Systemic lupus: basic mechanisms and prospects for specific immunotherapy

Abstract

Nucleosomes are the primary immunogens that initiate the pathogenic autoimmune response in SLE. The production of pathogenic anti-nuclear antibodies in murine as well as human lupus is mediated by a MHC class-II restricted, cognate interaction between select populations of autoimmune T helper (T_h) cells and autoimmune B cells that recognize epitopes in the different molecular components of the nucleosome particle. In the SNF₁ model of lupus, we have localized the critical peptide autoepitopes for lupus nephritis-inducing T_h cells in the core histones of nucleosomes, at amino acid positions 10–33 of H2B, and 16–39 and 71–94 of H4. Remarkably, the nephritogenic epitopes are located in the regions of histones that are also targeted by lupus autoantibodies, as well as the sites where the histones contact with DNA in the nucleosome, indicating that they are specially protected during antigen processing. The localization of the critical peptide autoepitopes in nucleosomes is a basic step towards defining how the pathogenic T_h cells emerge in lupus. In addition, the pathogenic T_h cells and B cells of lupus have a regulatory defect in the expression of CD40 ligand (CD40L or gp39), which mediates abnormal co-stimulatory signals sustaining the production of pathogenic autoantibodies. Immunotherapy that specifically blocks the pathogenic T and B cell interaction in lupus can be developed based on these studies.

Key words::

• autoimmunity
• systemic lupus
• T helper cells
• anti-DNA autoantibodies
• nucleosomes
• immunotherapy