D313Y variant in two related end-stage renal disease patients – Pathogenic or not yet? / Dos pacientes con enfermedad renal terminal con la variante de significado incierto D313Y: ¿patógena o aún no?

Fabry disease is a multisystem lysosomal storage disorder caused by mutations in the GLA gene that result in a deficient or absent activity of alpha-galactosidase A. There is a wide spectrum of GLA gene variants, some of which are described as non-pathogenic. The clinical importance of the D313Y variant is still under debate, although in recent years it has been considered as a variant of unknown significance or a benign variant. Despite this prevailing notion, there are multiple case reports of patients with D313Y variant that presented signs and symptoms consistent with FD without any other etiological explanation. In this article, we present two family members with an important renal phenotype and other typical manifestations of FD (white matter lesions and left ventricular hypertrophy) that only had the D313Y variant. These cases suggest that this variant of unknown significance may contribute to the development of common features of FD and should not be undervalued. (AU)

La enfermedad de Fabry (EF) es un trastorno de almacenamiento lisosómico multisistémico causado por mutaciones en el gen GLA que tienen como resultado una actividad deficiente o ausente de alfa-galactosidasa A. Existe un amplio espectro de variantes del gen GLA, algunas de las cuales se describen como no patógenas. La importancia clínica de la variante D313Y aún está en debate, aunque en los últimos años se ha considerado una variante de significado incierto o una variante benigna. A pesar de esta noción predominante, existen múltiples reportes de casos de pacientes con variante D313Y que presentaron signos y síntomas consistentes con EF sin ninguna otra explicación etiológica. En este artículo presentamos 2 familiares con un importante fenotipo renal y otras manifestaciones típicas de la EF (lesiones de la sustancia blanca e hipertrofia ventricular izquierda) que solo presentaban la variante D313Y. Estos casos indican que esta variante de significado incierto puede contribuir al desarrollo de características comunes de la EF y no debe subestimarse. (AU)

Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain.

Introduction: ZAP-70, a protein tyrosine kinase recruited to the T cell receptor (TCR), initiates a TCR signaling cascade upon antigen stimulation. Mutations in the ZAP70 gene cause a combined immunodeficiency characterized by low or absent CD8+ T cells and nonfunctional CD4+ T cells. Most deleterious missense ZAP70 mutations in patients are located in the kinase domain but the impact of mutations in the SH2 domains, regulating ZAP-70 recruitment to the TCR, are not well understood. Methods: Genetic analyses were performed on four patients with CD8 lymphopenia and a high resolution melting screening for ZAP70 mutations was developed. The impact of SH2 domain mutations was evaluated by biochemical and functional analyses as well as by protein modeling. Results and discussion: Genetic characterization of an infant who presented with pneumocystis pneumonia, mycobacterial infection, and an absence of CD8 T cells revealed a novel homozygous mutation in the C-terminal SH2 domain (SH2-C) of the ZAP70 gene (c.C343T, p.R170C). A distantly related second patient was found to be compound heterozygous for the R170C variant and a 13bp deletion in the ZAP70 kinase domain. While the R170C mutant was highly expressed, there was an absence of TCR-induced proliferation, associated with significantly attenuated TCR-induced ZAP-70 phosphorylation and a lack of binding of ZAP-70 to TCR-ζ. Moreover, a homozygous ZAP-70 R192W variant was identified in 2 siblings with combined immunodeficiency and CD8 lymphopenia, confirming the pathogenicity of this mutation. Structural modeling of this region revealed the critical nature of the arginines at positions 170 and 192, in concert with R190, forming a binding pocket for the phosphorylated TCR-ζ chain. Deleterious mutations in the SH2-C domain result in attenuated ZAP-70 function and clinical manifestations of immunodeficiency.

D313Y variant in two related end-stage renal disease patients - Pathogenic or not yet?

Fabry disease is a multisystem lysosomal storage disorder caused by mutations in the GLA gene that result in a deficient or absent activity of alpha-galactosidase A. There is a wide spectrum of GLA gene variants, some of which are described as non-pathogenic. The clinical importance of the D313Y variant is still under debate, although in recent years it has been considered as a variant of unknown significance or a benign variant. Despite this prevailing notion, there are multiple case reports of patients with D313Y variant that presented signs and symptoms consistent with FD without any other etiological explanation. In this article, we present two family members with an important renal phenotype and other typical manifestations of FD (white matter lesions and left ventricular hypertrophy) that only had the D313Y variant. These cases suggest that this variant of unknown significance may contribute to the development of common features of FD and should not be undervalued.

Lupus-like nephritis with positive anti-neutrophil cytoplasmic antibodies and negative antinuclear antibodies / Nefrite semelhante à lúpica com anticorpos citoplasmáticos antineutrófilos positivos e anticorpos antinucleares negativos

Abstract Antineutrophil cytoplasmic antibodies (ANCAs) are associated with small vessel vasculitis but their prevalence is not rare in other immune diseases. In lupus nephritis (LN), their pathological role and clinical relevance have been the target of controversial views. We present a case of acute kidney injury and nephrotic syndrome in a young woman with diffuse global proliferative and membranous nephritis on her kidney biopsy, showing a full-house immunofluorescence pattern, very allusive of class IV + V LN, but lacking associated clinical criteria and laboratory findings to support the diagnosis of systemic lupus erythematosus (SLE). Furthermore, the patient presented with high titers of ANCA, steadily decreasing alongside the renal function and proteinuria improvements, with mycophenolate mofetil (MMF) and steroid treatment. The authors believe this is a case of lupus-like nephritis, in which ANCAs are immunological markers, although they are not directly involved in the pathogenesis.

Resumo Os anticorpos anticitoplasma de neutrófilos (ANCAs) estão associados à vasculite de pequenos vasos, no entanto, a sua prevalência não é rara em outras doenças imunológicas. Na nefrite lúpica (LN), o seu papel patológico e relevância clínica têm sido alvo de pontos de vista controversos. Apresentamos um caso de lesão renal aguda e síndrome nefrótica em uma jovem com nefrite proliferativa difusa e membranosa em sua biópsia renal, muito alusivo a NL classe IV + V, com um padrão full house na imunofluorescência, mas sem critérios clínicos e achados laboratoriais para corroborar o diagnóstico de lúpus eritematoso sistêmico (LES). Não obstante, a paciente apresentou títulos elevados de ANCA, que diminuiram progressivamente com a melhoria da função renal e da proteinúria, após tratamento com micofenolato de mofetil (MMF) e esteróide. Os autores acreditam que se trata de um caso de nefrite semelhante à nefrite lúpica, em que os ANCAs são marcadores imunológicos, embora não estejam diretamente envolvidos na patogênese.

A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells.

Effective antitumour immunity depends on the orchestration of potent T cell responses against malignancies1. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies2-4. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined. Here we demonstrate that a trispecific antibody to HER2, CD3 and CD28 stimulates regression of breast cancers in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumour cell cycle progression. Although CD8 T cells directly mediated tumour lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression at G1/S. Furthermore, when T cell subsets were adoptively transferred into a humanized breast cancer tumour mouse model, CD4 T cells alone inhibited HER2+ breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumour cell cycle progression and proliferation, and also increased pro-inflammatory signalling pathways. Collectively, the trispecific antibody to HER2 induced T cell-dependent tumour regression through direct antitumour and indirect pro-inflammatory/immune effects driven by CD4 T cells.

Atypical presentation of fistula dysfunction due to brachial arterial embolization mimicking stroke.

Vascular access thrombosis is an important complication with great impact on access patency and, consequently, on a patient's quality of life and survival. We report the case of a 73-year-old woman with chronic kidney disease on hemodialysis with a radiocephalic arteriovenous fistula on the right arm that was brought to the emergency department with decreased strength in her right arm, ipsilateral hypoesthesia and facial hemi-hypoesthesia. The patient was given a brain computed tomographic scan that did not confirm suspicion of stroke. On re-examination, the patient had new-onset pain at arteriovenous fistula level, and her right arm was cold and pale. The nephrology department was called for arteriovenous fistula evaluation. On physical examination, her forearm fistula had a decreased thrill and arm elevation exacerbated its paleness. A bedside ultrasound was performed for arteriovenous fistula assessment. Doppler ultrasound revealed: partial thrombosis at brachial bifurcation, a flow of 80-105 mL/min at brachial artery level and a radial artery with a damped waveform. Anastomosis and draining vein were permeable. In this case, the diagnosis of acute embolic brachial artery occlusion was made by a fast bedside ultrasound evaluation. The patient underwent thromboembolectomy with Fogarty technique, recovering fistula thrill, radial and cubital pulses. Thromboembolism of the fistula feeding artery is a rare cause of vascular access thrombosis and it is rarely mentioned in the literature. In this report, failure to recognize the upper limb ischemia would have led to delayed treatment, potentially resulting in the fistula's complete thrombosis and further limb ischemia. We highlight the importance of a diagnosis method like Doppler ultrasound, which allows for rapid evaluation at the patient's bedside.

Lupus-like nephritis with positive anti-neutrophil cytoplasmic antibodies and negative antinuclear antibodies.

Antineutrophil cytoplasmic antibodies (ANCAs) are associated with small vessel vasculitis but their prevalence is not rare in other immune diseases. In lupus nephritis (LN), their pathological role and clinical relevance have been the target of controversial views. We present a case of acute kidney injury and nephrotic syndrome in a young woman with diffuse global proliferative and membranous nephritis on her kidney biopsy, showing a full-house immunofluorescence pattern, very allusive of class IV + V LN, but lacking associated clinical criteria and laboratory findings to support the diagnosis of systemic lupus erythematosus (SLE). Furthermore, the patient presented with high titers of ANCA, steadily decreasing alongside the renal function and proteinuria improvements, with mycophenolate mofetil (MMF) and steroid treatment. The authors believe this is a case of lupus-like nephritis, in which ANCAs are immunological markers, although they are not directly involved in the pathogenesis.

Rituximab use in adult glomerulopathies and its rationale / Uso do rituximabe em glomerulopatias em adultos e justificativas

Abstract Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

Resumo As glomerulopatias figuram entre as principais causas de doença renal terminal. Nos últimos anos, a pesquisa clínica efetuou contribuições significativas para a compreensão desse grupo de patologias. Recentemente, o rituximabe (RTX) surgiu como um tratamento razoavelmente seguro. As diretrizes do Kidney Disease: Improving Global Outcomes (KDIGO) recomendam o RTX apenas como tratamento inicial na vasculite associada ao ANCA (VAA) e em pacientes não respondedores com nefrite lúpica (NL), embora não sejam atualizadas desde 2012. Atualmente, o RTX parece ser pelo menos tão eficaz quanto outros esquemas imunossupressores na nefropatia membranosa idiopática (NMI). Na doença por lesão mínima (DLM), o medicamento pode proporcionar um período de remissão duradouro em pacientes córtico-dependentes ou com recidivas frequentes. Resultados preliminares corroboram o uso de RTX em pacientes com NL membranosa pura e glomerulonefrite membranoproliferativa (GNMP) mediada por imunoglobulina, mas não em pacientes com NL classe III/IV ou GNMP mediada por complemento. Os achados a respeito de glomeruloesclerose segmentar e focal (GESF) idiopática e doença por anticorpo antimembrana basal glomerular (anti-MBG) não são conclusivos em função do pequeno número, porte e heterogeneidade dos estudos publicados até o presente momento. Por fim, a imunossupressão com RTX não é particularmente útil na nefropatia por IgA. A presente revisão apresenta o racional da prescrição de RTX nas diferentes glomerulopatias, desfechos e segurança. Nesse sentido, foram incluídos ensaios clínicos randomizados (ECRs) realizados em adultos, sempre que possível. Pesquisas bibliográficas foram realizadas nas bases de dados do clinictrials.gov e no PubMed.

Rituximab use in adult glomerulopathies and its rationale.

Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation.

Despite the significant therapeutic advances provided by immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation and reduced regulatory T cells in non-human primates at well-tolerated doses. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.

Arthritis sensory and motor scale: predicting functional deficits from the clinical score in collagen-induced arthritis.

BACKGROUND: In the collagen-induced arthritis (CIA) mouse model, inflammation readouts are usually quantified using operator-dependent clinical scoring systems, and no systematic relationship with functional deficits has been detected. In this study, we extensively quantified sensory and motor deficits in CIA mice during natural disease progression and therapeutic treatment. Then, we used these data to build a scale to predict functional deficits on the basis of the classical clinical score. METHODS: Using the CIA mouse model, we longitudinally screened multiple approaches to assess locomotion (open field test, Catwalk™), sensitivity (Von Frey, Hargreaves, static weight-bearing tests), and inflammation (skin temperature), and identified the most accurate tests to correlate sensory and motor deficits with disease severity, measured by clinical score. We then used these tests to characterize functional deficits in control (naïve and mice injected with complete Freund's adjuvant) and CIA mice, either untreated or treated with methotrexate to prevent functional deficits. By mathematical approaches, we finally investigated the relationship between functional deficits and clinical score. RESULTS: We found that the functional disability scores obtained with the open field, Catwalk™, Hargreaves, and skin temperature tests significantly correlated with the clinical score in CIA mice, either untreated or treated with methotrexate. Mathematical correlation showed that motor deficits, robustly characterized by two different tests, were twice more responsive than thermal sensitivity deficits. CONCLUSION: We propose the arthritis sensory and motor (ArthriSM) scale as a new theranostic tool to predict motor and sensory deficit based on the clinical score, in the experimental mouse model of CIA. This ArthriSM scale may facilitate the transfer of knowledge between preclinical and clinical studies.

Cecum perforation associated with a calcium polystyrene sulfonate bezoar - a rare entity / Perfuração do ceco associada a bezoar de poliestirenossulfonato de cálcio - uma entidade rara

Abstract Hyperkalemia is one of the most common electrolyte disorders, responsible for a high number of adverse outcomes, including life-threatening arrhythmias. Potassium binders are largely prescribed drugs used for hyperkalemia treatment but unfortunately, there are many adverse events associated with its use, mostly gastrointestinal. Identification of patients at highest risk for the serious complications associated with the current potassium binders, such as colon necrosis and perforation, could prevent fatal outcomes. The authors present a case of a 56-year-old man with secondary diabetes and chronic renal disease that was treated for hyperkalemia with Calcium Polystyrene Sulfonate (CPS). He later presented with acute abdomen due to cecum perforation and underwent ileocecal resection but ultimately died from septic shock a week later. During surgery, a solid white mass was isolated in the lumen of the colon. The mass was identified as a CPS bezoar, a rare drug-mass formed in the gastrointestinal tract that contributed to the perforation. A previous history of partial gastrectomy and vagothomy was identified as a probable risk factor for the CPS bezoar development. Hopefully, the two new potassium binders patiromer and (ZS-9) Sodium Zirconium Cyclosilicate will help treat such high-risk patients, in the near future.

Resumo A hipercalemia é um dos distúrbios eletrolíticos mais comuns, responsável por um grande número de desfechos adversos, incluindo arritmias potencialmente fatais. Quelantes de potássio são amplamente prescritos para o tratamento da hipercalemia, mas infelizmente são muitos os eventos adversos associados ao seu uso, em particular os gastrointestinais. A identificação de pacientes com risco mais elevado para complicações graves associadas aos quelantes de potássio atualmente em uso, como necrose e perfuração do cólon, pode evitar desfechos fatais. O presente artigo descreve o caso de um homem de 56 anos com diabetes secundário e doença renal crônica em tratamento por hipercalemia com poliestirenossulfonato de cálcio (PSC). Posteriormente o paciente apresentou abdômen agudo devido a perfuração do ceco e foi submetido a uma ressecção ileocecal, mas acabou indo a óbito por choque séptico uma semana mais tarde. Durante a cirurgia, uma massa branca sólida foi isolada no lúmen do cólon. A massa foi identificada como um bezoar de PSC, uma massa de fármaco de rara ocorrência formada no trato gastrointestinal que contribuiu para a perfuração. História pregressa de gastrectomia parcial e vagotomia foi identificada como provável fator de risco para o desenvolvimento do bezoar de PSC. Espera-se que os dois novos quelantes de potássio - patiromer e ciclossilicato de zircônio sódico - ajudem a tratar pacientes de alto risco em um futuro próximo.

Cecum perforation associated with a calcium polystyrene sulfonate bezoar - a rare entity.

Hyperkalemia is one of the most common electrolyte disorders, responsible for a high number of adverse outcomes, including life-threatening arrhythmias. Potassium binders are largely prescribed drugs used for hyperkalemia treatment but unfortunately, there are many adverse events associated with its use, mostly gastrointestinal. Identification of patients at highest risk for the serious complications associated with the current potassium binders, such as colon necrosis and perforation, could prevent fatal outcomes. The authors present a case of a 56-year-old man with secondary diabetes and chronic renal disease that was treated for hyperkalemia with Calcium Polystyrene Sulfonate (CPS). He later presented with acute abdomen due to cecum perforation and underwent ileocecal resection but ultimately died from septic shock a week later. During surgery, a solid white mass was isolated in the lumen of the colon. The mass was identified as a CPS bezoar, a rare drug-mass formed in the gastrointestinal tract that contributed to the perforation. A previous history of partial gastrectomy and vagothomy was identified as a probable risk factor for the CPS bezoar development. Hopefully, the two new potassium binders patiromer and (ZS-9) Sodium Zirconium Cyclosilicate will help treat such high-risk patients, in the near future.

Mouse and human CD8(+) CD28(low) regulatory T lymphocytes differentiate in the thymus.

Regulatory T (Treg) lymphocytes play a central role in the control of immune responses and so maintain immune tolerance and homeostasis. In mice, expression of the CD8 co-receptor and low levels of the co-stimulatory molecule CD28 characterizes a Treg cell population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo. It has remained unclear if CD8(+) CD28(low) Treg cells develop in the thymus or represent a population of chronically activated conventional T cells differentiating into Treg cells in the periphery, as suggested by their CD28(low) phenotype. We demonstrate that functional CD8(+) CD28(low) Treg cells are present in the thymus and that these cells develop locally and are not recirculating from the periphery. Differentiation of CD8(+) CD28(low) Treg cells requires MHC class I expression on radioresistant but not on haematopoietic thymic stromal cells. In contrast to other Treg cells, CD8(+) CD28(low) Treg cells develop simultaneously with CD8(+) CD28(high) conventional T cells. We also identified a novel homologous naive CD8(+) CD28(low) T-cell population with immunosuppressive properties in human blood and thymus. Combined, our data demonstrate that CD8(+) CD28(low) cells can develop in the thymus of mice and suggest that the same is true in humans.

Cellular senescence impact on immune cell fate and function.

Cellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T-lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T-helper lymphocyte-dependent tissue homeostatic functions and T-regulatory cell-dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide-reaching role as a homeostatic orchestrator.

Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity.

Promising immunotherapeutic strategies are emerging to restore tolerance in autoimmune diseases by triggering an increase in the number and/or the function of endogenous regulatory T (Treg) cells, which actively control pathological immune responses. Evidence suggests a remarkable heterogeneity in peripheral Treg cells that warrants their better characterization in terms of phenotype and suppressive function, to determine which subset may be optimally suitable for a given clinical situation. We found that repetitive injections of immature dendritic cells expanded Foxp3-negative CD49b(+) Treg cells that displayed an effector memory phenotype. These expanded Treg cells were isolated ex vivo for transcriptome analysis and found to contain multiple transcripts of the canonical Treg signature shared mainly by CD25(+) but also by other subphenotypes. We characterized the CD49b(+) Treg cell phenotype, underscoring its similarities with the CD25(+) Treg cell phenotype and highlighting some differential expression patterns for several markers, including lymphocyte activation gene 3, KLRG1, CD103, ICOS, CTLA-4, and granzyme B. Comparison of the CD25(+) and CD49b(+) Treg cells' suppressive mechanisms, in vitro and in vivo, revealed the latter's potent suppressive activity, which was partly dependent on IL-10 secretion. Altogether, our results strongly suggest that expression of several canonical Treg cell markers and suppressive function could be Foxp3 independent, and underscore the therapeutic potential of IL-10-secreting CD49b(+) Treg cells in arthritis.

Deregulation and therapeutic potential of microRNAs in arthritic diseases.

Epigenetic abnormalities are part of the pathogenetic alterations involved in the development of rheumatic disorders. In this context, the main musculoskeletal cell lineages, which are generated from the pool of mesenchymal stromal cells (MSCs), and the immune cells that participate in rheumatic diseases are deregulated. In this Review, we focus on microRNA (miRNA)-mediated regulatory pathways that control cell proliferation, drive the production of proinflammatory mediators and modulate bone remodelling. The main studies that identify miRNAs as regulators of immune cell fate, MSC differentiation and immunomodulatory properties - parameters that are altered in rheumatoid arthritis (RA) and osteoarthritis (OA) - are also discussed, with emphasis on the importance of miRNAs in the regulation of cellular machinery, extracellular matrix remodelling and cytokine release. A deeper understanding of the involvement of miRNAs in rheumatic diseases is needed before these regulatory pathways can be explored as therapeutic approaches for patients with RA or OA.

Systemic LPS Translocation Activates Cross-Presenting Dendritic Cells but Is Dispensable for the Breakdown of CD8+ T Cell Peripheral Tolerance in Irradiated Mice.

Lymphodepletion is currently used to enhance the efficacy of cytotoxic T lymphocyte adoptive transfer immunotherapy against cancer. This beneficial effect of conditioning regimens is due, at least in part, to promoting the breakdown of peripheral CD8+ T cell tolerance. Lymphodepletion by total body irradiation induces systemic translocation of commensal bacteria LPS from the gastrointestinal tract. Since LPS is a potent activator of the innate immune system, including antigen presenting dendritic cells, we hypothesized that LPS translocation could be required for the breakdown of peripheral tolerance observed in irradiated mice. To address this issue, we have treated irradiated mice with antibiotics in order to prevent LPS translocation and utilized them in T cell adoptive transfer experiments. Surprisingly, we found that despite of completely blocking LPS translocation into the bloodstream, antibiotic treatment did not prevent the breakdown of peripheral tolerance. Although irradiation induced the activation of cross-presenting CD8+ dendritic cells in the lymphoid tissue, LPS could not solely account for this effect. Activation of dendritic cells by mechanisms other than LPS translocation is sufficient to promote the differentiation of potentially autoreactive CD8+ T cells into effectors in irradiated mice. Our data indicate that LPS translocation is dispensable for the breakdown of CD8+ T cell tolerance in irradiated mice.