Immune system pathology V. Žampachová I. ÚP LF MU Physiologic function nProtection + defence against external and/or internal noxae nDefence against infection incl. toxic products nAutotolerance against body-own antigenes nImmunologic internal control (removal of old, defective, some mutated cells) n nFailure possible due to inadequate immune function and/or too violent (event. evasive) noxae Disorders of the immune system nExaggerated immune reaction nHypersensitivity reactions nAutoimmune disorders n nTransplantation immunopathology n nDefective immune reaction nImmunodeficiency (primary, secondary) n Hypersensitivity Hypersensitivity reactions nsensitisation (previous exposition to an antigen) + repeated exposure → possible pathologic (excessive) response: hypersensitivity – imbalance between effector mechanisms of immune responses and control (+limiting) mechanisms nantigens exogenous (chemicals, organic substances incl. microorganisms, …); endogenous (autoimmune diseases) nassociation with inheritance of particular susceptibility genes (HLA, non-HLA) nabnormal – excessive/misdirected/poorly controlled reaction to common not harmful antigenes and/or self antigenes nsame effector mechanisms as in normal immune reaction nClassification according to the immunologic mechanism (→ mode of tissue injury and disease, manifestations) + time of response nCommonly multiple mechanisms in any one disease nAntibody-mediated allergies are immediate and subacute hypersensitivities nThe most important cell-mediated allergic condition is delayed hypersensitivity Hypersensitivity Hypersensitivity reactions Immediate (type I) hypersensitivity nRapid immunologic reaction occurring within minutes after the combination of an antigen with IgE bound to mast cells in individuals previously sensitized to the antigen („allergen“). nSystemic disorder or local reaction. nAnaphylaxis; allergies; bronchial asthma (atopic forms) nVascular dilatation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation n Immediate (type I) hypersensitivity nAnaphylaxis: systemic reaction mostly after injection of an antigen into a sensitized individual. In minutes → shock (may be fatal). nCauses: foreign proteins, polysaccharides, drugs (penicillin), food (nuts, shellfish), insect toxins nStarts with itching, hives, and skin erythema nContraction of bronchioles → respiratory distress. Laryngeal edema → hoarseness nVomiting, abdominal cramps, diarrhea nVascular shock, widespread edema Immediate (type I) hypersensitivity nLocal reactions: diverse, according to the entry of the allergen. Localized cutaneous swellings (skin allergy, hives); n nasal and conjunctival discharge (allergic rhinitis and conjunctivitis); n hay fever; bronchial asthma; n allergic gastroenteritis (food allergy). Immediate (type I) hypersensitivity nThe immediate or initial reaction: IgE production +TH2 response → release of preformed mediators of mast cells (histamin, etc.)→ vasodilation, vascular leakage, edema, smooth muscle spasm or glandular secretions (mucus production) nEvident within 5 - 30 minutes after exposure to an allergen, usually ↓ in 60 minutes Immediate (type I) hypersensitivity nLate-phase reaction (e.g., allergic rhinitis and bronchial asthma) in 2 - 24 hours later nWithout additional exposure to antigen, inflammatory reaction sustained by reactive cells recruited by sensitised T-cells, may last for several days. nInfiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells; tissue destruction (mucosal epithelial cell damage by major basic protein MBP, etc.). Allergic rhinitis Image002 Hyperemia + edema, mucus hyperproduction, reactive cells Image003 Allergic rhinitis Reactive infiltrate with eosinophils, mast cells, neutrophils, lymphocytes Bronchial asthma Image008 Smooth muscle and mucus glands hypertrophy, mucus hyperproduction, reactive infiltrate Atopy nGenetically determined susceptibility to immediate hypersensitivity reactions. nAtopy: predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens. n↑ serum IgE levels, ↑ IL-4–producing TH2 cells nPositive family history of allergy in 50% of atopic individuals. nAtopic eczema, allergic rhinitis, asthma (+ secondary hyper-responsiveness of bronchial mucosa to non-specific irritants, e.g. cold, tobacco smoke,… secondary neural triggering.) n Antibody-mediated (type II) hypersensitivity n nOnset usually slow (1–3 hours) after antigen exposure nProduction of IgG, IgM → binding to antigen on target cell or tissue → phagocytosis or lysis of target cell (by activated complement, etc.); recruitment of leukocytes nInflammation nIn some diseases functional problems without cell or tissue injury (type V hypersensitivity – Graves‘ disease) Antibody-mediated (type II) hypersensitivity nTransfusion reactions: preformed antibody in the host nHemolytic disease of the newborn (fetal erythroblastosis): IgG from the mother cross the placenta → destruction of fetal red cells nPart of drug reactions: drug attaching to the cell surface proteins, AB x drug-membrane protein complex nAutoimmune blood cells destruction → anemia, purpura (bleeding) Antibody-mediated (type II) hypersensitivity nInflammation nPemphigus vulgaris: Target proteins in intercellular junctions of epidermal cells (epidermal cadherin) → antibody-mediated activation of proteases, disruption of intercellular adhesions → skin vesicles (bullae) nVasculitis caused by ANCA: → neutrophil degranulation and inflammation → vasculitis (see the special lecture on vasculitis) 00863+ Pemphigus vulgaris 00075+ Pemphigus vulgaris – acantholytic bulla Antibody-mediated (type II) hypersensitivity nGoodpasture syndrome: target protein in basement membranes of kidney glomeruli and lung alveoli → nephritis, lung hemorrhage nAcute rheumatic fever: Streptococcal cell wall antigen; antibody cross-reaction → myocarditis, arthritis nInsulin-resistant pre/diabetes: Insulin receptor as target nAcute vascular rejection in organ grafts Antibody-mediated (type II) hypersensitivity nCellular dysfunction – metabolism affected nGraves disease (hyperthyroidism): target TSH receptor → antibody-mediated stimulation of TSH receptors → hyperthyroidism Hypersensitivity reactions nImmune complex–mediated (type III) hypersensitivity nAntigens widely distributed through the body or blood → stimulation, production of IgG, circulating/local nantigen-antibody complexes. nDeposition of antigen-antibody complexes (vessel wall)→ complement activation → recruitment of leukocytes → release of enzymes and other toxic molecules n Immune complex–mediated (type III) hypersensitivity nMorphology: nacute necrotizing vasculitis: necrosis of the vessel wall + neutrophilic infiltration. nnecrotic tissue + deposits of immune complexes, complement, and plasma protein → eosinophilic deposits - fibrinoid necrosis Immune complex–mediated (type III) hypersensitivity nSystemic lupus nuclear antigens; nephritis, skin lesions, arthritis, others nAcute (poststreptococcal) glomerulonephritis streptococcal cell wall antigen(s); may be „planted“ in glomerular basement membrane; formation of local IC → nephritis nChronic immune complex nephritis (persistent antigen exposure, abnormal immune response incl. local factors) nSome forms of vasculitis Polyarteriitis nodosa - acute Image043 Polyarteriitis nodosa - healing Image042 Hypersensitivity reactions nT cell–mediated (type IV) hypersensitivity nInitiated by antigen-activated (sensitized by primary exposure) T lymphocytes, including CD4+ and CD8+ T cells. nCD4+ cytokines → inflammatory reaction in a few days (approx. 3). nPossible cause of chronic inflammatory disease, incl. autoimmune diseases. nCD8+ cells may also be involved. esp. following viral infections, T cell–mediated (type IV) hypersensitivity n nPerivascular cellular infiltrates (T-cells, macrophages, eosinophils possible); edema; granuloma formation; cell destruction n nContact dermatitis; type I diabetes; multiple sclerosis; rheumatoid arthritis; inflammatory bowel disease (i.e. Crohn disease); tuberculosis Delayed-type hypersensitivity nPerivascular infiltration by T cells and mononuclear phagocytes. nImmunohistochemistry: predominantly perivascular cellular infiltrate CD4+. n n nfrom Robbin‘s Pathologic Basis of Disease n n bbmapAsset?appID=NGE&isbn=978-1-4377-0792-2&eid=4-u1 T cell–mediated (type IV) hypersensitivity n nContact dermatitis: nInduction phase: sensitising small exogenous molecules (chemicals, etc.) – immunogenic + intrinsic protein carrier → bound by antigen-presenting Langerhans cells → induction of T-cells nElicitation phase upon re-exposure, effector T-cells migrate into skin – inflammation with blisters – vesicular dermatitis nPatch testing response after approx. 3 days T cell–mediated (type IV) hypersensitivity nType 1 diabetes mellitus: antigens of pancreatic islet β cells; insulitis (chronic inflammation in islets), destruction of β cells; diabetes nMultiple sclerosis: protein antigens in CNS myelin; demyelination in CNS with perivascular inflammation; paralysis, ocular lesions, etc. T cell–mediated (type IV) hypersensitivity nRheumatoid arthritis: chronic arthritis with inflammation, destruction of articular cartilage and bone nCrohn disease: unknown antigen; role for commensal bacteria; chronic intestinal inflammation, obstruction 00350+ 1 fibrinoid necrosis 2 palisading histiocytes Rheumatoid nodules 1 2 Granulomatous inflammation n n nPersistent or nondegradable antigens (tb bacilli, …) nInfiltrate dominated by macrophages in 2-3 weeks. nActivated macrophages transform into epithelium-like cells epithelioid cells. nGranuloma: microscopic aggregation of epithelioid cells usually surrounded by a layer of lymphocytes. nGranulomatous inflammation typically associated with strong T-cell activation with cytokine production Cell-mediated cytotoxicity nReactions of CD8+ T cells: nCD8+ T-Ly kill antigen-bearing target cells. nImportant component of many T cell–mediated diseases (type 1 diabetes). nT-Ly directed against cell surface histocompatibility antigens: n important role in graft rejection. nReactions against viruses: virus-infected cell killing → elimination of the infection + cell damage (viral hepatitis). nTumor-associated antigens presented on the cell surface, T-Ly involved in tumor rejection AUTOIMMUNITY nNorm: ability of immune system to differentiate between self and non-self antigens nPathology: immune system response against self antigens n Autoimmune diseases nAutoimmunity arises from a combination of the inheritance of susceptibility genes (contribute to the breakdown of self-tolerance), and environmental triggers, (infections, tissue damage), promoting the activation of self-reactive lymphocytes. nAutoantibodies (AA) in clinically normal people. nPhysiologic AA in removal of breakdown products after tissue damage (antigen-antibody complex removed by macrophages) nImbalance between control mechanisms (normally preventing pathologic self-reactivity) and pathways leading to the generation and activation of pathogenic effector lymphocytes. n Autoimmune diseases nPathologic autoimmunity: presence of immune reaction specific for self-antigen n+ primary pathogenic, not secondary to tissue damage n+ absence of other cause nev. similar to experimental models of AI. nCommonly uncertain „pure“ autoimmunity – term immune-mediated inflammatory diseases Autoimmune diseases nChanges in self-antigens, that make them look like non-self to the immune system nprolongated expression/persistence od antigenes normally cleared out nposttranslational transformation of antigenes – „neoantigenes“ not recognized n n n Factors influencing autoimmune disease nInternal triggering factors ngenotype / HLA ncytokines napoptosis genes nhormones nExternal triggering factors n infections n UV n drugs n chemicals (including food) n stress Autoimmune diseases nMost autoimmune diseases: complex multigenic disorders nMany autoimmune diseases associated with infections, clinical flare-ups often preceded by infectious prodromes (stimulation of lymphocytes by preexisting innate immune reaction) nMany infectious diseases similar to autoimmune disease in pathology (Lyme disease) n n Breakdown of tolerance n n(Bypass of helper T cell tolerance n Imbalance of suppressor-helper T cell function n Genetic factors n Polyclonal lymphocyte activation ) Autoimmune diseases nProgressive tendency (ev. sporadic relapses and remissions) nEpitope spreading: tissue damage → self-antigen release + epitopes exposure (antigens normally concealed from the immune system) → continual activation of lymphocytes recognizing previously hidden epitopes; nThese epitopes not expressed normally – no lymphocytic tolerance Mechanisms of tissue injury nAuto-antibodies circulating in blood or at site of tissue injury nAutoreactive B and T cells in blood and at site of tissue injury nHypersensitivity reactions occurring at sites of tissue injury nHistology: chronic inflammation nPathway for apoptosis n Autoimmune diseases nDifferent autoimmune diseases show substantial clinical, pathologic, and serologic overlaps. nPrecise phenotypic classification often problematic. Autoimmune diseases nDISEASES MEDIATED BY ANTIBODIES AND IMMUNE COMPLEXES n Organ-specific autoimmune diseases (examples) n Autoimmune hemolytic anemia Autoimmune thrombocytopenia Graves disease Goodpasture syndrome Systemic autoimmune diseases n Systemic lupus erythematosus (SLE) Autoimmune diseases nDISEASES MEDIATED BY T-CELLS nOrgan-specific autoimmune diseases n Type 1 diabetes mellitus Multiple sclerosis Systemic autoimmune diseases n Rheumatoid arthritis RA (+ possible role of antibodies) Systemic sclerosis (+ possible role of antibodies) Sjogren syndrome (+ possible role of antibodies) Diseases caused by autoimmunity or by reactions to microbial antigens n Inflammatory bowel disease (Crohn disease, ulcerative colitis) Incidence of autoimmune diseases nRA 1-3% nSjögren´s sy 1/20 000 nVasculitis 1/100 000 n n n Prevalence of autoimmune diseases 5-7% of population Diagnosis nclinical picture nlaboratory nautoantibodies nautoreactive lymphocytes nautoantigens nrelated genes SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) nChronic systemic autoimmune disease nCause unknown nLoss of normal self-tolerance nAffects almost any organ(s) nCharacterized by chronic inflammation nAuto-antibodies formed against variety of self antigens nImmune circulating complexes deposit in tissues n n n SLE nThe course of the disease is variable and unpredictable. nRare acute cases result in death within weeks to months. nAppropriate therapy: flare-ups and remissions, years or even decades. nThe most common causes of death are renal failure and intercurrent infections. SLE – typical case nyoung woman with some of the following features: na butterfly rash over the face, nfever, npain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, fingers, wrists, elbows, shoulders), npleuritic chest pain nphotosensitivity SLE COPY SLE nAcute necrotizing vasculitis involving capillaries, small arteries and arterioles may be present in any tissue. nArteritis with fibrinoid deposits in the vessel walls. nChronic stages: fibrous thickening of vessels with luminal narrowing. serous membranes (common) pleuritis respiratory disease pneumonitis progressive interstitial fibrosis Selected SLE manifestations CNS disease life threatening complication - vasculitis leading to hemorrhage infarction - thromboembolic complications cardiac manifestations pericarditis (most common finding) Libman-Sacks endocarditis - sterile vegetative growths on valves SLE pericarditis shaggy%20heart7 f007030 Libman-Sacks endocarditis of the mitral (From Robbins Basic Pathology, 2003） 3c22 Libman-Sacks endocarditis in SLE (non-infectious endocarditis) Joint disease > 90% SLE patients have polyarthralgia - inflammatory synovitis +/- joint destruction (as in RA) Renal disease ~ 75% have glomerulonephritis, variable morphology possible f007024 Lupus nephritis. (From Robbins Basic Pathology, 2003） f007026 Immunofluorescence with anti-IgG mesangial and capillary wall deposits of IgG. (From Robbins Basic Pathology, 2003） SLE nSkin. Characteristic erythema affecting the facial „butterfly“ area (bridge of the nose and cheeks) in approximately 50% of patients, similar rash on the extremities and trunk. nUrticaria, bullae, maculopapular lesions, ulcerations n Exposure to sunlight starts or worsens the erythema. Clinical features of SLE n [USEMAP] [USEMAP] Chronic discoid lupus nSkin manifestations may mimic SLE, but systemic manifestations rare. nLater may be progression into systemic SLE in a minority of patients nSkin plaques with varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border. Rheumatoid arthritis nSystemic autoimmune disease (joints, skin, blood vessels, heart, lungs, muscles) nEtiology unknown, combination of gen. predisposition, environment (trigger), autoimmunity nRheumatoid factor (RF) – AA to a part of IgG, in 80% n n n Rheumatoid arthritis nChronic nonpurulent proliferative inflammation of synovial joints nProliferation of synovial lining cells, oedema, fibrin deposition → pannus (synovial cells + granulation tissue + inflammatory cells) → nErosion of articular cartilage and adjacent bone (osteoclasts) → nFibrous ankylosis → bony ankylosis Rheumatoid arthritis nVariable course, usual start in hands or other small joints. nArthritis + morning stiffness nWorsening limitation of motion nRheumatoid nodules in organs or tissues – skin, lungs (!x ca), myocardium,… n imp-hand Textové pole: RA IgG4-related disease nIgG4-associated systemic sclerosing disease nCombination of variable immune-mediated disorders nType 1 autoimmune pancreatitis nSclerosing sialoadenitis (mimicking tumor) nOrbital disease – pseudotumor – eye protrusion nRetroperitoneal fibrosis nIgG4 related sclerosing cholangitis nNephritis nOthers n IgG4-related disease nMore commonly middle-aged and older men nDense lymphoplasmocytic infiltrate, predominance of IgG4+ plasma cells – bioptic diagnosis nCommonly elevated serum IgG4 levels nGood response to corticosteroids Sjögren syndrome nchronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) due to destruction of the lacrimal and salivary glands. nMore often in association with another autoimmune disease (secondary form). Associated rheumatoid arthritis most common, possible SLE, thyroiditis nPossible vaginal dryness Sjögren syndrome nWomen between the ages of 50 and 60. nKeratoconjunctivitis → blurring of vision, burning, and itching nXerostomia → difficulty in swallowing solid foods, decrease in the ability to taste, cracks and fissures in the mouth, nEmergence of a dominant B cell clone → development of a marginal zone lymphoma (in the setting of chronic lymphocytic inflammation). 5% of Sjögren patients develop lymphoma, incidence 40x greater than normal. Systemic sclerosis nchronic inflammation thought to be the result of autoimmunity, ndamage to small vessels nlater progressive interstitial and perivascular fibrosis in the skin and multiple organs ngastrointestinal tract, kidneys, heart, muscles, lungs (interstitial fibrosis) ndeath from renal failure, cardiac failure, pulmonary insufficiency, or intestinal malabsorption n n n! it‘s not multiple sclerosis (CNS demyelinating disease) n Systemic sclerosis nfemale-to-male ratio of 3 : 1, peak incidence 50-60 nRaynaud's phenomenon: episodic vasoconstriction of the arteries and arterioles of the extremities nDysphagia due to esophageal fibrosis and its resultant hypomotility Raymonds-fingers-in-SLE Raynaud's phenomenon Noninfectious vasculitis ncommonly in form of: nnecrotizing inflammation of the walls of blood vessels and showing strong evidence of an immunological pathogenetic mechanism nThe general term noninfectious vasculitis n nSee the lecture on vascular diseases Organ-specific autoimmune diseases nEndocrine system nAutoimmune (Hashimoto’s) thyroiditis nHyperthyroidism (Graves’ disease; thyrotoxicosis) nType I diabetes mellitus (insulin-dependent or juvenile diabetes) nInsulin-resistant diabetes nAutoimmune adrenal insufficiency (Addison’s disease) nAutoimmune oophritis n Autoimmune diseases of thyroid nHashimoto´s thyroiditis n- hypofunction of thyroid n- autoantibodies against thyroglobulin and microsomes of follicular cells n nGraves-Basedow´s disease n- hyperfunction of thyroid, thyrotoxicosis n- autoantibodies against TSH receptor: LATS – long acting thyroid stimulants pajzsmirigybeteg_szeme_tn Type 1 diabetes (T1D) nAlso known as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes nOrgan-specific autoimmune disorder (pancreatic islets) nHyperglycaemia results from: - specific auto-destruction of insulin-secreting b-cells in the islets of Langerhans in the pancreas n Etiology and pathogenesis of autoimmune diabetes largely unknown n v . Organ-specific autoimmune diseases nHematopoietic system n Autoimmune haemolytic anemia n Autoimmune thrombocytopenia n Autoimmune neutropenia n Pernicious anemia n n Organ-specific autoimmune diseases nNeuromuscular system n Autoimmune polyneuritis n Multiple sclerosis n n Multiple sclerosis nautoimmune disorder, genetic (HLA etc.) + environmental factors (infection as trigger), amount of UV/ vitamin D, demyelinisation nplaque (active, inactive), astrocytic proliferation, gliosis – sclerosis nmuscular weakness, paraesthesia, sensoric dysfunction (ocular), etc. Organ-specific autoimmune diseases nSkin nPemphigus and other bullous diseases n Organ-specific autoimmune diseases nGIT nChronic ulcerative colitis nMalignant pernicious anaemia with chronic atrophic gastritis nAutoimmune hepatitis, AI pancreatitis nPrimary biliary cholangitis n n n n n Organ transplantation Rejection Organ transplantation nSelection of most suitable donor and recipient - AB0-system most important, complete match necessary n HLA-system: match in major antigenic determinants nUltimate goal: most possible immunologic tolerance Tolerance nsee Immunology for details nselected mechanisms of peripheral tolerance: nclonal deletion (apoptosis of T cells) in long functional grafts nsuppressor T cells or other host factors ndendritic cell from the donor surviving in the host → imunologic chimerism donor + recipient n Rejection ncomplex immunologic process, cellular and humoral reaction, may be in combination nFactors – genetic diversity, type of tissue (vascularisation, number of antigen presenting cells), host immune system activity (immunosuppression), graft condition nRejection in reaction on presence (+ demasking grade) of foreign antigenes. Hyperacute rejection nRare, within minutes or hours after transplantation. nPreexisting antibodies for graft endothelial cells– part of antibody-mediated rejection nDue to previous exposure of the host to foreign antigenes (transfusion, transplantaion, pregnancy) nA hyperacutely rejecting kidney rapidly cyanotic, mottled, flaccid, + excretion of a few drops of bloody urine. nThe kidney cortex necrotic (infarction), nonfunctioning kidneys have to be removed. nSimilar in other organs Hyperacute rejection nIg binding, complement acivation, endothelial injury + fibrin-platelet thrombi nNeutrophil accumulation in arterioles, glomeruli, and peritubular capillaries. nChanges diffuse and intense: thrombotic occlusion of the glomerular capillaries, fibrinoid necrosis in arterial walls nIschemic necrosis of the graft nNecessity of cross-match test n Hyperacute rejection nischemic necrosis of kidney, liver HumRe-Ledv-ma HumRe-J-ma Hyperacute rejection - glomerulitis HumRe-Ledv Hyperacute rejection -liver H00021e Acute rejection nWithin days of transplantation in the untreated recipient, or may appear suddenly months or even years later (↓ immunosuppression, other factors). nIn any one patient, cellular, antibody-mediated immune mechanisms may predominate, or combine. Acute antibody-mediated (humoral) rejection (AMR) nMediated by antidonor antibodies, manifestation mainly by damage to the blood vessels. nNecrotizing vasculitis with endothelial cell necrosis, neutrophilic/macrophagic infiltration, deposition of Ig, complement and fibrin, thrombosis, interstitial oedema possible. nSubacute vasculitis possible : thickening of the intima with proliferating fibroblasts, myocytes, foamy macrophages. Antibody-mediated (humoral) rejection (AMR) nDeposition of the complement breakdown product C4d in allografts - indicator of possible humoral rejection. C4d produced during activation of the complement system nAffected patients treated with B cell–depleting agents, plasmapheresis. nProliferative vascular lesions mimic arteriosclerotic thickening , proliferation of vascular smooth muscle cells – progression into chronic rejection. n Acute antibody-mediated (humoral) rejection (AMR) nVasculitis, thrombosis nC4d deposits - immunofluorescence AkReVaskCor AkReVakCor-imfl Acute antibody-mediated (humoral) rejection (AMR) C4d immunohistochemistry – luminal intravascular positivity, myocardium Acute antibody-mediated (humoral) rejection (AMR) CeReCor-obliter-arterio vasculitis + thrombosis Acute cellular rejection nMost common within the initial months after transplantation nClinical and biochemical signs of organ failure common nHistology: CD4+ and CD8+ T lymphocytes, edema, mild interstitial hemorrhage possible nFocal tubular/ductal necrosis nMore severe: necrotic hepatocytes, cardiomyocytes Acute cellular rejection nEndotheliitis: endothelial cells injury, T- cells between the endothelium and the vessel wall. nThe recognition of cellular rejection important, patients respond well to immunosuppressive therapy. nUntreated ACR may lead to the graft failure and/or chronic rejection n Acute cellular rejection (ACR) nClassification: organ specific indexes for establishing the rejection presence and activity (RAI – rejection activity index in liver grafts) nRejection grade – mild – moderate – severe → therapy nDiff. dg. x other pathol. lesions (ATN in kidney; oportunistic or recurrent infections in liver, …). nPossible co-existence of pathol. changes (rejection + infection, rejection + preservation injury, …) Acute cellular rejection - myocardium n AkReCor-mi AkReCor-mi1 Acute cellular rejection - myocardium AkReCelCor-im IHC: CD3+ T-cells infiltrate in interstitium Acute cellular rejection - endothelialitis + tubulitis + infiltrate AkRe-ledv-arteritis Acute rejection -liver Rejection Chronic rejection nImportant cause of graft failure, multifactorial (ac. rej. persistence, viral infections, chronic ischemia). nPatients with chronic rejection - progressive organ failure presentation. nChronic rejection dominated by vascular changes, interstitial fibrosis, and tubular/ductal atrophy with loss of parenchyma. Chronic rejection nVascular changes: dense, obliterative intimal fibrosis + macrophagic reaction („accelerated arteriosclerosis“)→ ischemia, loss of parenchymal cells, interstitial fibrosis and tubular/ductal atrophy, shrinkage of the parenchyma. n Chronic rejection ChrReREN-ma VaskularRej Failed atrophic renal graft, rejection vasculopathy Chronic rejection – ductopenic nliver graft – IHC CK7: duct loss Rejection rejekceschema Normal Hyperacute Acute Chronic GVHD nGraft-versus-host disease: immunologically competent cells or their precursors transplanted into immunologically non-functioning recipients, the transferred cells recognize/attack alloantigens in the host nDirect cytotoxicity (CD8+ T-cells) + cytokines GVHD nGraft-versus-host disease – most patient with bone marrow transplantation, possible in organs with higher amount of lymph. tissue – intestine, liver (immunologic competent T cells + precursors → in immunodeficient host) nprecise HLA typization/match necessary nhyperacute few days, fever, generaliz. erythrodermia nacute –skin rash, mucosal ulceration, liver cholestatic lesions, thrombocytopenia, anaemia nchronic – chron. lichenoid lesions + atrophy of skin, mucosa, bronchiolitis obliterans, chron. hepatitis,… GVHD GVHD-skin-ma GVHDchr-oral-ma Copy GVHD GVHD-SKIN-mi Apoptosis of keratinocytes GVHD nLiver cholestasis nApoptosis in intestinal mucosa GVHD-liver-cholest GVHD-intest-mimi Other problems in transplantation nalone or in combination nsurgical problems nopportunistic and other infections ndrug toxicity nneoplasia Acute rejection + infection in immunodeficient host Acute rejection + infection in immunodeficient host Acute rejection + infection in immunodeficient host Toxoplasmosis Immunodeficiency nNext week... n