechanisms
of peripheral tolerance
• Tolerogenic dendritic cells
• Regulatory T cells

17. • During normal B-cell development
• Still immature when they relocate to spleen T-cell zones
• Autoreactive B-cells are not necessarily eliminated during
negative selection
• B-cells that recognise autoantigens are eliminate via apoptosis
or become anergic
• Autoreactive B-cells that escape negative selection become
part of the a maximally-diverse immune repertoire
b CeLL
central tOLERANCE

18. b CeLL tOLERANCE

19. STAGES OF B CELL DEVELOPMENT
GENERATIVE
LYMPHOID
ORGANS
1. B Cells develop from pluripotent stem cells in the bone marrow. 1
2
2. The stem cell develops into a mature IgM+ B cell.
PERIPHERAL
LYMPHOID
ORGANS
3
3. The mature, naïve B cells circulates through the peripheral lymphoid
organs.
4. B cells that fail to encounter antigen die through apoptosis. 4
5. B cells that encounter antigen are activated
5

20. Immature B cell + self-antigen:
• B cells can continue to rearrange IgL genes, try to change
L chain and lose self-reactivity (“receptor editing”)
• B cells can die (“clonal deletion” or “negative selection”)
• B cells can become refractory to activation (“clonal
anergy”)
b CeLL
central tOLERANCE

21. Peripheral tolerance mechanisms (in secondary lymphoid tissues) exist for
various reasons :
• Imperfect T-cell tolerance: in most autoimmune diseases, B-cells are T-cell
dependent, requiring help from pre-activated cognate autoreactive T-cells
• T-independent B-cells can be activated by autoantigens without T-cell help
• Microbial antigens structurally similar to autoantigens can lead B-cells to
produce cross-reactive antibodies in a phenomenon known as molecular
mimicry
• B-cells hypermutate their receptors on activation, so there is a second
chance that they may become self-reactive
B CeLL
pheripheral tOLERANCE

22. SOMATIC HYPERMUTATION

23. SOMATIC HYPERMUTATION
• Process of generating antibody diversity
• Mutation is restricted to somatic cell and girm cell DNA is not affected
• Immature B cell eventually reach lymp node where maturation and
activation take place

24. Breaking Tolerance :
Autoimmunity and
Dysregulation

25. • Autoimmunity is the failure of an organism in recognizing its own
constituent parts as non self, which allows an immune response
against its own cells and tissues. Any disease that results from such an
aberrant immune response is termed an autoimmune disease.
Autoimmunity is often caused by a lack of germ development of a
target body and as such the immune response acts against its own
cells and tissues
autoimmunity

26. Genetic/Epigenetic factor

27. enviromEntal factor

28. enviromEntal factor
Vanderlugt dan Miller, 2002

29. • immunological tolerance is a complex processes in the body to avoid
recognition of self antigens are called
• Central tolerance occurs in lymphoid organs such as bone marrow and
thymus while pheripheral tolerance occurs in secondary lymphoid organs,
such as the spleen, lymph nodes and mucosal lymphoid tissue.
• Failure in the mechanism of tolerance causes, produces an immune
response to autoantigen and can develop into an autoimmune disease
• Autoimmune diseases, induced by genetic and environmental
• Infection is one of the environmental factors that play a role in the
occurrence of autoimmune processes
CONCLUSION

30. REFERENCE
• Murphy KM, weaver C, mowat A, Berg L, Chaplin D, Janeway CA,
Travers P and walport M, 2017. Janeway's immunobiology. 9th ed.
Garland Science:Newyork, pp 176-177, 187-199
• Storey M and Jordan S, 2008. An overview of the immune
system. Nursing Standard, 23(15), pp.47-56.
• Vanderlugt C and Miller S, 2002. Epitope spreading in immune-
mediated diseases: implications for immunotherapy. Nature Reviews
Immunology, 2(2), pp.85-95.