Production of pathogenic antibodies: cognate interactions between autoimmune T and B cells

Abstract

A select population of autoimmune T-helper (T(H)) cells drive the production of pathogenic anti-DNA autoantibodies in SLE. These T(H) cells recognize nucleosomal peptides that are processed and presented by the anti-DNA B cells that they help. The critical peptide epitopes for the T(H) cells reside in the core histones of the nucleosome particle. Remarkably, the nucleosomal peptide epitopes do not obey the rule of MHC-restriction; they can be promiscuously presented and recognized in the context of diverse MHC alleles. Such promiscuous antigens, called pantigens, are also recognized by autoimmune T cells, in a degenerate fashion, and this promiscuous recognition is conferred by the lupus TCR alpha chains. High-affinity interactions between the lupus TCRs and MHC-nucleosomal peptide complex due to reciprocally charged residues probably overcome the requirement for MHC restriction. These studies open up the possibility of developing 'universally' tolerogenic epitopes for therapy of lupus in humans despite their diversity of HLA alleles. The results also have profound implications regarding the selection of autoimmune T cells in the lupus-prone thymus and their expansion in the periphery. Furthermore, the T(H) cells, as well as B cells of lupus, have a regulatory defect causing markedly increased and prolonged expression of CD40 ligand (CD40L), which mediates abnormal co-stimulatory signals to autoimmune B cells, sustaining the production of pathogenic autoantibodies. These observations suggest a new paradigm for B cell hyperactivity in lupus and provide alternative targets for immunotherapy. Indeed, giving only three injections of anti-CD40L antibody in a one-week period to mice with manifest lupus selectively blocks the pathogenic autoimmune response and delays the development of lupus nephritis by one year (equivalent to three decades in humans). Thus, possession of promiscuous, high-affinity receptors and prolonged expression of CD40L by lupus T cells probably lowers activation threshold, leading to an autoimmune response against nucleosomes derived from apoptotic cells that are normally ignored by the immune system.