Autoimmune diseases

Chronic inflammatory conditions Repair mechanisms cannot compete with tissue destruction caused by the immune system Variety of symptoms and of target tissues Mechanisms of recognition and effector functions are the same as those acting against pathogens and environmental antigens AUTOIMMUNE DISEASES

CENTRAL TOLERANCE IS INDUCED AND MAINTAINED IN THE BONE MARROW AND THYMUS Clonal deletion of self agressive B and T cell clones (not complete) B AND T CELLS WITH SELF REACTIVITY ARE PRESENT IN THE AVAILABLE PERIPHERAL T CELL REPERTOIRE PERIPHERAL TOLERANCE Maintenance of self tolerance of T-lymphocytes against tissue- specific self proteins which are not represented in the thymus Active mechanisms at the level of CD4+ helper T-lymphocytes AUTOIMMUNE DISEASES Disturbance of tolerance Misdirected adaptive immunity to healthy cells and tissues

Deficiency in establishing central T-cell tolerance: Autoimmune PolyEndocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED), AIRE deficiency. AIRE: transcription factor inducing expression of many tissue-specific genes normally not expressed in the thymus. Rare disease, but more frequently seen in inbred populations Finnish, Iranian Jews and in the island of Sardine

Symptoms of APECED

Inhibition of autoreactive T-cells in the periphery by regulatory T-cells. Maintenance of peripheral tolerance IPEX: Immune dysregulation, Polyendocrinopathy, enteropathy, and X-linked syndrome FoxP3 deficiency

(autoimmune regulator- AIRE)

Sympathetic ophtalmia Autoimmunity induced by trauma Immunologically privileged sites (initiation rather than access is controlled)

Normal tissue cells do not express MHC class II NO SIGNAL 1. for CD4+ Th activation Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokines NO SIGNAL 2. for CD4+ Th activation Migration of naive T lymphocytes to normal tissues is limited Antigen presenting cells are not activated in normal tissues NO SIGNAL 3. PERIPHERAL TISSUES TOLERIZE THEMSELVES PERIPHERAL TOLERANCE IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY

Autoantibody production is dependent on the availability of autoreactive T cells Practically all autoimmune diseases Involve some T-cell defects In the absence of T cell help autoreactive B cells ate trapped in the T-cell zone and die

Expression of MHC-II on non-immune cells may contribute to autoimmunity in response to IFNγ MHCII expression is induced on thyroid cells, on the β cells of the pancreas as well as on microglia. Insufficient for the activation of naive T- cells (not normally present in the periphery anyway), BUT effector T-cells crossreacting with autoantigens may be activated

Molecular mimicry may lead to severe autoimmune reactions (T-cell epitopes)

Molecular mimicry may lead to severe autoimmune reactions (T-cell epitopes)

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS

Autoimmune hemolytic anemia

Goodpasture's syndrome Glomerulus stained for IgG deposition by immunofluorescence Glomerulonephritis uniform, Only 40% develop lung hemorrhages

Pemphigus is a rare skin disorder characterized by blistering of the skin and mucous membranes. The most common type is pemphigus vulgaris, which involves painful sores and blisters on the skin and in mouth. Autoantibodies attack desmosomes. Antigen: Desmoglein 3 Pemphigus vulgaris

Acute rheumatic fever Steptococcus pyogenes group A. Cross reactivity with self antigens present in hart tissue (M-protein shows sequence similarity with myosin. ) Main symptoms: Carditis polyarthritis (joints become hot, red, swollen) Sydenham’s chorea Infiltration of T and B (plasma) cells, macrophages. These look like granulomas…. They are called Aschoff bodies. However only 3% of all patients with untreated Streptococcal pharingytis develop rheumatic fever. Likely that genetic fctors contribute to the development of the disease !!!

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS

Graves’ disease

Graves' ophthalmopathy

Temporary symptoms of antibody-mediated autoimmune diseases can be passed from affected mothers to their newborn babies. TSHR, thyroid-stimulating hormone receptor.

Hashimoto’s disease – hypothyreosis (antibodies and effector T cells) Infiltration of lymphocytes Formation of ectopic lymphoid tissuesLimfocita infiltráció, extranodális limfoid szövetek. Mostly Th1 (inflammatory) response. Cell death, hypothyreosis

Nerve impulse Internalization NO Na+ influx NO muscle contraction MYASTENIA GRAVIS AUTO – ANTIBODIES IN MYASTENIA GRAVIS NEURO-MUSCULAR JUNCTION Muscle Acetilcholin receptor

In systemic lupus erythematosus (SLE) the immune response is broadened in a antigen-specific manner.

A synovial membrane specific cellular immune response CD4+ és CD8+ T cells, B cells, plasma cells, neutrophils, macrophages Rheumatoid factors– anti- IgG-Fc specific antibodies Reumathois Arthritis

Treatment of RA with anti TNFα antibody

With age there is an inverse correlation between the decreasing capacity of the thymus to make new T cells and the increasing incidence of rheumatoid arthritis.

Insulin  cell  cell  cell  cell  cell Pancreatic islet cells MECHANISM OF AUTOREACTIVITY IN INSULIN- DEPENDENT DIABETES Type IV hypersensitivity AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING β-CELLS glucagon Somatostatin 10 8 insulin secreting cells

Type I diabetes Comparison of histological sections of a pancreas from a healthy person and a patient with type 1 diabetes.

FACTORS INVOLVED IN THE PATHOMECHANISM OF AUTOIMMUNE DISEASES

ASSOCIATIONS OF HLA ALLOTYPE WITH SUSCEPTIBILITY TO AUTOIMMUNE DISEASE Maximum 20% of predisposed people develop the disease  environmental factors

Frequency of autoimmune diseases is elevated in vomen

Family studies reveal that HLA type correlates with susceptibility to type 1 diabetes.