Publications

Kidney involvement confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE). The pathogenesis of lupus nephritis (LN) involves diverse mechanisms instigated by elements of the autoimmune response which alter the biology of kidney resident cells. Processes in the glomeruli and in the interstitium may proceed independently albeit crosstalk between the two is inevitable. Podocytes, mesangial cells, tubular epithelial cells, kidney resident macrophages and stromal cells with input from cytokines and autoantibodies present in the circulation alter the expression of enzymes, produce cytokines and chemokines which lead to their injury and damage of the kidney. Several of these molecules can be targeted independently to prevent and reverse kidney failure. Tertiary lymphoid structures with true germinal centers are present in the kidneys of patients with lupus nephritis and have been increasingly recognized to associate with poorer renal outcomes. Stromal cells, tubular epithelial cells, high endothelial vessel and lymphatic venule cells produce chemokines which enable the formation of structures composed of a T-cell-rich zone with mature dendritic cells next to a B-cell follicle with the characteristics of a germinal center surrounded by plasma cells. Following an overview on the interaction of the immune cells with kidney resident cells, we discuss the cellular and molecular events which lead to the formation of tertiary lymphoid structures in the interstitium of the kidneys of mice and patients with lupus nephritis. In parallel, molecules and processes that can be targeted therapeutically are presented.

Genetic, environmental, and epigenetic factors simultaneously or serially contribute to immune cells and resident joint tissue cell abnormalities, invariably leading to joint destruction. Understanding the immune cell dysfunction in earlier years has brought forward life-changing therapeutics to patients with rheumatoid arthritis (RA). Further advances in the understanding of the immune and joint tissue-resident cell signaling and metabolic defects should produce additional tools to treat people with RA and foretell those who will respond to each biological or small drug. This review presents the latest evidence on RA pathogenesis and outlines the prospects for achieving precision medicine.

PURPOSE OF REVIEW: This review gives an overview of the recently published clinical trials in systemic lupus erythematosus (SLE). RECENT FINDINGS: Our continuously improving understanding of the cellular and molecular mechanisms, which are involved in the pathogenesis of SLE, has inspired the performance of multiple clinical trials in an attempt to modify recognized targets. Here, we summarize results obtained from recent trials, which used monoclonal antibodies blocking cytokines, blockers of costimulatory molecules or deleting immune cells, small drug inhibitors of kinases and replenishment of cytokines. SUMMARY: The therapeutic options for patients with SLE grow continuously and in parallel it raises the need for pathogenetic mechanism-based precision medicine so that we may select the right treatment for the right patient.

Failure of regulatory T (T(reg)) cells to properly control immune responses leads invariably to autoimmunity and organ damage. Decreased numbers or impaired function of T(reg) cells, especially in the context of inflammation, has been documented in many human autoimmune diseases. Restoration of T(reg) cell fitness and/or expansion of their numbers using low-dose natural IL-2, the main cytokine driving T(reg) cell survival and function, has demonstrated clinical efficacy in early clinical trials. Genetically modified IL-2 with an extended half-life and increased selectivity for T(reg) cells is now in clinical development. Administration of IL-2 combined with therapies targeting other pathways involved in the expression of autoimmune diseases should further enhance its therapeutic potential. Ongoing clinical efforts that capitalize on the early clinical success of IL-2 treatment should bring the use of this cytokine to the forefront of biological treatments for autoimmune diseases.

PURPOSE OF REVIEW: TCRalphabeta+CD4-CD8- double-negative T (DNT) cells, a principal subset of mature T lymphocytes, have been closely linked with autoimmune/inflammatory conditions. However, controversy persists regarding their ontogeny and function. Here, we present an overview on DNT cells in different autoimmune diseases to advance a deeper understanding of the contribution of this population to disease pathogenesis. RECENT FINDINGS: DNT cells have been characterized in various chronic inflammatory diseases and they have been proposed to display pathogenic or regulatory function. The tissue location of DNT cells and the effector cytokines they produce bespeak to their active involvement in chronic inflammatory diseases. SUMMARY: By producing various cytokines, expanded DNT cells in inflamed tissues contribute to the pathogenesis of a variety of autoimmune inflammatory diseases. However, it is unclear whether this population represents a stable lineage consisting of different subsets similar to CD4+ T helper cell subset. Better understanding of the possible heterogeneity and plasticity of DNT cells is needed to reveal interventional therapeutic opportunities.

T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases. Besides glycolysis and fatty acid oxidation/synthesis, amino acid metabolism is also crucial in T cell metabolism. It appears that each T cell subset favors a unique metabolic process and that metabolic reprogramming changes cell fate. Here, we review the mechanisms whereby amino acid transport and metabolism affects T cell activation, differentiation and function in T cells in the prototype systemic autoimmune disease systemic lupus erythematosus. New insights in amino acid handling by T cells should guide approaches to correct T cell abnormalities and disease pathology.

Interstitial kidney inflammation is present in various nephritides in which serum interleukin 23 (IL-23) is elevated. Here we showed that murine and human renal tubular epithelial cells (TECs) expressing the IL-23 receptor (IL-23R) responded to IL-23 by inducing intracellular calcium flux, enhancing glycolysis, and upregulating calcium/calmodulin kinase IV (CaMK4), which resulted in suppression of the expression of the arginine-degrading enzyme arginase 1 (ARG1), thus increasing in situ levels of free L-arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines. TECs from humans and mice with nephritis expressed increased levels of IL-23R and CaMK4 but reduced levels of ARG1. TEC-specific deletion of Il23r or Camk4 suppressed inflammation, whereas deletion of Arg1 exacerbated inflammation in different murine disease models. Finally, TEC-specific delivery of a CaMK4 inhibitor specifically curbed renal inflammation in lupus-prone mice without affecting systemic inflammation. Our data offer the first evidence to our knowledge of the immunosuppressive capacity of TECs through a mechanism that involves competitive uptake of arginine and signify the importance of modulation of an inflammatory cytokine in the function of nonlymphoid cells, which leads to the establishment of an inflammatory microenvironment. New approaches to treat kidney inflammation should consider restoring the immunosuppressive capacity of TECs.

In inflammatory rheumatic disorders, the immune system attacks and damages the connective tissues and invariably internal organs. During the past decade, remarkable advances having been made towards our understanding on the cellular and molecular mechanisms involved in rheumatic diseases. The discovery of IL-23/IL-17 axis and the delineation of its important role in the inflammation led to the introduction of many needed new therapeutic tools. We will present an overview of the rationale for targeting therapeutically the IL-23/IL-17 axis in rheumatic diseases and the clinical benefit which has been realized so far. Finally, we will discuss the complex interrelationship between IL-23 and IL-17 and the possible uncoupling in certain disease settings.

The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-alpha present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMalpha to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.