Do naturally occurring autoantibodies participate in the constitution of the pathological B-cell repertoire in systemic lupus erythematosus?
Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune diseases. In both human and mouse SLE diseases, the autoimmune response targets a restricted set of autoantigens. Many of them are nucleic acids and proteins involved in the synthesis and processing of DNA or RNA, a characteristic which should be taken into consideration to elucidate the origins of non organ-specific autoantibodies. Several observations, in particular those obtained from experimental models of SLE induced in normal mice, suggest that the breakdown of B-cell tolerance occurs in the periphery. Herewith, we present data further supporting the proposition that SLE-associated autoantibodies originate from natural autoantibody-secreting B cells activated in the internal environment of lupus mice. Thus, one may hypothesize that certain clones of the expanded primary B-cell repertoire are selected to differentiate into harmful IgG autoantibody-secreting clones, thereby raising the question of the nature of immunogenic structures involved in SLE. Our analysis of the immunochemical and structural properties of anti-nucleosome and anti-myeoloperoxidase monoclonal antibodies derived from (NZB x NZW)F1 mice leads us to propose that complexes formed by the association of DNA and DNA-binding proteins and, more generally, by anionic molecules associated with proteins, possess a selective advantage over other autoantigens to induce the differentiation of certain B-cell clones and the very special profile of the SLE-autoimmune response. These DNA/DNA-protein complexes could also play a role in the activation of the T-cell compartment in SLE.
Gilbert
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D
Groupe de Recherche en Immunopathologie (Institut Fédératif de Recherche Multidisciplinaire sur les Peptides, IFR 23), Hôpital Charles Nicolle et Faculté Mixte de Médecine et de Pharmacie, Rouen, France.
Brard
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F
Jovelin
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Tron
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F
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D009154:Mutation
D000888:Antibodies, Anti-Idiotypic; D001323:Autoantibodies