|
|
J Clin Invest. 1993 December; 92(6): 2821–2833. doi: 10.1172/JCI116902. | PMCID: PMC288483 |
Naturally occurring anti-i/I cold agglutinins may be encoded by different VH3 genes as well as the VH4.21 gene segment. L C Jefferies, C M Carchidi, and L E Silberstein Hospital of the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Philadelphia 19104. Abstract In the current study, we wished to determine if the V regions encoding the naturally occurring anti-i/I Cold Agglutinins (anti-i/I CA) differ from pathogenic anti-i/I CA that are exclusively encoded by the VH4.21 gene. After EBV transformation of B lymphocytes, we generated one anti-I secreting clone from each of two individuals; clone 4G (individual CM, PBL) and clone Sp1 (individual SC, spleen). Clone 4G expresses a VH3 gene sequence that is 92% homologous to the germline gene WHG26. Clone Sp1 also expresses a VH3 gene that is 98% homologous to the fetally rearranged M85/20P1 gene. Another clone, Sp2 (anti-i specificity), from individual SC is 98% homologous to the germline gene VH4.21. For correlation, we studied anti-i/I CA fractions purified from 15 normal sera and found no or relatively small amounts of 9G4 (VH4.21 related idiotype) reactive IgM. Five cold agglutinin fractions contained large amounts of VH3-encoded IgM (compared to pooled normal IgM) by virtue of their binding to modified protein Staph A (SPA), and absorption of three CA fractions with modified SPA specifically removed anti-i/I binding specificity entirely. Collectively, the data indicate that naturally occurring anti-i/I CA may be encoded to a large extent by non-VH4.21-related genes, and that the VH4.21 gene is not uniquely required for anti-i/I specificity. 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 (2.2M), 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. These references are in PubMed. This may not be the complete list of references from this article. - Carson DA, Chen PP, Fox RI, Kipps TJ, Jirik F, Goldfien RD, Silverman G, Radoux V, Fong S. Rheumatoid factor and immune networks. Annu Rev Immunol. 1987;5:109–126. [PubMed]
- Madaio MP, Schattner A, Shattner M, Schwartz RS. Lupus serum and normal human serum contain anti-DNA antibodies with the same idiotypic marker. J Immunol. 1986 Oct 15;137(8):2535–2540. [PubMed]
- Pruzanski W, Shumak KH. Biologic activity of cold-reacting autoantibodies (first of two parts). N Engl J Med. 1977 Sep 8;297(10):538–542. [PubMed]
- Roelcke D. Cold agglutination. Transfus Med Rev. 1989 Apr;3(2):140–166. [PubMed]
- Silverman GJ, Carson DA. Structural characterization of human monoclonal cold agglutinins: evidence for a distinct primary sequence-defined VH4 idiotype. Eur J Immunol. 1990 Feb;20(2):351–356. [PubMed]
- Silberstein LE, Jefferies LC, Goldman J, Friedman D, Moore JS, Nowell PC, Roelcke D, Pruzanski W, Roudier J, Silverman GJ. Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens. Blood. 1991 Nov 1;78(9):2372–2386. [PubMed]
- Leoni J, Ghiso J, Goñi F, Frangione B. The primary structure of the Fab fragment of protein KAU, a monoclonal immunoglobulin M cold agglutinin. J Biol Chem. 1991 Feb 15;266(5):2836–2842. [PubMed]
- Pascual V, Victor K, Lelsz D, Spellerberg MB, Hamblin TJ, Thompson KM, Randen I, Natvig J, Capra JD, Stevenson FK. Nucleotide sequence analysis of the V regions of two IgM cold agglutinins. Evidence that the VH4-21 gene segment is responsible for the major cross-reactive idiotype. J Immunol. 1991 Jun 15;146(12):4385–4391. [PubMed]
- Pascual V, Victor K, Spellerberg M, Hamblin TJ, Stevenson FK, Capra JD. VH restriction among human cold agglutinins. The VH4-21 gene segment is required to encode anti-I and anti-i specificities. J Immunol. 1992 Oct 1;149(7):2337–2344. [PubMed]
- Jefferies LC, Silverman GJ, Carchidi CM, Silberstein LE. Idiotypic heterogeneity of VKIII autoantibodies to red blood cell antigens. Clin Immunol Immunopathol. 1992 Nov;65(2):119–128. [PubMed]
- Stevenson FK, Wrightham M, Glennie MJ, Jones DB, Cattan AR, Feizi T, Hamblin TJ, Stevenson GT. Antibodies to shared idiotypes as agents for analysis and therapy for human B cell tumors. Blood. 1986 Aug;68(2):430–436. [PubMed]
- Silberstein LE, Goldman J, Kant JA, Spitalnik SL. Comparative biochemical and genetic characterization of clonally related human B-cell lines secreting pathogenic anti-Pr2 cold agglutinins. Arch Biochem Biophys. 1988 Jul;264(1):244–252. [PubMed]
- Goldberg LS, Barnett EV. Mixed gamma G-gamma M cold agglutinin. J Immunol. 1967 Oct;99(4):803–809. [PubMed]
- Sanz I, Kelly P, Williams C, Scholl S, Tucker P, Capra JD. The smaller human VH gene families display remarkably little polymorphism. EMBO J. 1989 Dec 1;8(12):3741–3748. [PubMed]
- Friedman DF, Cho EA, Goldman J, Carmack CE, Besa EC, Hardy RR, Silberstein LE. The role of clonal selection in the pathogenesis of an autoreactive human B cell lymphoma. J Exp Med. 1991 Sep 1;174(3):525–537. [PubMed]
- Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
- Silberstein LE, Jefferies LC, Goldman J, Spitalnik SL. Production of carbohydrate-specific human monoclonal antibodies in vitro. Methods Enzymol. 1989;179:299–304. [PubMed]
- Küppers R, Fischer U, Rajewsky K, Gause A. Immunoglobulin heavy and light chain gene sequences of a human CD5 positive immunocytoma and sequences of four novel VHIII germline genes. Immunol Lett. 1992 Sep;34(1):57–62. [PubMed]
- Schroeder HW, Jr, Wang JY. Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6146–6150. [PubMed]
- Silberstein LE, Litwin S, Carmack CE. Relationship of variable region genes expressed by a human B cell lymphoma secreting pathologic anti-Pr2 erythrocyte autoantibodies. J Exp Med. 1989 May 1;169(5):1631–1643. [PubMed]
- Olee T, Lu EW, Huang DF, Soto-Gil RW, Deftos M, Kozin F, Carson DA, Chen PP. Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia implicates an antigen-driven response. J Exp Med. 1992 Mar 1;175(3):831–842. [PubMed]
- Scott MG, Crimmins DL, McCourt DW, Chung G, Schäble KF, Thiebe R, Quenzel EM, Zachau HG, Nahm MH. Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. IV. The less frequently expressed VL are heterogeneous. J Immunol. 1991 Dec 1;147(11):4007–4013. [PubMed]
- Paul E, Livneh A, Manheimer-Lory AJ, Diamond B. Characterization of the human Ig V lambda II gene family and analysis of V lambda II and C lambda polymorphism in systemic lupus erythematosus. J Immunol. 1991 Oct 15;147(8):2771–2776. [PubMed]
- van Es JH, Gmelig Meyling FH, van de Akker WR, Aanstoot H, Derksen RH, Logtenberg T. Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus. J Exp Med. 1991 Feb 1;173(2):461–470. [PubMed]
- Shlomchik MJ, Aucoin AH, Pisetsky DS, Weigert MG. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9150–9154. [PubMed]
- Sharon J, Gefter ML, Wysocki LJ, Margolies MN. Recurrent somatic mutations in mouse antibodies to p-azophenylarsonate increase affinity for hapten. J Immunol. 1989 Jan 15;142(2):596–601. [PubMed]
- Ichihara Y, Matsuoka H, Kurosawa Y. Organization of human immunoglobulin heavy chain diversity gene loci. EMBO J. 1988 Dec 20;7(13):4141–4150. [PubMed]
- Pascual V, Andris J, Capra JD. Heavy chain variable region gene utilization in human antibodies. Int Rev Immunol. 1990;5(3-4):231–238. [PubMed]
- Adderson EE, Shackelford PG, Quinn A, Wilson PM, Cunningham MW, Insel RA, Carroll WL. Restricted immunoglobulin VH usage and VDJ combinations in the human response to Haemophilus influenzae type b capsular polysaccharide. Nucleotide sequences of monospecific anti-Haemophilus antibodies and polyspecific antibodies cross-reacting with self antigens. J Clin Invest. 1993 Jun;91(6):2734–2743. [PubMed]
- COSTEA N, YAKULIS V, HELLER P. EXPERIMENTAL PRODUCTION OF COLD AGGLUTININS IN RABBITS. Blood. 1965 Sep;26:323–340. [PubMed]
- Springer GF, Horton RE. Blood group isoantibody stimulation in man by feeding blood group-active bacteria. J Clin Invest. 1969 Jul;48(7):1280–1291. [PubMed]
|
This article has been 
