Alfred H.J. Kim

Rac1 activation in podocytes induces rapid foot process effacement and proteinuria.

ABSTRACT The kidneys vital filtration function depends on the structural integrity of the glomerulus, the proximal portion of the nephron. Within the glomerulus, the architecturally complex podocyte forms the final cellular barrier to filtration. Injury to the podocyte results in a morphological change called foot process effacement, which is a ubiquitous feature of proteinuric diseases. The exact mechanism underlying foot process effacement is not known, but recently it has been proposed that this change might reflect activation of the Rac1 GTPase. To test this hypothesis, we generated a podocyte-specific, inducible transgenic mouse line that expressed constitutively active Rac1. When the Rac1 transgene was induced, we observed a rapid onset of proteinuria with focal foot process effacement. Using superresolution imaging, we verified that the induced transgene was expressed in damaged podocytes with altered foot process morphology. This work sheds new light on the complex balance of Rho GTPase signaling that is required for proper regulation of the podocyte cytoskeleton.

Brief Report: Chikungunya Viral Arthritis in the United States: A Mimic of Seronegative Rheumatoid Arthritis

Chikungunya virus (CHIKV) is an arthritogenic mosquito‐transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV‐infected patients develop inflammatory arthritis that can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV‐related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.

Cardiac manifestations of systemic lupus erythematosus.

The heart is one of the most frequently affected organs in SLE. Any part of the heart can be affected, including the pericardium, myocardium, coronary arteries, valves, and the conduction system. In addition to pericarditis and myocarditis, a high incidence of CAD has become increasingly recognized as a cause of mortality, especially in older adult patients and those with long-standing SLE. Many unanswered questions remain in terms of understanding the pathogenesis of cardiac manifestations of SLE. It is not currently possible to predict the patients who are at greatest risk for the various types of cardiac involvement. However, with the rapid advancement of basic science and translational research approaches, it is now becoming easier to identify specific mutations associated with SLE. A better understanding of these genetic factors may eventually allow clinicians to categorize and predict the patients who are at risk for specific cardiac manifestations of SLE.

Chikungunya viral arthritis in the United States: a mimic of seronegative rheumatoid arthritis.

Chikungunya virus (CHIKV) is an arthritogenic mosquito‐transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV‐infected patients develop inflammatory arthritis that can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV‐related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.

Cell Depletion in Mice That Express Diphtheria Toxin Receptor under the Control of SiglecH Encompasses More Than Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDC) produce IFN-I in response to viruses and are routinely identified in mice by SiglecH expression. SiglecH is a sialic acid–binding Ig-like lectin that has an immunomodulatory role during viral infections. In this study, we evaluated the impact of SiglecH deficiency on cytokine responses in the presence and absence of pDC. We found that lack of SiglecH enhanced IFN-I responses to viral infection, regardless of whether pDC were depleted. We also examined the expression pattern of SiglecH and observed that it was expressed by specialized macrophages and progenitors of classical dendritic cells and pDC. Accordingly, marginal zone macrophages and pDC precursors were eliminated in newly generated SiglecH–diphtheria toxin receptor (DTR)–transgenic (Tg) mice but not in CLEC4C-DTR–Tg mice after diphtheria toxin (DT) treatment. Using two bacterial models, we found that SiglecH-DTR–Tg mice injected with DT had altered bacterial uptake and were more susceptible to lethal Listeria monocytogenes infection than were DT-treated CLEC4C-DTR–Tg mice. Taken together, our findings suggest that lack of SiglecH may affect cytokine responses by cell types other than pDC during viral infections, perhaps by altering viral distribution or burden, and that cell depletion in SiglecH-DTR–Tg mice encompasses more than pDC.

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the α-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes.

Novel Mechanism of Tumor Suppression by Polarity Gene Discs Large 1 (DLG1) Revealed in a Murine Model of Pediatric B-ALL

Using two different murine models of pre–B-cell leukemia, Sandoval and colleagues delineate the mechanism of tumor suppression by the PDZ domain polarity gene DLG1, which interacts with and stabilizes the PTEN protein in early-stage B cells. Drosophila melanogaster discs large (dlg) is an essential tumor suppressor gene (TSG) controlling epithelial cell growth and polarity of the fly imaginal discs in pupal development. A mammalian ortholog, Dlg1, is involved in embryonic urogenital morphogenesis, postsynaptic densities in neurons, and immune synapses in lymphocytes. However, a potential role for Dlg1 as a mammalian TSG is unknown. Here, we present evidence that loss of Dlg1 confers strong predisposition to the development of malignancies in a murine model of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Using mice with conditionally deleted Dlg1 alleles, we identify a novel “pre-leukemic” stage of developmentally arrested early B-lineage cells marked by preeminent c-Myc expression. Mechanistically, we show that in B-lineage progenitors Dlg1 interacts with and stabilizes the PTEN protein, regulating its half-life and steady-state abundance. The loss of Dlg1 does not affect the level of PTEN mRNAs but results in a dramatic decrease in PTEN protein, leading to excessive phosphoinositide 3-kinase signaling and proliferation. Our data suggest a novel model of tumor suppression by a PDZ domain-containing polarity gene in hematopoietic cancers. Cancer Immunol Res; 1(6); 426–37. ©2013 AACR.

From mechanism to therapies in systemic lupus erythematosus

Purpose of review Systemic lupus erythematosus (SLE) is a disabling and deadly disease. Development of novel therapies for SLE has historically been limited by incomplete understanding of immune dysregulation. Recent advances in lupus pathogenesis, however, have led to the adoption or development of new therapeutics, including the first Food and Drug Administration–approved drug in 50 years. Recent findings Multiple cytokines (interferon, B lymphocyte stimulator, IL-6, and IL-17), signaling pathways (Brutons Tyrosine Kinase, Janus kinase/signal transducer and activator of transcription), and immune cells are dysregulated in SLE. In this review, we cover seminal discoveries that demonstrate how this dysregulation is integral to SLE pathogenesis and the novel therapeutics currently under development or in clinical trials. In addition, early work suggests metabolic derangements are another target for disease modification. Finally, molecular profiling has led to improved patient stratification in the heterogeneous SLE population, which may improve clinical trial outcomes and therapeutic selection. Summary Recent advances in the treatment of SLE have directly resulted from improved understanding of this complicated disease. Rheumatologists may have a variety of novel agents and more precise targeting of select lupus populations in the coming years.

New roles revealed for T cells and DCs in glomerulonephritis

Little is known about the potential role of T cells in the inflammatory renal disease glomerulonephritis (GN). GN has been historically viewed as a product of immune complex-mediated complement activation, and the presence of autoantibodies made identifying T cell-specific effector contributions difficult to elucidate. In this issue of the JCI, Heymann et al. generate what they believe to be a novel, transgenic murine model of GN, demonstrating a direct role for CD8+ T cells, activated CD4+ T cells, and DCs in the pathogenesis of GN (see the related article beginning on page 1286).

B cell–derived IL-4 acts on podocytes to induce proteinuria and foot process effacement

The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria. This effect was mediated by IL-4, as transfer of IL-4-deficient B cells did not induce proteinuria. Overexpression of IL-4 in mice was sufficient to induce kidney injury and proteinuria and could be attenuated by JAK kinase inhibitors. Since IL-4 is a specific activator of STAT6, we analyzed kidney biopsies and demonstrated STAT6 activation in up to 1 of 3 of minimal change disease patients, suggesting IL-4 or IL-13 exposure in these patients. These data suggest that the role of B cells in nephrotic syndrome could be mediated by cytokines.