Phosphorylated vimentin at Ser72 is associated with epithelial-mesenchymal transition in lupus nephritis.

OBJECTIVES: To measure the expression of vimentin and its phosphorylated forms in lupus nephritis (LN) and explore their potential role in LN development. METHODS: Lupus renal biopsies from LN patients and normal renal biopsies from kidney transplant donors were collected. The expression of vimentin and its phosphorylated forms (p-vimentin (Ser39, Ser56, Ser72, Ser83, and Tyr117)) were measured by Western blots and immunohistochemistry. To construct stable cell line that overexpress vimentin and its phosphorylated forms, an immortalized proximal tubule epithelial cell line (HK-2 cells) was utilized. The roles of vimentin and its phosphorylated forms on the migration of HK-2 cells were examined by transwell migration assay and wound healing analysis. RESULTS: We first observed a significant upregulation of vimentin protein in TGFß1-induced HK-2 cells. This finding was further confirmed in renal tissues obtained from LN patients and animal model. Interestingly, among the five phosphorylated forms of vimentin, only vimentin phosphorylated at Ser72 was upregulated in LN. Through the establishment of stable vimentin and its phosphorylated forms overexpression in HK-2 cells, we found that the overexpression of vimentin and its phosphorylated forms at Ser72 significantly enhances the cell migration. CONCLUSIONS: Vimentin phosphorylated on Ser72 is important for renal epithelial cell migration, which would enhance the progression of vimentin-induced epithelial-mesenchymal transition during LN development.

Tertiary lymphoid structures as local perpetuators of organ-specific immune injury: implication for lupus nephritis.

In response to inflammatory stimuli in conditions such as autoimmune disorders, infections and cancers, immune cells organize in nonlymphoid tissues, which resemble secondary lymphoid organs. Such immune cell clusters are called tertiary lymphoid structures (TLS). Here, we describe the potential role of TLS in the pathogenesis of autoimmune disease, focusing on lupus nephritis, a condition that incurs major morbidity and mortality. In the kidneys of patients and animals with lupus nephritis, the presence of immune cell aggregates with similar cell composition, structure, and gene signature as lymph nodes and of lymphoid tissue-inducer and -organizer cells, along with evidence of communication between stromal and immune cells are indicative of the formation of TLS. TLS formation in kidneys affected by lupus may be instigated by local increases in lymphorganogenic chemokines such as CXCL13, and in molecules associated with leukocyte migration and vascularization. Importantly, the presence of TLS in kidneys is associated with severe tubulointerstitial inflammation, higher disease activity and chronicity indices, and poor response to treatment in patients with lupus nephritis. TLS may contribute to the pathogenesis of lupus nephritis by increasing local IFN-I production, facilitating the recruitment and supporting survival of autoreactive B cells, maintaining local production of systemic autoantibodies such as anti-dsDNA and anti-Sm/RNP autoantibodies, and initiating epitope spreading to local autoantigens. Resolution of TLS, along with improvement in lupus, by treating animals with soluble BAFF receptor, docosahexaenoic acid, complement inhibitor C4BP(ß-), S1P1 receptor modulator Cenerimod, dexamethasone, and anti-CXCL13 further emphasizes a role of TLS in the pathogenesis of lupus. However, the mechanisms underlying TLS formation and their roles in the pathogenesis of lupus nephritis are not fully comprehended. Furthermore, the lack of non-invasive methods to visualize/quantify TLS in kidneys is also a major hurdle; however, recent success in visualizing TLS in lupus-prone mice by photon emission computed tomography provides hope for early detection and manipulation of TLS.

Different pregnancy outcomes in patients with systemic lupus erythematosus treated with belimumab.

OBJECTIVES: Systemic lupus erythematosus (SLE) predominantly occurs in women of child-bearing age. Selecting drugs for pregnant SLE patients has always been a difficult choice. Although there have been several reports of safety of belimumab in SLE patients during pregnancy, the data are far from sufficient. METHODS: We report on 4 cases of belimumab exposure in pregnant SLE patients. We also summarized 6 case reports and case series which were previously published. Further, we compared the different outcomes among SLE patients and their babies who continued with belimumab during pregnancy with those who discontinued belimumab in early pregnancy. RESULTS: Two cases discontinued belimumab in the early pregnancy, while the other two received belimumab until the late pregnancy. All the four women tolerated belimumab. Newborns have all developed normally and continue without complications during 1 year of follow-up. CONCLUSION: In this small case series, we found that belimumab was well tolerated in pregnant SLE patients. There were no safety signals for the mothers or their babies.