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Immunology Part II Dr. Nadeem Ikram MBBS, DCP (Clinical Pathology), FCPS (Immunology) Tolerance Immune system reacts to an enormous variety of microbes but does not react against individuals own (self) antigens Unresponsiveness to antigens is called as immunological tolerance Inability to respond to...

Immunology Part II Dr. Nadeem Ikram MBBS, DCP (Clinical Pathology), FCPS (Immunology) Tolerance Immune system reacts to an enormous variety of microbes but does not react against individuals own (self) antigens Unresponsiveness to antigens is called as immunological tolerance Inability to respond to antigen stimulation or immunological unresponsiveness Tolerance The failure of these mechanisms to inactivate or eliminate self-reactive cells leads to autoimmunity or autoimmune disease Tolerance Central Tolerance: Inactivation or destruction of the lymphocytes may occur during early development in the generative lymphoid organs Peripheral Tolerance: Inactivation or destruction of the mature lymphocytes in the peripheral tissues on encounter with self antigens Autoimmune Disease Immune response against self antigens as a result of breakdown of tolerance It may be either systemic or organ specific Autoimmune diseases tend to be chronic and progressive Factors Influencing autoimmune diseases Genetic: MHC alleles, non-MHC genes, FcgR, Fas/FasL Environmental: microbes Gender: Hormones play a role. SLE affects women about 10 times more frequently than men Others: injury Graft rejection Histocompatibility antigens determine rejection between two genetically different individuals Major histocompatibilty complex (MHC class I and II molecules) cause strong, rapid responses principally responsible for transplant rejection Types of graft Xenograft Allograft Isograft Autograft Mechanism of graft rejection Cellular rejection: T cell mediated graft rejection Humoral rejection: Antibody mediated rejection T cell mediated rejection is induced by CD8+ CTLs CD4+ helper cells ( delayed hypersensitivity reactions) Allograft rejection/ Host versus graft rejection The rejection time of a graft may vary with the antigenic nature of the graft and the immune status of the host and is determined by the immune mechanism involved. Based on morphology and underlying mechanism Hyperacute rejection Acute rejection Chronic rejection Hyperacute rejection Time taken: immediately within minutes to hours Etiology: preformed antidonor antibodies (anti ABO blood group antibodies, anti HLA antibodies) Acute graft rejection Time taken: Days, weeks or months Pathogenesis: Acute cellular rejection Acute humoral rejection Clinical presentation Abrupt onset of oliguria (less urine) May be associated with fever and graft tenderness Chronic rejection Time taken: months to years Cause: Unclear Antibodies, immune complexes, slow cellular reaction Pathogenesis: T cells induce monocyte/ macrophages infiltration into the graft, along with endothelial cells to produce growth factors and cytokines (PDGF, Insulin like growth factor, epidermal growth factor, IL-1, IL-6, TNF and TGFβ) Prevention of rejection Screening of recipient and donor for blood group matches Rejection response reduced by tissue matching i.e. Donor and recipient share the same MHC class I and class II antigens Immunosuppressive therapy Immunodeficiency The immunodeficiency diseases are a group of disorders in which the defect appears to be in one or more components of the immune system Types Primary Immunodeficiency: Congenital and hereditary. Patient born with a genetic mutation that result in defect in either the innate or adaptive immune response Secondary Immunodeficiency: Acquired on a transient or permanent basis. The patient born with normal immune response but later experiences an event that damages the immune system Secondary Immunodeficiency Causes of secondary immunodeficiency Infections Malnutrition Cancer Immunosuppression Irradiation Chemotherapy Primary Immunodeficiency Total incidence of Primary immunodeficiency is about 1 in 5000 live births Most common Primary immunodeficiency is selective IgA deficiency Characteristics of infections Increasing susceptibility to infections Increasing severity of infection Increasing duration of infections Infection with opportunistic agents Continuous illness Dependence to antibiotics Primary Immunodeficiency: Frequency Phagocytic 18% Cellular 10% Combined 20% Antibody 50% Complement 2% Antibody deficiency Clinical Characteristics:  Onset is usually after 7-9 months  Recurrent infections with encapsulated organisms (strep. Pneumoniae, and Haemophilus influenzae )  Patients usually develop chronic or recurrent sinusitis, otitis media, pneumonia. They may also develop recurrent sepsis, meningitis, or osteomyelitis  Little growth failure Deficiencies in T-cell Immunity Clinical Characteristics Often present before 5 months of age Usually associated with recurrent infections with fungal, viral, or mycobacterial pathogens Patients may develop infections with opportunistic organisms. e.g: Pneumocystis jerovici (carinii) Clinical characteristics Severe failure to thrive Persistent thrush (candida) Often associated with humeral (B-cell) defect because of lack of T-cell help Live vaccines contraindicated Phagocytic dysfunction Fungal lung infections Gingivitis Delayed wound healing Recurrent abscesses Adenitis S. aureus lymphadenitis in a patient with CGD Immune response to Tumors Pathological cell masses derived by abnormal and uncontrollable clonal expansion of single cell Transformation of normal cells to malignant cells by: a- Spontaneous mutation during daily cell division b- It may be induced by chemical carcinogens physical carcinogens viruses Immune surveillance system Natural killer (NK) cells They kill directly tumor cells, helped by interferon, IL-2 2. Macrophages 3. Cytotoxic T-cells They kill tumor cells directly 1. Immune surveillance system 4. B-cells : - These specific antibodies bind together on tumor cell surface leading to destruction of tumor