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Immunodeficiences Autoimmunity – system attacks host cells and tissues Hypersensitivity- unfavorable immune response Immunodeficiency – system fails to protect Primary immunodeficiency ○ Genetic or developmental defect Secondary immunodeficiency - acquired Mechanisms of Immunodeficiency Loss or reduction of: Cell type Cell numbers Cell function Deficient humoral immunity usually results in increased susceptibility to infection by encapsulated, pus-forming bacteria and some viruses, whereas defects in cell-mediated immunity lead to infection by viruses and other intracellular microbes. Combined deficiencies in both humoral and cell mediated immunity make patients susceptible to infection by all classes of microorganisms. Immunodeficient patients, especially those with defects in cellular immunity, often present with infections by microbes that are commonly encountered but effectively eliminated by healthy persons; such infections are said to be opportunistic. Defects in innate immunity can result in different categories of microbial infections, depending on the pathway or cell type affected. Complement deficiencies, for instance, resemble antibody deficiencies in their clinical presentation, Natural killer (NK) cell deficiencies result mainly in recurrent viral infection. Primary Immunodeficiencies Lymphoid Immunodeficiences Combined – effects both B and T cells B-cell Immunodeficiency ○ Range from absence of B cells, plasma cells, immunoglobulins to absence of only certain classes of Abs ○ Subject to bacterial infections but do well against viral since T-cell branch is ok T-cell Immunodeficiency ○ Can effect both humoral and cell-mediated Progenitor Progenitor • Defects in the cell mediated system are associated with: increased susceptibility to viral, protozoan, and fungal infections. Intracellular pathogens such as Candida albicans, Mycobacteria are often implicated, reflecting the importance of T cells in eliminating intracellular pathogens. also affect the humoral system, because of the requirement for T-H cells in B-cell activation. particularly in the production of specific antibody Defect in T Cell Combined partial B & T cell defect Defect in cells that are critical to the development or activation of T cell (APC) Reduced MHC I molecules Decrease No. of functional CD8+ & NK Reduced MHC II molecules Decrease No. of functional CD4+ Defects in thymic development (abnormal embryonic changes) Prevent thymic education of T cell Defect in T cell development Progenitor Progenitor B and T-cell deficiency divided into these categories: A. Selective T-cell deficiency: Disease Defect Clinical manifestation DiGeorge syndrome Thymic aplasia Depression of T cell number with absence of responses. MHC class I deficiency Failure of TAP 1 molecule to transport peptide to endoplasmic reticulum Defects in transcription factors. 1.CD8+ T cell def. 2.CD4+ T cell normal. 3. Recurrent viral infection. 4.Normal Ab formation. MHC class II def(Bare lymphocyte syndrome) 1.def of CD4+ T cell. 2. Hypogammagloulinemia. 3.Clinically as SCID. Ataxia telangiectasia Defect in kinase 1. gait abnormality. involved in the 2. Telangectasia (capillary distortion cell cycle. in the eye). 3.def of IgA & IgE production. C. Complete functional B and T cell deficiency: Sever combined Defects in common 1. Opportunistic (fungal) ID(SCID). γ chain of IL-2 infection. receptor. 2. Low level of circulating lymphocyte. Primary Immunodeficiencies Combined Immunodeficiencies Thymus ○ DiGeorge Syndrome – decreased or absent thymus - Results from deletion of region on chromosome 22 in developing embryo, developmental anomaly - third and fourth pharyngeal pouches during fetal life. - Lowered T cell numbers, results in B cells not producing sufficient Abs MHC DEFICIENCY class I deficiency (Bare lymphocytes syndrome I or TAP- 1 or 2 deficiency): defect in their transport associated protein (TAP) gene and hence do not express the class-I MHC molecules and consequently are deficient in CD8+ T cells , CD4+ normal recurrent viral infection , normal DTH, normal Ab production MHC DEFICIENCY class II deficiency (Bare lymphocytes syndrome II): Due to defect in the MHC class II transactivator protein gene, which results in a lack of class-II MHC molecule on APC. Patients have fewer CD4 cells , immunoglobulin levels decreased owing to defective T-cell help Increased susceptibility to infection Combiend partial B- and T-cell deficiency Ataxia-telangiectasia: Defect in kinase involved in cell cycle Associated with a lack of coordination of movement (ataxis) and dilation of small blood vessels of the facial area (telangiectasis). T-cells and their functions are reduced to various degrees. B cell numbers and IgM concentrations are normal to low. Primary Immunodeficiences Combined Immunodeficiences Severe Combined Immunodeficiency (SCID) ○ ○ ○ ○ Low # of circulating lymphocytes Non-proliferating T cells Thymus doesn’t develop Usually fatal early years of life - Infant will have viral and fungal infections - Bacterial don’t show up until later because of placental transfer of Abs from mother - Chronic diarrhea, pneumonia, lesions ○ Many genetic defects can contribute to SCID ○ Defects in common γ chain of IL-2 receptor. Defects in B-cell function due to Early B cell maturation blocked Isotype switching dose not occur Terminal differentiati on of B cell blocked T-cell to B-cell is defective Defect in T cell development Progenitor Progenitor Examples for humoral immunity defects. Disease Bruton Xlinked hypogamma gloulinemia Molecular defect Symptoms/signs Def of tyrosine kinase so blocks Bcell maturation 1.Low Ig of all classes. Def of X-linked hyper-IgM CD40L on activated syndrome T cell 2. No circulating B cell. 3.B-cell maturation stopped at pre-B stage. 4. Normal CMI. Treatment 1.Monthly gammaglobulin replacement. 2.Antibiotic. 1.Higher serum titer Antibiotic & of IgM only. 2. Normal gammaglobulin B & T cell number. 3. . Susceptibility to EC bacteria & opportunists. Disease Molecular defect Symptoms/signs Treatment Selective IgA Deficienc Repeated Antibiotic, deficiency y of IgA sinopulmonary & GIT not Ig. infections. Common Unknown 1.onset in late teens. Antibiotics variable 2.B cell present in immunodef peripheral blood. 3.Ig level decrease with time. 4.increase autoimmunity & atopy Primary Immunodeficiences B cell Immunodeficiences X-linked Agammaglobulinemia ○ B cell defect - Defect in kinase that keeps B cells in pre-B stage ○ Low levels of IgG and absence of other classes ○ Recurrent bacterial infections Primary Immunodeficiences Combined Immunodeficiences X-linked Hyper-IgM Syndrome ○ Deficiency of IgG, IgE, IgA but elevated levels of IgM ○ Defect in T cell surface marker CD40L - This is needed for interaction between TH and B cell for class switching for T-dependent antigens - T independent antigens are not effected therefore there is production of IgM CD40 ligand B Th CD40 ligand Cytokines - IL-4, 5, 6 Primary Immunodeficiences B cell Immunodeficiences Common Variable Immunodeficiency (CVI) ○ Low levels of immunoglobulin – hypogammaglobulinemia ○ Manifests later in life Primary Immunodeficiences B cell Immunodeficiences Selective Deficiences of Immunoglobulin Classes ○ IgA deficiency is most common Recurrent respiratory and urinary tract infections, intestinal problems ○ IgG deficiencies are rare Can often be treated by administering immunoglobulin Defect in phagocytic cells (Myeloid): (phagocytes, neutrophils,) Defects are significant because of their key role in innate and adaptive I.R. affect both ability to kill microb ( Chronic granulomatous disease, Chediak-higashi syndrome ) interactions with other cell (Leukocyte adhesion defect 1) Defect in T cell development Progenitor Progenitor Defects of phagocytic cells Disease Molecular defect(s) Symptoms Chronic granulomatous disease(CGD). Def of NADPH oxidase; failure to generate superoxide anion & other O2 radicals, so the microorganisms will be ingested but not killed. Leukocyte adhesion deficiency(LAD Absence of CD18(LFA-1) Recurrent & (leukocyte integrins). chronic infections, Chediak-Higashi Syndrome Defect in organelle membrane which inhibits normal fusion of lysosomes Fail to destroy ingested microbes Recurrent infections with catalase-positive bacteria & fungi. fail to form pus. Recurrent infection with bacteria (chemotactic and degranulation defects, absent NK activity Chronic Granulomatous Disease (CGD) Defect in enzymes and microcidal molecules (NADPH oxidase; failure to generate superoxide anion & other O2 radicals) So the microorganisms will be ingested but not killed Symptoms : recurrent infections with catalase- positive bacteria and fungi specially Staphylococcus aureus Chediak- Higashi Syndrome Normal levels of enzymes(digestive) Defect in organelle membrane which inhibits normal fusion of lysosomes Fail to destroy ingested microbes Symptoms : Recurrent infection with bacteria (chemotactic and degranulation defects, absent NK activity) Leukocyte Adhesion Defect 1 ( LAD-1) β chain of leukocyte integrin, and become un able to migrate Symptoms : Recurrent and chronic infection , fail to form pus Absence of CD 18 – common Disorders of complement system Due to Classical pathway Both pathway Deficiencies in complement regulatory proteins Defects of complement. Components Deficiency Signs/diagnosis Classic pathway C1q,C1r,C1s, 1.Marked increase in immune C4,C2 complex disease. 2.Increased infection with pyogenic bacteria. Both pathways C3 1.Recurrent bacterial infection. 2.Immune complex disease. C5,C6,C7,C8 Recurrent meningococcal & gonococcal infections. Def of regulatory C1-INH proteins. (hereditary angioedema) 1.Overuse of C1,C4 or C2. 2.Edema at mucosal surfaces. Defect in classical pathway Deficiencies of the classical pathway C1q, C1r, C1s, C4, or C2 Result in a propensity to develop immune complex diseases such as SLE because it required for the dissolution of immune complexes Increasing the risk of immune complex diseases SLE and increased infections with pyogenic bacteria Deficiencies in complement regulatory proteins The most important deficiency of the complement system is C1 inhibitor which is responsible for dissociation of activated C1 by binding to C1r2 C1s2 Deficiency result in Hereditary angioedema (HAE) The low level of C1 inhibitor in the plasma leads to increased activation of pathways that release bradykinin, the chemical responsible for the increased vascular permeability, and the pain seen in individuals. Patients have recurrent Episodes of swelling at mucosal surfaces Treatments for Immunodeficiency Replacement of missing protein ○ Administering immunoglobulin ○ Express genes in vitro (in bacteria) for cytokines Replacement of missing cell type ○ Bone marrow transplantation Replacement of missing or defective gene ○ Gene therapy Secondary or Acquired Immunodeficiencies Agent-induced immunodeficiency: e.g. infections including HIV Metabolic disorders and trauma Splenectomy Drugs such as corticosteroids, cyclosporin A, radiation and chemotherapy Aging Human Immunodeficiency Virus Is a member of genus retrovirus (RNA virus) belonging to Lentiviridae Characterized by long incubation period and slow course of disease HIV-1 (Common in US) and HIV-2 (in Africa) AIDS patients have low CD4+ T cells Virus prevalent in homosexual, i.v. drug users, transfusion, infants born to infected mothers (prenatally, during birth and lactationally) Opportunistic infections with Candida albicans, Pnuemocystis carinii, Mycobacterium avium, etc. Patients with HIV have high incidence of cancers such as Kaposi sarcoma and lymphomas Oral Candidiasis (Thrush) Kaposi Sarcoma HIV strains are: (T-tropic strains) because it infect T cell and the receptor called CXCR4. (M-tropic strains) with receptor called CCR5 functions for the monocyte or macrophage. Pathogenesis of HIV Infection and AIDS HIV disease begins with acute infection, which is only partly controlled by the host immune response, and advances to chronic progressive infection of peripheral lymphoid tissues . The virus typically enters through mucosal epithelia. The subsequent events in the infection can be divided into several phases. Death Opportunistic infections <200CD4+ T cells/mm Mechanisms of Immunodeficiency Caused by HIV HIV infection ultimately results in impaired function of both the adaptive and innate immune systems. The most prominent defects are in cell-mediated immunity, and they can be attributed to several mechanisms, including direct cytopathic effects of the virus and indirect effects. An important cause of the loss of CD4+ T cells in HIV infected individuals is the direct effect of infection of these cells by HIV. Depletion and functional impairment of these cells in HIV-infected individuals by chronic activation of the T cells may predispose the cells to apoptosis. Apoptotic death of activated lymphocytes may account for loss of T cells greatly exceeds the numbers of HIVinfected cells. HIV-specific CTLs are present in many patients with AIDS, and these cells can kill infected CD4+ T cells. In addition, antibodies against HIV envelope proteins may bind to HIVinfected CD4+ T cells and target the cells for antibody-dependent cellmediated cytotoxicity. Immunological abnormalities associated with HIV infection in different stages •1. T HELPER (TH) CELLS: Early: No in vitro proliferative response to specific antigen Late: Decrease in TH-cell numbers and corresponding helper activities; no response to T-cell mitogens or alloantigens •2. ANTIBODY PRODUCTION: Early: Enhanced nonspecific IgG and IgA production but reduced IgM synthesis Late: No proliferation of B cells specific for HIV-1: no detectable anti-HIV antibodies in some patients; increased numbers of B cells with low CD21 and enhanced Ig secretion. •3. CYTOKINE PRODUCTION: Early: Increased levels of some cytokines Late: Shift in cytokine production from TH1 subset to TH2 subset •4. DELAYED-TYPE HYPERSENSITIVITY Early: Highly significant reduction in proliferative capacity of DTH cells and reduction in skin-test reactivity Late: Elimination of DTH response; complete absence of skin-test reactivity •5. T CYTOTOXIC (TC) CELLS Early: Normal reactivity Late: Reduction but not elimination of CTL activity due to impaired ability to generate CTLs from TC cells Diagnosis RT-PCR (Reverse transcriptase –Polymerase Chain reaction) – detects viral load ELISA (Enzyme linked immunosorbent assay) Abs against HIV proteins (sensitive and specific) Western Blot Ab detection Infected individuals who have developed Abs (2 wks-6 months after infection) Positive Vaccinated CD4+:CD8+ T cell counts Abs are ineffective to control HIV !!! Virus grows intracellularly Abs develop after ~2 weeks. Thus cannot be used as a diagnostic test initially Abs are not neutralizing Refferences : Immunology , Kuby, seventh edition Medical microbiology, Jawetz, 26th edition Cellular and Molecular Immunology, Abul K. Abbas, 8th edition.