The hyper IgM syndrome
- Ramsay L. Fuleihan MD
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The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/ CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene, while autosomal recessive hyper IgM is caused by defects in the CD40-activated RNAediting enzyme, activation-induced cytidine deaminase, which is required for immunoglobulin isotye switching and somatic hypermutation in B cells. The loss of interaction between CD40 and its ligand in X-linked hyper IgM results in an impairment of T cell function, of B cell differentiation, and of monocyte function, while only B cell differentiation appears to be affected in autosomal recessive hyper IgM. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitely, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.
- Fuleihan RL: The X-Linked Hyperimmunoglobulin M syndrome. Semin Hematol 1998, 35:321–331.
- Levy J, Espanol-Boern T, Thomas C, et al.: Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997, 131:47–54. CrossRef
- Hayward AR, Levy J, Facchetti F, et al.: Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol 1997, 158:977–983.
- Vogel LA, Noelle RJ: CD40 and its crucial role as a member of the TNFR family. Semin Immunol 1998, 10:435–442. CrossRef
- Conley ME, Larche M, Bonagura VR, et al.: Hyper IgM syndrome associated with defective CD40-mediated B cell activation. J Clin Invest 1994, 94:1404–1409.
- Durandy A, Hivroz C, Mazerolles F, et al.: Abnormal CD40-mediated activation pathway in B lymphocytes from patients with hyper-IgM syndrome and normal CD40 ligand expression. J Immunol 1997, 158:2576–2584.
- Revy P, Muto T, Levy Y, et al.: Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 2000, 102:565–575. This article demonstrates that mutations in AID cause autosomal recessive HIM. CrossRef
- Minegishi Y, Lavoie A, Cunningham-Rundles C, et al.: Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. Clin Immunol 2000, 97:203–210. This article shows that other gene defects may also cause autosomal recessive HIM because some of the study patients had no mutations in AID. CrossRef
- Kawabe T, Naka T, Yoshida K, et al.: The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994, 1:167–178. CrossRef
- Castigli E, Alt F, Davidson L, et al.: CD40 deficient mice generated by RAG-2 deficient blastocyst complementation. Proc Natl Acad Sci U S A 1994, 91:12135–12139. CrossRef
- Xu J, Foy TM, Laman JD, et al.: Mice deficient for the CD40 ligand. Immunity 1994, 1:423–431. CrossRef
- Renshaw BR, Fanslow WCr, Armitage RJ, et al.: Humoral immune responses in CD40 ligand-deficient mice. J Exp Med 1994, 180:1889–1900. CrossRef
- Notarangelo LD, Duse M, Ugazio AG: Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev 1992, 3:101–121.
- Villa A, Notarangelo LD, Di Santo JP, et al.: Organization of the human CD40L gene: implications for molecular defects in X chromosome-linked hyper-IgM syndrome and prenatal diagnosis. Proc Natl Acad Sci U S A 1994, 91:2110–2114. CrossRef
- Graf D, Korthauer U, Mages HW, et al.: Cloning of TRAP, a ligand for CD40 on human T cells. Eur J Immunol 1992, 22:3191–3194. CrossRef
- Ramesh N, Fuleihan R, Ramesh V, et al.: Deletions in the ligand for CD40 in X-linked immunoglobulin deficiency with normal or elevated IgM (HIGMX-1). Int Immunol 1993, 5:769–773. CrossRef
- Korthauer U, Graf D, Mages HW, et al.: Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 1993, 361:539–541. CrossRef
- Seyama K, Nonoyama S, Hollenbaugh D, et al.: X-linked hyper IgM syndrome (XHIM) mutation analysis, CD40L function and clinical phenotype [abstract]. J Allergy Clin Immunol 1997, 99:S474.
- Hollenbaugh D, Wu LH, Ochs HD, et al.: The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. J Clin Invest 1994, 94:616–622.
- Callard RE, Smith SH, Herbert J, et al.: CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM): comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers. J Immunol 1994, 153:3295–3306.
- deSaint Basile G, Tabone MD, Durandy A, et al.: CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization. Eur J Immunol 1999, 29:367–373. CrossRef
- Revy P, Geissmann F, Debre M, et al.: Normal CD40-mediated activation of monocytes and dendritic cells from patients with hyper-IgM syndrome due to a CD40 pathway defect in B cells. Eur J Immunol 1998, 28:3648–3654. This article demonstrates that, although CD40 signaling is defective in B cells from patients with autosomal recessive HIM, it is normal in their monocytes and dendritic cells. CrossRef
- Muramatsu M, Kinoshita K, Fagarasan S, et al.: Class switch recombination and hypermutation require activationinduced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000, 102:553–563. This article demonstrates the requirement for AID in immunoglobulin isotype switching and somatic hypermutation in B cells. CrossRef
- Notarangelo LD, Peitsch MC: CD40lbase: a database of CD40L gene mutations causing X-linked hyper-IgM syndrome. Immunol Today 1996, 17:511–516. CrossRef
- Nonoyama S, Hollenbaugh D, Aruffo A, et al.: B cell activation via CD40 is required for specific antibody production by antigen-stimulated human B cells. J Exp Med 1993, 178:1097–1102. CrossRef
- Ameratunga R, Lederman HM, Sullivan KE, et al.: Defective antigen-induced lymphocyte proliferation in the X-linked hyper-IgM syndrome. J Pediatr 1997, 131:147–150. CrossRef
- Inwald DP, Peters MJ, Walshe D, et al.: Absence of platelet CD40L identifies patients with X-linked hyper IgM syndrome. Clin Exp Immunol 2000, 120:499–502. CrossRef
- Farrington M, Grosmaire LS, Nonoyama S, et al.: CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci U S A 1994, 91:1099–1103. CrossRef
- Conley ME, Notarangelo LD, Etzioni A: Diagnostic criteria for primary immunodeficiencies: representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999, 93:190–197. This article provides criteria for the diagnosis of several primary immune deficiency diseases. CrossRef
- Facchetti F, Appiani C, Salvi L, et al.: Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM: abortive germinal center cell reaction and severe depletion of follicular dendritic cells. J Immunol 1995, 154:6624–6633.
- Allen RC, Armitage RJ, Conley ME, et al.: CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 1993, 259:990–993. CrossRef
- Arpin C, Déchanet J, Van Kooten C, et al.: Generation of memory B cells and plasma cells in vitro. Science 1995, 268:720–722. CrossRef
- Jain A, Atkinson TP, Lipsky PE, et al.: Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome. J Clin Invest 1999, 103:1151–1158. CrossRef
- Subauste CS, Wessendarp M, Sorensen RU, Leiva LE: CD40-CD40 ligand interaction is central to cell-mediated immunity against Toxoplasma gondii: patients with hyper IgM syndrome have a defective type 1 immune response that can be restored by soluble CD40 ligand trimer. J Immunol 1999, 162:6690–6700. This article demonstrates defective TH1 cell-mediated immunity to a pathogen, Toxoplasma gondii, in patients with X-HIM and correction of the defect in vitro by soluble CD40 ligand.
- Grewal IS, Flavell RA: The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev 1996, 153:85–106. CrossRef
- Mackey MF, Barth RJ Jr, Noelle RJ: The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells. J Leukoc Biol 1998, 63:418–428.
- Shu U, Kiniwa M, Wu CY, et al.: Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol 1995, 25:1125–1128. CrossRef
- Wiley JA, Harmsen AG: CD40 ligand is required for resolution of Pneumocystis carinii pneumonia in mice. J Immunol 1995, 155:3525–3529.
- Urban JF Jr, Fayer R, Chen SJ, et al.: IL-12 protects immunocompetent and immunodeficient neonatal mice against infection with Cryptosporidium parvum. J Immunol 1996, 156:263–268.
- Wang WC, Cordoba J, Infante AJ, Conley ME: Successful treatment of neutropenia in the hyper-immunoglobulin M syndrome with granulocyte colony-stimulating factor. Am J Pediatr Hematol Oncol 1994, 16:160–163.
- Thomas C, de Saint Basile G, Le Deist F, et al.: Brief report: correction of X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation. N Engl J Med 1995, 333:426–429. CrossRef
- Scholl PR, O’Gorman MR, Pachman LM, et al.: Correction of neutropenia and hypogammaglobulinemia in X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation. Bone Marrow Transplant 1998, 22:1215–1218. CrossRef
- Ziegner U, Dovat S, Wakim M, et al.: Partially mismatched cord blood transplants in X-linked immunodeficiencies [abstract]. J Allergy Clin Immunol 1998, 101:S101.
- Hadzic N, Pagliuca A, Rela M, et al.: Correction of the hyper-IgM syndrome after liver and bone marrow transplantation. N Engl J Med 2000, 342:320–324. This article demonstrates that liver failure and immune deficiency in X-HIM can be corrected by liver and bone marrow transplantation. CrossRef
- DiSanto JP, Markiewicz S, Gauchat JF, et al.: Brief report: prenatal diagnosis of X-linked hyper-IgM syndrome. N Engl J Med 1994, 330:969–973. CrossRef
- Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al.: Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000, 288:669–672. This article demonstrates that gene therapy can correct immune deficiency disease, namely X-linked severe combined immunodeficiency. CrossRef
- Brown MP, Topham DJ, Sangster MY, et al.: Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nat Med 1998, 4:1253–1260. This article demonstrates that gene transfer of regulated expression of CD40 ligand will be required for gene therapy of X-HIM because transfer of constitutive CD40 ligand expression in CD40 ligand-deficient mice resulted in thymic lymphoproliferative disease. CrossRef
- Datta SK, Kalled SL: CD40-CD40 ligand interaction in autoimmune disease. Arthritis Rheum 1997, 40:1735–1745. CrossRef
- Seyama K, Osborne WR, Ochs HD: CD40 ligand mutants responsible for X-linked hyper-IgM syndrome associate with wild type CD40 ligand. J Biol Chem 1999, 274:11310–11320. CrossRef
- Garber E, Su L, Ehrenfels B, et al.: CD154 variants associated with hyper-IgM syndrome can form oligomers and trigger CD40-mediated signals. J Biol Chem 1999, 274:33545–33550. CrossRef
- The hyper IgM syndrome
Current Allergy and Asthma Reports
Volume 1, Issue 5 , pp 445-450
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- 1. Department of Pediatrics and Yale Child Health Research Center, Yale University School of Medicine, POB 208081, CT 06520-8081, New Haven, USA