Lupus nephritis: the central role of nucleosomes revealed

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune syndrome characterized by autoantibodies to nuclear constituents. Some of these antibodies are diagnostically important, whereas others act as disease-modifying factors. One clinically important factor is autoantibodies against dsDNA and nucleosomes, which have overlapping diagnostic and nephritogenic impact in SLE. Although a scientific focus for 5 decades, the molecular and cellular origin of these antibodies, and why they are associated with lupus nephritis, is still not fully understood. A consensus has, however, evolved that antibodies to dsDNA and nucleosomes are central pathogenic factors in the development of lupus nephritis. In contrast, no agreement has been reached as to which glomerular structures are bound by nephritogenic anti-nucleosome antibodies in vivo. Mutually contradictory paradigms and models have evolved simply because we still lack precise and conclusive data to provide definitive insight into how autoantibodies induce lupus nephritis and which specificity is critical in the nephritic process(es). In this review, data demonstrating the central role of nucleosomes in inducing and binding potentially nephritogenic antibodies to DNA and nucleosomes are presented and discussed. These autoimmune-inducing processes are discussed in the context of Matzinger's danger model (Matzinger P: Friendly and dangerous signals: is the tissue in control? Nat Immunol 2007, 8:11-13; Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301-305; Matzinger P: Tolerance, danger, and the extended family. Annu Rev Immunol 1994, 12:991-1045) and Medzhitov's and Janeway's (Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002, 296:298-300; Medzhitov R, Janeway CA Jr: How does the immune system distinguish self from nonself? Semin Immunol 2000, 12:185-188; Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197-216) distinction of noninfectious self (NIS) and infectious nonself (INS). The mechanisms leading to production of potentially nephritogenic anti-nucleosome antibodies and to overt lupus nephritis are interpreted in the context of these paradigms.

Figure 1

A model to indicate how affinity maturation may affect the diagnostic and pathogenic impact of induced anti-dsDNA antibodies. Although short-lived stimuli result in antibodies that should be regarded as transient epiphenomenons, antibodies resulting from recurrent or sustained stimulation by immunogenic DNA (nucleosomes) may have strong clinical impact. (Modified from Moens U, Rekvig OP: Molecular biology of BK virus and clinical and basic aspects of BK virus renal infection. Human Polyomaviruses—Molecular and Clinical Perspectives. Edited by Khalili K, Stoner GL. New York, Wiley-Liss, 2001, pp 359–408).

Figure 2

A model to explain how a nonself molecule such as the DNA-binding polyomavirus T antigen, when physically linked to histones through complex formation with nucleosomes, may initiate processes that result in induction of antibodies to DNA. Expressed T antigen forms complexes with nucleosomes., DNA-specific B cells binding and processing such complexes may simultaneously present peptides derived from T antigen and histones. T cells not tolerant for T antigen will respond, produce IL-2, and proliferate. IL-2 has the potential to induce proliferation of anergic cells and terminate the state of anergy., During this process, anergic histone-specific T cells receive two different stimuli, the first as a nonspecific, bystander stimulus by IL-2 produced by T-antigen-specific responder T cells and the other by a conventional, antigen-specific stimulus by presented histone peptides. In this situation, T-cell anergy for histones may be terminated. Thus, if DNA-specific B cells present both T antigen and histones to responder T cells, activation of autoimmune, histone-specific T cells and production of anti-DNA antibodies will be the final result. If this process is sustained, affinity maturation of the anti-DNA antibodies may transform them into high-affinity anti-dsDNA antibodies as a consequence of somatic mutations, particularly within the variable CDR regions of the heavy chain,, (modified from Andreassen et al54). T cells marked in red indicate they are activated.

Figure 3

A principal outline of the impact of chromatin in lupus nephritis. In A, a typical transmission electron microscopy observation in lupus nephritis is glomerular basement membrane (GBM)-associated EDSs. By performing immune electron microscopy, it is evident that these EDSs, and only these, contain targets for autoantibodies in vivo (B, bound antibodies are stained with gold particles). In C, the EDSs are shown as dark unique structures. In D, we show how nucleosomes bind glomerular capillary membranes or the mesangial matrix (GBM) where they are observed as EDSs. These are in complex with antibodies reactive with nucleosomes (homologous recognition). Whether these have bound nucleosomes in situ, or whether nucleosomes and antibodies bound in the glomeruli as preformed immune complexes, has not been determined. In sum, this model is consistent with recently published data that demonstrate that the EDSs bind antibodies in vivo, that they bind experimental antibodies to dsDNA, histones, or transcription factors in vitro, and that they contain TUNEL-positive DNA., There is no evidence that nephritogenic anti-dsDNA antibodies cross-react with inherent glomerular constituents such as membrane structures or α-actinin in vivo (see text for details).