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AUTOIMMUNITY Transplant Rejection AIDS

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AUTOIMMUNITY Transplant Rejection AIDS AUTOIMMUNITY Transplant rejection AIDS P. Babál ÚPA LFUK AUTOIMMUNITY Allergy - reaction to an allergen from the environment Autoimmunity- immune mechanisms oriented against components of self tissues Ehrlich: “horror autotoxicus” - reparative processes - frequently accompanied by antibodies against altered tissues (faster removal of these tissues) - if autoantibodies persist permanently -> autoimmunity - organ specific - systemic MECHANISMS BY WHICH AUTOIMMUNITY DEVELOPS Release of sequestered Ag - spermatozoa, lens, myelin Abnormal T-cell function: - Systemic lupus erythematodes, diminished Ts function other AI diseases Enhanced Th cell function - hemolytic anemias Polyclonal B cell activation - SLE, EBV-induced anti-DNA Ab GENETIC FACTORS in autoimmunity HLA system of genes - regulates immune responses = individuals with certain HLA genes expression are at higher risk to develop AI disease Ankylotic spondyllitis B27 87.4 % Autoimmune thyreotoxicosis DR3 3.7 Hashimoto thyroiditis DR5 3.2 Diabetes mellitus II. DR3 3.3 Sclerosis multiplex DR2 4.1 Goodpasture sy. DR2 15.9 Autoimmune diseases of NERVE SYSTEM Systemic polyradiculoneuropathy (Guillain-Barre sy.) - 3/4 weeks after viral infection = demyelinization of motor neurons … anti-myelin Ab Myastenia gravis autoAb reacting with receptors for ACH at the neuro-muscular disc (block, destruction) -> weakness. Result of Ts failure to suppress autoimmune B-cell clones Acute allergic encephalomyelitis - 2 weeks after viral infection, usually measles (morbilli) typical perivascular demyelinization Sclerosis multiplex = diffuse demyelinization of CNS cell-mediated immunity against basic myelin Myastenia gravis Thymus Autoimmune diseases of THYROID GLAND Autoimmune thyrotoxicosis IgG Ab against TSH receptor on thyriod gland cells - binding of anti-TSH Ab = stimulation of proliferation and T4 secretion -> struma - Exophtalmus ... Ab against TSH receptors on ophtalmic muscles Hashimoto struma thyroglobuline - sequestered Ag ? … NO ! it is drained by lymphatics Histology - accumulation of lymphoid tissue -> autoAb against thyroid cells (autoreactive Th, not controlled by Ts) DIABETES MELLITUS I. = “autoimmune ß-cell insufficiency”, =juvenile diabetes (genetic basis) Starting stimulus - usually viral infection mediated by autoreactive Tc lymphocytes COLLAGENOSES = systemic autoimmune diseases with collagen damage - “fibrinoid necrosis” = mediated by immunocomplex mechanism with complement action Systemic lupus erythematodes - serum Ab against different cell components, especially nucleus Ag-Ab complexes -> tissue damage, prevalently glomeruli (membranous glomerulonephritis), arteries (arteriolitis, periarteriolar fibrosis) -> lead to tissue damage (parenchymatous organs, dermis, epidermis, CNS) Rheumatoid arthritis = symetrical disease of joints (knees, small joins of the hand) Hyperplastic synovial membrane, destruction of cartillage. Start = pathologic IgG synthesis against some Ag (EBV ?!), “antiglobuline” synthesis = rheumatoid factor (IgM). Immune complexes destroyed in circulation, in synovial fluid … attract PMN -> damage COLLAGENOSES cont. Polyarteriitis nodosa - similar to arteritis in serum disease. Starting factor - viral infection, medicines…, immune Ag-Ab complexes are deposited in arterial walls -> fibrinoid necrosis, thrombosis. Sclerodermia (progressive systemic sclerosis) - sclerosis, perivascular mononuclear infiltration -> skin, synovia, mucosas Ab against different antigens Dermatomyositis dominant symptoms = muscle weaknes, skin erythema Autoreactive T lymphocyte infiltration of muscles and dermis, different autoreactive antibodies -> sclerosis of dermis, dystrophy/necrosis of muscles PERNICIOUS ANEMIA - serum autoAb against binding locus of B12 vitamin on intrinsic factor of parietal cells of gastric mucosa. Ab sythetized by plasma cells in gastric mucosa in chronic atrophic gastritis. Other autoimmune diseases: PRIMARY BILIARY CIRRHOSIS RHEUMATIC FEVER BULLOUS SKIN DISEASES - PEMPHIGUS - PEMPHIGOID PSORIASIS ERYTHEMA NODOSUM GLOMERULONEPHRITIS GOODPASTURE SYNDROMA INSULINE RESISTANT DIABETES SJÖGREN SYNDROMA Bullous pemphigoid IgG C3 Pemphigus vulgaris * * * C3 * IgG TRANSPLANTATION REJECTION Based on genetic relation between donor and recipient - transplantations Classify into 4 groups: 1. Autotransplantation (autofraft), donor and recipient are the same organism. 2. Isotransplantation (isograft), donor and recipient are the same genotype. 3. Alotransplantation (allograft), donor is from the same species, with different genotype. 4. Xenotransplantation (xenograft), donor is from different species than recipient. Most frequent transplantations: Skin, kidney, heart, lung, liver, pancreas, cornea and bone marrow Successful transplantation w/out immunological rejection - pared HLA antigens of donor and recipient Particular problem in cases of bone marrow transplantation, graft-versus-host (GVH) reaction Mechanisms of graft rejection 1. CELL-MEDIATED REJECTION. - mediated by T-cells: - cytotoxic T-cells (CD8+) - hypersensitivity reaction iniciated by T helper cells (CD4+) 2. ANTIBODY-MEDIATED REACTIONS. - present circulating antibodies in recipient as consequence of pre- sensibilisation of recipient before transplantation, e.g. transfusion of blood, pregnancy; - in non-sensibilised individuals it may be complement-mediated cytotoxicity, antibody-related cell cytotoxicity and formation of antigen-antibody complexes. Types of rejection reactions hyperacute, acute and chronic 1. HYPERACUTE REJECTION. - minutes to hours after introduction of transplanted organ (mediated by circulating antibodies of recipient against antigens of the donor: lymphocyte cross test of donor and recipient) hyperacute rejection is noticed immediately after vascular linking - organ usually swells, becomes hemorrhagis, pink to dark blue instead of rose. -fibrin-platelets thrombi plug capillaries, vascular wall may necrotize... necrosis and focal hemorrhage. Types of rejection reactions 2. ACUTE REJECTION. - days to months after transplantation - rejection of graft is caused by cell-mediated or antibody reaction Acute cell-mediated rejection - infiltration intersticium of transplanted tissue by lymphocytes (mainly T-cells), damage cells and vessel walls in transplantate. Acute humoral rejection appears at insufficient response to immunosupressive therapy - characteristic vasculitis and focal necrosis of small vessels ACUTE REJECTION Ly Ly Types of rejection reaction 3. CHRONIC REJECTION - developes in months to years - immunologic and ischemic mechanisms - stepwise fibrosis of vascular intima, interstícial fibrosis and atrophy of parenchymatous cells. (in renal alogenic graft glomerulonephritis induced by recipient may develope, or rarely developes glomerulonephritis de novo). Graft-versus-host reaction --- intestine vessel---- HE HE CD8 CD8 Graft-versus-host reaction --- liver HE CD8 AIDS - developing counties participate with high numbers of HIV infected, Africa has over 50 % of world-wide registered new cases - ½ = women, 5% children - high incidence of new AIDS cases in southeast Asia ! Russia, Ucraine ! - 2.5 mil. new cases yearly (world > 80 mil.) Etiological agens: RNA retrovirus HIV (human immunodefficiency virus), belongs to the group of human T-cell leukemia/lymphoma (HTLV). Tropism to CD4 molecule HIV 1 ... USA, centr. Africa HIV 2 ... western Africa, Asia AIDS HIV virion - Nucleus with nuclear proteins (p24 and p18), two strings of genomic RNA, enzyme reverse transcriptase. - Cover by double layer lipidic membrane (derived from infected host cell), cover glycoproteins gp120 and gp41. virion contains code of 3 important genes: 1. gag (grouping antigen) nuclear proteins. 2. pol (polymerase) for reverse transcriptase, 3. env (envelope) for envelope proteins. - markers for lab. dg. HIV infection - + tat (transcription activator)gene (replication and budding). WAYS OF TRANSFER: 1. Sexual transfer. homosexual / bisexual men – America, Europe heterosexual promiscuity – dominant in Africa and Asia - other STD = cofactors in spread of HIV (gonococci, chlamydia) Transfer man-man and man-woman > woman-man. 2. Transfer by blood and blood derivates. - Intravenous application of drugs - patients with hemophilia (blood derivates) - patients who received HIV-infected blood or blood products 3. Perinatal transfer. transplacental After birth contamination with maternal blood, infected amniotic fluid, maternal milk. 4. Professional transfer. !!! Use of protective means, desinfection and sterilisation. 5. Transfer by other body fluids. - nonexisting proofs of such HIV transfer. PATOGENESIS CD4 tropism ... Gp 120 -> Th Ly, Mo/Mf, microglia, epithelium (cervix), dendritic cells, megakaryocytes CD4-gp120 fusion of membranes -> internalization reverse transcription RNA -> DNA -> 2-DNA .... => integration into DNA (HIV provirus) latency Replication of HIV With help of tat gene multiplication of HIV particles (stimulated by IL-2, INFγ) - budding of HIV particles -> death of Th Ly ... dissemination (lymphatic tissue) immune system - Mo/Mf destroyed, some survive -> reservoar HIV - dendritic cells -> hyperplastic follicles (lymphadenopathy in AIDS) - ↓ NK cells, CD8 Ly, B-Ly nerve system - microglia (CD4+), glia – directly infected(?), neurons – toxicity of gp120 on microglia Clinical course: 1. Acute HIV syndrome (3-12 weeks). - viremia as consequence of vírus replication. - specific immune answer - anti-HIV antibodies (seroconversion) after 3-6 weeks. - drop of CD4+ T-cells (helper T ly) – later return back
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