A Key Role for IL-17 in SLE Nephritis?







    Interleukin (IL)-17 is a "hallmark" proinflammatory cytokine and is made primarily by the T helper cell subset, Th-17. Multiple recent studies have shown that inflammation instigated by IL-17-producing cells is key to the development and pathogenesis of several human autoimmune diseases (see, for example, this review). One of these autoimmune diseases is systemic lupus erythematosus [SLE; a.k.a. "lupus"; see this article for a review], an autoimmune disorder in which patients make antibodies directed against their own tissues and constituent cells, principally double stranded DNA and nucleosomes (a by-product of defective apoptosis). Deposition of these “autoantibodies” within various organs can eventually lead to organ failure and even death. Amongst the various organs in the body, kidneys seem particularly susceptible with roughly 50% of SLE patients developing kidney disease (lupus glomerulonephritis).


     There is currently no cure for SLE, but a number of treatment options are available, including corticosteroids, hydroxychloroquine, and other select immunosuppressive agents such as mycophenolate, methotrexate, and cyclophosphamide. In March of 2011, the FDA approved the use of belimumab (BENLYSTA®; HGS-GSK) for the treatment of SLE patients with active disease despite standard treatment (ref). Belimumab is a fully human mAb that targets and blocks B Lymphocyte Stimulator [BLyS; a.k.a. BAFF], a protein that plays a key role in the activation and differentiation of B cells.   Belimumab is the first new therapy for SLE approved in over 50 years and has helped inspire a host of other therapies that are in advanced clinical development (see this article  and this article). However, belimumab efficacy is modest and the mAb is not approved for those patients with renal or CNS disease involvement.  Moreover, there is no evidence, yet, that belimumab treatment impacts long term survival or the incidence of disease-related cardiovascular disease.


     Thus, research is focused on developing new therapies directed at targets responsible for progression of potentially fatal lupus glomerulonephritis.  While IL-17 has been suspected of playing a role in the pathogenesis of lupus nephritis, the linkage has been largely associative (see papers such as this  and this).


    Now a team lead by Ulrich Siebenlist at the NIH has provided more definitive proof that IL-17 drives lupus nephritis. As noted in their article  just appearing in advance online form at Immunity, the authors “….have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcγR2b-deficient mouse model of lupus.” It has previously been shown that FcγR2b-deficient mice develop autoantibodies and autoimmune glomerulonephritis in a strain-dependent fashion and therefore serves as a model of lupus nephritis. In the present report, the investigators found that “Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis.” For example, FcγR2b-deficient mice were further engineered to oblate expression of CIKS and monitored over a 1 year period. Both murine lines still generated autoantibodies signaling disease onset. However, while 12/13 FcγR2b-deficient mice died of lupus nephritis during this period, only 3/12 further engineered mice perished. Similar results were obtained with FcγR2b-deficient mice further engineered to oblate expression of IL-17.


     Other key findings in the report, as summarized on the Immunity website, include:  1) loss of IL-17 cytokine signaling in B cells fails to prevent glomerulonephritis, 2) IL-17 cytokines promote GC formation but are not required for autoantibodies, and 3) IL-17 cytokines promote inflammatory cell infiltration and NET formation in kidneys.


     Promising new therapeutic targets for the treatment of SLE, especially in cases with kidney involvement, are emerging as demonstrated in this paper as well as in other recent reports (see, for example, this report and this report). And most importantly, these efforts hold open the possibility of not just “nibbling around the edges” in treating SLE patients but instead tackle disease progression itself.





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