Hypersensitivity, Autoimmunity and Immunodeficiency Part III Nancy L Jones, MD August 29, 2011

Cellular maturation pathway where immunodeficiency occurs

 Increased susceptibility to infection due to failure of one or more divisions of the immune system  Primary immunodeficiencies are inherited and may affect any part of the immune system  Secondary (acquired) immunodeficiencies are a consequence of many pathogenic infections or other disease states which may directly attack the immune system or may subvert effective immune responses. Immunodeficiency Disorders

 Failure of lymphocyte development  Impaired granulocyte function  Lack of macrophage receptors  Absence of particular complement components  Apparent in early life as conferred maternal immunity wanes Primary immunodeficiencies

 Patients have normal T cell function and cell-mediated immunity to viral infections but have very low immunoglobulin levels and cannot make antibody responses.  B cells fail to express a tyrosine kinase BTK, required for the maturation of pre-B cells to mature B cells  B-cell maturation stops after the initial heavy-chain gene rearrangement due to the mutation in BTK associated with the pre-B-cell receptor and involved in pre-B-cell signal transduction. No Ig light chains are produced though heavy chains may be found in the cytoplasm X-linked agammaglobulinemia (XLA, Bruton’s Disease))

 Absent or markedly decreased numbers of B cells in circulation with depressed levels of all classes of immunoglobulins  Pre-B-cells in bone marrow normal or reduced  Underdeveloped, rudimentary germinal centers in lymph nodes, Peyer’s patches, appendix and tonsils  Absence of plasma cells  Normal T-cell-mediated responses XLA, Bruton’s Disease

 Apparent at about 6 months of age with recurrent acute and chronic pharyngitis, sinusitis, otitis media, bronchitis and pneumonia due to organisms typically cleared by antibody-mediated opsonization and phagocytosis  H. influenzae, S. pneumonia, or S. aureus  Also susceptible to Giardia lamblia due to lack of IgA  Treatment with transfusion of IV Ig from pooled serum  20% may develop autoimmune disease such as RA and dermatomyositis XLA, Bruton’s Disease

 A variety of conditions with no clear pattern of inheritance, which affect B cell differentiation  Similar to XLA, but sexes affected equally and symptoms occur in the second or third decade of life  A diagnosis of exclusion  B cells are present, but do not develop into plasma cells because of lack of T cell help, T-cell suppressor activity, or intrinsic B-cell defects  Relatively high incidence of autoimmune disorders and lymphoreticular neoplasias in these patients Common Variable Immunodeficiency (CVID)

 Most common primary immunodeficiency disorder  Affects 1 in 700 white individuals  IgA is major Ig in mucosal secretions therefore have airway and GI defense problems  Significant association with autoimmune diseases  Have normal or supranormal levels of IgM and IgG subclasses by have a block in terminal differentiation of IgA secreting B cells to plasma cells Isolated IgA Deficiency

 An immunodeficiency due to mutation in CD40L, the T cell ligand which binds to CD40 on B cells- an interaction required for class switching in secondary responses  Normal Ig sequence is IgM followed by sequential elaboration of IgG, IgA and IgE antibodies due to heavy chain class (isotype) switching  Have normal or supranormal levels of IgM, but lack the ability to produce IgG, IgA or IgE isotypes  The CD40L gene is located on the x chromosome, 70% of cases are x-linked  Other cause is a defect in activation-induced deaminase and enzyme involved in class switching X-linked hyper-IgM (HIGM)

 Defect in cell-mediate immunity as CD40-Cd40L interaction is critical for helper t cell-mediated activation of macrophages in cell-mediated immunity  Male patients with X-HIGM present with recurrent pyogenic infections due to low levels of opsonizing IgG and have a variety of intracellular pathogens including Pneumocystis jiroveci (carinii) X-HIGM

 Result from failed development of the third and fourth pharyngeal pouches which leads to thymic hypoplasia with low numbers of functionally active T cells. The T cell number may rise to normal within 1 to 2 years of life thymus tissue transplant is effective  Lack of T cells in lymph nodes, spleen and peripheral blood and infants with this defect are extremely vulnerable to viral, fungal and protozoal infections and intracellular bacteria  B cells and serum immunoglobulins are unaffected  May have parathyroid gland hypolasia leading to hypocalcemic tetany and other midline development abnormalities including the face and aortic arch  90% of cases have a deletion in chromosome 22q11 DiGeorge Syndrome

 A group of conditions with leukocytopenia, impaired cell- mediated immunity, low or absent antibody levels and undeveloped secondary lymphoid tissues  Autosomal recessive adenosine deaminase deficiency or purine nucleoside phosphorylase deficiency  X-linked or autosomal recessive traits where enzymes are not affected but due to an inability to recombine antigen receptor molecules  Different forms of SCID may be correlated to points on the lymphomyeloid differentiation pathways Severe Combined Immumodeficiency (SCID)

 X-linked recessive disease  Thrombocytopenia, eczema and susceptibility to recurrent infections leading to early death  Treatment with bone marrow transplantation  Normal thymus with progressive age-related depletion of T cells and loss of cellular immunity  Cannot synthesize antibodies to polysaccharide antigens even though B cell response to these antigens does not require T cell help Immune Deficiency with Thrombocytopenia and Eczema: Wiskott-Aldrich Syndrome

 Patients are prone to developing malignant lymphomas  The gene maps to the X chromosome and encodes the Wiskott-Aldrich protein that links several membrane receptors to the cytoskeleton leading to abnormal cell shape, defective activation signals, abnormal cell-cell adhesions and leukocyte migration Immune Deficiency with Thrombocytopenia and Eczema: Wiskott-Aldrich Syndrome

 Hereditary deficiencies in complement components (C3 classical and alternative pathways) result in increased susceptibility to infection with pyogenic bacteria  Deficiencies in C1q, C2 and C4 increase the risk of immune complex-mediated disease (SLE) possibly by impairing clearance of apoptotic cells or antigen- antibody complexes  Deficiencies of C5-C8 of the classical pathway result in recurrent infections by Neisseria gonococci and meningococci only  Lack of regulatory protein C1 inhibitor allows increased C1 activation increased vasoactive complement mediators and results in hereditary angioedema. Genetic Deficiencies of Components of Innate Immunity

 There are congenital defects in phagocytes including defects in phagocyte oxidase enzyme leading to chronic granulomatous disease and defects in integrins and selectin ligands with resultant leukocyte adhesion deficiencies Genetic Deficiencies of Components of Innate Immunity

 Caused by mutations in genes involved in lymphocyte maturation or function or in innate immunity leading to increased susceptibility to infections in early life  XLA failure of B-cell maturation; lack of antibodies; mutations in BTK gene  CVI; defects in antibody production, unknown cause  IgA deficiency; failure of IgA production, cause unknown  X-SCID failure of T and B cell maturation mutation of the common γ chain of cytokine receptor leading to failure of IL-7 signaling and defective lymphopoiesis  Autosomal SCID; failure of T-cell development, secondary defect in antibody responses, approximately 50% of cases due to mutation of gene encoding ADA leading to accumulation of toxic metabolites  X-linked hyper-IgM syndrome; failure to produce isotype-switched high-affinity antibodies (IgG, IgA, IgE; mutation in gene encoding CD40L Primary Immune Deficiency Diseases

 More common than primary immune disorders  Found in malnutrition, infection, cancer, renal disease or sarcoidosis  Most common cause is therapy induced suppression of the bone marrow and of lymphocyte function  AIDS is a retroviral disease caused by HIV characterized by infection and depletion of CD4+ T cells and profound immunosuppression with opportunistic infections, secondary neoplasms, and neurologic manifestations. Secondary Immune Deficiencies

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