H-2 control of the magnitude and heterogeneity of the immune response.
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Animals↗
Biomedical subjects
T J Kipps
Publications and source records attributed to T J Kipps.
Regulation of antibody heterogeneity by suppressor T cells: diminishing suppressor T cell activity increases the number of dinitrophenyl clones in mice immunized with dinitrophenyl-poly(Glu,Lys,Phe) or dinitrophenyl-poly(Glu,Lys,Ala).
The anti-hapten responses to the dinitrophenyl (Dnp) conjugate of the random linear terpolymers poly(L-Glu,LLys,LPhe), GLphi, or poly(LGlu,LLys,LAla), GLA, are of highly restricted heterogeneity. Thus, individual mice of most responder strains express an average of two to four anti-Dnp clones to Dnp-GLphi or Dnp-GLA, as measured by isoelectric focusing techniques. To explore whether suppressor T cells regulate the heterogeneity of the anti-hapten response to Dnp conjugates of these polypeptides, various procedures aimed at reducing suppressor T-cell activity were tested for their ability to alter the restricted isoelectric focusing spectrotypes. These procedures, such as adult thymectomy, administration of low doses of cyclophosphamide, and in vivo treatment with anti-I-J antisera, significantly increased the magnitude and heterogeneity of the anti-Dnp antibody response to Dnp-GLphi and Dnp-GLA in strains of mice that possessed responder Ir genes. Such methods failed to alter the nonresponder status of mice that lacked the appropriate Ir genes. Thus, in systems under Ir gene control suppressor T-cell mechanisms appear to be involved in the regulation of the heterogeneity of hapten-specific B-cell responses.
Animals↗
[Analysis of the restricted dinitrophenyl (DNP) antibody response to the DNP conjugate of poly-(L-Glu56, L-LYS35, L-PHE9)].
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Antibody Formation↗
Idiotypic analysis of anti-GAT antibodies. I. Presence of common idiotypic specificities in both responder and nonresponder mice.
The synthetic terpolymer of L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) induced anti-GAT antibodies in D1.LP mice. Some of these antibodies shared common idiotypic specificities. The interaction between idiotypic antibody and anti-idiotypic antiserum was specifically inhibited by GAT and the closely related polymer of L-glutamic acid and L-tyrosine (GT) but not by the copolymer of L-glutamic acid and L-alanine (GA). The binding of labeled GAT by the anti-GAT antibodies was also specifically inhibited by the anti-idiotypic antiserum. These results indicated a close association of idiotypic determinants with the antibody-combining sites. Furthermore, such active site-related common idiotypic specificities were found in individual sera of both responder mice (D1.LP) and nonresponder mice (DBA/1) immunized with GAT and GAT-MBSA, respectively, indicating that both responder and nonresponder mice carry B cells with common clonotypes.
Alanine↗
Presence of common idiotypes on antibodies induced by glutamic acid-lysine-containing terpolymers in responder and nonresponder mice with the Ig-1b heavy chain allotype.
A B10.A (5R) responder mouse to the random linear terpolymer, poly--(Glu, Lys, Phe), GLphi, can produce immunoglobulins which bind poly-L (Glu, Lys), GL, that share idiotypic determinants with GL-binding antibodies produced by other members of the same strain. Expression of these common idiotypic determinants, termed BGL, is independent of the H-2 halotype and closely linked to the Ig-lb heavy chain allotype. Moreover, nonresponder mice with the Ig-lb heavy chain allotype, when immunized with GLphi that has been chemically coupled to an immunogenic carrier, chicken IgG, can produce GL-binding antibodies that share BGL idiotypic specificities with anti-GLphi antibodies produced by responder animals. Also, the responses to other GL-containing polymers, such as poly-L (Glu, Lys, Ala) and poly-L (Glu, Lys, Pro), which are under the control of distinct Ir genes, can stimulate the production of GL-binding antibodies that share common BGL idiotypic determinants with antibodies induced with GLphi. These findings are discussed with respect to their implications concerning the mechanism(s) of Ir gene control.
Animals↗
Regulation of rheumatoid factor synthesis.
Rheumatoid arthritis is associated with high titers of IgM and IgG autoantibodies against IgG (rheumatoid factors, RF) and is prevalent in individuals with the HLA haplotypes Dw4, Dw14 and DR1. Our investigations have aimed to determine the molecular genetic basis for RF autoantibody synthesis in people, in an effort to understand eventually how RF production may become improperly regulated in rheumatoid patients. The results have defined several cross-reactive idiotypes on the heavy and light chains of RFs that are serologic markers for specific immunoglobulin variable region genes. These autoantibody associated genes are highly conserved in human populations and are preferentially rearranged and expressed during early B cell development, and in certain lymphoproliferative diseases. They may be associated with a B cell subpopulation that is important for the processing and presentation to T cells of protein antigens trapped in immune complexes. These RF-associated idiotypes are eventually lost during the T cell dependent antibody diversification that accompanies rheumatoid arthritis. The stimuli for the diversification have not been clearly established. However, the rheumatoid arthritis disease susceptibility determinant on the beta-1 chain of individuals with the HLA Dw4, Dw14 or DR1 haplotypes is reproduced by the gp110 protein of the Epstein-Barr virus, and is a potent stimulus for T cell proliferation. Moreover, anti-gp110 antibodies are abundant in rheumatoid arthritis patients. Thus, it is possible that their continual binding and processing of gp110-IgG immune complexes by RF precursor B cells in the joints and other extravascular sites may lead to the emergence of self-reactive T cells that can trigger anti-IgG autoantibody synthesis in the absence of an external antigen.
Arthritis, Rheumatoid↗
Autoantibody production in Sjögren's syndrome: a hypothesis regarding defects in somatic diversification of germ line encoded genes.
Patients with primary Sjögren's syndrome (SS) have rheumatoid factor (anti-IgG Fc antibody, RF) in their sera that contains a crossreactive idiotype (CRI) defined by monoclonal antibody 17-109. This CRI is shared by SS patients and certain patients with Waldenstrom's macroglobulinemia. This CRI was not found in increased frequency in RF from rheumatoid arthritis patients lacking SS. The structural basis for this CRI is the highly conserved kappa chain of the Vk IIIb sub-subgroup. In SS patients, the CRI is present on both IgA RF and IgM RF, accounting for 5-20% of the total RF. Recent studies have shown that a germ line encoded kappa variable region gene (Humkv 325, cloned from a placental DNA library) has DNA sequence that encodes the variable region amino acid sequences of CRI positive kappa chains. Using MoAb 17-109, we have been able to determine the tissue distribution of CRI+ B-cells. We found an increased frequency in the salivary gland biopsies of SS patients and also in their intestinal mucosal tissues (i.e. Peyer's patch). In comparison, we also detected an increased frequency of CRI+ B-cells in the Peyer's patch regions of normals. Taken together, these results suggest that CRI+ B-cells may play an important role in normal mucosal immunity and these CRI+ B-cells have migrated to the salivary gland in SS patients as part of the inflammatory process directed at autoantigens or exogenous antigen(s) located at a mucosal surface.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗