Incremental hemodialysis transition in veterans and nonveterans with kidney failure.

Purpose Of Review: Initiation of hemodialysis treatment with a thrice-weekly prescription is currently the standard of care irrespective of patients' residual kidney function (RKF), comorbidities, and preferences.

Recent Findings: Each year ∼12 000 Veterans with advanced kidney disease progress to end-stage kidney disease (ESKD) requiring dialysis and comprise greater than 10% of the US incident ESKD population. Dialysis is costly and is associated with impaired health-related quality of life (HRQOL) and high mortality risk, especially in the first year of treatment.

Genetic Reduction of IRF5 Expression after Disease Initiation Reduces Disease in a Mouse Lupus Model by Impacting Systemic and End-Organ Pathogenic Pathways.

Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. Global homozygous or heterozygous deficiency of IRF5 from birth confers protection in many lupus mouse models. However, less is known about the effects of IRF5 targeting after autoimmunity has already developed.

EGF-Receptor-Dependent TLR7 Signaling in Macrophages Promotes Glomerular Injury in Crescentic Glomerulonephritis.

Glomerulonephritis (GN) is a group of inflammatory diseases and an important cause of morbidity and mortality worldwide. The initiation of the inflammatory process is quite different for each type of GN; however, each GN is characterized commonly and variably by acute inflammation with neutrophils and macrophages and crescent formation, leading to glomerular death. Toll-like receptor (TLR) 7 is a sensor for self-RNA and implicated in the pathogenesis of human and murine GN.

Monoallelic IRF5 deficiency in B cells prevents murine lupus.

Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model.

Novel ELISA Protocol Links Pre-Existing SARS-CoV-2 Reactive Antibodies With Endemic Coronavirus Immunity and Age and Reveals Improved Serologic Identification of Acute COVID-19 Multi-Parameter Detection.

The COVID-19 pandemic has drastically impacted work, economy, and way of life. Sensitive measurement of SARS-CoV-2 specific antibodies would provide new insight into pre-existing immunity, virus transmission dynamics, and the nuances of SARS-CoV-2 pathogenesis. To date, existing SARS-CoV-2 serology tests have limited utility due to insufficient reliable detection of antibody levels lower than what is typically present after several days of symptoms.

Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses.

Cyclic AMP (cAMP) is involved in many biological processes but little is known regarding its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent mechanism) regulates conventional type-2 Dendritic Cells (cDC2s) in mice and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors essential for cDC2-mediated Th2 induction. In mice, genetic loss of IRF4 phenocopies the effects of cAMP on Th17 induction and restoration of IRF4 prevents the cAMP effect.

c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth.

Casitas B lymphoma (c-Cbl) is an E3 ubiquitin ligase and a negative regulator of colorectal cancer (CRC). Despite its high expression in immune cells, the effect of c-Cbl on the tumor microenvironment remains poorly understood. Here we demonstrate that c-Cbl alters the tumor microenvironment and suppresses Programmed cell death-1 (PD-1) protein, an immune checkpoint receptor.

TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects.

The spores of pathogenic bacteria are involved in host entry and the initial encounter with the host immune system. How bacterial spores interact with host immunity, however, remains poorly understood. Here, we show that the spores of (BA), the etiologic agent of anthrax, possess an intrinsic ability to induce host immune responses.

Follicular Dendritic Cell Activation by TLR Ligands Promotes Autoreactive B Cell Responses.

A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus.

Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model.

Objective: Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development.

Methods: K/BxN serum-transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated.

The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model.

ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus, resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.

IRF5 deficiency ameliorates lupus but promotes atherosclerosis and metabolic dysfunction in a mouse model of lupus-associated atherosclerosis.

Premature atherosclerosis is a severe complication of lupus and other systemic autoimmune disorders. Gain-of-function polymorphisms in IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing lupus, and IRF5 deficiency in lupus mouse models ameliorates disease. However, whether IRF5 deficiency also protects against atherosclerosis development in lupus is not known.

CpGB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin.

Toll-like receptor 9 (TLR9) drives innate immune responses after recognition of foreign or endogenous DNA containing unmethylated CpG motifs. DNA-mediated TLR9 activation is highly implicated in the pathogenesis of several autoimmune skin diseases, yet its contribution to the inflammation seen in these diseases remains unclear. In this study, TLR9 ligand, CpGB DNA, was administered to mice via a subcutaneous osmotic pump with treatment lasting 1 or 4 weeks.

Inhibition of type 4 cyclic nucleotide phosphodiesterase blocks intracellular TLR signaling in chronic lymphocytic leukemia and normal hematopoietic cells.

A subset of chronic lymphocytic leukemia (CLL) BCRs interacts with Ags expressed on apoptotic cells, suggesting that CLL BCRs have the potential to internalize apoptotic cell RNA- or DNA-containing fragments with resultant activation of TLR7 or TLR9, respectively. By blocking cAMP degradation, type 4 cAMP phosphodiesterase (PDE4) inhibitors activate cAMP-mediated signaling and induce apoptosis in CLL cells. In this study, we show that autologous irradiated leukemic cells induce proliferation in CLL cells and that such proliferation is blocked by a TLR7/8/9 inhibitor, by DNase, and by the PDE4 inhibitor rolipram.

Gene expression during the generation and activation of mouse neutrophils: implication of novel functional and regulatory pathways.

As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid-induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking.

Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2.

Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease pathogenesis. However these mouse studies were confounded by the recent demonstration that the IRF5 knockout mouse line contained a loss-of-function mutation in the dedicator of cytokinesis 2 (DOCK2) gene.

Evaluating the role of nucleic acid antigens in murine models of systemic lupus erythematosus.

Impaired apoptotic cell clearance is thought to contribute to the pathogenesis of systemic autoimmune disease, in particular systemic lupus erythematosus (SLE). Endogenous RNA- and DNA-containing autoantigens released from dying cells can engage Toll-like receptors (TLR) 7/8 and TLR9, respectively in a number of immune cell types, thereby promoting innate and adaptive immune responses. Mouse models of lupus reliably phenocopy many of the characteristic features of SLE in humans and these models have proved invaluable in defining disease mechanisms.

Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus.

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to have many immunomodulatory effects. We have previously shown that the PPARγ agonist rosiglitazone is beneficial when used early in prevention of disease in murine models of systemic lupus erythematosus (SLE) and SLE-related atherosclerosis. In this report, we demonstrate that another PPARγ agonist, pioglitazone is also beneficial as a treatment for early murine lupus, indicating that this is a class effect and not agent-specific.

The effect of mycophenolate mofetil on disease development in the gld.apoE (-/-) mouse model of accelerated atherosclerosis and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by autoantibody production and inflammatory disease involving multiple organs. Premature atherosclerosis is a common complication of SLE and results in substantial morbidity and mortality from cardiovascular disease (CVD). The reasons for the premature atherosclerosis in SLE are incompletely understood, although chronic inflammation is thought to play an important role.

Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2.

Interferon regulatory factor 5-deficient (IRF5 (-/-) ) mice have been used for many studies of IRF5 biology. A recent report identifies a mutation in dedicator of cytokinesis 2 (DOCK2) as being responsible for the abnormal B-cell development phenotype observed in the IRF5 (-/-) line. Both dedicator of cytokinesis 2 (DOCK2) and IRF5 play important roles in immune cell function, raising the issue of whether immune effects previously associated with IRF5 are due to IRF5 or DOCK2.

Role for toll-like receptors in autoimmune disease: the example of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem disease characterized by an autoimmune response to nuclear antigens. Although the pathophysiology of SLE remains incompletely understood, many recent studies indicate a major role for innate immunity. The toll-like receptors (TLRs), which play a key role in innate responses to infections, are also involved in acute and chronic inflammatory processes induced by endogenous ligands.

Role for interferon regulatory factors in autoimmunity.

Interferon regulatory factors (IRFs) were first identified during studies of type I interferons. Since then, many investigations have established that IRFs are involved in regulating the innate immune response, the development of various immune cell types, and carcinogenesis. Several genetic studies have identified genetic variants, most notably IRF5, associated with an increased risk of autoimmune disease.