title: Cytokine imbalance and autoantibody production in T cell receptor-alpha mutant mice with inflammatory bowel disease.
abstract: Spontaneous inflammatory bowel disease (IBD) resembling human ulcerative colitis develops in mice mutant for the T cell receptor alpha gene (TCR-alpha-/-). TCR-alpha-/- mice lack TCR-alpha/beta+ cells but contain TCR-gamma/delta+ cells and a small population of a unique CD4+, TCR-alpha-/beta+(low) cells. Since all the immunoglobulin (Ig) classes are present in these mice, help to B cells must be provided by cells other than TCR-alpha/beta+ cells. In the present study, we found serum levels of IgG1 and IgG2 to be markedly increased in TCR-alpha-/- mice with IBD as compared to TCR-alpha-/- mice without IBD or TCR-alpha+/- controls. An increase in IgG1-, IgG2a- and IgA- but not IgM-secreting mesenteric lymph node (MLN) B cells was detected in TCR-alpha-/- mutant mice. There was also a marked increase in MLN B cells secreting autoantibody (IgG) to tropomyosin, a cytoskeletal protein. Examination of the hyperplastic MLN showed a marked increase in the number of B, TCR-delta+, and CD4+ TCR-alpha-/beta+ cells, similar to the cell population observed at the site of colonic inflammation. Analysis of spontaneous cytokine production by MLN cells using an enzyme-linked immunospot assay, immunohistochemistry, and reverse transcription/polymerase chain reaction showed a decrease of interleukin 2 (IL-2) but a marked increase of IL-4 and interferon gamma (IFN-gamma) production in TCR-alpha-/- mice with IBD as compared to TCR-alpha-/- mice without IBD and TCR alpha+/- control mice. Both TCR-alpha-/beta+ and TCR-delta+ cells were found to be capable of producing IL-4; IFN-gamma was produced mostly by non-T cells, many of which were shown to be CD3- NK 1.1+ cells. We propose that the cytokine imbalance present in these mice results in expansion of B cells, production and switching of autoantibodies to IgG2 subclass, and development of IBD. It is possible that the unusual CD4+ TCR-alpha-/beta+ population and expanded TCR-gamma/delta+ population present in TCR-alpha-/- mice plays a central role in this abnormal immune response.
authors.affiliation: Immunopathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mizoguchi
authors.forename: E
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: C
authors.initials: C
authors.lastname: Chiba
authors.forename: G M
authors.initials: GM
authors.lastname: Spiekermann
authors.forename: S
authors.initials: S
authors.lastname: Tonegawa
authors.forename: C
authors.initials: C
authors.lastname: Nagler-Anderson
authors.forename: A K
authors.initials: AK
authors.lastname: Bhan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000032:analysis / Q000096:biosynthesis; D016130:Immunophenotyping; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D017931:DNA Primers; D007132:Immunoglobulin Isotypes; D016693:Receptors, Antigen, T-Cell, alpha-beta