Primary disorders of T-cell function and combined T-cell defects come in many forms. One combined immunodeficiency, Wiskott-Aldrich syndrome (WAS), results from defects in the gene for the WAS protein (WASP), encoded on the X chromosome. WASP is a complex protein that functions in phagocytosis of microorganisms and apoptotic cells and regulation of cytoskeletal architecture in T-cells and platelets. WAS results in to profound humoral and cellular deficiency hallmarked by eczema, excessive bleeding, and thrombocytopenia. Patients usually have elevated levels of IgE and IgA accompanied by low levels of IgM. Atopic dermatitis and recurrent infections, including otitis media, pneumonia, sinusitis, meningitis, or sepsis, with pneumococci or other encapsulated bacteria present during the first 12 mo. BMT from HLA-identical siblings or HLA-matched unrelated donors have resulted in complete correction of both platelet and immunological abnormalities.
DiGeorge syndrome (DGS) is a primary immunodeficiency commonly caused by deletions on chromosome 22 or 10 and presents as a heterogeneous group of disorders with variable degrees of penetrance. Afflicted individuals often present with conotruncal cardiac defects, cleft palate, hypocalcemia, speech delay, musculoskeletal defects, thy-mic hypoplasia, and immunodeficiency. The highest degree of penetrance or complete DGS is associated with the absence of T-cells. Patients with the milder phenotype or partial DGS have low to normal T-cell levels and a highly variable T-cell proliferative response to stimuli. T-cell serum concentrations have been shown to change during the course of disease, requiring long-term assessment of T-cell numbers in DiGeorge patients. In partial DGS, an increased incidence of IgA deficiency has been reported, but normal immunoglobulin levels with good antibody responses to pathogens are more common. In contrast, patients with complete DiGeorge present with severe infections with opportunistic pathogens and require BMT.
An immunodeficiency also associated with physiological abnormalities, ataxia-telangiectasia (AT), is characterized by both humoral and cellular deficiency in conjunction with cerebellar ataxia, ocular and skin telangiectasia, and a marked predisposition to the development of lymphoid malignancies. AT is autosomal recessive in inheritance, wherein the genetic defect is located on chromosome 11 and codes for the ATM (AT, mutated) protein. The ATM protein has been implicated in the control of cell cycle checkpoints, DNA repair, and maintaining telomere length. The thymus is often poorly developed or absent and patients present with a predisposition to sinopulmonary infections. Patients commonly have low or absent IgA, IgG, and IgE levels along with an increased percentage of monomeric forms of IgM. AT patients frequently present with an inverted CD4+:CD8+ ratio as a result of low numbers of CD4+ cells and elevated a-fetoprotein and carcinoembryonic antigen levels in serum. Long-term prognosis is poor, and most individuals die because of neurological deterioration or malignant disease by the second decade, although some have reached adulthood.
A variant of AT, Nijmegen breakage syndrome (NBS), is also characterized by T- and B-cell defects as well as radiosensitivity and a predisposition to cancer. NBS is unique in presenting with moderate mental retardation, facial dysmorphism, and an increased frequency of microcephaly while lacking telangiectasia and progressive ataxia. The defect results from mutations in the gene that codes for nibrin, a protein similar to ATM in that it functions in DNA repair and cell-cycle control. Blood CD4+ T-cell counts are low with an inverted CD4:CD8 ratio and low or absent IgG and IgA while NK cell and IgM levels are elevated.
Severe combined immunodeficiency (SCID) represents a diverse group of genetic defects and the most severe group of primary immunodeficiencies. This group of disorders often presents within the first 6 mo of life with failure to thrive, diarrhea, skin rash, otitis, sepsis, and severe infections. T-cell development is greatly impaired in all SCID, whereas defects in B- and NK cell development varies from one form of SCID to the next. The most commonly recognized genetic defect, X-linked SCID (XSCID), is the result of mutations in the gene that encodes the common y-chain receptor subunit shared by interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The common y-chain receptor subunit functions as a signal transducer through interactions with cytokines and intracellular kinases. As a whole, total lymphocyte counts are markedly decreased with low percentages of T- and NK cells. B-cell percentages are usually elevated. Tonsils are absent, and frequently the thymus gland is hypoplastic and devoid of lymphocyte precursors. As a result, no thymic shadow is present in chest radiograms. Survival is dependent on HLA-matched and HLA-haploidentical T-cell-depleted BMT, which has been shown to be curative; however, patients still may not make antibody appropriately and require IVIG-replacement therapy.
Defects in Janus-associated kinase 3 (Jak3), an intracellular signal transducer, results in an autosomal recessive SCID phenotypically similar to XSCID, called Jak3 deficiency. Jak3 functions in the activation of signal transducers and activators of transcription factors downstream from receptors containing the common y-chain. Another form of SCID, in which T-cells are absent but both B- and NK cells are present, has been shown to be due to defects in a-chain of the IL-7 receptor.
Aberrant mutations in the gene encoding another tyrosine kinase, Zap-70, leads to the autosomal recessive ZAP-70 deficiency, resulting from a block in signal transduction from CD8 receptors. T-cells do not undergo normal maturation. ZAP-70 deficiency is characterized by the absence of CD8+ T-cells with elevated percentages of CD4+ T-cells in the peripheral blood. Defects, upstream from ZAP-70, in protein subunits of the CD3 T-cell receptor result in CD3 deficiency characterized by depressed levels of TCR/CD3 expression. A mutation in the gene coding for the common leukocyte surface protein CD45 has resulted in a receptor defect that presents with the SCID phenotype as well. Other defects include T-cell antigen receptor defects, cytokine deficiencies, and the bare lymphocyte syndrome (BLS), in which major histocompatibility antigens are not expressed on peripheral blood lymphocytes.
An important part of T- and B-cell growth involves the development of Ig and T-cell receptor (TCR) variable domains. Variable domains are composed of variable (V), diversity (D), and joining (J) elements. The selection of these elements during DNA transcription, processing, and recombination is has been termed V(D)J recombination and allows for the vast antigen receptor diversity of Ig and TCR. Some patients present with SCID as a result of a block in V(D)J recombination. Defects in recombinase-activating genes, RAG-1 or RAG-2, lead to the arrest of T- and B-cell maturation at early stages of development. Another aberrant mutation has been found in the Artemis gene that codes for a novel V(D)J recombination/DNA repair factor necessary for repairing the double-stranded cuts made by RAG1 or RAG2 gene products. Both RAG deficiencies and Artemis deficiency are autosomal recessive and present with low or absent levels of Tand B-cells.
Adenosine deaminase (ADA) deficiency is an autosomal recessive disorder in which this enzyme is not produced, and metabolites of adenosine, which are toxic to lymphocytes, cause immunodeficiency. Lymphocyte numbers are very low. The diagnosis is made by demonstrating absent or low levels of ADA, typically in erythrocytes, or in granulocytes if the patient has received red blood cell (RBC) transfusion. In addition to the recurrent and severe bacterial, viral, fungal, or parasitic infections, affected individuals have skeletal and rib-cage abnormalities. HLA-identical and HLA-haploidentical T-cell-depleted BMT has been curative for the T-cell defect. Replacement enzyme injections with polyethylene glycol conjugated, bovine adenosine deaminase can improve lymphocyte function. Gene therapy has been successful in a few patients, but there is a need to improve the efficacy of the therapy.
Another enzyme defect, purine nucleoside phosphorylase (PNP) deficiency, results in the clinical picture of SCID; however, the attrition of lymphocyte function is slower than in ADA deficiency, and these patients may be several years of age before the disease is noted. PNP levels are low, and lymphocytes numbers are low. BMT is the current treatment of choice.
The X-linked lymphoproliferative syndrome (XLP or Duncan disease), which results in unregulated B-cell proliferation secondary to Epstein-Barr virus (EBV) infection, is now known to be a result of an X-chromosome defect in the gene that codes for signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) found on T-cells. SAP is an inhibitor of T-cell-B-cell interactions induced by SLAM. XLP typically presents with fulminant infectious mononucleosis, lymphoma, and/or dysgammaglobulinemia. IVIG can provide some degree of protection, whereas BMT is curative.
In contrast to the unregulated lymphoproliferation in XLP, autoimmune lymphoproliferative syndrome (ALPS) results from defects in programmed cell death or apoptosis. As an essential feature of the immune system, apoptosis allows the negative selection of autoreactive lymphocytes and the removal of activated cells after an immune response. Apoptosis may be induced through the activation of the Fas pathway. Fas, a member of the tumor necrosis factor (TNF) receptor superfamily, is one of the main receptors used by the immune system to control the peripheral lymphocyte pool. Binding of Fas (CD95) by the Fas ligand leads to the activation of the caspase 8 and 10, triggering the caspase cascade, activation of caspase 3, 6, 7, and cell death. Patients with defects in the Fas pathway commonly present with autoimmune diseases and lymphoproliferative disorders or ALPS. The most common defect in ALPS patients results from the mutations in the intracellular domain of the Fas receptor. However, defects in the Fas ligand, caspase 8, and caspase 10 have also been shown to cause ALPS. Patients commonly present with malignant and nonmalignant lymphoproliferation that results in lymphad-enopathy, splenomegaly, and hepatomegaly early in life. Autoimmunity in ALPS commonly results in anemia, thrombocytopenia, or neutropenia. Autoimmune manifestations not involving hematological lineages are also quite frequent. Lymphocyte counts are elevated with an increased percentage of CD4-CD8- T-cells in the peripheral blood. Elevated levels of IgG and IgA are also quite common in ALPS patients. Although there is no specific treatment for ALPS, for some individuals treatment with steroids, mycophenolate mofetil, or pyrimethamine and sulfadoxine has aided in control, while BMT has proven curative in several patients with Fas deficiency and severe disease.
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