Advertisement

Journal of Clinical Immunology

, Volume 28, Supplement 1, pp 62–66 | Cite as

Autoimmunity in Hyper-IgM Syndrome

  • Adriana A. Jesus
  • Alberto J. S. Duarte
  • João B. OliveiraEmail author
Article

Abstract

Introduction

Immunodeficiency with hyper-IgM (HIGM) results from genetic defects in the CD40–CD40 ligand (CD40L) pathway or in the enzymes required for immunoglobulin class switch recombination and somatic hypermutation. HIGM can thus be associated with an impairment of both B-cell and T-cell activation.

Results and discussions

There are seven main subtypes of HIGM and the most frequent is X-linked HIGM, resulting from CD40L mutations. In addition to the susceptibility to recurrent and opportunistic infections, these patients are prone to autoimmune manifestations, especially hematologic abnormalities, arthritis, and inflammatory bowel disease. Furthermore, organ-specific autoantibodies are commonly found in HIGM patients.

Conclusions

The mechanisms by which HIGM associates to autoimmunity are not completely elucidated but a defective development of regulatory T cells, the presence of IgM autoantibodies and an impaired peripheral B-cell tolerance checkpoint have been implicated. This article reviews the main subtypes of HIGM syndrome, the clinical autoimmune manifestations found in these patients, and the possible mechanisms that would explain this association.

Keywords

Autoimmunity CD40 CD40L hyper IgM inflammatory bowel disease 

References

  1. 1.
    Notarangelo LD, Hayward AR. X-linked immunodeficiency with hyper-IgM (XHIM). Clin Exp Immunol 2000;120:399–405.PubMedCrossRefGoogle Scholar
  2. 2.
    Lougaris V, Badolato R, Ferrari S, Plebani A. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev 2005;203:48–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Hervé M, Isnardi I, Ng YS, Bussel JB, Ochs HD, Cunningham-Rundles C, et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med 2007;204:1583–93.PubMedCrossRefGoogle Scholar
  4. 4.
    Hess S, Engelmann H. A novel function of CD40: induction of cell death in transformed cells. J Exp Med 1996;183:159–67.PubMedCrossRefGoogle Scholar
  5. 5.
    Etzioni A, Ochs HD. The hyper IgM syndrome—an evolving story. Pediatr Res 2004;56:519–25.PubMedCrossRefGoogle Scholar
  6. 6.
    Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997;131:47–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Facchetti F, Appiani C, Salvi L, Levy J, Notarangelo LD. 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;154:6624–33.PubMedGoogle Scholar
  8. 8.
    Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, et al. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood 1998;92:2421–34.PubMedGoogle Scholar
  9. 9.
    Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of class-switch recombination. J Allergy Clin Immunol 2006;117:855–64.PubMedCrossRefGoogle Scholar
  10. 10.
    van Kooten C, Banchereau J. CD40–CD40 ligand. J Leukoc Biol 2000;67:2–17.PubMedGoogle Scholar
  11. 11.
    Van Hoeyveld E, Zhang PX, De Boeck K, Fuleihan R, Bossuyt X. Hyper-immunoglobulin M syndrome caused by a mutation in the promotor for CD40L. Immunology 2007;120:497–501.PubMedCrossRefGoogle Scholar
  12. 12.
    Cron RQ. CD154 transcriptional regulation in primary human CD4 T cells. Immunol Res 2003;27:185–202.PubMedCrossRefGoogle Scholar
  13. 13.
    Durandy A, Peron S, Fischer A. Hyper-IgM syndromes. Curr Opin Rheumatol 2006;18:369–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Durandy A, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev 2005;203:67–79.PubMedCrossRefGoogle Scholar
  15. 15.
    Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 2000;102:565–75.PubMedCrossRefGoogle Scholar
  16. 16.
    Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2001;2:223–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Gulino AV, Notarangelo LD. Hyper IgM syndromes. Curr Opin Rheumatol 2003;15:422–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Lacroix-Desmazes S, Resnick I, Stahl D, Mouthon L, Espanol T, Levy J, et al. Defective self-reactive antibody repertoire of serum IgM in patients with hyper-IgM syndrome. J Immunol 1999;162:5601–8.PubMedGoogle Scholar
  19. 19.
    Seyama K, Kobayashi R, Hasle H, Apter AJ, Rutledge JC, Rosen D, et al. Parvovirus B19-induced anemia as the presenting manifestation of X-linked hyper-IgM syndrome. J Infect Dis 1998;178:318–24.PubMedGoogle Scholar
  20. 20.
    Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003;82:373–84.CrossRefGoogle Scholar
  21. 21.
    Webster EA, Khakoo AY, Mackus WJ, Karpusas M, Thomas DW, Davidson A, et al. An aggressive form of polyarticular arthritis in a man with CD154 mutation (X-linked hyper-IgM syndrome). Arthritis Rheum 1999;42:1291–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Melegari A, Mascia MT, Sandri G, Carbonieri A. Immunodeficiency and autoimmune phenomena in female hyper-IgM syndrome. Ann N Y Acad Sci 2007;1109:106–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Quartier P, Bustamante J, Sanal O, Plebani A, Debré M, Deville A, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency. Clin Immunol 2004;110:22–9. Erratum in: Clin Immunol. 113:220, 2004.PubMedCrossRefGoogle Scholar
  24. 24.
    Orange JS, Levy O, Geha RS. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunol Rev 2005;203:21–37.PubMedCrossRefGoogle Scholar
  25. 25.
    Kumanogoh A, Wang X, Lee I, Watanabe C, Kamanaka M, Shi W, et al. Increased T cell autoreactivity in the absence of CD40–CD40 ligand interactions: a role of CD40 in regulatory T cell development. J Immunol 2001;166:353–60.PubMedGoogle Scholar
  26. 26.
    Rathmell JC, Townsend SE, Xu JC, Flavell RA, Goodnow CC. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell 1996;18(87):319–29.CrossRefGoogle Scholar
  27. 27.
    Datta SK, Kalled SL. CD40–CD40 ligand interaction in autoimmune disease. Arthritis Rheum 1997;40:1735–45.PubMedCrossRefGoogle Scholar
  28. 28.
    Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996;97:2063–73.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Adriana A. Jesus
    • 1
  • Alberto J. S. Duarte
    • 2
  • João B. Oliveira
    • 2
    • 3
    Email author
  1. 1.Pediatric Rheumatology Unit, Pediatrics DepartmentUniversidade de São PauloSão PauloBrazil
  2. 2.Laboratory of Medical Investigation Unit 56 (LIM-56), Dermatology DepartmentUniversidade de São PauloSão PauloBrazil
  3. 3.Research InstituteHospital do CoraçãoSão PauloBrazil

Personalised recommendations