Systemic lupus erythematosus is an autoimmune disease characterized by overproduction of type 1 IFN that causes multiple organ dysfunctions. Plasmacytoid dendritic cells (pDCs) that secrete large amounts of IFN have recently been implicated in the initiation of the disease in preclinical mouse models. Sphingosine‐1‐phosphate, a bioactive sphingolipid metabolite, is produced by 2 highly conserved isoenzymes, sphingosine kinase (SphK) 1 and SphK2, and regulates diverse processes important for immune responses and autoimmunity. However, not much is known about the role of SphK2 in autoimmune disorders. In this work, we examined the role of SphK2 in pDC development and activation and in the pristane‐induced lupus model in mice that mimics the hallmarks of the human disease. Increases in pDC‐specific markers were observed in peripheral blood of SphK2 knockout mice. In agreement, the absence of SphK2 increased the differentiation of FMS‐like tyrosine kinase 3 ligand dendritic cells as well as expression of endosomal TLRs, TLR7 and TLR9, that modulate production of IFN. Surprisingly, however, SphK2 deficiency did not affect the initiation or progression of pristane‐induced lupus. Moreover, although absence of SphK2 increased pDC frequency in pristane‐induced lupus, there were no major changes in their activation status. Additionally, SphK2 expression was unaltered in lupus patients. Taken together, our results suggest that SphK2 may play a role in dendritic cell development. Yet, because its deletion had no effect on the clinical lupus parameters in this preclinical model, inhibitors of SphK2 might not be useful for treatment of this devastating disease.—Mohammed, S., Vineetha, N. S., James, S., Aparna, J. S., Lankadasari, M. B., Allegood, J. C, Li, Q.‐Z., Spiegel, S., Harikumar, K. B. Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus. FASEB J. 33, 7061–7071 (2019). http://www.fasebj.org

Clinical features of dengue fever were different in renal transplant recipients and patients with CKD. Severe worsening of renal function was common in CKD patients. Worsening of renal function in renal transplant recipients was less severe and transient.

Plasmacytoid dendritic cells (pDCs) express Toll like receptors (TLRs) that modulate the immune response by production of type I interferons. Here, we report that sphingosine kinase 1 (SphK1) which produces the bioactive sphingolipid metabolite, sphingosine 1‐phosphate (S1P), plays a critical role in the pDC functions and interferon production. Although dispensable for the pDC development, SphK1 is essential for the pDC activation and production of type I IFN and pro‐inflammatory cytokines stimulated by TLR7/9 ligands. SphK1 interacts with TLRs and specific inhibition or deletion of SphK1 in pDCs mitigates uptake of CpG oligonucleotide ligands by TLR9 ligand. In the pristane‐induced murine lupus model, pharmacological inhibition of SphK1 or its genetic deletion markedly decreased the IFN signature, pDC activation, and glomerulonephritis. Moreover, increases in the SphK1 expression and S1P levels were observed in human lupus patients. Taken together, our results indicate a pivotal regulatory role for the SphK1/S1P axis in maintaining the balance between immunosurveillance and immunopathology and suggest that specific SphK1 inhibitors might be a new therapeutic avenue for the treatment of type I IFN‐linked autoimmune disorders.

Background There is no consensus regarding dose and frequency of rituximab in Nephrology with extrapolation of dose used in treating lymphoproliferative disorders. There are no guidelines on targeting initial and subsequent doses based on CD19 + B cells. Methods 100 mg rituximab was given initially in 42 adults with steroid dependent (SDNS) and frequently relapsing nephrotic syndrome (FRNS), idiopathic membranous nephropathy (MN) and high immunologic risk kidney transplantation. Absolute and percentage CD19 B cells and clinical status were assessed at baseline, days 30, 90, 180 and 1 year. Subsequent doses of rituximab were based on CD19 B cell reconstitution and clinical response. Results CD19 B cell percentage decreased from 16.3+7.6 to 0.3±0.3 (P=<0.001), 1.9±1.7 (P=<0.001) and 4.0±4.5 (P=0.005) by 30, 90 and 180 days respectively. Suppression of CD 19 B cell count below 1% at day 30, 90 and 180 was 40/42 (95.2%), 18/42(42.9%) and 7/42(16.7%) respectively. Of 30 with SDNS and FRNS followed up for one year, 29(96.7%) went into remission at day 30. Remission was sustained in 23(76.6%) at day 180 and 21(70%) at 1 year. There was significant decrease [P <0.001] in the dose of steroids needed to maintain remission at 180 days following rituximab (0.27±0.02mg/Kg to 0.02±0.00mg/Kg). CD 19 B cell percentage at 90 days correlated with relapse (P=0.001, OR 1.422, 95% CI 1.246-2.574). Eighteen (60%) required an additional dose. Of five with MN, four achieved remission by 6 months which was sustained in three by 1 year. Of the 7 kidney transplant recipients, 2 had antibody mediated rejections though CD19 B cells were suppressed even at one year. Conclusions Low dose rituximab induces sustained depletion of CD19 B cells up to 90 days. Its role in preventing relapses in SDNS, FRNS, MN and rejection needs further studies.

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