Publications

Skin pigmentation has been linked to the development, prevalence, and severity of several immune-mediated diseases such as SLE. Here, we asked whether fibromodulin (FMOD), which is highly expressed in skin with light complexion, can explain the known differences in the magnitude of inflammation. C57 mice with different levels of pigmentation and FMOD were injected with human lupus serum to induce skin inflammation. Histopathologic studies revealed that black C57 FMOD+/+ that produce low levels of FMOD and white C57 FMOD -/- mice develop more severe inflammation compared with white FMOD +/+ mice. This study also revealed that dark pigmentation and FMOD deletion correlates with the increased numbers of Langerhans cells. Altogether, we identify low pigmentation and FMOD are linked to low severity of inflammation and approaches to promote FMOD expression should offer clinical benefit.

Aberrant IL-17A expression together with reduced IL-2 production by effector CD4(+) T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report that Sirtuin 2 (SIRT2), a member of the family of NAD(+)-dependent histone deacetylases, suppresses IL-2 production by CD4(+) T cells while promoting their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K, activation of the mTORC1/HIF-1alpha/RORgammat pathway and induction of Th17-cell differentiation. Additionally, SIRT2 was shown to be responsible for the deacetylation of c-Jun and histones at the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, bound directly to the Sirt2 promoter and promoted its transcription. AK-7, a SIRT2 inhibitor, limited the ability of adoptively transferred antigen-specific CD4(+) T cells to cause autoimmune encephalomyelitis in mice and limited disease in lupus-prone MRL/lpr mice. Finally, CD4(+) T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4(+) T cells from patients with SLE attenuated the ability of these cells to differentiate into Th17 cells and promoted the generation of IL-2-producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential in the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new SLE therapies.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects almost any organ. Multiple immunological abnormalities involving every domain of the immune system contribute to the expression of the disease. It is now recognized that elements of the immune system instigate processes in tissue resident cells which execute organ damage. Although correction of ongoing immune aberrations is important in the control of disease activity, targeting tissue specific injurious processes may prove desirable in limiting organ damage.

Gut microbiota dysbiosis is involved in the development of systemic lupus erythematosus (SLE). The safety and efficacy of fecal microbiota transplantation (FMT) for the treatment of SLE patients has not been explored. In this 12-week, single-arm pilot clinical trial of oral encapsulated fecal microbiome from healthy donors to patients with active SLE, we aimed to evaluate the safety and efficacy of FMT in patients with SLE (ChiCTR2000036352). 20 SLE patients with SLEDAI >/=6 were recruited. FMT was administered once a week for three consecutive weeks along with standard treatment and the patients were followed for 12 weeks. Safety was evaluated throughout the trial. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. Microbiome composition, levels of short chain fatty acids (SCFAs) in the gut and of cytokines in the sera were measured along with lymphocyte phenotyping. No serious adverse events were observed after FMT. At week 12, the SRI-4 response rate was 42.12%, and significant reductions in the SLEDAI-2K scores and the level of serum anti-dsDNA antibody were observed compared to baseline. Significant enrichment of SCFAs-producing bacterial taxa and reduction of inflammation-related bacterial taxa were observed, along with increased production of SCFAs in the gut and reduced levels of IL-6 and CD4(+) memory/naive ratio in the peripheral blood. Furthermore, SRI-4 responding patients displayed specific microbiota signatures both before and after FMT. The first clinical trial of FMT in active SLE patients provide supportive evidence that FMT might be a feasible, safe, and potentially effective therapy in SLE patients by modifying the gut microbiome and its metabolic profile.

Lupus nephritis (LN) is common in people with systemic lupus erythematosus (SLE) and advances, almost invariably, to end-stage renal disease (ESRD). In this issue of the JCI, Abraham, Durkee, et al. presented a large-scale immune cell landscape of kidney biopsies from patients with LN by combining multiplexed confocal microscopy imaging with customized computer vision and quantification. The presence of diverse CD4- T cells in small neighborhoods, but not of B cells or CD4+ T cells in large neighborhoods, is linked to the development of ESRD. Unexpectedly, B cells in the kidney heralded a good prognosis. The precise location of different types of immune cells allows inference on possible interactions between different immune cells and also between immune and kidney-resident cells. The data have important implications on the development of prognostic tools and effective targeted therapies in patients with LN.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and sustained production of autoantibodies. Multiple and profound T cell abnormalities in SLE are intertwined with disease expression. Both numerical and functional disturbances have been reported in main CD4(+) T helper cell subsets including Th1, Th2, Th17, regulatory, and follicular helper cells. SLE CD4(+) T cells are known to provide help to B cells, produce excessive IL-17 but insufficient IL-2, and infiltrate tissues. In the absence of sufficient amounts of IL-2, regulatory T cells, do not function properly to constrain inflammation. A complicated series of early signaling defects and aberrant activation of kinases and phosphatases result in complex cell phenotypes by altering the metabolic profile and the epigenetic landscape. All main metabolic pathways including glycolysis, glutaminolysis and oxidative phosphorylation are altered in T cells from lupus prone mice and patients with SLE. SLE CD8(+) cytotoxic T cells display reduced cytolytic activity which accounts for higher rates of infection and the sustenance of autoimmunity. Further, CD8(+) T cells in the context of rheumatic diseases lose the expression of CD8, acquire IL-17(+)CD4(-)CD8(-) double negative T (DNT) cell phenotype and infiltrate tissues. Herein we present an update on these T cell abnormalities along with underlying mechanisms and discuss how these advances can be exploited therapeutically. Novel strategies to correct these aberrations in T cells show promise for SLE treatment.

T-cells are critically involved in the pathogenesis of systemic lupus erythematosus. Although treatment with the anti-CD3 antibody has been reported to be effective in several autoimmune disease animal models including lupus, the immunosuppressive mechanisms remain obscure because of its pleiotropic in vivo kinetics. In this study, a conventional anti-CD3 (2C11C) and a non-mitogenic anti-CD3 with a manipulated Fc region (2C11S) were compared to elucidate the underlying mechanism of action. The efficacy and safety of 2C11S in vivo were demonstrated by sustained TCR reduction for a longer period as compared to 2C11C and no induction of cytokine release or T-cell depletion. Anti-CD3s were administered to NZB/W F1 (BWF1) mice at different time points for individual periods. The short-term treatment with 2C11S in the early phase of lupus suppressed the autoantibody associated with the reduction of germinal center B-cells. Treatment in the late phase attenuated lupus nephritis without affecting autoantibodies or differentiation of effector T-cells. The effect of reduced TCR in the development of autoimmunity was examined by CD3zeta heterozygous-deficient mice, in which T-cells had reduced TCR intensity but showed normal TCR signaling response. Autoantibody and lupus nephritis were attenuated significantly in CD3zeta heterozygous-deficient lupus-prone mice. Collectively, the reduction of surface TCR by non-mitogenic anti-CD3 could sufficiently suppress the development of lupus.

We had shown previously that the protein phosphatase 2A regulatory subunit PPP2R2D suppresses IL-2 production, and PPP2R2D deficiency in T cells potentiates the suppressive function of regulatory T (Treg) cells and alleviates imiquimod-induced lupus-like pathology. In this study, in a melanoma xenograft model, we noted that the tumor grew in larger sizes in mice lacking PPP2R2D in T cells (Lck(Cre)R2D(fl/fl)) compared with wild type (R2D(fl/fl)) mice. The numbers of intratumoral T cells in Lck(Cre)R2D(fl/fl) mice were reduced compared with R2D(fl/fl) mice, and they expressed a PD-1(+)CD3(+)CD44(+) exhaustion phenotype. In vitro experiments confirmed that the chromatin of exhaustion markers PD-1, LAG3, TIM3, and CTLA4 remained open in Lck(Cre)R2D(fl/fl) CD4 T conventional compared with R2D(fl/fl) T conventional cells. Moreover, the percentage of Treg cells (CD3(+)CD4(+)Foxp3(+)CD25(hi)) was significantly increased in the xenografted tumor of Lck(Cre)R2D(fl/fl) mice compared with R2D(fl/fl) mice probably because of the increase in the percentage of IL-2-producing Lck(Cre)R2D(fl/fl) T cells. Moreover, using adoptive T cell transfer in mice xenografted with melanoma, we demonstrated that PPP2R2D deficiency in T cells enhanced the inhibitory effect of Treg cells in antitumor immunity. At the translational level, analysis of publicly available data from 418 patients with melanoma revealed that PPP2R2D expression levels correlated positively with tumor-infiltration level of CD4 and CD8 T cells. The data demonstrate that PPP2R2D is a negative regulator of immune checkpoint receptors, and its absence exacerbates effector T cell exhaustion and promotes Treg cell expansion. We conclude that PPP2R2D protects against melanoma growth, and PPP2R2D-promoting regimens can have therapeutic value in patients with melanoma.