Abstract
We have proposed that significant subsets of individuals with IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) may represent polar ends of a clinical spectrum reflecting a single underlying genetic defect. This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles. Here we present our analysis of the MHC haplotypes of 12 IgA-D and 19 CVID individuals from 21 families and of 79 of their immediate relatives. MHC haplotypes were defined by analyzing polymorphic markers for 11 genes or their products between the HLA-DQB1 and the HLA-A genes. Five of the families investigated contained more than one immunodeficient individual and all of these included both IgA-D and CVID members. Analysis of the data indicated that a small number of MHC haplotypes were shared by the majority of immunodeficient individuals. At least one of two of these haplotypes was present in 24 of the 31 (77%) immunodeficient individuals. No differences in the distribution of these haplotypes were observed between IgA-D and CVID individuals. Detailed analysis of these haplotypes suggests that a susceptibility gene or genes for both immunodeficiencies are located within the class III region of the MHC, possibly between the C4B and C2 genes.
Full text
PDF![1914](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/e46ab7ead245/jcinvest00066-0226.png)
![1915](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/131006d301a7/jcinvest00066-0227.png)
![1916](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/d86bb2bccb43/jcinvest00066-0228.png)
![1917](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/5d4dfc8efe21/jcinvest00066-0229.png)
![1918](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/3c548bbc35c1/jcinvest00066-0230.png)
![1919](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/181d187098ac/jcinvest00066-0231.png)
![1920](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/6df717db4402/jcinvest00066-0232.png)
![1921](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/45c08d1f1b6b/jcinvest00066-0233.png)
![1922](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/091a/295891/eeb785ddb182/jcinvest00066-0234.png)
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ahearn J. M., Fearon D. T. Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21). Adv Immunol. 1989;46:183–219. doi: 10.1016/s0065-2776(08)60654-9. [DOI] [PubMed] [Google Scholar]
- Ambrus M., Hernádi E., Bajtai G. Prevalence of HLA-A1 and HLA-B8 antigens in selective IgA deficiency. Clin Immunol Immunopathol. 1977 May;7(3):311–314. doi: 10.1016/0090-1229(77)90062-9. [DOI] [PubMed] [Google Scholar]
- Awdeh Z. L., Raum D., Yunis E. J., Alper C. A. 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. doi: 10.1073/pnas.80.1.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Belt K. T., Yu C. Y., Carroll M. C., Porter R. R. Polymorphism of human complement component C4. Immunogenetics. 1985;21(2):173–180. doi: 10.1007/BF00364869. [DOI] [PubMed] [Google Scholar]
- Bentley D. R., Campbell R. D., Cross S. J. DNA polymorphism of the C2 locus. Immunogenetics. 1985;22(4):377–390. doi: 10.1007/BF00430921. [DOI] [PubMed] [Google Scholar]
- Bird P., Lachmann P. J. The regulation of IgG subclass production in man: low serum IgG4 in inherited deficiencies of the classical pathway of C3 activation. Eur J Immunol. 1988 Aug;18(8):1217–1222. doi: 10.1002/eji.1830180811. [DOI] [PubMed] [Google Scholar]
- Campbell R. D., Porter R. R. Molecular cloning and characterization of the gene coding for human complement protein factor B. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4464–4468. doi: 10.1073/pnas.80.14.4464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carroll M. C., Fathallah D. M., Bergamaschini L., Alicot E. M., Isenman D. E. Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6868–6872. doi: 10.1073/pnas.87.17.6868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carroll M. C., Palsdottir A., Belt K. T., Porter R. R. Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region. EMBO J. 1985 Oct;4(10):2547–2552. doi: 10.1002/j.1460-2075.1985.tb03969.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conley M. E., Cooper M. D. Immature IgA B cells in IgA-deficient patients. N Engl J Med. 1981 Aug 27;305(9):495–497. doi: 10.1056/NEJM198108273050905. [DOI] [PubMed] [Google Scholar]
- Cooper M. D., Lawton A. R., Bockman D. E. Agammaglobulinaemia with B lymphocytes. Specific defect of plasma-cell differentiation. Lancet. 1971 Oct 9;2(7728):791–794. doi: 10.1016/s0140-6736(71)92742-5. [DOI] [PubMed] [Google Scholar]
- Dawkins R. L., Leaver A., Cameron P. U., Martin E., Kay P. H., Christiansen F. T. Some disease-associated ancestral haplotypes carry a polymorphism of TNF. Hum Immunol. 1989 Oct;26(2):91–97. doi: 10.1016/0198-8859(89)90094-3. [DOI] [PubMed] [Google Scholar]
- Dodds A. W., Law S. K., Porter R. R. The origin of the very variable haemolytic activities of the common human complement component C4 allotypes including C4-A6. EMBO J. 1985 Sep;4(9):2239–2244. doi: 10.1002/j.1460-2075.1985.tb03920.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Faustman D., Li X. P., Lin H. Y., Fu Y. E., Eisenbarth G., Avruch J., Guo J. Linkage of faulty major histocompatibility complex class I to autoimmune diabetes. Science. 1991 Dec 20;254(5039):1756–1761. doi: 10.1126/science.1763324. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
- French M. A., Dawkins R. L. Central MHC genes, IgA deficiency and autoimmune disease. Immunol Today. 1990 Aug;11(8):271–274. doi: 10.1016/0167-5699(90)90110-u. [DOI] [PubMed] [Google Scholar]
- Gathings W. E., Lawton A. R., Cooper M. D. Immunofluorescent studies of the development of pre-B cells, B lymphocytes and immunoglobulin isotype diversity in humans. Eur J Immunol. 1977 Nov;7(11):804–810. doi: 10.1002/eji.1830071112. [DOI] [PubMed] [Google Scholar]
- Hammarström L., Axelsson U., Björkander J., Hanson L. A., Möller E., Smith C. I. HLA antigens in selective IgA deficiency: distribution in healthy donors and patients with recurrent respiratory tract infections. Tissue Antigens. 1984 Jul;24(1):35–39. doi: 10.1111/j.1399-0039.1984.tb00395.x. [DOI] [PubMed] [Google Scholar]
- Hammarström L., Smith C. I. HLA-A, B, C and DR antigens in immunoglobulin A deficiency. Tissue Antigens. 1983 Jan;21(1):75–79. doi: 10.1111/j.1399-0039.1983.tb00375.x. [DOI] [PubMed] [Google Scholar]
- Hebell T., Ahearn J. M., Fearon D. T. Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science. 1991 Oct 4;254(5028):102–105. doi: 10.1126/science.1718035. [DOI] [PubMed] [Google Scholar]
- Horiuchi T., Macon K. J., Kidd V. J., Volanakis J. E. cDNA cloning and expression of human complement component C2. J Immunol. 1989 Mar 15;142(6):2105–2111. [PubMed] [Google Scholar]
- Isenman D. E., Young J. R. The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4. J Immunol. 1984 Jun;132(6):3019–3027. [PubMed] [Google Scholar]
- Kendall E., Sargent C. A., Campbell R. D. Human major histocompatibility complex contains a new cluster of genes between the HLA-D and complement C4 loci. Nucleic Acids Res. 1990 Dec 25;18(24):7251–7257. doi: 10.1093/nar/18.24.7251. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lévi-Strauss M., Carroll M. C., Steinmetz M., Meo T. A previously undetected MHC gene with an unusual periodic structure. Science. 1988 Apr 8;240(4849):201–204. doi: 10.1126/science.3353717. [DOI] [PubMed] [Google Scholar]
- Meinkoth J., Wahl G. Hybridization of nucleic acids immobilized on solid supports. Anal Biochem. 1984 May 1;138(2):267–284. doi: 10.1016/0003-2697(84)90808-x. [DOI] [PubMed] [Google Scholar]
- Mole J. E., Anderson J. K., Davison E. A., Woods D. E. Complete primary structure for the zymogen of human complement factor B. J Biol Chem. 1984 Mar 25;259(6):3407–3412. [PubMed] [Google Scholar]
- Morel P. A., Dorman J. S., Todd J. A., McDevitt H. O., Trucco M. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8111–8115. doi: 10.1073/pnas.85.21.8111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morley B. J., Campbell R. D. Internal homologies of the Ba fragment from human complement component Factor B, a class III MHC antigen. EMBO J. 1984 Jan;3(1):153–157. doi: 10.1002/j.1460-2075.1984.tb01776.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oen K., Petty R. E., Schroeder M. L. Immunoglobulin A deficiency: genetic studies. Tissue Antigens. 1982 Mar;19(3):174–182. doi: 10.1111/j.1399-0039.1982.tb01437.x. [DOI] [PubMed] [Google Scholar]
- Olerup O., Smith C. I., 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. doi: 10.1038/347289a0. [DOI] [PubMed] [Google Scholar]
- Ostergaard P. A., Eriksen J. Association between HLA-A1,B8 in children with extrinsic asthma and IgA deficiency. Eur J Pediatr. 1979 Aug;131(4):263–270. doi: 10.1007/BF00444347. [DOI] [PubMed] [Google Scholar]
- Oxelius V. A., Laurell A. B., Lindquist B., Golebiowska H., Axelsson U., Björkander J., Hanson L. A. IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency. N Engl J Med. 1981 Jun 11;304(24):1476–1477. doi: 10.1056/NEJM198106113042408. [DOI] [PubMed] [Google Scholar]
- Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
- Porter R. R. Complement polymorphism, the major histocompatibility complex and associated diseases: a speculation. Mol Biol Med. 1983 Jul;1(1):161–168. [PubMed] [Google Scholar]
- Primary immunodeficiency diseases. Report of a WHO sponsored meeting. Immunodefic Rev. 1989;1(2):173–205. [PubMed] [Google Scholar]
- Ratanachaiyavong S., Demaine A. G., Campbell R. D., McGregor A. M. Heat shock protein 70 (HSP70) and complement C4 genotypes in patients with hyperthyroid Graves' disease. Clin Exp Immunol. 1991 Apr;84(1):48–52. [PMC free article] [PubMed] [Google Scholar]
- Sargent C. A., Dunham I., Campbell R. D. Identification of multiple HTF-island associated genes in the human major histocompatibility complex class III region. EMBO J. 1989 Aug;8(8):2305–2312. doi: 10.1002/j.1460-2075.1989.tb08357.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sargent C. A., Dunham I., Trowsdale J., Campbell R. D. Human major histocompatibility complex contains genes for the major heat shock protein HSP70. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1968–1972. doi: 10.1073/pnas.86.6.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schaffer F. M., Monteiro R. C., Volanakis J. E., Cooper M. D. IgA deficiency. Immunodefic Rev. 1991;3(1):15–44. [PubMed] [Google Scholar]
- Schaffer F. M., Palermos J., Zhu Z. B., Barger B. O., Cooper M. D., Volanakis J. E. 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. doi: 10.1073/pnas.86.20.8015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schneider P. M., Carroll M. C., Alper C. A., Rittner C., Whitehead A. S., Yunis E. J., Colten H. R. Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants. J Clin Invest. 1986 Sep;78(3):650–657. doi: 10.1172/JCI112623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Segall M., Bach F. H. HLA and disease--the perils of simplification. N Engl J Med. 1990 Jun 28;322(26):1879–1881. doi: 10.1056/NEJM199006283222609. [DOI] [PubMed] [Google Scholar]
- Spies T., Blanck G., Bresnahan M., Sands J., Strominger J. L. A new cluster of genes within the human major histocompatibility complex. Science. 1989 Jan 13;243(4888):214–217. doi: 10.1126/science.2911734. [DOI] [PubMed] [Google Scholar]
- Sykes B. C. DNA in heritable disease. Lancet. 1983 Oct 1;2(8353):787–788. doi: 10.1016/s0140-6736(83)92314-0. [DOI] [PubMed] [Google Scholar]
- Todd J. A., Bell J. I., McDevitt H. O. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. doi: 10.1038/329599a0. [DOI] [PubMed] [Google Scholar]
- Todd J. A. Genetic control of autoimmunity in type 1 diabetes. Immunol Today. 1990 Apr;11(4):122–129. doi: 10.1016/0167-5699(90)90049-f. [DOI] [PubMed] [Google Scholar]
- Waldmann T. A., Blaese R. M., Broder S., Krakauer R. S. Disorders of suppressor immunoregulatory cells in the pathogenesis of immunodeficiency and autoimmunity. Ann Intern Med. 1978 Feb;88(2):226–238. doi: 10.7326/0003-4819-88-2-226. [DOI] [PubMed] [Google Scholar]
- White P. C., Grossberger D., Onufer B. J., Chaplin D. D., New M. I., Dupont B., Strominger J. L. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1089–1093. doi: 10.1073/pnas.82.4.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilton A. N., Cobain T. J., Dawkins R. L. Family studies of IgA deficiency. Immunogenetics. 1985;21(4):333–342. doi: 10.1007/BF00430799. [DOI] [PubMed] [Google Scholar]
- Wollheim F. A., Williams R. C., Jr Immunoglobulin studies in six kindreds of patients with adult hypogammaglobulinemia. J Lab Clin Med. 1965 Sep;66(3):433–445. [PubMed] [Google Scholar]
- Woods D. E., Edge M. D., Colten H. R. Isolation of a complementary DNA clone for the human complement protein C2 and its use in the identification of a restriction fragment length polymorphism. J Clin Invest. 1984 Aug;74(2):634–638. doi: 10.1172/JCI111461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu L. C., Morley B. J., Campbell R. D. Cell-specific expression of the human complement protein factor B gene: evidence for the role of two distinct 5'-flanking elements. Cell. 1987 Jan 30;48(2):331–342. doi: 10.1016/0092-8674(87)90436-3. [DOI] [PubMed] [Google Scholar]
- Yu C. Y., Belt K. T., Giles C. M., Campbell R. D., Porter R. R. Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity. EMBO J. 1986 Nov;5(11):2873–2881. doi: 10.1002/j.1460-2075.1986.tb04582.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yu C. Y., Campbell R. D. Definitive RFLPs to distinguish between the human complement C4A/C4B isotypes and the major Rodgers/Chido determinants: application to the study of C4 null alleles. Immunogenetics. 1987;25(6):383–390. doi: 10.1007/BF00396104. [DOI] [PubMed] [Google Scholar]
- Zhu Z. B., Volanakis J. E. Allelic associations of multiple RFLPs of the gene encoding complement protein C2. Am J Hum Genet. 1990 May;46(5):956–962. [PMC free article] [PubMed] [Google Scholar]
- de la Concha E. G., Oldham G., Webster A. D., Asherson G. L., Platts-Mills T. A. Quantitative measurements of T- and B-cell function in "variable" primary hypogammaglobulinaemia: evidence for a consistent B-cell defect. Clin Exp Immunol. 1977 Feb;27(2):208–215. [PMC free article] [PubMed] [Google Scholar]