Antibodies lupus nephritis

Anti-dsDNA antibodies are both specific and pathogenic to SLE. As mentioned previously, these autoantibodies are produced by an antigen-driven mechanism. They are organ-specific, especially kidney. We will discuss the close relationship between anti-dsDNA and lupus nephritis and the proposed mechanism by which anti-dsDNA leads to lupus nephritis. 

The close correlation between disease activity of SLE and level of anti-dsDNA has been documented repeatedly (D4, L24). Anti-dsDNA also represents a reliable marker for acute exacerbation of disease activity (S37, T3). Some report that high-avidity anti-dsDNA correlates with renal manifestations and active lupus nephritis (S37), whereas low-affinity antibodies are associated with cerebral complications (S21, S22). 

Evidence That Anti-dsDNA Antibodies Cause Lupus Nephritis... 

In spite of the strong evidence just cited, lupus nephritis is not invariably correlated with serum anti-dsDNA. (NZB x NZWjFi x NZW backcross mice may develop nephritis without anti-DNA antibodies (Y5). Patients with lupus nephritis also do not always have anti-dsDNA antibodies or have only low levels of antibodies (A23, H7, L21). Swaak et al. noted a sharp drop at the time of flareup of anti-dsDNA antibodies accompanied by low levels of Clq and C3 in patients with severe SLE flares (S36). 

Circulating Immune Complex. Anti-dsDNA/DNA immune complexes have long been considered responsible for the development of lupus nephritis. The level of immune complexes in SLE patients with active disease detected by monoclonal anti-DNA antibodies is higher (T7). About half of SLE patients had elevated amounts of DNA antigen in the immune complexes (N4, R2, S27). 

Recent studies show that nucleosome/antinucleosome immune complexes contribute more to lupus nephritis. Serum anti-dsDNA reactivity is always associated with antinucleosome reactivity (A18, B26, B28, B29, C9). Even the highly purified monoclonal and polyclonal anti-dsDNA antibodies selected by affinity chromatography bind to isolated dsDNA and also to nucleosomes (C9, L23). Hybridoma-secreting anti-DNA can also form immune complexes in vitro with nucleosomes released from dying hybridomas in culture (F9). Finally, the binding of an anti-DNA antibody to a nucleosome may render the immune complex more positive and thereby make it more prone to bind to the GBM (T2). 

Suenaga, R., and Abdou, N. I., Anti-(DNA-histone) antibodies in active lupus nephritis. J. 

Similar antibodies are found in patients with systemic lupus erythematosus and it has been proposed that lupus nephritis results from IgG binding to I(H2A-H2B)-DNA] in nucleosomal material that is deposited in the glomerulus by the circulation (78). Because renal involvement is not a feature of drug-induced lupuS/ it appears that factors other than antibody binding to I(H2A-H2B)-DNA] are responsible for nephritis. However/ the systemic symptoms of drug-induced lupus may result from inflammatory mechanisms involved in the clearance of immune complexes. 

Another phase-3 placebo-controlled trial called PEARL (Program Enabling Antibody Reduction in Lupus) was conducted in the USA in 317 patients with lupus nephritis, who were treated with abetimus 100 mg/week. The trial was completed in December 2002 and preliminary results were reported in February 2003. However, in April 2003, La Jolla Pharmaceuticals ended the trial, in order to conserve resources for the continued development of the drug. 

Clinical trials have revealed that diseases that are related directly to excessive TNF production, such as septic shock, GVHD, and lupus nephritis, may be amenable to treatment either with anti-TNFa antibodies or with antiinflammatory agents that reduce TNF production, such as cyclosporin A and steroids. ... 

Immune complexes (IC). Antigen-antibody complexes formed every time antibody meets antigen. May become pathogenic by triggering a variety of inflammatory processes if not removed effectively from circulation or if formed in situ. Immune complexes play a role in vasculitic manifestations of autoimmune diseases (e.g. lupus nephritis). 

Assays show that shed and solubilized TAM (Tyro3, Axl, MER) receptors circulate in high levels in the blood of patients with active systemic lupus erythematosus (SLE). These high titers of solubilized receptors correlated directly with disease activity, especially with that of lupus nephritis of low Clq and high anti-DNA antibody levels. In contrast, solubilized sMER levels did not correlate... 

A 47-year-old asplenic man with hemophilia, co-infected with HIV and hepatitis B, was given interferon. He developed a rash, abdominal pains, and a headache and later developed grade IV lupus nephritis. Antinuclear antibody (ANA), which had formerly been negative, became strongly positive (>1 1280, homogeneous) in association with raised anti-double-stranded DNA (dsDNA) antibodies (>1 100), and hypocomplementemia. 

Several studies have reported that retinoids are effective for animal models of autoimmune diseases. Lupus nephritis is a major cause of mortality among systemic lupus erythematosus patients. ATRA inhibits IFN-y cytokine production from Thl and production and deposition to the kidneys of anti-DNA antibody IgG2a, and suppresses proteinuria and renal involvement in NZB/WFl mice, which are used as a lupus nephritis model (Nozaki et al. 2005). In an open clinical trial, seven patients with active lupus nephritis were treated with ATRA. As a result, four patients showed improvements in clinical symptoms and laboratory findings, including proteinuria and anti-dsDNA antibody levels. There were no adverse effects of ATRA therapy in any patient (Kinoshita et al. 2009). 

The presence of anti-dsDNA antibodies correlates with nephritis both in mice and in human patients (A21, H7). Anti-dsDNA antibodies are concentrated within human and murine glomeruli in vivo, and injection of DNA to lupus-prone mice that are positive for anti-dsDNA antibodies accelerates the progression of nephritis (El, K7, L5). Injection of anti-dsDNA monoclonal antibodies into nonautoimmune mice also has been shown to produce nephritis (D5,05, G7, V9). In addition, injection of bacterial DNA induces the formation of anti-DNA antibodies in nonautoimmune mice and subsequent development of nephritis (G8). 

Siegert, C., Daha, M., Westedt, M. L., van der Voort, E., and Breedveld, F., IgG autoantibodies against Clq are correlated with nephritis, hypocomplementemia, and dsDNA antibodies in systemic lupus erythematosus. J. Rheum. 18, 230-234 (1991). 

Early, G. C., Laman, J. D., Zhao, W., Noelle, R. J., and Burns, C. M. Anti-CD40 ligand antibody treatment of NZB/NZW mice prevents the development of lupus-like nephritis without generating an antibody response in responding mice. 

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