Immunodeficiency: Primary immune deficiency: -Caused by intrinsic or congenital defects. -Over 100 diseases of this type are known in humans, and for many of these diseases, the specific defective genes have been identified. -Types: 1-Defects in stem cells. 2-Defects in T lymphocytes. 3-Defects in B lymphocytes. 4-Defects in phagocytes and NK cells. 5-Defects in complement system.
Defects in stem cells: 1-Severe combined immune deficiency (SCID): Genetics: Mode of Inheritance: Autosomal recessive (chrom. 11). X-linked recessive. Defective genes: RAG 1,2 gene. IL2RG gene. Function:Rearrangement of DNA to form variable regions of Immunoglobulin and TCR. Production of γ chain (common cytokine receptor) : IL-2R, IL-4R, IL-9R, IL-15R, INFγR.
N Effect: Defect in B and T lymphocytes maturation. Features: Lethal susceptibility to both viral and bacterial infections due to deficiency of both humoral and cellular immunity. 2-Ataxia telangiectasia: Genetics: AR -Rearrangement of gene at chromosome 7, 14. -Gene: T cell receptor genes. -Function: T lymphocyte clonal selection.
N Feature: -Oculocutaneous telangiectasia (dilated blood vessels in the conjunctivae, ears, and face). - Low serum IgA, and IgG. -Thymus hypoplasia. - Recurrent infection: Sinusitis, and pneumonia. - Increased risk of Leukemia and Lymphoma.
N 3-Wiskott-Aldrich syndrome: Genetics: - XR gene mutation. - Etiology: defect in lymphocyte cytoskeleton. Feature: Boys have eczema, diarrhoea and recurrent infections, thrombocytopenia, low IgM level, and Tc -Th function.
Defect in T Lymphocytes: 1-bare Lymphocyte syndrome: Genetics:AR gene on Chromosome 1 or 16. Etiology: Type 1: Mutationin the TAP gene prevent export of Class I MHC to the cell surface. Type 2 : Defectsin MHC II specific transcription factor, cause defect in T-helper function. Features: -Increased susceptibility to infection. -CD4 and CD8 cells numbers decreased. - Intracellular infection could cause lethal effect.
N 2-DiGeorge syndrome: Genetics: AD gene deletion in chromosome 22 q 11. Etiology: 1- Completeor partial absence of thymus. 2- Defectin T-cell clonal selection and maturation. Features: -Increased susceptibility to viral infection. -Reduced active T cell production.
Defect in B Lymphocytes: 1-Bruton’sagammaglobulinaemia: Genetics: X-linked recessive gene (BTK). Etiology: Defective B-cell tyrosine kinase prevents the B cell maturation. Features: -Increased susceptibility to infection(capsulated bacteria). -Very low level of Immunoglobulin or lost level. -5-6 months boys develop lethal multiple infections of lung.
N 2-Immunodeficiency with Hyper-IgM: Genetics : X-linked recessive gene (CD40L G). Etiology: 1-Defect in expression of CD40L on B lymphocyte. 2-Inability of B lymphocyte to undergo isotype switching. Features: -Elevated IgM and IgD in blood stream. -Decreased IgG, IgA, and IgEconcentration. -Increased susceptibility to pyogenic infection.
N 3-Selective IgA deficiency: Genetics: Multiple genes and forms. Etiology: -Defect in IgA production in body fluids. Features: -No increased susceptibility to infection. -Low IgA level. -Normal level of other antibodies.
Defect in Phagocytes and Natural Killer cell: 1-Chronic granulomatous disease (CGD): Genetics: -XR ;Beta-chain of cytochrome b oxidase. -AR (chr.1,7); NADPH oxidase. -AR (chr.16); alpha chain of cytochrome b oxidase. Etiology: -Inability of Phagocytes to generate superoxide metabolites. Features: -Granulomatous infection in skin, lymph nodes, lung, liver.
N 2-Chediak- Higashi syndrome: Genetics: -AR (Chromosome 1) Gene (LYST). (Lysosomal trafficking regulator). Etiology: -Defect in fusion of lysosome to phagosomes. -Defect of release of cytotoxicgranules. Features: -Increased susceptibility to pyogenic bacteria. -Reduced ability of phagocytes to kill ingested microbes. - Decreased functions of NK cell (Cytotoxicity). -Risk for development of Lymphoma.
N 3- Leucocyte adhesion deficiency: Genetics: AR gene (ITGB2 or CD18) The leukocyte surface integrin Beta chains. Etiology: -Defect in migration of WBCs from circulation to the site of infection (tissue). Features: -Increased susceptibility to infection. -Frequent abscesses. -Defective chemotaxis.
Defect in complement system: 1- C1,2,3,…,9 immunodeficiency: Genetics: Autosomal recessive gene (Chr. 1,2,5,6,9,12,19). Etiology: C1,2,3,...,9 deficiency. Features: -Increased susceptibility to infection. -associated with lupus like syndrome. -Defect in production of MAC unit of Classical pathway.
N 2-Hereditary angioneuroticedema: Genetics: Autosomal dominant gene (Chr. 11). C1 inhibitor protein. Etiology: Defect in inhibition of Classical pathway. Features: - Fluids accumulation in soft tissue and airways due to uncontrolled production of C2a. -Swelling of tracheal and bronchial passages that can be life-threatening.
Secondary (acquired) immune deficiency: -The immunodeficiency that associated with exposure to environmental factors. -Not related to inheritance of genetic mutations. -Types: 1-Therapeutic immunodeficiency. 2-Malignant tumor- associated deficiency. 3-Infectious immunodeficiency.
N Therapeutic immunodeficiency: Examples: -Some Anti-inflammatory drugs (corticosteroids) ; treatment of Rheumatoid arthritis : Interfere with production of some cytokines. -Immunosuppressive drugs (cyclosporine); used during organ transplantation: Interfere with production of some cytokines.
N Malignant tumor- associated deficiency: Examples: -Multiple myeloma: Increased polyclonal B cell activation non-specifically. - Lymphoma (HK): Uncontrolled proliferation of B lymphocytes (E.B virus). -Chronic lymphocytic leukemia: Reduced production of Immunoglobulin.
Infectious immunodeficiency: Examples: -Schistosoma species: Enzymatic degradation of immunoglobulins. -Herpesvirus: inhibits MHC class I maturation within E.R. -CMV: Interferes with TAP of E.R. Redirects MHC I into cytoplasm rather than to cell surface. -Chlamydia: prevents phagosomes-lysosomes fusion.
N -Staphylococcus: -Kills phagocytes by its toxins. -Protein A prevents opsonization. -Mycobacterium: -Kills phagocytes. -Prevents phagosome-lysosome fusion. -Inhibits oxidative degradation within phagosome. -Plasmodiumspecies: -RBCs infection. -Human Immunodeficiency virus (HIV): -Kills CD4, Monocytes, and CD8 cells. -Nef gene redirects MHC I into lysosome.
N Human Immunodeficiency Virus (HIV): HIV infection in humans is considered pandemic by the World Health Organization (WHO). From its discovery in 1981 to 2006, AIDS killed more than 25 million people . Tropism: Some immune cells have a specific HIV susceptibility due to presence of specific receptors. -Macrophages, and dendriticcells carry the chemokine receptor CCR5. -CD4 T helper cells express the chemokine receptor CXCR4.
N 1-Asymptomatic period: CD4:8 Ratio= 2:1 2-Latency and chronic period : -The virus is preserved in the dendritic cells of Lymph nodes. -Late Latency : CD4:8 Ratio= 1:1 3-AIDS period: -No cytotoxic Tc response. -No Humoral immunity. -CD4:8 Ratio= 1:2 -CD4 count less than 200 cell per μL.