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Study materials: Disorders of Immunity, MIIC 1 Repetition - Basic Immunology from MIB and Immunopathology M IIA – see web materials and textbook: Roitt I, Essential Immunology 2 Immunodeficiency Pathogenesis of ID, explanation of reasons – gene defects or external events leading to ID. Basic features, typical laboratory findings Primary missing enzyme, missing cell type, nonfunctional component, caused by gene defect. Severe, prevalent in childhood Secondary due to underlying disease - lymphoid malignancy, infection, egg. HIV, malnutrition, burns, glomerulopathies, loss by GI tract, therapy and events. Any time, usually less severe. 2.1 Primary Immunodeficiency Antibody deficiency clues from history Recurrent sinus, chest infections are common (history of repeat ENT surgery), another system is usually involved, gut infection, meningitis), infection are bacterial and due to common microorganisms (Strepto pneumoniae, Hemofilus influenzae) Noninfectious features are common (autoimmune thyroid disease, Immunotrombocytopenic purpura, artritis), higher risk of tumors. Designation Immunoglobulins Pathogenesis Inheritance 1. X-linked agammaglobulinemia All isotypes decreased 2. Selective Ig deficiency IgA def. Decrease IgA1, IgA2 Mutations in btk Failure of terminal differentiation of IgM1 B cells IgG subcl.def. Decrease in 1 or more subcl. Def. of isotype dif. 3. Common variable ID Decrease in IgG and usually Unknown IgA, +- IgM 4. X-Hyper IgM syndrome Decrease in IgG, IgA, Mutation in CD40 ligand IgM usually elevated 5. Transient hypogamaglobulinemia IgG,IgA low Delayed helper function in infancy 6. Antibody deficiency with Normal Unknown normal or elevated Ig levels XL Variable Unknown Variable XL Unknown Unknown Management of antibody deficiency: Ig replacement therapy, treatment of infection, bone marrow (BM) or Stem cell (SC) transplantation, gene therapy experimentally 2.2 Combined, dominantly cellular (T cell) immunodeficiency Clues from history: Present in first few weeks/months of life, infections are often viral or fungal rather then bacterial, chronic diarrhea is common and often labeled as “gastroenteritis”, respiratory infections and oral thrush are common, failure to thrive in absence of obvious infections should be investigated Lymphopenia is present in almost all affected infants Designation Ig Circulating B T cells Pathogenesis Inheritance 1. T-B+SCID Decreased Normal or incr. Low chain mutation Jak 3 mutation XL AR 2. T-B- SCID RAG 1/2 deficiency Decreased Normal or incr. Low AR Decreased Low Low Decreased Low Low Mutation in RAG1/2 genes T, B cells defect AR from toxic metabolites Stem cell defect AR Adenosin deaminase deficiency Reticular dysgenesis Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC 3. T+B- SCID Decreased 4. Purine nucleoside phosphorylase def. Normal or low Low Present Restricted heterogeneity Missense mutation in RAG1/2 genes Normal Low T cell defect from toxic metabol. AR AR Management: Antimicrobial therapy, bone marrow, SC transplantation, gene therapy experimental 2.3 Primary cell. mediated ID with other symptoms DiGeorge anomaly ( ID, hypoparathyroidism, cardiovascular defects), chronic mucocutaneous candidosis, WA syndrome. 2.4 Primary defects of non-specific immunity Infections are recurrent and prolonged, clinical features may be minimal despite severe infection Infections are: poorly responsive to antibiotics, common staphylococcal, involve skin and mucous membranes, complicated by suppurative lymphadenopathy Defects of neutrophils – disorder of phagocytosis – Chromic granulomatous disease, LAD syndrome. Treatment: Antibiotic treatment and prophylaxis, Gamma interferon 2.5 Complement deficiency Def C1, C2, C4 – Susceptibility to immune-complex diseases D, B, P recurrent Neisserial infection Def C3 Recurrent bacterial infection C 1 inhibitor deficiency hereditary angioedema 2.6 Secondary immunodeficiency Secondary causes of immunodeficiency are far more common than primary immunodeficiency. Decreased synthesis Increased loss Malnutrition Nephrotic syndrome Lymphoproliferative diseases Protein-losing enteropathy Drugs Burns Infection (viral infection, chronic infection) Alcoholism (maternal) Iradiation Major surgery Anesthesia Some chronic diseases (diabetes) 3 Autoimmunity and Autoimmune diseases Autoimmunity is an immune response against self antigen or antigens. Autoimmune disease is tissue damage or disturbed physiological function due to autoimmune response. (Autoimmune response can occur without disease, caution is required in making the assumption that autoimmune responses necessarily imply autoimmune disease) Slight autoimmune reactivity is normal; many self proteins induce an autoimmune response in animals when injected with an appropriate adjuvant. 3.1 Etiopathogenesis – risk factors Around 3 % of the population has an autoimmune disease. Many of the major chronic disabling diseases affecting people have autoimmune diseases. Rare in childhood, peak between puberty and retirement age, more common in women, prevalence higher in northern latitudes, higher in westernized industrial societies, clustering within families Central T-Cell Tolerance Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Peripheral Mechanisms of the Induction of Tolerance. Molecular mimicry - Structural similarity between self proteins and those from microorganisms may trigger autoimmune response. Once tolerance has broken down to a particular peptide, the process of inflammation will allow presentation of further peptides – epitope spreading The basis for autoimmune disease definition is the knowledge of the autoantigens and pathophysiology of immune reaction (please recognize autoAg for each autoimmune disease group) 3.2 Antigenic mimicry – example. Microbial protein autoantigen Streptococcal M protein myocardial myosin EBV GP110 HLA Dw4 EBV capside antigen Human IgG Adenoviral E1B protein Gliadin protein A Hepatitis B polymerase Myelin basic protein Coxsackie B4 nuclear protein islet glutamate decarboxylase Campylobacter jejune glycoproteins Myelin associated gangliosides and glycolipids 3.3 Genetic factors . Multiple genetic factors may cluster within the same family. The genetic contributions to autoimmune disease almost always involve multiple genes. Association between HLA and diseases Spondylartritis deformans HLA B27 Rheumatoid arthritis DR4+DR1 Type I DM DR3+DR4 SLE DR3 Organ specific autoimmune DR3 (in association with A1B8DR3 Disease: Addisons, Thyroid, Pernicious anemia, Myasthenia gravis) Rare autoimmune diseases are monogenous – AIRE protein defect (central tolerance), FoxP3 defect (peripheral tolerance). 3.4 Environmental factors on autoimmunity development Hormones females are far more likely to be affected than males Infection molecular mimicry, up- regulation of co-stimulatory molecules Drugs will induce pathological immune response-reversible with withdrawal (immunological response to the drug, mechanism is unknown) Drug induced autoimmune syndrome 3.5 Treatment of autoimmune disease Replacement of function, particularly endocrinology autoimmune disease, Immunosupression (lack of specificity, toxic effects!!), biological therapy (MAb). bone marrow transplantation - experimental 3.6 Kidney disease - pathogenic mechanisms Ab directly react with glomerular, tubular basal membrane, Ag-Ab immunocomplexes are deposited in kidney or Ag my bind with glomerular BM and react with the antibody Ab may induce a vasculitis process that damages the capillary plexus of glomerulus 3.7 Autoimmune endocrine diseases Thyroidal: Thyrotoxicosis, Graves disease Autoimmune thyroiditis , Hashimoto thyroiditis Type I DM Adrenal disease - AI adrenalitis, Addison disease Gonadal disease AI polyendocrine syndrome Type 1 parathyroid, adrenal cortex, gonads, MC candid Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Type 2 adrenal, thyroid, insulitis Type 3 thyroid, pernicious anemia or DM I, myasthenia 3.8 Autoimmune disease of joints and muscles Immune mechanisms are responsible for many rheumatology diseases - joint, muscles, or systemic involvement- „connective tissue diseases“ (CTD) CTD typically associated with non-organ-specific diseases autoantibodies (AutoAb-typically against nucleus). AutoAb are diagnostically useful, not usually responsible for damage Rheumatoid artritis - Chronic, relapsing systemic inflammatory disease, joint usually involved destructive artritis. Otherwise any organ Main immunologic features: rheumatoid factors-IgM Ab which binds aggregated IgG , in serum or synovial fluid. Vasculitis, synovitis, decrease C level Pathogenesis - probably CD 4+ cells promote macrophages to destroy joints, synovial infiltration by CD4+ cells, association with DR4, effective therapy against T cells (Cy A), anti TNF alpha, or B cells anti CD20. Ankylosing spondylitis - spine, SI joints Reiter disease - artritis, urethritis, conj,-uveitis - T response to sequestrated bacterial antigens Lupus erythematodes Blotchy erythema on the dorsum of the hands in a patient with SLE. Not all patients with SLE have the classical photosensitive 'butterfly' rash. Well-demarcated digital ischemia due to Raynaud's phenomenon Systemic lupus erythematodes defin. -Multisystemic inflammatory disease, characterized by antinuclear antibodies. ACR criteria (at least 4) malar, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, serositis, renal involvement (proteinuria, casts), neurological disorder (seizures/psychosis), hematological symptoms, ANA, anti dsDNA, anti-ENA, antiphospholipid antibodies Immunopatogenesis SLE - Immunopathologic reaction type II. and III. Deposition of complex dsDNA – antiDNA. Deposition of Ig and complement - inflammations and tissue damage Anti-erythrocyte Ab, anti-platelet Ab, coagulation factors Ab - direct pathogenic role Etiology of SLE – unknown, some hypothesis: Complement deficiency. Classical pathway defect (C1, C4, and C3) is a risk factor. Secondary deficiency by consumption maintains the inflammation. Autoantibody production directed against nuclear molecules involved in transcription and translation. Infection induced? Polyclonal B activation. Defective apoptosis (no FAS defect). Drugs (slow acethylators) - hydralazin, prokainamid, INH. UV light - apoptosis induction on keratinocytes, Ro, La Ag expression Hormones - estrogens accelerate the disease? Other connective tissue disease Mixed connective tissue disease (MCTD) - artritis, polymyositis, lung fibrosis, skin, anti RNP. Sjogren syndrome - autoimmune destruction of exocrine glands. Systemic sclerosis, scleroderma- diffuse sclerosis of skin, GIT, heart, muscle. Vasculitis - polyarteritis nodosa - multiple aneurysm Polymyositis primary idiopathic PM/DM, with malignancy, juvenile DM, with other AI disease Anticardiolipin syndrome (ACS) – recurrent thrombotic vessel occlusions, coagulation disorders, thrombocytopenia. Primary, secondary, synthesis of Ab against phospholipids with cofactor beta2GPI is typical. 3.9 Cardiovascular autoimmune diseases - acute rheumatoid fever – example of AI heart disease induced by Ab crossreactivity between Streptococus antigens and myocardial proteins. Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC 3.10 Vasculitis syndrome Classification according to vessel size, immunohistochemistry. Vessel wall inflammation leads to occlusion or aneurysma, rupture. Frequently ischemia is the principle of symptoms. Classification Polyartrteritis nodosa – 7 % of all vasculitis. Systemic inflammatory disease, aorta and main branches are usually not involved. ANCA associated vasculitis – Wegener granulomatosis, microscopic polyangitis. Role PMN in pathogenesis, role of ANCA on Ly activation 3.11 Neuroimmunology Multiple sclerosis – probable AutoAg is myelin basic protein, inducing T cell response. Antibody response against cytosceletal proteins is present. Myasthenia gravis – Ab against ACH receptors Autoimmune inflammatory neuropathy – anti MAG, ganglioside, sulfatides 3.12 Bullous skin disease Pemphigus Most patients have circulatinganti-desmosomal Ab (desmoglein 3), amount correlate with disease activity Plasmapheresis reduce Ab titer and disease activity. Similar lesion can be induced in animals by patients serum IgG from pemphigoid serum in the culture will cause epithelial cell detachment Direct immunofluorescence is diagnostic- IgG, C3 react with keratinocytes Treatments - systemic corticosteroids Bullous pemphigoid Dermatitis herpetiformis Duhring-itchy, small vesicles. Induced by immune response to food antigens, similar pathogenesis to CD. Systemic sclerosis Cryoglobulinemia - Ig which form precipitates, gels or crystals in the cold Type I - monoclonal IgM Type II - mixed type, IgM against Fc IgG Type III - mixed polyclonal Cutaneous vasculitis - circulating IK, or ANCA Hereditary angioedema – inborn defect of C1 inactivator Urticarial vasculitis Urticaria - marked wheals with surrounding erythema 3.13 Autoimmune eye diseases Stevens-Johnson sy - severe form of erythema multiforme - IC - drugs, microorganisms Uveitis - anterior uveitis, posterior uveitis, lens-induced uveitis 3.14 Autoimmune chest diseases Granulomatous diseases - TBC, sarcoidosis - multisystem granulomat. disorder Interstitial lung diseases - Fibrosing alveolitis - cryptogenic f. alveolitis, Pulmonary eosinophilia Hypersenzitivity pneumonitis (Farmers lungs) - vasculitis – ID diseases induced by Microorganisms inhalation – IC, lymphocyte infiltration Vasculitis - M. Wegener, Goodpasture´ syndrom Allergic Bronchopulmonary Aspergillosis 3.15 GIT and liver disease Atrophic gastritis and pernicious anemia (APCA) Gluten enteropathy, celiac disease (CD) – Ab and T cell mediated response to gluten and antigens of gut enterocytes – (transglutaminase, calreticulin) IBD - ulcerative colitis,Crohn disease Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Hepatitis - infection - A, B, C autoimmune - Type I - ANA, ASMA Type II LKM (IIa), with virus hepatitis C (IIb) Type III SLA Primary biliary cirrhosis – antimitochondrial antibodies (against M2 pyruvatdehydrogenase) highly diagnostic and prognostic 4 Allergy and Anaphylaxis Atopy – inherited tendency for hyperproduction of IgE antibodies to common environmental allergens. (about 80 % of atopic individuals have a family history of “allergy”¨), usually with typical clinical picture. The prevalence of allergic diseases is increasing Risk factors for allergic diseases – Atopy Age – commoner in children than adults Gender – commoner in boys than girls Family size – less common in large families Smoking. high levels of antigen exposure Dietary factors – good intrauterine nutrition Type I hypersensitivity – most of the reactions are IgE mediated – IgE mediated release of preformed, newly generated mediators from mastocytes and basophils Immediate reactions – wheal-flare reaction in 15-20 minutes, mucosal or systemic reaction (parenteral – reaction to insect venom, drugs). Direct activation of mast cells – aspirin, tartrazine, myorelacants, opioides, activation via complement split products C3a, C5a) Late-phase response – 4-6 h after exposure, lasting for 24 hours. (accumulation of activated inflammatory cells - eosinophils and T cells) 4.1 Anaphylaxis Acute, severe, multisystemic potentially lifethreating allergic reaction - generalized degranulation of sensitized mast cells and basophils after antigen exposure. Clinically – sudden, generalized, dominantly cardiovascular reaction (collapse) and/or bronchospasm, usually with other systems involved The most common causes of anaphylaxis – food, bee and wasp venom, drugs, latex rubber Anaphylactoid reaction – (anaphylaxis-like reaction) is not mediated by IgE antibodies. Prior sensitization is not needed. Pharmacological mediators – histamine, direct mast cells activators, drugs 4.2 Allergic conjunctivitis – seasonal (hay fever) and perennial. Vernal conjunctivitis – perennial, self limiting conjunctivitis, with giant papillae on the upper tarsal conjunctiva. 4.3 Allergic rhinitis The most common allergic disease – seasonal, perennial (pollen, animals, mites, molds as sources of allergens – characteristics, biological and immunology similarity) 4.4 Bronchial Asthma Pathophysiology: Generalized, reversible airway obstruction Bronchial hyperresposiveness Airway inflammation Asthma is simple to treat, difficult to manage, impossible to cure. Precipitating specific factors in asthma - Seasonal tree, grass, weed pollen Perennial – hose dust mites, animal danders, feathers, fungal spores, occupational allergens – metals Non – specific factors Infections, Irritants – smoking, fumes, Diesel exhaust particles, sulphur dioxide, some ingested foods and preservatives Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Airway cooling – exercise, cold air temperature Causes of eosinophilic infiltration in chronic allergen exposure: Upregulation of VCAM enabling eosinophil recruitment Maturation and increased survival mediated by IL-3, IL-5 and GM-CSF Selective eosinophil migration induced by IL-8 and RANTES Pathological changes of asthma -epithelial cell shedding, subepithelial fibrosis, mucosal edema, smooth muscle hypertrophy and hyperplasia, thickening of the basement membrane, Eo and mononuclear infiltration in the mucosa 4.5 Food allergy and intolerance Principles of intolerance: Food fad Psychological aversion Food intolerance (mechanism unknown) Food allergy - immune Food idiosyncrasy (nonimmunological mechanism) – irritants, pharmacological, metabolic effects, enzyme deficiency. IgE reaction – Food allergens Type I – capable to induced sensitization. Type II, structurally similar to other inhalation allergens Components in food – traces of antibiotics, food additives (monosodium glutamate), coloring agents, preservatives Clinical syndromes – GI symptoms, acute angioedema, urticaria, perioral erythema (children), atopic eczema, bronchospasm, hypotension “Non IgE reactions” T cell reactivity probable, Eo involvement. Diagnosis of food allergy – history, eliminations and challenge diet form the basis of the diagnosis of food allergy. Skin test and IgE testing is not usually reliable 4.6 Drug allergy Minor part of drug side effects have immune mechanisms, all type (I – IV) of hypersensitivity are involved. Younger age, women, genetic factors, chemical structure of drug, previous exposition, application are risk factor for allergy. Common triggers – penicillin ATB, nonsteroidal anti-inflammatory, general anesthesia drugs, Radio contrast media, vaccines, latex (show immunopathologic reactions) 4.7 Urticaria and angioedema Urticaria refers to transient episodes of demarcated, edematous, erythematous, pruritic lesions with a raised edge. Clinical diagnosis is easy, finding the cause is very difficult Angioedema is a similar process occurring in the deep dermis, subcutaneous tissue or mucous membranes. U and A commonly coexist. Mechanisms of urticaria production - Immune mechanisms IgE, complement. Autoimmune (?) FcRI antibodies Direct action on mast cells – Aspirin, NSAID, ACE inhibitors, opioids, azo dyes Acute urtica versus chronic urtica (more than 6 weeks) Physical urticaria – itching and wheals are provoked by physical stimuli (stroking, cold, sun, water, exercise, heat) Urticarial vasculitis – immune complex disease, histological evidence of vasculitis Clinical identification wheals are usually tender, painful rather than itchy Generally last longer than 24 hours Wheals fade to leave purpura or bruising Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Often accompanied by systemic features such as fever artralgie, patients may have underlying disease (SLE) 4.8 Atopic eczema Common, chronic, severely pruritic, eczematous skin disease, usually in individuals with a hereditary predisposition to atopic disorders Prevalence children under the age of 2 years – 10 % Adults 2 % Complication – bacterial superinfection Diagnosis – on the basis of clinical features Immunologic abnormality: Raised serum total IgE in about 90 % of patients. Abnormal T cell function – increased susceptibility to skin infection, normally controlled by T cells (vaccinia, herpes simplex, viral warts) Impaired delayed hypersensitivity skin test response. Decrease number of Th1 cells, expansion of Th2 cells, chronic macrophage activation. Food allergy common in childhood, rare in adulthood. 4.9 Contact dermatitis Inflammatory skin disease caused by T-cell mediated hypersensitivity to external agents – dominantly occupational disease Agents responsible for contact dermatitis Metals nickel, chromate (cement), cobalt Medication “para” -group chemicals – anesthetics, sulphonamide antibiotics, PABA containing substances, Phenothiazines, neomycin Plastics acrylates Rubber accelerators Plants Primula, Poison Ivy, chrysanthemum Cosmetics Perfumes, preservatives, lanolin 5 Immunopathology of reproduction Immunity related to –conception, nidation , intrauterine tolerance, response to sperm antigens (men, women), mother immune response during pregnancy, sterility and infertility Survival of fetus as a allograft - hemochorial placenta - syntitiotrofoblast - no HLA Class I but class G expression, fetal antigens expressed weakly. Uterus is not a privileged site, mild exchange of soluble factors and cells between the mother and the fetus (200 000 cells / day). Placental immunoglobulin crossing - only IgG immunoglobulin. autonomous IgM, IgA production (infection) crossing Ab in case of incompatibility A,B,O or Rh = HDN crossing of autoantibodies - mother AI disease Maternal immune response during pregnancy- Decreased number of lymphocytes, decrease of CD4 cells, increase of CD8 cells, decreased proliferate response of T lymphocytes, Increased Ig concentration Immune reaction after repeated abortions - Negative influence of the same HLA antigens - therapy: immunization of mother by father antigens. Antiphospholipid antibodies, Autoimmunity to trophoblast, endometrium, Autoimmunity of thyroidal AI Immune response to sperms - Man = autoimmunity, women = alloimmunity 6 Transplantation immunology 6.1 ALLOIMMUNITY AS AN INFLAMMATORY RESPONSE In patients who are serologically presensitized to alloantigens (ie, graft antigens recognized as "non-self"), this can rapidly proceed to a pathologic thrombotic response (hyperacute rejection). When graft alloantigens are encountered by T cells, the inflammatory responses intensify, and pathologic tissue destruction ensues (acute rejection). Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC When these T-cell-dependent responses to graft alloantigens are controlled by immunosuppressive drugs, acute rejection is avoided, but tissue repair mechanisms are allowed to engage. If the repair and structural reinforcement process is prolonged, pathologic tissue remodeling occurs (chronic rejection). Mechanisms of tissue damage antigen-independent causes of tissue damage associated with allograft transplantation, including peritransplant ischemia, mechanical trauma, and reperfusion injury antigen-dependent causes, such as immune-mediated damage to graft tissues. Any tissue damage in the graft compromises graft acceptance by promoting graft inflammation, a complicated array of events that promotes control, pathogen surveillance/eradication, and tissue repair. 6.2 Pathways for the presentation of alloantigenic peptides 1. Proteins derived from graft cells are obtained by recipient antigen-presenting cells (APCs), processed, and displayed via recipient major histocompatibility complex (MHC) class II molecules to recipient CD4+ T cells. 2. Proteins produced by graft-derived antigen-presenting cells (APCs) are processed and displayed via graft-associated major histocompatibility complex (MHC) class I molecules to the recipient CD8+ T cells. 3. Proteins produced by graft-derived antigen-presenting cells (APCs) are processed and displayed via graft-associated major histocompatibility complex (MHC) class I molecules to the recipient CD8+ T cells. 6.3 TYPES OF GRAFT REJECTION Hyperacute rejection Presence of large numbers of polymorphonuclear leukocytes. Occurs within minutes to hours of graft implantation. Dependent on the presence within the graft recipient of preformed circulating antibodies with specificities for foreign protein polymorphisms displayed by the graft endothelia (ABO, MHC encoded proteins) . 1 %. Avoidance of high-risk donor-recipient combinations Acute Rejection Acute rejection is characterized by the presence of leukocytes - macrophages and T cells Within the interstitial infiltrate of acutely rejecting grafts is a small number of recipient-derived, donor alloantigen-reactive T cells, on which the process of acute rejection is absolutely dependent 50 % . Immunosuppressive drugs Chronic Rejection Development of blood vessel luminal occlusion due to progressive neointimal formation within the large to medium arteries and, to a lesser extent, veins of the graft. It represents a pathologic tissue-remodeling response. 10-year graft survival can be reliably evaluated, chronic graft rejection occurs in about 50% of transplant patients. Currents IS have little effect Transplantation History First kidney transplantation - 1954 First heart transplantation 1967 First bone marrow transplantation - 1968 6.4 Selection of donor/recipient for kidney Living relative - two kidneys, no transmissible disease, no anomalous blood vessels, good psychologically health Cadaver - good renal function, no infection, malignancy, systemic disease Recipient selection ABO compatible, negative serum cross match (T ly), HLA match, particularly D loci 6.5 Pre - transplantation testing Blood group - A,B,O, HLA antigens Class I and II . Mixed lymphocyte culture - MLR , Cross - match Alloreactivitiy testing of T cells - mixture of donor and host lymphocytes - positive result - lymphocytes lysis Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Immunologically privileged sites (gonads, cornea) No rejection in allogenic transplantation Stem cell transplantation - indication Severe aplastic anemia, Acute/chronic myeloid leukemia-1rst remission, acute lymphoblast leukemia Immunodeficiency - SCID, CGD, WA, hyper IgM - severe cases. Inborn errors of metabolism Autoimmune diseases - peripheral SC 6.6 Graft versus host disease It occurs in most patients with allogenic transplants. Presence of immunocompetent T cells in graft HLA incompatibility between donor and recipient, cellular immune deficiency in the host Clinical picture - Rash, fever, hepatosplenomegaly, bloody diarrhea, breathlessness, 7 - 14 days after transplantation Prevention - Irradiated blood products in immunosupressed hosts ( T cells inactivation), T cells depletion 7 Immunohematology and lymphoproliferation 7.1 Immune reactions against blood elements Two classes of antibodies, IgG and IgM, are each associated with distinctive serologic reactions and different clinical forms of immune hemolytic anemia. Similarly, thrombocytopenia, neutropenia, against soluble clotting factors, ("lupus anticoagulant"/ antiphospholipid antibody (APA) syndrome. Direct antiglobulin test (DAT) uses the patient's own cells as the targets for the Coombs reagent; a positive test result indicates the presence of antibodies or complement directly on the patient's cells. However, the frequency of positive test results in hospitalized patients may run as high as 15%. Mechanisms of autoimmune hemolytic anemia Warm reactive IgG autoantibodies, best detected at 37 ° C Cold reactive IgM autoantibodies, detected at the temperature bellow 37 ° C Drug provoked immune hemolytic anemias Complement activating IgG of paroxysmal cold hemoglobinuria Classification of AIHA warm (IgG) primary secondary lymphoproliferation, autoimmune disease, AIHA drugs, infection cold (IgM) primary secondary – infection, lymphoproliferation, paroxysmal cold hemoglobinuria, 7.2 Warm autoimmune hemolytic anemia Clearance of IgG-coated red blood cells (RBCs). Removal is mediated by attachment to Fcgamma receptors located predominantly in the spleen. Red blood cells that survive this process partially phagocytized become spherocytes, a characteristic morphologic feature of immune hemolysis. The IgGcoated cells undergo accelerated destruction by attachment to Fc receptors present on macrophages of the RES, primarily those located in the spleen 7.3 Cold Agglutinin Hemolytic Anemia Cold-reactive IgM autoantibodies fix early complement components to the red blood cell membrane. Rewarming results in additional activation of the complement system, leading to extravascular removal ( hepatic RES cell C3 receptor binding) or intravascular destruction. Cold agglutinin disorders are subdivided into primary (idiopathic) and secondary forms; the idiopathic form can be considered to be a form of paraproteinemia with an IgM monoclonal autoantibody. The mechanism of hemolysis that results from the presence of cold agglutinins differs significantly from WAIHA. Paroxysmal cold hemoglobinuria is the rarest form of an autoimmune hemolytic disease. It results from a cold-reacting IgG antibody (the Donath-Landsteiner antibody), usually with specificity for a universal RBC determinant, the P antigen. The antibody fixes early complement components to the cell; on rewarming, the remainder of the complement sequence is activated, leading to intravascular lysis Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC 7.4 Drug-Induced Hemolysis A large number of drugs are capable of causing immune hemolytic reactions in susceptible individuals (1) the drug adsorption type (2) the immune complex type (3) the autoantibody type Penicillin is the prototypical example of the drug adsorption mechanism (very high doses - 10 - 20 million 7.5 Hemolytic disease of the newborn consequence of the binding of maternal alloantibodies or isoantibodies to the inherited paternal antigens present on fetal RBCs, which the mother lacks. The commonest cause - rhesus incompatibility Rh Dwomen are at risk Prevention - anti - D antibody after delivery in the first pregnancy (destroy Rh+ fetal cells) 7.6 Hemolytic Transfusion Reactions The most common cause of AHTR - the transfusion of ABO-incompatible RBCs because of a clerical error Delayed hemolytic transfusion reactions - a result of an anamnestic response from exposure to minor RBC antigens, typically those belonging to the Rh, Kell, Kidd, or Duffy blood groups 7.7 Immune Thrombocytopenia Immune mechanisms similar to those described for RBCs can also cause thrombocytopenia The major diagnostic criteria are : (1) a low platelet count (2) evidence for a destructive cause of the thrombocytopenia (eg, large platelets in the peripheral blood, a bone marrow that shows normal to increased numbers of megakaryocytes) (3) the absence of other causes of a destructive thrombocytopenia. 7.8 Immune Neutropenia Neonatal alloimmune neutropenia (transient congenital neutropenia) occurs when maternal neutrophilspecific antibodies cross the placenta.. Drug induced neutropenia. Secondary neutropenia - SLE 7.9 ANTIBODIES AGAINST CLOTTING FACTORS The antibody is directed against a specific clotting factor, such as factor VIII antibodies (15 % of patients with severe hemophilia, the antibody act as a nonspecific blocking factor (prothrombin converter complex - the lupus anticoagulant/APA - different antibodies, related pathogenesis of AP syndrome) Lupus Anticoagulant/APA Syndrome The lupus anticoagulant is an IgG or IgM antibody that prolongs clotting tests by binding to anionic phospholipids that have formed complexes with proteins. Lupus anticoagulants are one of the most common coagulation abnormalities seen in clinical medicine and have been associated with thrombosis and recurrent fetal loss 7.10 IMMUNOHEMATOLOGIC ASPECTS OF B-CELL DISORDERS Clonal neoplasms, such as CLL, macroglobulinemia of Waldenstrom, and multiple myeloma, can be considered to represent a maturation arrest in the normal sequence of the cellular responses of B lymphocytes to antigenic stimulation. B lymphoproliferative disease Chronic lymphocyte Leukemia, Monoclonal Gammopathies, Macroglobulinemia of Waldenstrom, Amyloidosis - the extracellular tissue deposition of an insoluble fibrillar protein Cryoglobulinemia - proteins that precipitate when exposed to cold and redissolve with rewarming 8 8.1 Tumor immunology MECHANISMS OF ESCAPE OF TUMOR CELLS FROM THE IMMUNE SYSTEM Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Downregulation of MHC Class I expression, Lack of costimulatory function. Immunoselection of tumor cells with weak immunogenicity. Tolerance of the host to respond to tumor antigens. Suppression of immune response by tumor secreted products. Induction of regulatory/suppressor cells 8.2 Tumor immunotherapy: active immunization – cytokine use – IL-2, dendritic cells pulsing by tumor antigens – specific T cell induction passive – targeted drug by tumor Ag specific Ab (MAb), directed polymers. Monoclonals against vascular growth factors, specific cell (tumor) Ag – rituximab anti CD20 etc. Activated killer cells. 9 Immunomodulation and immunotherapy Goals of immunotherapy Immunostimulation specific - immunization against infection nonspecific - synthetic stimulators, bacterial lysates, derivates Immunosuppression nonspecific - synthetic drugs, cytokine intervention (AI, transplantation, severe allergy) specific - allergy, AI diseases (research) 9.1 Vaccination against infectious diseases Active immunization natural infection (survived) artificial-mimic the immunological stimulus Passive immunization natural artificial Ideal vaccine: effective, safe, cheap, ready available, stable, easy administered, with long last effect Vaccination against infectious diseases-immunization Immunization is undergoing important changes, with improved vaccines replacing less immunogenic or less safe vaccines, new vaccines for common diseases. Immunological requirements of a vaccine Activation of APC to initiate antigen processing and production of cytokines Activation of both T and B cells to give a high yield of memory cells Generation of T cells to several epitopes to overcome: antigenic variation of pathogens genetic variability in the host´s immune response due to MHC polymorphism Persistence of antigen on follicular dendritic cells in lymphoid tissue where memory B cells are recruited. Live attenuated vaccines fulfill these criteria par excellence 9.2 Vaccines Live vaccines - infect, replicate, and immunize, without causing significant disease (BCG, Polio-Sabin, MMR) Not a fully virulent organism - attenuated - !!Risk for ID!! Killed vaccine - suspension of killed organisms (cholera) or products or fractions (pertussis). Toxoids (tetanus), subunits of viruses (split vaccines) Adjuvants - enhance the immune response to another antigen given simultaneously - Freund´s, aluminium, muramyl dipeptid, polymers 9.3 Nonspecific stimulation Synthetic levamisol isoprinosine Bacterial immunomodulators Products of immune system - transfer factor , thyme hormones, cytokines 9.4 Immunosuppressive therapy AI disease, transplantation Corticosteroids IS targeted to DNA metabolism Antagonists and inhibitors of nucleotides - azathioprin, mycofenolic acid, cyklofosfamid, antimetabolites Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera Study materials: Disorders of Immunity, MIIC Molecular effects of glucocorticosteroids Immunosuppressive therapy - corticosteroids Immunosuppressive therapy - selective for immune cells IS antibiotics - molds products, bound to cytoplasmic immunophillins - transcription inhibition for gee for IL-2 - cyclosporine A, FK506 (tacrolimus), rapamycin Antibodies to T cells antilymphocyte serum, antithymocyte serum, anti CD3 Interferons - Antitumor effect, antiprolipherative effect, increase antigenicity of tumor cells, NK activity stimulation, Immunomodulatory effect -Macrofages activation, MHC induction. Antiviral activity (IFN-alpha). Side effect - vascular leak syndrome Mechanisms of Action of Intravenous Immunoglobulin (IVIG). Chimeric, humanized antibodies Immunosuppression by antigen - Tolerance induction by oral antigen. Limited by the knowledge of the autoantigen, probably tissue specific still experiments 9.5 Therapy of atopic diseases – allergy vaccination/allergen immunotherapy causal therapy of atopic diseases. – inducing clinical tolerance to causal allergen. Immune changes increased T regulatory activity, suppressive cytokine production IL-10), reduced mast cells, basophil activity, decrease eosinophil tissue recruitment and activation Parenteral, or sublingual application (negative signals induction from mucosal dendritic cells) 9.6 Use of cytokines, cytokine antagonists membrane antigens Neutralizing of IL-4 anti-IL-4 prevent development of all.Sp.IgE, reduce IL-5, eosinophilia, airway hyperreactivity. Soluble cytokine receptor represent endogenous homeostatic mechanism, at high dose can block IL function a modify the disease Proinflammatory cytokines inhibition- IL-1Ra (rheumatoid artritis), anti TNF 9.7 Monoclonal Ab as Immunosuppression Anti CD3 renal, heart graft rejection Anti TNF.-alpha – rheumatoid arthritis, M.Crohn – disease modification anti-CD20 (rituximab) chimeric antibody - human Fc part combined with mouse variable domains – CD20 expressing lymphoma, rheumatoid artritis, IBD anti-integrin (natalizumab) – multiple sclerosis anti-IgE (omalizumab) asthma, allergy anti-VEGF, EDGF (growth factors) – solid tumors therapy 9.8 Gene therapy for immunodeficiency diseases Gene therapy is the process by which exogenous genetic material is transferred into somatic cells to correct an inherited or acquired gene defect or to introduce a new function or property into cells. The first human protocol for gene therapy was performed in patients with ADA (T cell ID) deficiency in 1990 at the National Institutes of Health Recommended literature: Medical Immunology. Parslow TG, Stites DP, Terr AI,. - 10th ed. - London: Mc Graw-Hill, 2001. Essentials of Clinical Immunology, Chapel H, Haeney M et al. Blackwell Science, 5th ed. 2006 Primer on Allergic and Immunologic Diseases , Shearer WT, Li JT, J Allergy Clinical Immunology. 2003, 111, 2, Supplement. Dept. Immunology, 3rd Medical Faculty, Charles Univ Doc. Kučera