Publications

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (T(reg)) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands T(reg) cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In T(reg) cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4(-/-) T(reg) cells and improved their function and stability in vitro and in vivo. In SLE CD4(+) T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced T(reg) cell function. In conclusion, we provide molecular insights in the defective metabolism and function of T(reg) cells in SLE and identify PFKP as a target to fine-tune T(reg) cell metabolism and thereby restore their function.

The complement system is involved in the origin of autoimmunity and systemic lupus erythematosus. Both genetic deficiency of complement components and excessive activation are involved in primary and secondary renal diseases, including lupus nephritis. Among the pathways, the classical pathway has long been accepted as the main pathway of complement activation in systemic lupus erythematosus. However, more recent studies have shown the contribution of factors B and D which implies the involvement of the alternative pathway. While there is evidence on the role of the lectin pathway in systemic lupus erythematosus, it is yet to be demonstrated whether this pathway is protective or harmful in lupus nephritis. Complement is being explored for the development of disease biomarkers and therapeutic targeting. In the current review we discuss the involvement of complement in lupus nephritis.

To explore bias in lupus erythematosus (LE) randomized clinical trials (RCTs) and to help the development of benchmarks for future trials and management. We searched systematically three databases and three registries to summarize the interventional randomized clinical trials (RCTs) and identify factors associated with participant loss. Trials which examined pharmacological interventions with control group were included and a meta-analysis was carried out by using fixed and random effects models to calculate risk ratio of participant loss in the intervention and control groups. A total of 481 trials with 68,582 participants met our inclusion criteria, organ specific interventional studies along with trials that address quality of life attributes and geopolitical disparities are missing or lagging behind. 90 trials were involved in the meta-analyses, the withdrawal ratio between intervention and control groups was distinctly influenced by national income of the trial-conducted country. In high income countries, the withdrawal ratio was relatively constant, while for trials conducted in low and middle income countries, the results were altered by trial registration, year of start, number of centers, number of participants, and primary outcome identification. Moreover, the comparability of participants was also worrying, trial location and registration status altered basal participant adherence. Our study reveals the unexpectedly huge heterogeneity brought by national income and trial registration in lupus RCTs worldwide. To maintain the fundamental repeatability and referenceability of LE RCTs, rigorously designed single-country trials with diverse inclusion criteria are needed.

OBJECTIVE: To evaluate the long-term efficacy and safety of ustekinumab through 2 years in patients with active systemic lupus erythematosus (SLE). METHODS: This was a placebo-controlled (week 24), phase II study in 102 patients with seropositive active SLE. Patients were randomized to ustekinumab (approximately 6 mg/kg single intravenous infusion, then subcutaneous [SC] injections of 90 mg every 8 weeks) or placebo, added to background therapy. Placebo patients initiated ustekinumab (90 mg SC every 8 weeks) at week 24. Patients could enter an optional open-label study extension after week 40 (final ustekinumab administration at week 104). Efficacy assessments included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLEDAI-2K Responder Index-4 (SRI-4), physician global assessment (PGA), and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Observed data are reported for the extension period. The final efficacy assessment was at week 112; safety was monitored through week 120. RESULTS: In this subset of patients who entered the study extension, 24 in the ustekinumab group and 14 in the placebo crossover group completed study treatment. At week 112, 79% and 92%, respectively, had an SRI-4 response; 92% in both groups had >/= 4-point improvement from baseline in SLEDAI-2K score; 79% and 93%, respectively, had >/= 30% improvement from baseline in PGA; 86% and 91%, respectively, had >/= 50% improvement in active joint (pain and inflammation) count; and 79% and 100%, respectively, had >/= 50% improvement in CLASI Activity Score. No deaths, malignancies, opportunistic infections, or tuberculosis cases occurred. Safety events were consistent with the known ustekinumab safety profile. CONCLUSION: Of the 46 patients who entered the voluntary extension of this phase II study, clinical benefit in global and organ-specific SLE activity measures was observed with ustekinumab through 2 years with no new or unexpected safety findings. [ClinicalTrials.gov: NCT02349061].

Autoimmune diseases are characterized by dysregulation and aberrant activation of cells in the immune system. Therefore, restoration of the immune balance represents a promising therapeutic target in autoimmune diseases. Interleukin-2 (IL-2) can promote the expansion and differentiation of different immune cell subsets dose-dependently. At high doses, IL-2 can promote the differentiation and expansion of effector and memory T cells, whereas at low doses, IL-2 can promote the differentiation, survival, and function of regulatory T (T(reg)) cells, a CD4(+) T cell subset that is essential for the maintenance of immune homeostasis and immune tolerance. Therefore, IL-2 exerts immunostimulatory and immunosuppressive effects in autoimmune diseases. The immunoregulatory role of low-dose IL-2 has sparked excitement for the therapeutic exploration of modulating the IL-2-T(reg) axis in the context of autoimmune diseases. In this review, we discuss recent advances in the therapeutic potential of IL-2 or IL-2-derived molecules in the treatment of autoimmune diseases.

About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic-pituitary-adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID. We suggest that the inability of hypothalamic-pituitary-adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1(fl/fl)) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1(fl/fl) mice show remarkable muscle atrophy compared to Hmox1(fl/fl) controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.

Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3beta (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.