Combined Immunodeficiency Caused by a Transactive Regulatory Mutation: A New Mutational Class

  • Donald A. Pious


Our laboratory research has focused on the genes, gene regulation, protein structure, and function of HLA, the human major histocompatibility complex (MHC) of humans. In this paper I will focus on our work on HLA gene regulation and its defects as newly recognized causes of combined immunodeficiency. The HLA complex is a cluster of genes located on the short arm of chromosome six. HLA class II genes code for the heterodimeric cell surface glycoproteins HLA-DR, -DQ and -DP; both the heavy (A) and light (B) chain genes of class II molecules are in the MHC cluster. HLA class II molecules are expressed on B cells, activated T cells, macrophages, and some epithelial and other cells. In some cells, the levels of class II expression are coordinately increased by γ-interferon, IL-4, or tumor necrosis factor (TNF). Class II molecules function by binding peptides derived from degraded exogenous protein antigens; the generation by cells of immunogenic peptides from soluble exogenous proteins is known as antigen processing. The resulting peptide class II complex “presents antigen to” (ie, activates) specific helper or suppressor T cells by binding to a peptide-and HLA class II antigen-specific T cell receptor, expressed clonally. The ability of HLA molecules to bind given peptides is allele specific; the high degree of polymorphism in these genes therefore results in genetic differences in the capacity to mount immune responses to particular immunogens. In addition, certain HLA alleles are strong susceptibility factors for particular auto-immune diseases.


Major Histocompatibility Complex Somatic Cell Hybrid Severe Combine Immunodeficiency Human Major Histocompatibility Complex Transcriptional Regulatory Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gladstone P, Pious D: Stable variants affecting a B cell alloantigen in human somatic cells. Nature 271;459–461, 1978.PubMedCrossRefGoogle Scholar
  2. 2.
    Gladstone P, Pious D: Identification of a trans-acting function regulating HLA-DR expression in a DR-negative B cell variant. Somatic Cell Genet 6:285–298, 1980.PubMedCrossRefGoogle Scholar
  3. 3.
    Levine F, Pious D: Revertants of the HLA class II regulatory mutant 6.1.6: Implications for the regulation of la gene expression. J Immunol 132:959–962, 1984.PubMedGoogle Scholar
  4. 4.
    Levine F, Mach B, Erlich H, Pious D: Transcriptional regulation of HLA class II and invariant chain genes. J Immunol 134:637–640, 1985.PubMedGoogle Scholar
  5. 5.
    Levine F, Pious D: Different roles for cytosine methylation in HLA class II gene expression. Immunogenetics 22:427–440, 1985.PubMedCrossRefGoogle Scholar
  6. 6.
    Stimac E, Lyons S, Pious D: Transcription of HLA class II genes in the absence of B-cell-specific octamer-binding factor. Mol Cell Biol 8:3734–3739, 1988.PubMedGoogle Scholar
  7. 7.
    Salter R, Alexander J, Levine F, Pious D, Cresswell P: Evidence for two trans-active genes regulating HLA class II antigen expression. J Immunol 135:4235–4238, 1985.PubMedGoogle Scholar
  8. 8.
    Touraine J, Betael H, Souillet G, et al: Combined immunodeficiency disease associated with absence of cell surface HLA-A and -B antigens. J Pediatr 93:47–51, 1978.PubMedCrossRefGoogle Scholar
  9. 9.
    Accolla R: Human B cell variants immunoselected against a single la antigen subset have lost expression of several la antigen subsets. J Exp Med 157:1053–1058, 1983.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhi Y, Accolla R, Pious D, Zegers B, Strominger J: Two distinct loci regulating class II gene expression are defective in human mutant and patient cell lines. EMBO J 7:1965–1972, 1988.Google Scholar
  11. 11.
    Hume C, Lee J: Congenital immunodeficiencies associated with absence of HLA class II antigens on lymphocytes result from distinct mutations in trans-acting factors. Hum Immunol (in press).Google Scholar
  12. 12.
    Saito H, Maki R, Clayton L, Tonegawa S: Complete primary structures of the γ chain and gene of the mouse major histocompatibility complex. Proc Natl Acad Sci USA 80:5520–5624, 1983.PubMedCrossRefGoogle Scholar
  13. 13.
    Kelly A, Trowsdale J: Complete nucleotide sequence of a functional HLA-DRγ gene and the region between the DPγ1 and DPαl genes: Comparison of the 5’ ends of the HLA class II genes. Nucleic Acids Res 13:1607–1621, 1985.PubMedCrossRefGoogle Scholar
  14. 14.
    Reith W, Satola S, Sanchez C, et al: Congenital immunodeficiency with a regulatory defect in the MHL class II gene expression lacks a specific HLA-DR promoter binding protein. Cell 53:897–906, 1988.PubMedCrossRefGoogle Scholar
  15. 15.
    Sherman P, Basta P, Ting J: Upstream sequences required for tissue specific expression of HLA-DRα gene. Proc Natl Acad Sci USA 84:4254–4258, 1987.PubMedCrossRefGoogle Scholar
  16. 16.
    Tsang S, Nakanishi N, Peterlin B: B-cell-specific and interferon-gamma-inducible regulation of the HLA-DR alpha gene. Proc Natl Acad Sci USA 85:8598–8602, 1988.PubMedCrossRefGoogle Scholar
  17. 17.
    Stimac E, Shoval S, Kempin S, Pious D: Manuscript in preparation.Google Scholar
  18. 18.
    Staudt L, Clerc R, Singh H, et al: Cloning of a lymphoid-specific cDNA encoding a protein binding the regulatory octamer DNA motif. Science 241:577–580, 1988.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1990

Authors and Affiliations

  • Donald A. Pious
    • 1
  1. 1.Department of Pediatrics, Immunology and GeneticsUniversity of WashingtonSeattleUSA

Personalised recommendations