Primary Immunodeficiency Disorders (Overview)

Primary immunodeficiencies (aka, PIDs) are inherited, as opposed to the acquired secondary disorders. PIDs can arise as defects in the innate and/or adaptive immune systems. Defects in the innate system include: dysfunctional leukocytes, complement proteins, and toll-like receptors. Defects in the adaptive immune system include dysfunctional or absent T cells, natural killer cells, B cells, or antibodies (aka, immunoglobulins). Primary immunodeficiencies increase an individual's susceptibility to infection, allergy, and autoimmune disorders; they are often diagnosed in infancy or early childhood. Treatment: Primary immunodeficiencies of the adaptive system are often treatable with hematopoietic stem cell transplants or antibody therapy. Adhesion deficiencies Impair leukocyte trafficking: Leukocyte adhesion deficiency 1 is due to defects in the CD 11/CD18 integrins, which adhere neutrophils to the vessel endothelium during recruitment. Leukocyte adhesion deficiency 2 is due to defects in the selectin receptor, which neutrophils use to roll along the vessel wall to the site of diapedesis. See acute inflammation for a reminder of leukocyte trafficking. Chediak-Higashi syndrome Defective phagosome-lysosome fusion prevents neutrophilic antimicrobial products from reaching their pathogen targets. Chronic granulomatous disease Caused by defects in NADPH oxidase; reactive oxygen species production and neutrophil respiratory burst are inhibited. Myeloperoxidase deficiency Impairs antimicrobial effects, though this deficiency tends to have less severe consequences. Dysfunctional complement proteins Interruption of the complement cascade, and, in many cases, leave individuals more susceptible to invasive meningococcal infections. C2 and/or C4 deficiencies interrupt the classical pathway, and are associated with the symptoms of lupus due to persistent immune complexes. Defects in C3 interrupt both classical and alternative pathways. Properdine &/or factor D deficiencies inhibit the alternative pathway. Defects in late-acting complement proteins inhibit the formation of membrane attack complexes (MACs). C1 inhibitor deficiency Leads to angioedema caused by Bradykinin production; swellings in the gastrointestinal and respiratory tracts can have dire consequences. Dysfunctional toll-like receptors Impairs cytokine production; defective TLR also contribute some adaptive immune disorders. Lymphocyte Cell Lineage Common lymphoid progenitor gives rise to Pro-T and Pro-B cells. Pro-T cells give rise to immature T cells; these cells ultimately give rise to CD4+ Helper and CD8+ Cytotoxic cells. Pro-B cells give rise to Pre-B cells. Upon stimulation by Bruton's Tyrosine Kinase, Pre-B cells become immature B cells with IgM antibodies on their cell surfaces. Further maturation and class switching produces the full range of antibodies, including IgM, IgG, IgA, and IgE antibodies (we omit IgD, here, for simplicity). MATURATION DEFECTS: Adenosine deaminase deficiency - Severe combined immunodeficiency (ADA SCID) Impairs T lymphocyte maturation. This is an autosomal recessive form of SCID. Individuals have low T cells and natural killer cells, and, because T cells are required for most B cell activation, reduced B cells and antibodies. Clinically, ADA SCID manifests as thrush, rash, diarrhea and susceptibility to infections; neurologic abnormalities, pulmonary proteinosis, and liver dysfunction are also possible. X-linked SCID Impairs progression from the Pro-T cell to immature T cell stage. Serum values include low T cells, natural killer cells, and antibodies. Individuals have increased susceptibility to thrush, rash, diarrhea, slow growth, and infection, particularly pneumonia. DiGeorge Syndrome Impairs progression from the immature T cell to mature T cell stage. Low T cell counts, and normal to low antibody levels. Also known as thymic hypoplasia, DiGeorge syndrome presents with hypoparathyroidism, hypoplastic thymus, conotruncal heart defects, and facial abnormalities. X-linked ammaglobulinemia, aka, Bruton's agammaglobulinemia Interrupts the development of Pre-B cells to the immature B cell stage. Low B cells and antibodies, and an absence of plasma cells. Individuals present with recurrent bacterial infections, especially in the respiratory tract, and viral infections in the gastrointestinal tract. Antibody therapy is required. ACTIVATION DEFECTS: Common variable immunodeficiency (CVID) A group of disorders that blocks activation of B cells. This is the most common symptomatic primary adaptive immunity disorder. Reduced antibody production. Susceptible to pyogenic (pus-forming) and sinopulmonary infections, herpesvirus, enterovirus, and autoimmune disorders. Unlike most of the other primary immunodeficiency disorders, CVID is commonly diagnosed in adults. Hyper-IgM disorder Occurs when class switching fails to occur, for example, when the gene for the CD40 ligand is mutated. As its name suggests, IgM levels are high, but all other antibody levels are reduced. Thus, individuals are susceptible to pyogenic and sinopulmonary infections, autoimmune disorders, particularly hemolytic anemia, and diseases of the liver. Selective IgA deficiency The most common asymptomatic disorder. Occurs when class-switching to IgA is inhibited. Though usually benign, individuals may have increased susceptibility to sinopulmonary and gastrointestinal infections, autoimmune disorders, and allergy. X-linked lymphoproliferative syndrome Results in abnormal, usually low, antibody production and reduced levels of natural killer cells. In many cases, this disorder is triggered by Epstein-Barr virus, and is associated with increased risk of lymphoma and fulminant infectious mononucleosis.

• SYSTEMIC DISORDRES W/IMMUNOLOGICAL COMPONENTS

Wiskott-Aldrich syndrome Characterized by low levels of IgM, but elevated levels of IgE and IgA; individuals tend to present with thrombocytopenia, eczema, recurrent infections, autoimmune disorders, and B-cell lymphoma. Ataxia telangiectasia Characterized by low levels of A, G, and E antibodies; as the name suggests, individuals present with ataxia and telangiectasia, and have increased susceptibility to respiratory tract bacterial infections and cancers. They are sensitive to radiation exposure (including X-rays).