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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1993 June; 91(6): 2761–2768.
PMCID: PMC443342

Antigen nonspecific effect of major histocompatibility complex haplotype on autoantibody levels in systemic lupus erythematosus-prone lpr mice.


MHC-linked genes strongly influence susceptibility to autoimmune diseases and also regulate responses to exogenous antigens. To begin to understand the mechanism of this MHC effect on disease, we have investigated MHC-congenic mouse strains that develop spontaneous autoimmunity because of the lpr gene. C57BL6/lpr (B6/lpr) mice (H-2b) are known to have substantial levels of autoantibodies to chromatin, single stranded DNA (ssDNA3), and IgG of different murine subclasses (rheumatoid factor). We have crossed the H-2d and the H-2bm12 (la mutant) haplotypes onto the B6/lpr background. Surprisingly, levels of all the autoantibodies were markedly lower in B6/lpr.H-2d, but levels in B6/lpr.H-2bm12 were no different from those in B6/lpr mice. The downregulating influence of the H-2d allele was dominant, and there was no effect on autoantibody fine specificities. The genetics of the H-2d effect and its diffuse influence on multiple autoantibody specificities, in addition to the lack of effect of the bm12 mutation, which modifies the peptide-binding groove of I-A, together raise the question of whether MHC-linked genes other than classical (IR) genes may be responsible for MHC disease associations in this model.

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  • Goldstein R, Arnett FC. The genetics of rheumatic disease in man. Rheum Dis Clin North Am. 1987 Dec;13(3):487–510. [PubMed]
  • Olsen ML, Goldstein R, Arnett FC, Duvic M, Pollack M, Reveille JD. C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus. Immunogenetics. 1989;30(1):27–33. [PubMed]
  • Fujisaku A, Frank MB, Neas B, Reichlin M, Harley JB. HLA-DQ gene complementation and other histocompatibility relationships in man with the anti-Ro/SSA autoantibody response of systemic lupus erythematosus. J Clin Invest. 1990 Aug;86(2):606–611. [PMC free article] [PubMed]
  • Reveille JD, Anderson KL, Schrohenloher RE, Acton RT, Barger BO. Restriction fragment length polymorphism analysis of HLA-DR, DQ, DP and C4 alleles in Caucasians with systemic lupus erythematosus. J Rheumatol. 1991 Jan;18(1):14–18. [PubMed]
  • Knight JG, Adams DD. Three genes for lupus nephritis in NZB x NZW mice. J Exp Med. 1978 Jun 1;147(6):1653–1660. [PMC free article] [PubMed]
  • Chiang BL, Bearer E, Ansari A, Dorshkind K, Gershwin ME. The BM12 mutation and autoantibodies to dsDNA in NZB.H-2bm12 mice. J Immunol. 1990 Jul 1;145(1):94–101. [PubMed]
  • Merino R, Fossati L, Lacour M, Lemoine R, Higaki M, Izui S. H-2-linked control of the Yaa gene-induced acceleration of lupus-like autoimmune disease in BXSB mice. Eur J Immunol. 1992 Feb;22(2):295–299. [PubMed]
  • Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. [PubMed]
  • Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. [PubMed]
  • Hansen TH, Walsh WD, Rubocki RJ, Kapp JA. Responses of B6.C-H-2bm12 to heterologous insulins show no correlation with the putative gene conversion but define Iabm12 as functionally unique. J Mol Cell Immunol. 1986;2(6):359–368. [PubMed]
  • Fisher CL, Eisenberg RA, Cohen PL. Quantitation and IgG subclass distribution of antichromatin autoantibodies in SLE mice. Clin Immunol Immunopathol. 1988 Feb;46(2):205–213. [PubMed]
  • Morris SC, Cheek RL, Cohen PL, Eisenberg RA. Autoantibodies in chronic graft versus host result from cognate T-B interactions. J Exp Med. 1990 Feb 1;171(2):503–517. [PMC free article] [PubMed]
  • Warren RW, Caster SA, Roths JB, Murphy ED, Pisetsky DS. The influence of the lpr gene on B cell activation: differential antibody expression in lpr congenic mouse strains. Clin Immunol Immunopathol. 1984 Apr;31(1):65–77. [PubMed]
  • Ghatak S, Sainis K, Owen FL, Datta SK. T-cell-receptor beta- and I-A beta-chain genes of normal SWR mice are linked with the development of lupus nephritis in NZB x SWR crosses. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6850–6853. [PubMed]
  • Cohen PL, Ellner JJ, Shevach EM. Induction of guinea pig antibody responses in vitro. J Immunol. 1977 Jun;118(6):2034–2039. [PubMed]
  • Nishimoto H, Kikutani H, Yamamura K, Kishimoto T. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature. 328(6129):432–434. [PubMed]
  • Reich EP, Sherwin RS, Kanagawa O, Janeway CA., Jr An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. Nature. 1989 Sep 28;341(6240):326–328. [PubMed]
  • Mirtcheva J, Pfeiffer C, De Bruijn JA, Jacquesmart F, Gleichmann E. Immunological alterations inducible by mercury compounds. III. H-2A acts as an immune response and H-2E as an immune "suppression" locus for HgCl2-induced antinucleolar autoantibodies. Eur J Immunol. 1989 Dec;19(12):2257–2261. [PubMed]
  • Rudensky AYu, Preston-Hurlburt P, al-Ramadi BK, Rothbard J, Janeway CA., Jr Truncation variants of peptides isolated from MHC class II molecules suggest sequence motifs. Nature. 1992 Oct 1;359(6394):429–431. [PubMed]
  • Okuyama R, Abo T, Seki S, Ohteki T, Sugiura K, Kusumi A, Kumagai K. Estrogen administration activates extrathymic T cell differentiation in the liver. J Exp Med. 1992 Mar 1;175(3):661–669. [PMC free article] [PubMed]
  • Bellone M, Ostlie N, Lei SJ, Wu XD, Conti-Tronconi BM. The I-Abm12 mutation, which confers resistance to experimental myasthenia gravis, drastically affects the epitope repertoire of murine CD4+ cells sensitized to nicotinic acetylcholine receptor. J Immunol. 1991 Sep 1;147(5):1484–1491. [PubMed]
  • McDevitt HO, Benacerraf B. Genetic control of specific immune responses. Adv Immunol. 1969;11:31–74. [PubMed]
  • Inoko H, Trowsdale J. Linkage of TNF genes to the HLA-B locus. Nucleic Acids Res. 1987 Nov 11;15(21):8957–8962. [PMC free article] [PubMed]
  • Milner CM, Campbell RD. Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics. 1990;32(4):242–251. [PubMed]
  • Cho S, Attaya M, Brown MG, Monaco JJ. A cluster of transcribed sequences between the Pb and Ob genes of the murine major histocompatibility complex. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5197–5201. [PubMed]
  • Glynne R, Powis SH, Beck S, Kelly A, Kerr LA, Trowsdale J. A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC. Nature. 1991 Sep 26;353(6342):357–360. [PubMed]
  • Brown MG, Driscoll J, Monaco JJ. Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes. Nature. 1991 Sep 26;353(6342):355–357. [PubMed]
  • Martinez CK, Monaco JJ. Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene. Nature. 1991 Oct 17;353(6345):664–667. [PubMed]
  • Powis SJ, Deverson EV, Coadwell WJ, Ciruela A, Huskisson NS, Smith H, Butcher GW, Howard JC. Effect of polymorphism of an MHC-linked transporter on the peptides assembled in a class I molecule. Nature. 1992 May 21;357(6375):211–215. [PubMed]

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