Immunopathology Dr. Amitabha Basu MD OUR TOPIC 1. TRANSPLANT REJECTION 2. Graft Vs Host disease 3. AUTOIMMUNE DISEASES TRANSPLANT REJECTION and MHC matching Type of graft. Mechanism of rejection. Graft survival. Complication of immunosuppression. Management. Graft Vs Host reaction. Type of Grafts 1. Allograft: An organ or tissue transplanted from one individual to another of the same species, i.e. human to human. 2. Auto graft: Tissue that is taken from one site and grafted to another site on the same person; "skin from his thigh replaced the burned skin on his arms“ 3. Xenograft: A xenograft is a transplantation of tissue from a donor of one species to a recipient of another species 4. Fetal tissue grafts: Less chance of reaction. Mechanism of allograft rejection 1. T cell mediated reaction a. Involve Cytotoxic T cell ( CD8+) b. Type IV hypersensitivity reaction 2. Antibody mediated reaction (mainly ADCC). When you give a graft….. • The organ contain – Tissues of the organ – Some lymphocytes of the donor – Some macrophage (APC) of the donor In the direct pathway, • Donor class I and class II antigens on APC of the graft are recognized by CD8+ cytotoxic T cells and CD4+ helper T cells of host. • CD4+ cells→ cytokines→ tissue damage by a local delayed hypersensitivity reaction. • CD8+ T cells→ kill graft cells In the indirect pathway 1. Activate macrophage= tissue damage. 2. Form antigen antibody complex and produce vasculitis= tissue damage. Types of rejection reaction 1. Hyper acute rejection 2. Acute rejection: 3. Chronic rejection Hyper acute Acute rejection Chronic ↓ ↓ rejection ↓ Minutes to Within months Years hours Hyperacute rejection • Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of the recipient. • Morphology: shrunken liver, necrotic swollen tubular epithelial cell, may show pyknotic nuclei. • Scanty bloody urine. Transplant reaction Hyper acute Antibody Fibrinoid necrosis of rejection mediated. arterioles, thrombus in [localized vessels Arthus Neutrophils in the area. reaction] Acute rejection 1. Acute CD4+ and CD8+ cell in cellular tissue. rejection. Acute 2. Acute Necrotizing Vasculitis. rejection= Humoral And Neutrophils in the rejection rejection. tissue. vasculitis Chronic Antibody mediated Vascular intimal Rejection vascular damage proliferation. Kidney change Hyper acute rejection kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete a mere few drops of bloody urine. Swollen necrotic epithelial cells. Management • Drug cyclosporine (block nuclear factor of activated T cells- thus inhibit the gene for IL-2). • Monoclonal anti-T-cell antibodies (e.g., monoclonal anti-CD3 and antibodies against the IL-2 receptor α chain). Methods of Increasing Graft Survival • HLA ( both Class I and class II antigen) matching in transplants. • Immunosuppressive therapy. Survival of grafts: HLA matching in transplants • HLA matching ( of donor and recipient cells) for both class I and class II antigens improves survival: MHC MHC Donor R = Good MHC MHC = Bad Immunosuppressive therapy As a method of graft survival What are the risks? Complications of Global Immunosuppression Opportunistic infections: Pneumocystis Cytomegalovirus pseudohyphae Carinii (CMV) : Candida Sliver stain. Candida (C. albicans ) infection Location: skin, mouth, gastrointestinal tract, and vagina . Risk : DM and immuno compromised patient. Presentation: (thrush-oral). Gray-white, dirty-looking pseudomembranes composed of matted organisms and inflammatory debris , Others • Risk for developing EBV-induced lymphomas, • Human papillomavirus-induced squamous cell carcinomas, and • Kaposi sarcoma Transplantation of Hematopoietic Cells • Develop Graft vs host reaction. – GVH disease occurs in any situation in which immunologically competent cells are transplanted into immunologically crippled recipients. • Example: bone marrow, whole blood. Mechanism • Results from the donor lymphocytes attacking the recipient tissues that has offending HLA antigens. Lymphocyte of Host donor tissue [CD8+ cells] Types • Acute – days to week – Donor cells infiltrate host’s epithelia, liver, bile duct , Gut, lymphnode and dysfunction them. – Infection – CMV – Clinical: Jaundice, skin rash, bloody diarrhea, hepatomegaly heavy infiltration of lymphocytes in the host tissue. d/d of acute type of GVH • Transfusion reaction (TR) – in contract to GVH, TR occur immediately after transfusing a mismatched blood. – ( if you donate A+ blood to a person with B+ blood group etc) Types • Chronic – skin atrophy and cholestatic jaundice. C/F=GVH disease : Jaundice and Rash, Time for Autoimmunity Topic 1. Immune tolerance 2. Termination of tolerance 3. Definition: AUTOIMMUNITY 4. Mechanisms proposed for development of autoimmunity 5. Mediators 6. Autoantibody 7. Diseases Immune tolerance • A state of unresponsiveness to a specific antigen or group of antigens to which a person is normally responsive. • Self tolerance: Immune tolerance against self- antigen. Termination of tolerance • X-irradiation • Immunization with cross reactive antigens. • Autoimmune diseases. AUTOIMMUNITY • Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance. Mechanisms proposed for development of autoimmunity include: 2 1. Failure of “activation induced death” of self reactive T cell. Self reactive T cell So these T cells kills the cell of our body in spite they contain self antigen. Mechanisms proposed for development of autoimmunity include: 2. Molecular mimicry ; Some cells of our body share similar antigen like that of microbes, when antibodies produced to kill these microbes , they destroy cells of the body also. Host cell bacteria Termination of tolerance : examples (nice to know) Molecular mimicry: Rheumatoid In Streptococcus infection arthritis, Rheumatic and EBV infections. Heart disease. Mediators • Cytokines. • Compliments. Cytokines • Interleukins • TNF-alpha • Interferons Few examples • IL-1, TNF-α, type 1 interferons & IL-6: innate immunity • IL-2 : Growth factor for T-cells • IL-12 and IFN-γ: involved in both innate and adaptive immunity • IL-10 and TGF-β: down-regulate immune responses Cytokines induce their effects in three ways: • Autocrine effect: IL-2 produced by antigen- stimulated T cells stimulates the growth of the same cells • Paracrine effect: IL-7 produced by bone marrow or thymic stromal cells promotes the maturation of B- cell progenitors in the marrow or T-cell precursors in the thymus, respectively • Endocrine effect: IL-1 and TNF- produce the systemic acute-phase response during inflammation. • Acute Inflammatory effect: IL1 and IL8. Autoantibody • Definition : Antibody against “self antigen”. • Mainly against various component of Nuclei. • These are celled : Antinuclear Antibodies (ANA). ANA DETECTION A. By estimation of serum titer B. By staining pattern the tissue. Disease Staining pattern ANA SLE Rim and diffuse dsDNA MCTD Speckled Anti-RNP PSS Nucleolar Scl-70 (Scleroderma) CREST Centro mere anti Centro- syndrome mere antibody Sjogren's SS-A & SS-B syndrome Inflammatory Jo-1 myopathy SLE Diffuse and Rim Systemic Lupus Erythematosus (SLE) 1. *Skin rash - Malar or discoid 2. Sensitivity to light (photo dermatitis) 3. Serositis/synovitis - inflammation of serosal surfaces along with effusions Typical skin lesion in SLE An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermal-epidermal junction. SLE 4. Glomerulonephritis – Lupus nephritis = Nephrotic syndrome . 5. *Cytopenias - anemia, leucopenia, thrombocytopenia. 6. Heart: Libman-Sachs Endocarditis 7. Thrombosis - Antiphospholipid syndrome (APS) can occur in patients with SLE. 8. Splenomegaly: periarteriolar fibrosis ("onion skinning") . SLE • *Arthritis, fever, weight loss. • Vasculitis – with fibrinoid necrosis. Lupus nephritis : Wire loop lesion. Deposit of C1q occur. Chronic Discoid Lupus Erythematosus • Less severe. • Skin plaques showing varying degrees of edema, erythema, scaliness. • Diagnosis: positive ANA test, but dsDNA are rarely present. Drug induced lupus • Hydralazine, procainamide, INH, and D- penicillamine. • Diagnoses: – Positive antihistone antibodies. – Negative (mostly( dsDNA). Diagnosis SLE 1. Antinuclear antibody - rim pattern, anti double stranded-DNA. 2. Decreased serum complement - especially C1q. Staining patterns in Autoimmune disease. Nucleolar Speckled (PSS) MCTD Scleroderma 1. Progressive Systemic Sclerosis, PSS 2. Limited scleroderma, or CREST syndrome. Scleroderma (Progressive Systemic Sclerosis, PSS) • Def : Characterized by excessive fibrosis in a variety of tissues due to collagen deposition. • About 75% of cases are in women, mostly middle aged. • Patient may have hypertension. Scleroderma: dermal fibrosis: no adenexa seen Positive for Scl-70 Scleroderma ; reduced figure and limb movements. Important clinical feature in PSS • Skin thickening by fibrosis and collagen deposition. • Malignant Hypertension • And difficulty in swallowing. Limited scleroderma, or CREST syndrome: • Positive for anti-Centro mere antibody. • C = Calcinosis in skin and elsewhere. • R = Raynaud's phenomenon, sensitivity to cold. • E = Esophageal dysmotility from sub mucosal fibrosis. • S = Sclerodactyly from dermal fibrosis. • T = Telangiectasias . Calcinosis in skin Early gangrenous necrosis from vasospasm with Raynaud's phenomenon. Sclerodactyly from dermal fibrosis Features PSS CREST Collagen Initial skin Limited areas, Deposition involvement : wide like face and fingers spread Visceral Early and common Late and not involvement common Course of Rapid Benign disease Frequent Wide spread Skin CREST features involvement, malignant Hypertension and difficulty in swallowing. Prognosis Bad Better / benign course Sjogren's syndrome • Autoimmune disease that involves:- 1. Salivary glands (with xerostomia) and 2. Lacrimal glands (with xerophthalmia). • Most patients are middle-aged women. Sjogren's syndrome; salivary gland histopathology Diagnosis ; ANA in Sjogren's syndrome • The auto antibodies SS-A (Ro) and SS-B (La). Sicca syndrome • Isolated Autoimmune destruction of salivary and Lacrimal glands. • This is not common. • Same ANAs are present like Sjogren syndrome (SS- A and SS-B) Inflammatory myopathy Polymyositis 1. Common in women 2. Associate with visceral cancer. 3. Symmetric weak-ness of the large muscles. (difficulty in getting up from the chair/climbing steps) 4. DIAGNOSIS: Jo-1 autoantibody Dermatomyositis ( skin + muscle weakness) • Clinical feature: Heliotrope Rash PRIMARY IMMUNODEFICIENCY SYNDROMES PRIMARY IMMUNODEFICIENCY SYNDROMES 1. Congenital B- cell deficiency: 1. X-linked Agammaglobulinemia of Bruton 2. Selective IgA Deficiency 3. Common Variable Immunodeficiency 2. Congenital T- cell deficiency 1. DiGeorge Syndrome 2. Wiskott-Aldrich Syndrome 3. Congenital Both B cell and T cell deficiency 1. Severe Combined Immunodeficiency Key words ; Pathophysiology Bruton Defect in Humoral immunity: B cell defect. Disease Intact CMI. Tyrosine kinase deficiency. DiGeorge Thymic hypoplasia and T cell defect. Syndrome Deletion of Chromosome 22q Wiskott- Thymus normal: present with viral and Aldrich fungal infection. Thrombocytopenia, Syndrome eczema SCID Both Humoral and cell mediated depressed. Adenosine deaminase deficiency. X-Linked Agammaglobulinemia of Bruton • Abnormal Ig due to lack of light chain ( abnormal B cell)= low Ig in serum. • Seen after 6 months. • Infection: H. influenzae, S. pneumoniae. • Pathogenesis: lack of opsonization by Ig but opsonization by complement may be normal. • No germinal center in LN. • Polio vaccination may produce disease! X-linked Agammaglobulinemia of Bruton • C/F; Chronic pharyngitis, sinusitis infection with bacterial organisms (Hemophilus, Staphylococcus). • More in male. • Rarely infection with Virus( because of intact T cell immunity). Common Variable Immunodeficiency • Relatively common a heterogeneous group of disorders with low Igs. • They have normal B cell, but they do not differentiated to plasma cells. Selective IgA Deficiency: most common • Incidence:1 in 700 • Asymptomatic. • Virtual lack of circulating IgA as well as secretory IgA. • Increased risk for respiratory, gastrointestinal (diarrhea). Severe Combined Immunodeficiency (SCID) • Autosomal recessive: Adenosine deaminase deficiency. (50 %) 1. No IgM or IgA 2. Ineffective B/T cell. Severe Combined Immunodeficiency (SCID) Morphology: Lympnnode and Thymic atrophy can occur. Severe Combined Immunodeficiency • Some patients develop a skin rash – shortly after birth owing to transplacental transfer of maternal T cells or, – by a blood transfusion that cause GVH disease. Infants develop 1. Candida skin rashes and thrush, 2. Persistent diarrhea, severe respiratory tract infections 3. Pneumocystis carinii and Pseudomonas soon after birth. Wiskott-Aldrich Syndrome • Def: Immunodeficiency with Thrombocytopenia and Eczema. • X-linked recessive disease : thrombocytopenia, eczema, and recurrent infection, ending in early death. DiGeorge Syndrome • Age : Children • Etiology: Deletion on the long arm of chromosome 22. • Pathogenesis : • Markedly decreased numbers of circulating T lymphocytes and Thymic hypoplasia. • T-cell deficiency that results from failure of development of the third and fourth pharyngeal pouches DiGeorge Syndrome : Clinical manifestation CATCH 22 C = Cardiac defect A = Abnormal facies T = Thymic hypoplasia C = Cleft palate H = Hypocalcemia DiGeorge Syndrome : Clinical features • Susceptible to fungal and viral infections. Defective mandible. Deletion of chromosome 22. Key words: clinical features Bruton Occur after 6 months. Disease Commonly bacterial Infection No viral, fungal infection DiGeorge Thymus hypoplasia, viral, fungal infection Syndrome common. SCID Thymus and lymph node atrophy, all types of infections (both bacterial and viral) Thank you.
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