Histones are a set of highly cationic proteins essentially involved in the binding and compaction of DNA in the cell nucleus chromatin (1-3). In mammals, five subclasses of histones exist: H1 (f1), H2a (f2a2), H2b (f2b), H3 (f3), and H4 (f2a1) (4,5), whereby four histones form an octameric core protein aggregate (H2a, H2b, H3, H4) around which a 145-bp DNA molecule is wrapped, forming the core particle followed by a variable (-55 bp) DNA region, complexed with H1 (6). In the cell nucleus, histones and DNA are present in similar quantities .These components of the cell nucleus are two of the most important antigens for autoantibody formation in SLE (7-12), and it has been reported that the titers of both groups of autoantibodies correlate well with disease activity (13-16).A prominent manifestation oforgan involvement in SLE patients is the occurrence of immune complex (IC)' glomerulonephritis . After the original report by Koffler et al. (17), attention has been focussed on the role of DNA-anti-DNA IC for >20 yr. Two proposals have been widely discussed in connection with the glomerular deposition of DNA-anti-DNA complexes: the now unfashionable notion that preformed soluble ICs can locate in the glomerular filter (18); and second, an affinity of DNA for the glomerular basement membrane (GBM) in vivo has been suggested (19-23), which could then initiate in situ IC formation. Extensive studies in animals on the kinetics and clearance of circulating free or immune complexed DNA (24-27) in regard to size and strandedness of DNA, however, revealed rapid nonrenal uptake and clearance. Prolonged DNA persistence is difficult to explain by accepted concepts; new proposals are needed (28). Contradictory findings on the occurrence of free or IC-bound DNA in sera from normal individuals and SLE patients have been reported (for review see reference 29). There are a number of technical problems involved here and it is now accepted that DNA-anti-DNA immune complexes represent only a minor part of the ICs found in lupus patients, and that increased levels ofcirculating DNA are found in a variety of conditions in which lysis ofcells occurs . Preliminary studies by Fournie (29) suggest that nucleosomes, which consist ofDNA This work was supported by the Deutsche Forschungsgemeinschaft, Ba 907/1-1.

In spite of intensive endeavours, attempts to identify nephritogenic antigens in cases of immune complex glomerulonephritis have not yielded convincing results. Cationic antigens can have high affinity for the glomerular basement membrane and are prime candidates as nephritogens. They can be expected to play a role in post-infectious and in autoimmune glomerular disease. Histones show great promise in the latter case: we are able to demonstrate (1) a high affinity for the glomerular basement membrane and (2) their ability to promote glomerular deposition of anionic antigens as an additional target. Histones were detectable in glomerular deposits in two murine models of glomerulonephritis: the spontaneous lupus-like disease of NZB/W F1 mice and in graft-versus-host disease. We propose that histones may be responsible for the induction of glomerulonephritis in lupus-like syndromes, as well as other types of autoimmune renal disease. As an analogue, histone-like proteins from micro-organisms may also be responsible for glomerular disease in post-infectious nephritis.

SUMMARYChronic grafl-vcnwA-host disease (GVHD) was induced in female (C57 B10S/DBA/2)F| hybrid mice with two successive injections of lymphoid cells from parental DBA/2 strain. Serial bleedings of 27 GVHD mice were screened with a panel of antigens including the five histones HI, H2A, H2B, H3 and H4, 15 histonc peptides. core particles. dsDNA. heat-shoek proteins hsp70 and ubiquitin, a branched peptide of ubiquitinaled H2A (U-H2A), poly(ADP-ribose) and SSB/l,a protein. The predominant IgG response to histone peptides was directed against regions 204-218 of HI, 1-25 of H2B and 1 29 of H4. GVHD mice also produced IgG antibodies lo dsDNA and chromatin core particles as reported previously. IgG antibodies reacting with dsDNA appeared before antibodies to core particles and histones. Raised levels ofantibodies to U'H2A. but not to monomeric ubiquitin. were also found. While the level ofantibodies to dsDNA. histones and core particles decreased significantly before ihe appearance of proteinuria, suggesting their involvement in glomerular injury, the longitudinal pattern of anti-U-H2A peptide response was apparently not linked to the manifestation of lupus nephritis in GVHD mice.

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