AIDS and other Immunodeficiencies cHAPTER 19 43 DEf rosine L-R (XHM) kinase (XLa) CD4OL CD40 Class lI mhc T cell B cell Defect in DEfective recombination- tivating genes f Class lI mhc RAG-1/2) FIGURE Defects in cell interaction and signaling can lead to of receptors for IL-2, 4, 7, 9, and 15(IL-RY): (3)JAK-3, which trans- severe immunodeficiency. The interaction of T cell and B cell is duces signals from the gamma chain of the cytokine receptor: or(4) shown here with a number of the components important to the intra- expression of the class ll MHC molecule(bare lymphocyte syn- and extracellular signaling pathways. A number of primary immuno- drome). XLA results from defective transduction of activating signals deficiencies are rooted in defects in these interactions. SCID may re- from the cell-surface IgM by Bruton's tyrosine kinase( Btk). XHM re- lt from defects in (1)the recombination-activating genes(RAG-1 sults from defects in CD40L that preclude normal maturation of B and) required for synthesis of the functional immunoglobulins and lls. Adapted from B. A. Smart and H. D. Ochs, 1997, Curr. Opin T-cell receptors that characterize mature B and T cells: (2)the y chain Pediatr. 9: 570. phenotype because the Il receptors signal through this mol- nucleoside phosphorylase(PNP)causes immunodeficiency ecule, accounted for 9 of the cases(see Figure 12-10). A rare by a mechanism similar to the ADa defect. As described in defect found in only 2 of the patients involved the IL-7 recep- Chapters 5 and 9, both immunoglobulin and T-cell receptor tor;these patients have impaired T and B cells but normal genes undergo rearrangement to express the active forms of NK cells. Another common defect is the adenosine deami- these molecules. a defect in the genes that encode mediators nase or ada deficiency found in 22 patients. Adenosine of the rearrangement processes (recombination-activating deaminase catalyzes conversion of adenosine to inosine, and proteins RAG-1 and RAG-2)precludes development of B and its deficiency results in accumulation of adenosine, which in- T cells with functional receptors and leads to SCID terferes with purine metabolism and DNA synthesis. The a defect leading to general failure of immunity similar to remaining cases included single instances of reticular dysge- SCID is failure to transcribe the genes that encode class II nesis and cartilage hair dysplasia or were classified as autos- MHC molecules. Without these molecules, the patient's lym- mal recessive defects not related to known IL-2Ry or JAK-3 phocytes cannot participate in cellular interactions with T mutations. Thirteen of the 141 cases were of unknown ori- helper cells. This type of immunodeficiency is also called the gin, with no apparent genetic defect or family history of im- bare-lymphocyte syndrome. Molecular studies of a class II munodeficien MHC deficiency revealed a defective interaction between a 5 There are other known defects that give rise to SCID. There promoter sequence of the gene for the class ll MHC molecule is a defect characterized by depletion of CD8* T cells that in- and a DNA-binding protein necessary for gene transcription. volves the tyrosine kinase ZAP-70, an important element in Other patients with SCID-like symptoms lack class I MHC T-cell signal transduction(see Figures 10-11 and 10-12). In- molecules. This rare variant of immunodeficiency was fants with defects in ZAP-70 may have normal levels of im- ascribed to mutation in the taP genes that are vital to anti- munoglobulin and CD4 lymphocytes, but their CD4 t gen processing by class I MHc molecules(see Clinical Focus cells are nonfunctional. a deficiency in the enzyme purine Chapter 8). This defect causes a deficit in CD8-mediatedphenotype because the IL receptors signal through this mol￾ecule, accounted for 9 of the cases (see Figure 12-10). A rare defect found in only 2 of the patients involved the IL-7 recep￾tor; these patients have impaired T and B cells but normal NK cells. Another common defect is the adenosine deami￾nase or ADA deficiency found in 22 patients. Adenosine deaminase catalyzes conversion of adenosine to inosine, and its deficiency results in accumulation of adenosine, which in￾terferes with purine metabolism and DNA synthesis. The remaining cases included single instances of reticular dysge￾nesis and cartilage hair dysplasia or were classified as autoso￾mal recessive defects not related to known IL-2R or JAK-3 mutations. Thirteen of the 141 cases were of unknown ori￾gin, with no apparent genetic defect or family history of im￾munodeficiency. There are other known defects that give rise to SCID. There is a defect characterized by depletion of CD8 T cells that in￾volves the tyrosine kinase ZAP-70, an important element in T-cell signal transduction (see Figures 10-11 and 10-12). In￾fants with defects in ZAP-70 may have normal levels of im￾munoglobulin and CD4 lymphocytes, but their CD4 T cells are nonfunctional. A deficiency in the enzyme purine nucleoside phosphorylase (PNP) causes immunodeficiency by a mechanism similar to the ADA defect. As described in Chapters 5 and 9, both immunoglobulin and T-cell receptor genes undergo rearrangement to express the active forms of these molecules. A defect in the genes that encode mediators of the rearrangement processes (recombination-activating proteins RAG-1 and RAG-2) precludes development of B and T cells with functional receptors and leads to SCID. A defect leading to general failure of immunity similar to SCID is failure to transcribe the genes that encode class II MHC molecules. Without these molecules, the patient’s lym￾phocytes cannot participate in cellular interactions with T helper cells. This type of immunodeficiency is also called the bare-lymphocyte syndrome. Molecular studies of a class II MHC deficiency revealed a defective interaction between a 5 promoter sequence of the gene for the class II MHC molecule and a DNA-binding protein necessary for gene transcription. Other patients with SCID-like symptoms lack class I MHC molecules. This rare variant of immunodeficiency was ascribed to mutation in the TAP genes that are vital to anti￾gen processing by class I MHC molecules (see Clinical Focus Chapter 8). This defect causes a deficit in CD8-mediated AIDS and Other Immunodeficiencies CHAPTER 19 435 FIGURE 19-3 Defects in cell interaction and signaling can lead to severe immunodeficiency. The interaction of T cell and B cell is shown here with a number of the components important to the intra￾and extracellular signaling pathways. A number of primary immuno￾deficiencies are rooted in defects in these interactions. SCID may re￾sult from defects in (1) the recombination-activating genes (RAG-1 and -2) required for synthesis of the functional immunoglobulins and T-cell receptors that characterize mature B and T cells; (2) the chain of receptors for IL-2, 4, 7, 9, and 15 (IL-R); (3) JAK-3, which trans￾duces signals from the gamma chain of the cytokine receptor; or (4) expression of the class II MHC molecule (bare lymphocyte syn￾drome). XLA results from defective transduction of activating signals from the cell-surface IgM by Bruton’s tyrosine kinase (Btk). XHM re￾sults from defects in CD40L that preclude normal maturation of B cells. [Adapted from B. A. Smart and H. D. Ochs, 1997, Curr. Opin. Pediatr. 9:570.] IL-2, IL-4, IL-7, IL-9, IL-15 IL-Rγ IL-Rγ Ag IgM Ig B7 CD28 CD4 Class II MHC CD40L CD40 TCR T cell B cell Btk RAG-1/2 RAG-1/2 JAK-3 Deficiency in JAK-3 pathway Defect in CD40L (XHM) Defect in Bruton's tyrosine kinase (XLA) Defect in recombination￾activating genes (RAG-1/2) Defective expression of Class II MHC (bare lymphocyte syndrome) Defect in γ chain of receptors for IL-2, 4, 7, 9, 15