Alcances y limitaciones de la investigación

SLE is a complex disease with polyclonal activation of B cells resulting in autoantibodies and impaired clearances of immune complexes. Tissue damage is caused by deposition of immune complexes which leads to inflammation, vasculopathy and sclerosis. Anti-double stranded (ds) DNA antibodies are a diagnostic feature of SLE and their pathogenic potential is derived from their ability to form immune deposits (Ebling et al 1980, Vlahakos et al 1992a, Gilkeson et al 1995). The presence of anti-DNA antibodies in the serum and in the kidneys of affected individuals with nephritis has been shown both in mice and in humans (Krishnan et al 1967, Koffler et al 1974, Hecht et al 1976, Andrews et al 1978). Nephritogenic anti-DNA antibodies are predominantly high avidity IgG antibodies with preferential reactivity to dsDNA, a cationic charge and are able to fix complement (Hahn et al 1982, Foster et al 1993).

Adoptive transfer of monoclonal anti-DNA antibodies in non autoimmune mice has been shown to produce nephritis (Vlahakos et al 1992b,Ohnishi et al 1994, Gilkeson et al 1995). In addition, administration of bacterial DNA induces formation of anti-DNA antibodies in non autoimmune mice followed by development of nephritis (Gilkeson et al 1993). Ehrenstein et al (1995) investigated the potential of five human IgG anti-DNA antibodies derived from lupus patients to produce glomerular immune deposits. The hybridomas secreting these antibodies were administered intraperitoneally to severe combined immunodeficiency (SCID) mice. Three (B3, 35.21, 33.C9) of five antibodies were detected in the kidneys. B3 and 35.21 both gave a positive ANA reaction that was seen in other tissues as well while in contrast 33.C9 deposited in the glomeruli in the mesangium and capillary wall. This study demonstrates that some human monoclonal IgG anti-dsDNA antibodies are capable of binding to the glomerulus while others can penetrate cells and bind to nuclei in vivo. Ravirajan et al (1998) generated two IgG DNA binding monoclonal antibodies (mAb) RH-14 and DlL-6 from the peripheral blood lymphocytes of two SLE patients with glomerulonephritis using the heteromyeloma cell line CBF-7. RH- 14 is an IgGl lambda antibody which also bind single stranded DNA, histones and nucleosomes. DlL-6 is an lgG3 lambda antibody with restricted antigen binding specificity. The nephritogenic properties of these mAbs were analysed by implanting and growing the hybridoma cells secreting the mAb in the peritoneum of SCID mice. The animals that received RH-14 hybridoma produced higher levels of proteinuria compared to the groups that received DIL- 6. Electron microscopy of kidney sections from all RH-14 implanted animals

showed granular immunoglobulin deposits in the renal glomerular capillaries and mesangium. These studies show that anti-DNA antibodies of the IgG isotype which sufficiently fix complement are found in the nephritic kidney and deposition of these antibodies in the kidneys is sufficient to induce renal damage.

Other potentially nephritogenic autoantibodies in human lupus include anti-histones, anti-nucleosomes, anti-Clq, anti-fibronectin, anti-collagen, anti-Ro and anti-ribosome (Lefkowith et al 1996). There are three mechanisms hypothesized to explain the deposition of immune complexes in the kidney. The first is the circulating immune complex hypothesis which proposes that immune complexes that are preformed in the periphery get passively trapped in the glomeruli. The second model suggests the direct binding of crossreactive anti- DNA antibodies to glomerular antigens leading to immune deposit formation. In studies by Sabbaga et al (1990) they showed that anti-DNA antibodies from the kidney eluates were the most crossreactive exhibiting binding to polynucleotides, phospholipids and the SmRNP complex.

The third hypothesis is the “planted antigen” hypothesis which suggests that intracellular antigens that are released after cell death, bind to certain sites within the glomerulus and act as antigenic determinants for anti-DNA antibodies leading to immune deposit formation.

DNA, histones and nucleosomes have all been shown to bind glomeruli or glomerular basement membrane (GBM) (Izui et al 1976, Schmiedeke et al 1989,Coritsidis et al 1995,Termaat et al 1992). These antigens may then be bound by autoantibodies such as anti-DNA antibodies and anti-nucleosomal antibodies and cause renal disease.

In studies by Chan et al (1999), they have shown that independent of serum autoantibody, functional B cells expressing surface immunoglobulin are essential for disease expression. In studies by Chan et al, the individual contributions of circulating antibodies and B cells were analysed using MRL/lpr mice that expressed a mutant transgene encoding surface immunoglobulin (Ig) but which did not permit the secretion of circulating Ig. These mice developed nephritis, characterized by cellular infiltration within the kidney, indicating that B cells themselves, without soluble autoantibody production, exert a pathogenic role.

Boes et al (2000) showed that in the absence of secreted IgM, there was an accelerated development of IgG autoantibodies to dsDNA and histones in lupus prone 1 ymphoproliferative (Ipr) mice. These mice also showed more abundant deposits of immune complexes in the glomeruli and showed severe glomerulonephritis and succumbed to the disease at an earlier age. These findings suggest that secreted IgM or IgM autoantibodies produced naturally (or as part of an autoimmune response) may lessen the severity of autoimmune pathology associated with IgG autoantibodies.