The autoantigen-binding B cell repertoires of normal and of chronically graft-versus-host-diseased mice.

Abstract

A quantitative analysis of the frequencies of autoantibody-producing B cells in GVHD and in normal mice has been undertaken by generating collections of hybridomas of activated B cells. These hybridomas secreted sufficient quantities of Ig to allow binding analyses on a panel of autoantigens. B cells have been activated in a variety of ways. In vivo they were activated by injection of alloreactive T cells of one parent, leading to GVHD by a foreign antigen, sheep erythrocytes, in a secondary response, or by the polyclonal activator LPS. B cells from an experimentally unstimulated animal were used for an analysis of the normal background. In vitro B cells were activated by alloreactive T cells or by LPS. The frequencies of hybridomas and, therefore, of activated B cells producing autoantibodies to DNA or to kidney were not significantly different in mice activated by a graft-vs.-host T cell response as compared with B cell populations activated by any of the other procedures. They were found to compose 7.1-17.1% of the total repertoire of activated B cells. Moreover, the frequencies of autoantibody-producing activated B cells does not change with time after induction of the graft-vs.-host reaction. The pattern and frequencies of autoantigen-binding specificities to cytoskeleton, smooth muscle, nuclei, mitochondria, and DNA were not found to be different in any of the groups of hybridomas. The single notable exception, found in GVHD mice, were hybridomas producing autoantibodies to kidney proximal tubular brush border. These results allow the conclusion that autoantigen-binding B cells exist in an activated state in GVHD mice, as well as in mice activated by a foreign antigen or by a polyclonal activator, in B cell populations activated in vitro either by alloreactive T cells or by a polyclonal activator, and even in the background of experimentally unstimulated animals. T cell-mediated graft-vs.-host activation, in large part, does not lead to a selective expansion of autoantigen-binding B cells. The main difference between the graft-vs.-host-activated B cell repertoire and all others is that approximately 90% of teh autoantibodies were of the IgG class, whereas al autoantibodies found in the other groups were IgM.

Effective treatment of experimental lupus nephritis by combined administration of anti-CD11a and anti-CD54 antibodies

“…Additionally, the blockage of the CD11a/CD54 co-stimulatory pathway in T-B cell interaction or in antigen presentation [31,38] may have interfered with the epitope specificity of the autoantibodies produced. Several studies suggest that in chronic GVHD, and in other models of immune complex glomerulonephritis, pathogenic autoantibodies are secreted by B cells that have received a 'second signal' after being polyclonally activated [39][40][41][42]. The importance of the epitope specificity of autoantibodies in the induction of proteinuria was recently established in active Heymann nephritis [43].…”

The Experimental Model of the Autoimmune Glomerulonephritis Induced by the Chronic Graft versus Host Reaction

“…There are a polyclonal activation of B cells, an increase of a total IgG level, a formation of multiple autoantibodies including antibodies to DNA. Autoantibodies found in this GVHR are of the IgG class whereas antibodies binding to a variety of self antigens and found in the peripheral blood of normal individuals are of the IgM class (Rolink et al, 1987). Chronic GVHD results in a development of autoimmune disorder similar human systemic lupus erythematosis (SLE) and in a formation of lupus-like immune complex glomerulonephritis (Via & Shearer, 1988).…”

Starting at the end

“…He was one of the rare immunologists who could do an adoptive transfer experiment, and he was thinking with a mind prepared for autoimmunity in the immune system. Hence, we joined to analyze the autoreactive repertoire of mice in LPS-polyclonally activated B cells cloned by limiting dilution [31]. Ton began to grow into the role of the elder in the lab, taking care of graduate students such as Andreas Strasser, Ulf Grawunder, Dirk Haasaer and Edwin ten Boekel whenever I was gone.…”

“…Within these polyclonally activated B cell populations, we measured the repertoires of antigen-specific, idiotype-expressing B cells in normal, immunodeficient, autoimmune-prone and graft-versus-host-diseased mice [28][29][30][31].…”