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Susceptibility Locus for IgA Deficiency and Common Variable Immunodeficiency in the HLA-DR3, -B8, -A1 Haplotypes

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Abstract

Background

A common genetic basis for IgA deficiency (IgAD) and common variable immunodeficiency (CVID) is suggested by their occurrence in members of the same family and the similarity of the underlying B cell differentiation defects. An association between IgAD/CVID and HLA alleles DR3, B8, and A1 has also been documented. In a search for the gene(s) in the major histocompatibility complex (MHC) that predispose to IgAD/CVID, we analyzed the extended MHC haplotypes present in a large family with 8 affected members.

Materials and Methods

We examined the CVID proband, 72 immediate relatives, and 21 spouses, and determined their serum immunoglobulin concentrations. The MHC haplotype analysis of individual family members employed 21 allelic DNA and protein markers, including seven newly available microsatellite markers.

Results

Forty-one (56%) of the 73 relatives by common descent were heterozygous and nine (12%) were homozygous for a fragment or the entire extended MHC haplotype designated haplotype 1 that included HLA-DR3, -C4A-0, -B8, and -A1. The remarkable prevalence of haplotype 1 was due in part to marital introduction into the family of 11 different copies of the haplotype, eight sharing 20 identical genotype markers between HLA-DR3 and HLA-B8, and three that contained fragments of haplotype 1.

Conclusion

Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.

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Acknowledgments

We thank the family members in this study for their cooperation, with special thanks to the proband’s spouse, who was instrumental in gathering family members for study. We thank Dr. David Chaplin, Washington University, St. Louis, for providing the C4 DNA probe. Dr. J. F. Kaumeyer, Genentech, Inc., South San Francisco, for providing the plasmid Sp64, Dana DePew and Marsha Brand for their help in collecting blood samples and nursing care of family members, and Sarah Robinson for excellent technical assistance.

This work was supported in part by U.S. Public Health Service grants AI07051, AI30879, AI33621, AI34568, AR44505, and RR00032, and by The British Diabetic Association. S. A. N. and R. L. T. are International Research Scholars of the Howard Hughes Medical Institute. M. D. C. is a Howard Hughes Medical Institute Investigator.

The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

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Authors and Affiliations

  1. Division of Developmental and Clinical Immunology, University of Alabama at Birmingham Wallace Tumor Institute, 364, UAB Station, Birmingham, Alabama, 35294-3300, USA

    Harry W. Schroeder Jr., T. Prescott Atkinson & Max D. Cooper

  2. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Zeng-Bian Zhu, Seth Mark Berney & John E. Volanakis

  3. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Harry W. Schroeder Jr., Zeng-Bian Zhu, Seth Mark Berney, Max D. Cooper & John E. Volanakis

  4. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Harry W. Schroeder Jr. & Max D. Cooper

  5. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA

    T. Prescott Atkinson & Max D. Cooper

  6. Department of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Rodney C. P. Go

  7. Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Max D. Cooper

  8. MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, Oxford, UK

    Ruth E. March & R. Duncan Campbell

  9. Laboratory of Molecular Immunoregulation, DBS and Intramural Research Support Program, SAIC Frederick, National Cancer Institute—Frederick Cancer Research and Development Center, Frederick, Maryland, USA

    Sergei A. Nedospasov & Regina L. Turetskaya

  10. Engelhardt Institute of Molecular Biology and Belozersky Institute of Physico-Chemical Biology, Moscow, Russia

    Sergei A. Nedospasov & Regina L. Turetskaya

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  1. Harry W. Schroeder Jr.
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Correspondence to Harry W. Schroeder Jr..

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Communicated by M. D. Cooper.

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Schroeder, H.W., Zhu, ZB., March, R.E. et al. Susceptibility Locus for IgA Deficiency and Common Variable Immunodeficiency in the HLA-DR3, -B8, -A1 Haplotypes. Mol Med 4, 72–86 (1998). https://doi.org/10.1007/BF03401731

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