Search tips
Search criteria 


Logo of molmedLink to Publisher's site
Mol Med. 1998 February; 4(2): 72–86.
PMCID: PMC2230309

Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes.


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.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.9M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Burrows PD, Cooper MD. IgA deficiency. Adv Immunol. 1997;65:245–276. [PubMed]
  • Matamoros Florí N, Mila Llambi J, Español Boren T, Raga Borja S, Fontan Casariego G. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. 1997 Jul;17(4):333–339. [PubMed]
  • Cooper MD, Lawton AR. Circulating B-cells in patients with immunodeficiency. Am J Pathol. 1972 Dec;69(3):513–528. [PubMed]
  • Oxelius VA, Laurell AB, Lindquist B, Golebiowska H, Axelsson U, Björkander J, Hanson LA. IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency. N Engl J Med. 1981 Jun 11;304(24):1476–1477. [PubMed]
  • French MA, Denis KA, Dawkins R, Peter JB. Severity of infections in IgA deficiency: correlation with decreased serum antibodies to pneumococcal polysaccharides and decreased serum IgG2 and/or IgG4. Clin Exp Immunol. 1995 Apr;100(1):47–53. [PubMed]
  • Cunningham-Rundles C. Genetic aspects of immunoglobulin A deficiency. Adv Hum Genet. 1990;19:235–266. [PubMed]
  • Buckley RH. Clinical and immunologic features of selective IgA deficiency. Birth Defects Orig Artic Ser. 1975;11(1):134–142. [PubMed]
  • Kanoh T, Mizumoto T, Yasuda N, Koya M, Ohno Y, Uchino H, Yoshimura K, Ohkubo Y, Yamaguchi H. Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis. Vox Sang. 1986;50(2):81–86. [PubMed]
  • Melamed I, Kark JD, Zakuth V, Margalit G, Spirer Z. Serum immunoglobulin A levels and ethnicity in an Israeli population sample. Clin Immunol Immunopathol. 1987 Mar;42(3):259–264. [PubMed]
  • Oen K, Petty RE, Schroeder ML. Immunoglobulin A deficiency: genetic studies. Tissue Antigens. 1982 Mar;19(3):174–182. [PubMed]
  • Wollheim FA, Williams RC., Jr Immunoglobulin studies in six kindreds of patients with adult hypogammaglobulinemia. J Lab Clin Med. 1965 Sep;66(3):433–445. [PubMed]
  • Schaffer FM, Palermos J, Zhu ZB, Barger BO, Cooper MD, Volanakis JE. Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8015–8019. [PubMed]
  • Volanakis JE, Zhu ZB, Schaffer FM, Macon KJ, Palermos J, Barger BO, Go R, Campbell RD, Schroeder HW, Jr, Cooper MD. Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. J Clin Invest. 1992 Jun;89(6):1914–1922. [PMC free article] [PubMed]
  • Wilton AN, Cobain TJ, Dawkins RL. Family studies of IgA deficiency. Immunogenetics. 1985;21(4):333–342. [PubMed]
  • Olerup O, Smith CI, Hammarström L. Different amino acids at position 57 of the HLA-DQ beta chain associated with susceptibility and resistance to IgA deficiency. Nature. 1990 Sep 20;347(6290):289–290. [PubMed]
  • Ashman RF, Schaffer FM, Kemp JD, Yokoyama WM, Zhu ZB, Cooper MD, Volanakis JE. Genetic and immunologic analysis of a family containing five patients with common-variable immune deficiency or selective IgA deficiency. J Clin Immunol. 1992 Nov;12(6):406–414. [PubMed]
  • Cunningham-Rundles C, Fotino M, Rosina O, Peter JB. Selective IgA deficiency, IgG subclass deficiency, and the major histocompatibility complex. Clin Immunol Immunopathol. 1991 Nov;61(2 Pt 2):S61–S69. [PubMed]
  • Howe HS, So AK, Farrant J, Webster AD. Common variable immunodeficiency is associated with polymorphic markers in the human major histocompatibility complex. Clin Exp Immunol. 1991 Mar;83(3):387–390. [PubMed]
  • Bućin D, Truedsson L, Hammarström L, Smith CI, Sjöholm AG. C4 polymorphism and major histocompatibility complex haplotypes in IgA deficiency: association with C4A null haplotypes. Exp Clin Immunogenet. 1991;8(4):233–241. [PubMed]
  • Olerup O, Smith CI, Björkander J, Hammarström L. Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10653–10657. [PubMed]
  • Johnson ML, Keeton LG, Zhu ZB, Volanakis JE, Cooper MD, Schroeder HW., Jr Age-related changes in serum immunoglobulins in patients with familial IgA deficiency and common variable immunodeficiency (CVID). Clin Exp Immunol. 1997 Jun;108(3):477–483. [PubMed]
  • Sim E, Cross SJ. Phenotyping of human complement component C4, a class-III HLA antigen. Biochem J. 1986 Nov 1;239(3):763–767. [PubMed]
  • Udalova IA, Nedospasov SA, Webb GC, Chaplin DD, Turetskaya RL. Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics. 1993 Apr;16(1):180–186. [PubMed]
  • D'Alfonso S, Richiardi PM. A polymorphic variation in a putative regulation box of the TNFA promoter region. Immunogenetics. 1994;39(2):150–154. [PubMed]
  • Monos DS, Kamoun M, Udalova IA, Csanky E, Cizman B, Turetskaya RL, Smirnova JB, Zharkov VG, Gasser D, Zmijewski CM, et al. Genetic polymorphism of the human tumor necrosis factor region in insulin-dependent diabetes mellitus. Linkage disequilibrium of TNFab microsatellite alleles with HLA haplotypes. Hum Immunol. 1995 Oct;44(2):70–79. [PubMed]
  • Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3195–3199. [PubMed]
  • Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO. Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1233–1237. [PubMed]
  • Cudworth AG, Wolf E, Gorsuch AN, Festenstein H. A new look at HLA genetics with particular reference to type-1 diabetes. Lancet. 1979 Aug 25;2(8139):389–391. [PubMed]
  • Miller AP, Rich S, Barbosa J. Insulin dependent diabetic families: sex ratio and HLA haplotype segregation. Lancet. 1981 Feb 14;1(8216):388–388. [PubMed]
  • Serjeantson S. Distorted HLA segregation or biased ascertainment? Lancet. 1980 Jan 5;1(8158):40–41. [PubMed]
  • Vadheim CM, Rotter JI, Maclaren NK, Riley WJ, Anderson CE. Preferential transmission of diabetic alleles within the HLA gene complex. N Engl J Med. 1986 Nov 20;315(21):1314–1318. [PubMed]
  • Awdeh ZL, Raum D, Yunis EJ, Alper CA. Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man. Proc Natl Acad Sci U S A. 1983 Jan;80(1):259–263. [PubMed]
  • Weitkamp LR. HLA segregation ratios. Lancet. 1979 Oct 6;2(8145):745–745. [PubMed]
  • Klitz W, Lo SK, Neugebauer M, Baur MP, Albert ED, Thomson G. A comprehensive search for segregation distortion in HLA. Hum Immunol. 1987 Feb;18(2):163–180. [PubMed]
  • Conley ME, Cooper MD. Immature IgA B cells in IgA-deficient patients. N Engl J Med. 1981 Aug 27;305(9):495–497. [PubMed]
  • Vukmanović S, Vucković S, Stosić-Grujicić S, Ramić Z, Abinun M. An unusual T-cell surface phenotype in vivo correlates with the failure to proliferate and produce IL-2 in vitro in a patient with common variable immunodeficiency. Clin Immunol Immunopathol. 1992 Dec;65(3):261–270. [PubMed]
  • Vorechovský I, Zetterquist H, Paganelli R, Koskinen S, Webster AD, Björkander J, Smith CI, Hammarström L. Family and linkage study of selective IgA deficiency and common variable immunodeficiency. Clin Immunol Immunopathol. 1995 Nov;77(2):185–192. [PubMed]
  • Clerget-Darpoux F, Bonaïti-Pellié C, Hochez J. Effects of misspecifying genetic parameters in lod score analysis. Biometrics. 1986 Jun;42(2):393–399. [PubMed]
  • Abraham LJ, Leelayuwat C, Grimsley G, Degli-Esposti MA, Mann A, Zhang WJ, Christiansen FT, Dawkins RL. Sequence differences between HLA-B and TNF distinguish different MHC ancestral haplotypes. Tissue Antigens. 1992 Mar;39(3):117–121. [PubMed]
  • Greenberg DA, Doneshka P. Partitioned association-linkage test: distinguishing "necessary" from "susceptibility" loci. Genet Epidemiol. 1996;13(3):243–252. [PubMed]
  • Cucca F, Zhu ZB, Khanna A, Cossu F, Congia M, Badiali M, Lampis R, Frau F, De Virgiliis S, Cao A, et al. Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region. Clin Exp Immunol. 1998 Jan;111(1):76–80. [PubMed]
  • Congia M, Frau F, Lampis R, Frau R, Mele R, Cucca F, Muntoni F, Porcu S, Boi F, Contu L, et al. A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201. Tissue Antigens. 1992 Feb;39(2):78–83. [PubMed]
  • Liu YJ, Banchereau J. Mutant mice without B lymphocyte follicles. J Exp Med. 1996 Oct 1;184(4):1207–1211. [PMC free article] [PubMed]
  • Ware CF, VanArsdale TL, Crowe PD, Browning JL. The ligands and receptors of the lymphotoxin system. Curr Top Microbiol Immunol. 1995;198:175–218. [PubMed]
  • Watanabe Y, Jacob CO. Regulation of MHC class II antigen expression. Opposing effects of tumor necrosis factor-alpha on IFN-gamma-induced HLA-DR and Ia expression depends on the maturation and differentiation stage of the cell. J Immunol. 1991 Feb 1;146(3):899–905. [PubMed]
  • Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, Hession C, O'Brine-Greco B, Foley SF, Ware CF. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell. 1993 Mar 26;72(6):847–856. [PubMed]
  • Crowe PD, VanArsdale TL, Walter BN, Ware CF, Hession C, Ehrenfels B, Browning JL, Din WS, Goodwin RG, Smith CA. A lymphotoxin-beta-specific receptor. Science. 1994 Apr 29;264(5159):707–710. [PubMed]
  • De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994 Apr 29;264(5159):703–707. [PubMed]
  • Rennert PD, Browning JL, Mebius R, Mackay F, Hochman PS. Surface lymphotoxin alpha/beta complex is required for the development of peripheral lymphoid organs. J Exp Med. 1996 Nov 1;184(5):1999–2006. [PMC free article] [PubMed]
  • Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity. 1997 Apr;6(4):491–500. [PubMed]
  • Banks TA, Rouse BT, Kerley MK, Blair PJ, Godfrey VL, Kuklin NA, Bouley DM, Thomas J, Kanangat S, Mucenski ML. Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol. 1995 Aug 15;155(4):1685–1693. [PubMed]
  • Alimzhanov MB, Kuprash DV, Kosco-Vilbois MH, Luz A, Turetskaya RL, Tarakhovsky A, Rajewsky K, Nedospasov SA, Pfeffer K. Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9302–9307. [PubMed]
  • Fu YX, Molina H, Matsumoto M, Huang G, Min J, Chaplin DD. Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses. J Exp Med. 1997 Jun 16;185(12):2111–2120. [PMC free article] [PubMed]
  • Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med. 1996 Oct 1;184(4):1397–1411. [PMC free article] [PubMed]
  • Freund YR, Sgarlato G, Jacob CO, Suzuki Y, Remington JS. Polymorphisms in the tumor necrosis factor alpha (TNF-alpha) gene correlate with murine resistance to development of toxoplasmic encephalitis and with levels of TNF-alpha mRNA in infected brain tissue. J Exp Med. 1992 Mar 1;175(3):683–688. [PMC free article] [PubMed]
  • Müller KM, Lisby S, Arrighi JF, Grau GE, Saurat JH, Hauser C. H-2D haplotype-linked expression and involvement of TNF-alpha in Th2 cell-mediated tissue inflammation. J Immunol. 1994 Jul 1;153(1):316–324. [PubMed]
  • Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW. An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles. J Exp Med. 1993 Feb 1;177(2):557–560. [PMC free article] [PubMed]
  • Abraham LJ, Du DC, Zahedi K, Dawkins RL, Whitehead AS. Haplotypic polymorphisms of the TNFB gene. Immunogenetics. 1991;33(1):50–53. [PubMed]
  • Bouma G, Crusius JB, Oudkerk Pool M, Kolkman JJ, von Blomberg BM, Kostense PJ, Giphart MJ, Schreuder GM, Meuwissen SG, Peña AS. Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand J Immunol. 1996 Apr;43(4):456–463. [PubMed]
  • Messer G, Spengler U, Jung MC, Honold G, Blömer K, Pape GR, Riethmüller G, Weiss EH. Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production. J Exp Med. 1991 Jan 1;173(1):209–219. [PMC free article] [PubMed]
  • Garcia-Merino A, Alper CA, Usuku K, Marcus-Bagley D, Lincoln R, Awdeh Z, Yunis EJ, Eisenbarth GS, Brink SJ, Hauser SL. Tumor necrosis factor (TNF) microsatellite haplotypes in relation to extended haplotypes, susceptibility to diseases associated with the major histocompatibility complex and TNF secretion. Hum Immunol. 1996 Sep 15;50(1):11–21. [PubMed]
  • McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994 Oct 6;371(6497):508–510. [PubMed]
  • Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL. Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. J Inflamm. 1995;46(1):32–41. [PubMed]
  • Stuber F, Udalova IA, Book M, Drutskaya LN, Kuprash DV, Turetskaya RL, Schade FU, Nedospasov SA. -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm. 1995;46(1):42–50. [PubMed]
  • Marino MW, Dunn A, Grail D, Inglese M, Noguchi Y, Richards E, Jungbluth A, Wada H, Moore M, Williamson B, et al. Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8093–8098. [PubMed]
  • Amiot F, Boussadia O, Cases S, Fitting C, Lebastard M, Cavaillon JM, Milon G, Dautry F. Mice heterozygous for a deletion of the tumor necrosis factor-alpha and lymphotoxin-alpha genes: biological importance of a nonlinear response of tumor necrosis factor-alpha to gene dosage. Eur J Immunol. 1997 Apr;27(4):1035–1042. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ