Autoimmunity, breakdown of the immune tolerance Jan Novák

Autoimmunity Pathologic reaction of the immune system against self antigens

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

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

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

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

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

Why tolerance is broken? Genetic factors Environmental factors

Genetics of autoimmunity MHC molecules Non MHC genes

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

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)

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

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

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

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