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Gene Review

Ighg3  -  Immunoglobulin heavy constant gamma 3

Mus musculus

Synonyms: AI324046, IgG3
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Disease relevance of AI324046

  • Aged C57BL/6(B6)-PD-1(-/-) congenic mice spontaneously developed characteristic lupus-like proliferative arthritis and glomerulonephritis with predominant IgG3 deposition, which were markedly accelerated by introduction of a Fas mutation (lpr) [1].
  • Cryoglobulinemia induced by a murine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms [2].
  • An IgG3 monoclonal antibody, 6-19, derived from unmanipulated MRL/MpJ-lpr/lpr mice, exhibiting cryoglobulin and anti-IgG2a rheumatoid factor activities, induces skin leukocytoclastic vasculitis and glomerulonephritis when injected into normal mice [3].
  • The present study indicates that the cryoglobulin activity associated with the gamma 3 isotype is critically involved in the pathogenicity of 6-19 anti-IgG2a rheumatoid factor monoclonal antibody and highlights the pathogenic relevance of autoantibodies of the IgG3 subclass in murine systemic lupus erythematosus [3].
  • These results suggest that the balance of formation of IgG3 autoantibodies with or without the cryoglobulin activity may be critical for the development of IgG3 cryoglobulin-mediated tissue lesions in murine lupus, particularly in MRL-lpr/lpr mice [4].

Psychiatry related information on AI324046

  • These repeated injections revealed that the immunogenicity of Ids was lost by switching to IgG1 and IgG3, restored when the Fc piece of IgG1 was removed, maintained by switching to IgE and monomeric IgA, and lost in polymeric IgA [5].

High impact information on AI324046

  • In vivo, chimeric mice containing only 3'EH-/- B cells were deficient in serum IgG2a and IgG3 [6].
  • A direct comparison of hybridomas and plasmacytomas making the same products (IgG3 or IgG1) indicates that hybridomas display a low frequency (2/12) of nonexpressed C alpha gene rearrangements in contrast to the high frequency (7/10) displayed by plasma-cytomas [7].
  • Our results show that both types of TH cells induce the secretion of IgM and IgG3, whereas clones of TH1 and TH2 cells specifically induce antigen-specific B cells to secrete IgG2a and IgG1, respectively [8].
  • Despite normal B cell development in CD21/35(-/-) mice, T cell-independent and -dependent antibody responses to low-dose antigens were significantly decreased, with a striking impairment in IgG3 responses [9].
  • The absence of TbetaRII in B cells leads to a reduced life span of conventional B cells, expansion of peritoneal B-1 cells, B cell hyperplasia in Peyer's patches, elevated serum immunoglobulin, and substantial IgG3 responses to a normally weak immunogen [10].

Chemical compound and disease context of AI324046

  • Although B7 and 5B10 were equally able to protect mice from a lethal challenge of E. coli 0111:B4 organisms, the outer core-specific IgG2a antibody was much more efficient at mediating the binding of human complement C3 than the O-antigen-specific IgG3 monoclonal antibody [11].
  • 7. RESULTS: MAb 8G9, an IgG3 directed against the O-antigen polysaccharide region of Escherichia coli 0111:B4 LPS, significantly reduced LPS-induced TNF-alpha secretion and promoted a more than 40-fold increase in LPS uptake by macrophages [12].
  • Immunoglobulin G1 (IgG1), IgG2a, and IgG2b switch variants were derived from an IgG3 monoclonal antibody directed against the VP3 envelope glycoprotein of lactate dehydrogenase-elevating virus (LDV) [13].
  • We tested if (1-->3),(1-->4)-beta-D-glucan (beta-glucan) can synergize with anti-GD2 monoclonal antibody (MoAb) 3F8 (mouse IgG3) in therapy of human neuroblastoma xenografts [14].
  • The IgM and IgG3 isotype preference in antibody responses to polysaccharide antigens in mice may translate to a lack of toxicity of antigen-antibody complexes during the course of infections with encapsulated pathogens [15].

Biological context of AI324046

  • Apoptosis, programmed cell death, was previously shown to be induced by the mAb anti-APO-1 (IgG3, kappa) by binding to the APO-1 cell surface Ag, a new member of the nerve growth factor/TNF receptor superfamily [16].
  • IgM, IgG2a, and IgG3 levels are reduced, and T cell-independent antibody production is absent [17].
  • Although cathepsin S-deficient mice have normal numbers of B and T cells and normal IgE responses, they show markedly impaired antibody class switching to IgG2a and IgG3 [18].
  • Here we demonstrate that mice, with the CBA/N phenotype have perferential deficiencies of IgM and IgG3 immunoglobulin expression, both when measured in serum and in cells secreting these isotypes, and that this deficiency is only partially corrected by polyclonal activation of B cells [19].
  • It is unaffected by treating the macrophages with trypsin or cytochalasin B and occurs at both 4 degrees and 37 degrees C. IgG3, like all other IgG subclasses, mediates phagocytosis [20].

Anatomical context of AI324046

  • To examine molecular characteristics of IgG3 responsible for GN in these mice, hybridoma clones producing IgG3 antibodies were prepared from one unmanipulated MRL/lpr mouse [21].
  • Fyn provides a signal for both the expansion of autoreactive T cells and the production of IgG3 anti-DNA autoantibody by B cells [22].
  • Second, the increased production of IgG antibodies, including the IgG3 subclass, was totally regulated by CD4+ T cells in both autoimmune mice [23].
  • These are IGM-bearing B lymphocytes from the normal spleen of unprimed mice, hybridomas prepared by fusing spleen cells from antigen-primed mice with the SP2/O permanent cell line and selected to secrete one of five different isotypes (IgM, IgG3, IgG1, IgG2 and IgA) and a set of plasmacytoma lines [7].
  • Passive sensitization with anti-OVA IgG1 but not IgG2a or IgG3 was similarly associated with development of skin test reactivity and increased AR after airway challenge, accompanied by an increase in eosinophils in bronchoalveolar lavage fluid [24].

Associations of AI324046 with chemical compounds

  • In the mutant mice, the production of IgG3 anti-DNA autoantibody was significantly (p < 0.005%) reduced, and glomerular deposits of IgG3 and C3 were remarkably diminished [22].
  • Second, cyclosporin A, which ameliorates GN in MRL/lpr mice despite autoantibody production, was found to reduce serum IgG3 and mRNA levels, associated with the revision of cationic shift of the serum IgG3 spectrotype seen in isoelectric focusing [25].
  • In response to repetitive polysaccharide antigens (T-independent type II (TI-II)) Pyk-2-deficient mice displayed marked suppression of IgM, IgG3 and IgG2a production [26].
  • The antibody 3F8, an IgG3 murine monoclonal antibody (MoAb) against disialoganglioside GD2, could target iodine-131 (131I) to established subcutaneous human neuroblastoma (NB) xenografts in BALB/c nude mice [27].
  • Here, Neil Greenspan and Laurence Cooper propose that intermolecular cooperativity, a novel mechanism of antibody binding, may help to explain the preferential expression of IgG3 antibodies in these responses [28].

Physical interactions of AI324046

  • These results suggest that IgG3-containing immune complexes represent the major source of cryoglobulins occurring in mice bearing the lpr gene [29].

Other interactions of AI324046

  • Both clones significantly augmented OPN expression in renal tubuli, but a non-nephritogenic IgG3 clone, 1G3, derived from the same MRL/lpr mouse, did not [30].
  • Because of their different in vitro activity we selected IgG3-, IgG2b-, and IgA anti-APO-1 to test their antitumor activity against solid human B lymphoblastoid tumors in SCID mice [16].
  • Rheumatoid factor activity was detected in all the IgG subclasses, but particularly elevated levels were seen in IgG3 and IgG1 [31].

Analytical, diagnostic and therapeutic context of AI324046

  • The cDNA sequence analysis of 7B6.8 antibody and the other IgG3 antibody, 1G3, non-nephritogenic, revealed that the C regions of the heavy and light kappa chains were completely the same between them [21].
  • To analyze further the effect of charge on cryoprecipitation, the sequence of an IgG3 monoclonal cryoprecipitating rheumatoid factor was modified by site-directed mutagenesis [32].
  • The serum concentrations of IgM, IgG1, IgG2b, IgG3 and IgA were determined in mice of C57BL/6 background, from weaning to one year of age, by quantitative isotype-specific, indirect double sandwich enzyme-linked immunosorbent assays (ELISAs) [33].
  • The segmental flexibility and complement fixation activity were measured of six genetically engineered molecules (the four human IgG isotypes, mouse IgG3 and rabbit IgG) and the remaining three mouse IgG isotypes, (IgG1, IgG2a and IgG2b), isolated previously by somatic cell genetic techniques [34].
  • In flow cytometry, there was weak reactivity with granulocytes, a reactivity also observed with two previously described highly specific Le(y) mouse mAbs--BR55-2 (IgG3) and B3 (IgG1) [35].


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  2. Cryoglobulinemia induced by a murine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms. Reininger, L., Berney, T., Shibata, T., Spertini, F., Merino, R., Izui, S. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  3. Immunoglobulin heavy chain constant region determines the pathogenicity and the antigen-binding activity of rheumatoid factor. Fulpius, T., Spertini, F., Reininger, L., Izui, S. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  4. Murine cryoglobulinemia: pathogenic and protective IgG3 self-associating antibodies. Berney, T., Shibata, T., Izui, S. J. Immunol. (1991) [Pubmed]
  5. Immunoglobulin heavy chain constant regions regulate immunity and tolerance to idiotypes of antibody variable regions. Reitan, S.K., Hannestad, K. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  6. A class switch control region at the 3' end of the immunoglobulin heavy chain locus. Cogné, M., Lansford, R., Bottaro, A., Zhang, J., Gorman, J., Young, F., Cheng, H.L., Alt, F.W. Cell (1994) [Pubmed]
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  8. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Stevens, T.L., Bossie, A., Sanders, V.M., Fernandez-Botran, R., Coffman, R.L., Mosmann, T.R., Vitetta, E.S. Nature (1988) [Pubmed]
  9. Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses. Haas, K.M., Hasegawa, M., Steeber, D.A., Poe, J.C., Zabel, M.D., Bock, C.B., Karp, D.R., Briles, D.E., Weis, J.H., Tedder, T.F. Immunity (2002) [Pubmed]
  10. TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo. Cazac, B.B., Roes, J. Immunity (2000) [Pubmed]
  11. Immunoprotective murine monoclonal antibodies specific for the outer-core polysaccharide and for the O-antigen of Escherichia coli 0111:B4 lipopolysaccharide (LPS). Coughlin, R.T., Bogard, W.C. J. Immunol. (1987) [Pubmed]
  12. Anti-endotoxin monoclonal antibodies inhibit secretion of tumor necrosis factor-alpha by two distinct mechanisms. Burd, R.S., Battafarano, R.J., Cody, C.S., Farber, M.S., Ratz, C.A., Dunn, D.L. Ann. Surg. (1993) [Pubmed]
  13. Increased efficacy of the immunoglobulin G2a subclass in antibody-mediated protection against lactate dehydrogenase-elevating virus-induced polioencephalomyelitis revealed with switch mutants. Markine-Goriaynoff, D., Coutelier, J.P. J. Virol. (2002) [Pubmed]
  14. Oral (1-->3),(1-->4)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma. Cheung, N.K., Modak, S. Clin. Cancer Res. (2002) [Pubmed]
  15. Monoclonal antibody-mediated toxicity in Cryptococcus neoformans infection: mechanism and relationship to antibody isotype. Lendvai, N., Casadevall, A. J. Infect. Dis. (1999) [Pubmed]
  16. Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. Dhein, J., Daniel, P.T., Trauth, B.C., Oehm, A., Möller, P., Krammer, P.H. J. Immunol. (1992) [Pubmed]
  17. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Wang, D., Feng, J., Wen, R., Marine, J.C., Sangster, M.Y., Parganas, E., Hoffmeyer, A., Jackson, C.W., Cleveland, J.L., Murray, P.J., Ihle, J.N. Immunity (2000) [Pubmed]
  18. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Shi, G.P., Villadangos, J.A., Dranoff, G., Small, C., Gu, L., Haley, K.J., Riese, R., Ploegh, H.L., Chapman, H.A. Immunity (1999) [Pubmed]
  19. Immunoglobulin subclass-specific immunodeficiency in mice with an X-linked B-lymphocyte defect. Perlmutter, R.M., Nahm, M., Stein, K.E., Slack, J., Zitron, I., Paul, W.E., Davie, J.M. J. Exp. Med. (1979) [Pubmed]
  20. A new Fc receptor on mouse macrophages binding IgG3. Diamond, B., Yelton, D.E. J. Exp. Med. (1981) [Pubmed]
  21. Cloning and cDNA sequence analysis of nephritogenic monoclonal antibodies derived from an MRL/lpr lupus mouse. Takahashi, S., Itoh, J., Nose, M., Ono, M., Yamamoto, T., Kyogoku, M. Mol. Immunol. (1993) [Pubmed]
  22. Suppression of autoimmune disease and of massive lymphadenopathy in MRL/Mp-lpr/lpr mice lacking tyrosine kinase Fyn (p59fyn). Takahashi, T., Yagi, T., Kakinuma, S., Kurokawa, A., Okada, T., Takatsu, K., Aizawa, S., Katagiri, T. J. Immunol. (1997) [Pubmed]
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  27. Complete tumor ablation with iodine 131-radiolabeled disialoganglioside GD2-specific monoclonal antibody against human neuroblastoma xenografted in nude mice. Cheung, N.K., Landmeier, B., Neely, J., Nelson, A.D., Abramowsky, C., Ellery, S., Adams, R.B., Miraldi, F. J. Natl. Cancer Inst. (1986) [Pubmed]
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  30. Augmentation of osteopontin expression in renal tubuli is independent of a histopathological type of glomerular lesions in mouse lupus nephritis. Sasaki, Y., Yamamoto, Y., Miyazaki, T., Ito, M.R., Nose, M., Watanabe, M. Pathol. Int. (2006) [Pubmed]
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  32. The effect of VH residues 6 and 23 on IgG3 cryoprecipitation and glomerular deposition. Panka, D.J., Salant, D.J., Jacobson, B.A., Minto, A.W., Marshak-Rothstein, A. Eur. J. Immunol. (1995) [Pubmed]
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