1. Autoimmunity, breakdown of the immune tolerance
Jan Novák

2. Autoimmunity
Pathologic reaction of the immune system against self antigens

3. Key players of the autoimmune reaction
Autoantigen
Autoreactive T and B cells

4. Autoantigens
Organ specific (insulin, thyreoglobulin, myelin basic protein)
Systemic (DNA, histones, ribosomes, IgG)

5. How autoreactive lymphocytes are created?
Random rearrangement – generation of T and B cells with infinite variability and specifity, capable to recognize infinite diversity of antigens
Generation of T and B cells recognizing self antigens – autoreactive

6. How autoreactive T and B cells are deleted in normal body?
Central (thymic/bone marrow) deletion
Peripheral passive mechanisms
Ignorance
Anergy
Phenotype skewing
Peripheral deletion
Peripheral active mechanisms
Tolerogenic dendritic cells
Regulatory T cells

7. Peripheral active mechanisms of tolerance
Regulatory T cells
CD4+CD25+ T cells
NKT cells
 T cells
CD8+CD25+ T cells
Tolerogenic dendritic cells (DC)
Antigen presentation by immature DC
Antigen presentation by plasmocytoid DC

8. Why tolerance is broken?
Genetic factors
Environmental factors

9. Genetics of autoimmunity
MHC molecules
Non MHC genes

10. MHC genes Confer both susceptibility and protection
Disease
Risk HLA allele
Ankylosing spondylitis
B27
Acute anterior uveitis
Goodpasture's syndrome
DR2
Multiple sclerosis
Graves disease
DR3
Myasthenia gravis
SLE
T1DM
DR3/DR4
Rheumatoid arthritis
DR4
Pemphigus vulgaris
Hyshimoto's thyroiditis
DR5
Confer both susceptibility and protection
MHC class II and I alleles
HLA DR3/DR4, HLA B27
Capacity to present antigens and to induce central and peripheral deletion

11. Non MHC risk genes in autoimmunity
Genes associated with thymic antigen presentation (AIRE, VNTR)
Genes assiciated with antigen clearance (complement proteins)
Genes associated with tolerance induction (CTLA-4, Fas-FasL)

12. Environmental factors in the pathogenesis of autoimmunity
Studies on monozygotic twins
Epidemiological, migration studies

13. Infection can protect against autoimmunity
Infection with parazites induce Th2 schift and can protect against Th1 mediated autoimmune diseases
Some autoimmune mouse strains develop autoimmunity strictly in pathogen free conditions

14. How the tissues are destroyed?
Participation of both innate and adaptive immune responses.
T cells, cytokines, B cells, antibodies, immunocomplexes
Macrophages, complement
Types II-V of immunopathologic reactions

15. Autoimmune diseases Organ specific Systemic T1DM
Goodpasture‘s syndrome
Multiple sclerosis
Graves disease
Systemic
Rheumatoid arthritis
Scleroderma
Systemic lupus erythematosus
Polymyositis