title: Liver-infiltrating T helper cells in autoimmune chronic active hepatitis stimulate the production of autoantibodies against the human asialoglycoprotein receptor in vitro.
abstract: Autoantibodies against the human asialoglycoprotein receptor (ASGPR) occur in the sera of patients with autoimmune liver disorders. Liver-infiltrating T cell clones that specifically recognize the ASGPR have been described in patients with autoimmune chronic active hepatitis (AI-CAH) and primary biliary cirrhosis (PBC). Recently, we have shown that peripheral blood mononuclear cells (PBMC) from patients with AI-CAH or PBC but not chronic viral hepatitis secreted anti-ASGPR antibodies in vitro. In this study we characterized the influence of liver-infiltrating T cells on the secretion of ASGPR-specific autoantibodies by autologous B cells in cell culture supernatants. T cell clones from liver biopsies of three patients with chronic autoimmune liver disorders (one with AI-CAH, two with PBC) were isolated and investigated for their proliferative response to soluble ASGPR and their helper function provided to autoantibody-secreting B lymphocytes. PBMC from these patients secreted autoantibodies spontaneously in their cell culture supernatants and showed a proliferative response to ASGPR. T cell-depleted PBMC, however, lacked spontaneous antibody secretion. Four CD4+CD8- liver-infiltrating T cell clones showed a proliferative response to ASGPR and also induced spontaneous anti-ASGPR antibody production in cell culture supernatants when added to autologous T cell depleted PBMC. Activated supernatants of these T cell clones failed to induce antibody production. None of seven CD4+CD8- and two CD4-CD8+ T cell clones non-responding to ASGPR provided this help for antibody secretion. Anti-ASGPR secretion in vitro could not be inhibited by the addition of MoAbs raised against monomorphic determinants on HLA class II molecules. The addition of purified ASGPR or polyclonal-activating pokeweed mitogen showed no influence on the production of autoantibodies in these cultures. These data show that B lymphocytes require T cell help for the production of ASGPR-specific antibodies. This help can be provided by ASGPR-responsive T helper cells via cellular interactions.
authors.affiliation: First Department of Internal Medicine, University of Mainz, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Löhr
authors.forename: U
authors.initials: U
authors.lastname: Treichel
authors.forename: T
authors.initials: T
authors.lastname: Poralla
authors.forename: M
authors.initials: M
authors.lastname: Manns
authors.forename: K H
authors.initials: KH
authors.lastname: Meyer zum Büschenfelde
mesh_terms: D000328:Adult; D037263:Asialoglycoprotein Receptor; D001323:Autoantibodies / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002478:Cells, Cultured; D005260:Female; D006521:Hepatitis, Chronic / Q000276:immunology*; D006801:Humans; D008099:Liver / Q000276:immunology*; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
chemical_list: D037263:Asialoglycoprotein Receptor; D001323:Autoantibodies; D015704:CD4 Antigens; D016827:CD8 Antigens; D011971:Receptors, Immunologic