Chronic Autoimmunity Research Articles

Tetraspanin CD53 modulates lymphocyte trafficking but not systemic autoimmunity in Lyn-deficient mice.

The leukocyte-restricted tetraspanin CD53 has been shown to promote lymphocyte homing to lymph nodes (LNs) and myeloid cell recruitment to acutely inflamed peripheral organs, and accelerate the onset of immune-mediated disease. However, its contribution in the setting of chronic systemic autoimmunity has not been investigated. We made use of the Lyn-/- autoimmune model, generating Cd53-/- Lyn-/- mice, and compared trafficking of immune cells into secondary lymphoid organs and systemic autoimmune disease development with mice lacking either gene alone. Consistent with previous observations, absence of CD53 led to reduced LN cellularity via reductions in both B and T cells, a phenotype also observed in Cd53-/- Lyn-/- mice. In some settings, Cd53-/- Lyn-/- lymphocytes showed greater loss of surface L-selectin and CD69 upregulation above that imparted by Lyn deficiency alone, indicating that absence of these two proteins can mediate additive effects in the immune system. Conversely, prototypical effects of Lyn deficiency including splenomegaly, plasma cell expansion, elevated serum immunoglobulin M and anti-nuclear antibodies were unaffected by CD53 deficiency. Furthermore, while Lyn-/- mice developed glomerular injury and showed elevated glomerular neutrophil retention above than that in wild-type mice, absence of CD53 in Lyn-/- mice did not alter these responses. Together, these findings demonstrate that while tetraspanin CD53 promotes lymphocyte trafficking into LNs independent of Lyn, it does not make an important contribution to development of autoimmunity, plasma cell dysfunction or glomerular injury in the Lyn-/- model of systemic autoimmunity.

Is There a Place for Chimeric Antigen Receptor-T Cells in the Treatment of Chronic Autoimmune RheumaticDiseases?

Chimeric antigen receptor-T (CAR-T) cell therapy is based on specific targeting of tumor antigens, leading to lysis and destruction of tumor cells. The high potency of CAR-T cells in the management of B cell malignancies has been demonstrated. Following the success of this therapeutic strategy, new CAR-T cell-derived constructs that have the ability to eradicate pathogenic B cells or restore tolerance have been developed. The present review discusses how the knowledge and technology generated by the use of CAR-T cells may be translated and integrated into ongoing therapeutic strategies for autoimmune rheumatic diseases. To this end, we describe the details of CAR-T cell technology, as well as the meaningful achievements attained with the use of CAR-T cells in onco-hematology. In addition, we review the preliminary data obtained with CAR-T cells and their derivative constructs in experimental models of autoimmune diseases. Finally, we focus on how CAR-T cell engineering interferes with the pathogenesis of 3 chronic autoimmune rheumatic diseases-rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis-and discuss whether these constructs might yield greater efficacy and be associated with fewer adverse events compared to current treatment strategies.

Early and Late Processes Driving NET Formation, and the Autocrine/Paracrine Role of Endogenous RAGE Ligands.

Neutrophil extracellular trap (NET) formation has emerged as an important response against various pathogens; it also plays a role in chronic inflammation, autoimmunity, and cancer. Despite a growing understanding of the mechanisms underlying NET formation, much remains to be elucidated. We previously showed that in human neutrophils activated with different classes of physiological stimuli, NET formation features both early and late events that are controlled by discrete signaling pathways. However, the nature of these events has remained elusive. We now report that PAD4 inhibition only affects the early phase of NET generation, as do distinct signaling intermediates (TAK1, MEK, p38 MAPK). Accordingly, the inducible citrullination of residue R2 on histone H3 is an early neutrophil response that is regulated by these kinases; other arginine residues on histones H3 and H4 do not seem to be citrullinated. Conversely, elastase blockade did not affect NET formation by several physiological stimuli, though it did so in PMA-activated cells. Among belated events in NET formation, we found that chromatin decondensation is impaired by the inhibition of signaling pathways controlling both early and late stages of the phenomenon. In addition to chromatin decondensation, other late processes were uncovered. For instance, unstimulated neutrophils can condition themselves to be poised for rapid NET induction. Similarly, activated neutrophils release endogenous proteic factors that promote and largely mediate NET generation. Several such factors are known RAGE ligands and accordingly, RAGE inbibition largely prevents both NET formation and the conditioning of neutrophils to rapidly generate NETs upon stimulation. Our data shed new light on the cellular processes underlying NET formation, and unveil unsuspected facets of the phenomenon that could serve as therapeutic targets. In view of the involvement of NETs in both homeostasis and several pathologies, our findings are of broad relevance.

Effects of Selenium Supplementation on Sperm Parameters and DNA-Fragmentation Rate in Patients with Chronic Autoimmune Thyroiditis.

Background: Selenium (Se) is an essential component of selenoenzymes, which have catalytic and antioxidant functions. A low Se status has been reported in patients with chronic autoimmune thyroiditis (AT) who benefit from Se supplementation. The role of Se in male reproduction is still a matter of debate. Although Se and selenoenzymes ensure sperm viability and protect against increased oxidative stress, only a few studies have assessed the effects of the administration of Se alone on sperm parameters, providing contrasting results. Aim: The aim of this study was to assess the effects of oral Se supplementation on conventional sperm parameters and DNA fragmentation (SDF) in patients with AT of reproductive age with normal thyroid function. Patients and Methods: Only patients with AT and normal thyroid function were selected for this study. All included patients underwent oral Se supplementation at the dose of 83 µg once daily (Syrel®, IBSA) for six months. Sperm conventional parameters, SDF, and thyroid function were assessed before and at the end of the treatment. Results: Twenty AT patients with normal weight were enrolled. After Se supplementation, they showed a higher sperm concentration, a higher percentage of sperm with progressive motility, and a higher percentage with normal morphology. They also had lower semen leukocyte concentration, and a lower percentage of spermatozoa with DNA fragmentation compared with pre-treatment values. Free-thyroxine serum levels increased significantly, whereas free triiodothyronine showed an upward trend. The thyroid-stimulating hormone did not change significantly. Conclusion: Se supplementation may represent a possible non-hormonal therapeutic choice for the treatment of male infertility, although further studies are needed to confirm this evidence. The possible thyroid hormone dependency of these findings needs to be clarified.

Immune checkpoints and the multiple faces of B cells in systemic lupus erythematosus.

B-lymphocytes are crucial in the pathogenesis of systemic lupus erythematosus (SLE), including autoantibody production, antigen presentation, co-stimulation, and cytokine secretion. Co-stimulatory and co-inhibitory molecules control interactions between B and T cells during an inflammatory response, which is essential for an appropriate host protection and maintenance of self-tolerance. Here, we review recent findings about checkpoint molecules and SLE B cells including their potential therapeutic implications and experiences from clinical trials. Most prominent checkpoint molecules involved in pathologic B and T cell interaction in SLE are CD40/CD40L and inducible co-stimulator/ICOSL, both also intimately involved in the formation of germinal centers and ectopic lymphoid tissue. Dysregulations of inhibitory checkpoint molecules, like programmed death-1/programmed death-ligand 1 and B- and T-lymphocyte attenuator have been suggested to impair B cell functions in SLE recently. Accumulating evidence indicates that dampening immune responses by either blocking co-activating signals or enhancing co-inhibitory signals in different cell types is a promising approach to treat autoimmune diseases to better control active disease but may also allow resolution of chronic autoimmunity.

The Role of the IL-6 Cytokine Family in Epithelial-Mesenchymal Plasticity in Cancer Progression.

Epithelial–mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.

CDC1 Dependent Accumulation of Memory T Cells Is Required for Chronic Autoimmune Inflammation in Murine Testis.

As an immune privilege site, there are various types of immune cells in the testis. Previous research has been focused on the testicular macrophages, and much less is known about the T cells in the testis. Here, we found that T cells with memory phenotypes were the most abundant leukocyte in the testis except for macrophages. Our results showed that the proportion of testicular T cells increases gradually from birth to adulthood in mice and that the primary type of T cells changed from γδTCR+ T cells to αβTCR+ T cells. In addition, under homeostatic conditions, CD8+ T cells are the dominant subgroup and have different phenotypic characteristics from CD4+ T cells. We found that cDC1, but not cDC2, is necessary for the presence of T cells in the testis under physiological state. A significant decrease of T cells does not have a deleterious effect on the development of the testis or spermatogenesis. However, cDC1-dependent T cells play an indispensable role in chronic autoimmune orchitis of the testis. Collectively, our multifaceted data provide a comprehensive picture of the accumulation, localization, and function of testicular T cells.

Abstract 1760: Role of Batf-dependant Th17 immune response in PTEN-null mouse model

Abstract Basic leucine zipper transcription factor ATF-like (BATF) belongs to the activator protein 1 (AP-1) family of transcription factors and has been shown to be predominantly expressed in cells of hematopoietic origin, especially in T cells. Mice deficient for BATF were first described to lack T helper cell type 17 (Th17). Th17 cells are a distinct lineage of CD4+ T helper cells that provide protective immunity to infections but are also involved in chronic inflammation and autoimmunity. However, the role of Th17 response in prostate cancer remains controversial. In this study, we took a genetic approach to explore the role of BATF-dependent Th17 cells in prostate cancers by interbreeding BATF-deficient (Batf-/-) mice with mice that are conditionally mutant for PTEN, an established preclinical model for prostate cancer. Batf+/+;Pten-/- and Batf+/-;Pten-/- mice presented similar prostate phenotypes thus were put into one group (named Batf+), which were compared to the Batf-/-;Pten-/- group (named Batf-). We found that Batf- prostates were clearly smaller than Batf+ prostates at 30 weeks. The genitourinary bloc weight was significantly heavier in Batf+ mice than in Batf- mice at 12 and 30 weeks. Batf+ mice developed significantly higher percent of invasive adenocarcinomas in different prostate lobes at 9, 12, and 30 weeks, respectively compared to Batf- mice. Tumors in Batf- mice exhibited lower rates of cellular proliferation and higher apoptosis, as well as reduced inflammatory cell infiltration and angiogenesis in the prostatic stroma. Moreover, Batf- mice exhibited significantly reduced mRNA and protein levels of Th17 cytokines, AP-1 family members and IL-23R, and reduced NF-kB pathway activity in both spleen and prostate tissues. CD4+ T cells from Batf- mice cultured under Th17 conditions for 4 days, expressed reduced AP-1 family-regulated genes compared to Batf+ mice. Prostate cancer cells (LNCaP) with overexpression of BATF in vitro exhibited increased IL-23R expression. Prostate tissues from Batf- mice cultured under IL-6 or Th17 conditions for 4 days had reduced IL-23R expression compared to that from Batf+ mice. Taken together, our results suggest that Batf promotes the initiation and progression of prostate adenocarcinoma via Th17-mediated inflammatory immune responses and that the Batf-IL-23-IL-17 axis is a critical pathway that is needed for prostate adenocarcinoma development and progression. This work was supported by the NIH-National Institute of General Medical Sciences COBRE on Aging and Regenerative Medicine (P20GM103629, PD: S. Michal Jazwinski; PI: Q.Z.) and the Carol Lavin Bernick Faculty Grant from Tulane University (PI: Q.Z.). Citation Format: Qiuyang Zhang, Sen Liu, Bing Zhang. Role of Batf-dependant Th17 immune response in PTEN-null mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1760.

Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases.

Interleukin 7 (IL-7) is a cell growth factor with a central role in normal T cell development, survival and differentiation. The lack of IL-7–IL-7 receptor(R)-mediated signaling compromises lymphoid development, whereas increased signaling activity contributes to the development of chronic inflammation, cancer and autoimmunity. Gain-of-function alterations of the IL-7R and the signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are enriched in T cell acute lymphoblastic leukemia (T-ALL) and autocrine production of IL-7 by T-ALL cells is involved in the phenotypes of leukemic initiation and oncogenic spreading. Several IL-7-associated pathologies are also characterized by increased presence of matrix metalloproteinase-9 (MMP-9), due to neutrophil degranulation and its regulated production by other cell types. Since proteases secreted by neutrophils are known to modulate the activity of many cytokines, we investigated the interactions between IL-7, MMP-9 and several other neutrophil-derived proteases. We demonstrated that MMP-9 efficiently cleaved human IL-7 in the exposed loop between the α-helices C and D and that this process is delayed by IL-7 N-linked glycosylation. Functionally, the proteolytic cleavage of IL-7 did not influence IL-7Rα binding and internalization nor the direct pro-proliferative effects of IL-7 on a T-ALL cell line (HPB-ALL) or in primary CD8+ human peripheral blood mononuclear cells. A comparable effect was observed for the neutrophil serine proteases neutrophil elastase, proteinase 3 and combinations of neutrophil proteases. Hence, glycosylation and disulfide bonding as two posttranslational modifications influence IL-7 bioavailability in the human species: glycosylation protects against proteolysis, whereas internal cysteine bridging under physiological redox state keeps the IL-7 conformations as active proteoforms. Finally, we showed that mouse IL-7 does not contain the protease-sensitive loop and, consequently, was not cleaved by MMP-9. With the latter finding we discovered differences in IL-7 biology between the human and mouse species.

Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity.

CD8+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.

Glycolysis Inhibition Induces Functional and Metabolic Exhaustion of CD4+ T Cells in Type 1 Diabetes.

In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

Exercise acutely increases vitaminD receptor expression in Tlymphocytes in vitaminD-deficient men, independent of age.

What is the central question of this study? Does exercise affect vitaminD receptor expression in Tlymphocytes in young, middle-aged and older adults? What is the main finding and its importance? Moderate-intensity cycling exercise increases vitaminD receptor expression in vitaminD-deficient men, independent of age, presenting a strategy to combat the prevalence of vitaminD deficiency. Vitamin D plays a key role in the modulation of the immune system, mediated through the intracellular vitaminD receptor (VDR). Exercise has been shown to influence the activity and availability of the VDR. The aim of this study was to investigate the effect of age on basal immune cell (T-lymphocyte) VDR expression and the subsequent effect of acute aerobic exercise to modulate VDR expression in peripheral Tcells. Thirty-five men were included in the study (mean±SD: age 44±17years and body mass index 25.7±3.1kg/m2 ), separated into three age groups: 18-30 (n=12), 31-45 (n=11) and 60-75years (n=12). Participants completed two trials [control (CON) and aerobic exercise (AE)], with blood samples collected pre- and postexercise (0, 1 and 3 h). Peripheral blood Tcells were isolated and analysed for VDR expression by flow cytometry. The results show that advanced age is associated with lower VDR expression in Tcells (882±274, 796±243 and 594±174 geomean in the 18-30, 31-45 and 60-75year age groups, respectively). Acute AE was successful at acutely increasing VDR expression in Tcells, irrespective of age. Advanced age corresponds to a lower T-cell VDR expression, which might be responsible for age-associated development of chronic conditions and autoimmunity. Exercise was successful in increasing VDR expression in Tcells irrespective of age and independent of exercise-induced T-cell mobilization.

Case Report: Dental Findings Can Aid in Early Diagnosis of APECED Syndrome.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1), is a rare genetic disorder caused most often by biallelic mutations in the AIRE gene. Classic clinical findings of the disease are chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues, such as hypoparathyroidism and adrenal insufficiency. Recently, however, it has been appreciated that enamel hypoplasia, together with intestinal malabsorption and a characteristic APECED rash, is a prominent early disease manifestation of APECED which can aid in the diagnosis of disease before other potentially life-threatening disease manifestations occur. To demonstrate this point, we present data from a cohort of APECED patients, approximately 70% of who present with enamel dysplasia at an early age. Importantly, early life presentation with enamel dysplasia was predictive of likelihood of development of a subsequent APECED diagnosis. Furthermore, we present a case of a patient with APECED and severe enamel defects and discuss the utility of medical-dental professional co-operation in the diagnosis and management of this complex disorder.

Clozapine Regulates Microglia and Is Effective in Chronic Experimental Autoimmune Encephalomyelitis.

ObjectiveProgressive multiple sclerosis is characterized by chronic inflammation with microglial activation, oxidative stress, accumulation of iron and continuous neurodegeneration with inadequate effectiveness of medications used so far. We now investigated effects of iron on microglia and used the previously identified neuroprotective antipsychotic clozapine in vitro and in chronic experimental autoimmune encephalomyelitis (EAE).MethodsMicroglia were treated with iron and clozapine followed by analysis of cell death and response to oxidative stress, cytokine release and neuronal phagocytosis. Clozapine was investigated in chronic EAE regarding optimal dosing and therapeutic effectiveness in different treatment paradigms. Animals were scored clinically by blinded raters. Spinal cords were analyzed histologically for inflammation, demyelination, microglial activation and iron accumulation and for transcription changes of regulators of iron metabolism and inflammation. Effects on immune cells were analyzed using flow cytometry.ResultsIron impaired microglial function in vitro regarding phagocytosis and markers of inflammation; this was regulated by clozapine, reflected in reduced release of IL-6 and normalization of neuronal phagocytosis. In chronic EAE, clozapine dose-dependently attenuated clinical signs and still had an effect if applied in a therapeutic setting. Early mild sedative effects habituated over time. Histologically, demyelination was reduced by clozapine and positive effects on inflammation strongly correlated with reduced iron deposition. This was accompanied by reduced expression of DMT-1, an iron transport protein.ConclusionsClozapine regulates microglial function and attenuates chronic EAE, even in a therapeutic treatment paradigm. This well-defined generic medication might therefore be considered as promising add-on therapeutic for further development in progressive MS.

STAT1 gain of function mutation impairs immune response to viral infections

Abstract Regulation of T cells by interferons and other cytokines, which act via STAT family transcription factors, is critical for host defense. Patients with STAT1 gain-of-function (GOF) mutations exhibit heightened STAT1 activation after cytokine stimulation and develop lifelong ailments, including chronic infections, autoimmunity, and cancer. A characteristic feature of this disorder is chronic mucocutaneous candidiasis (CMC), related to exagerated type 1/IFNγ bias that antagonizes a type 3/Th17 response required for fungal clearance. However, this type 1/IFNγ bias does not explain why almost 40% of reported patients exhibit chronic and sometimes lethal viral infections. This observation is unexpected, as cells with STAT1-GOF mutations exhibit increased expression of interferon stimulated genes following IFNα/β and IFNγ stimulation and patients show more IFNγ-producing CD4 T cells. This paradox emphasizes the critical need to understand basic principles of cytokine signaling, specifically how a STAT1-GOF mutation alters cytokine output. Using a novel conditional knock-in mouse expressing a common GOF STAT1 mutation, T385M, we found that this model recapitulates observations in patients (i.e. elevated STAT1 activation, increased total STAT1 protein, susceptibility to CMC), as well as a strong type 1/interferon bias at steady state. Despite this type 1 bias, STAT1-GOF exhibit impaired NK and CD8 T cell response to systemic viral infections. These results reveal that STAT1 activity must be tuned for proper immune response to viral infections.

CD8 follicular T cells provide helper and cytolytic function in the B cell follicule during antibody-mediated autoimmunity

Abstract CXCR5+ CD8 T cells arise during situations of chronic antigen and inflammation, including chronic viral infection, cancer, and antibody-mediated autoimmunity. In some conditions CXCR5 expression facilitates CD8 T cell homing to B cell follicles, while some studies find persistent CCR7 expression prevents follicle entry. Despite robust research within this fairly new field variance in tissue localization, expression profiles, inflammatory conditions and developmental stages limit comparisons between existing CXCR5+CD8 T cell studies. We demonstrate that CXCR5+PD-1+ CD8 T follicular (Tfc) cells comprise a functionally non-redundant subset of CXCR5+ CD8 T cells in systemic autoimmune disease. CD8 Tfc develop in the absence of functional Tregs and expand during lymphoproliferation. CD8 Tfc acquire the capacity to produce helper cytokines including co-expression of IL-21 and IL-4, and maintain capacity for cytolytic function expresing granzyme B and TNFα, suggesting the potential for functional mechanisms that diverge from CD4 Tfh cells. IL-4+IL-21+ CD8 Tfc localization in the follicle and germinal center suggest that CD8 Tfc may promote B cell activities in either location during autoimmune disease. B cell activities influenced by CD8 Tfc cells are not fully defined such as regulating somatic mutation, memory and plasma cell differentiation, and germinal center movement. However CD8 T cells promote plasma cell differentiation and antibody class switch, but do not alter germinal center B cell numbers. CD8 Tfc position coupled with cytokine production in the germinal center and follicle, and induction of activation-induced cytidine deaminase by B cells suggest a dominant helper-like role with cytolytic potential.

Clinical Characteristics of Acquired Chronic Autoimmune Polyneuropathies Associated with Nodal/Paranodal Autoantibodies at UCSD Neuromuscular Center (2784)

Clinical Characteristics of Acquired Chronic Autoimmune Polyneuropathies Associated with Nodal/Paranodal Autoantibodies at UCSD Neuromuscular Center (2784)

Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice.

Simple SummaryTumor necrosis factor (TNF) and its closely related cytokine, lymphotoxin alpha (LTα), are part of the TNF superfamily and exert their functions via both overlapping and non-redundant signaling pathways. Reported pro- and antitumorigenic effects of TNF and lymphotoxin are often context-dependent and may be contingent on a particular experimental approach, such as transplantable and chemically induced tumor models; tissue and organ specificity; types of cells producing these cytokines or responding to them; and the genotype and genetic background of mice. Here, we review the mechanisms of TNF/LTα involvement in cancer promotion and suppression as studied in mouse models. We also discuss the impact of microbiota on tumor development and manipulations of the TNF/LT system, which may be effective as anti-cancer therapy.Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) are two related cytokines from the TNF superfamily, yet they mediate their functions in soluble and membrane-bound forms via overlapping, as well as distinct, molecular pathways. Their genes are encoded within the major histocompatibility complex class III cluster in close proximity to each other. TNF is involved in host defense, maintenance of lymphoid tissues, regulation of cell death and survival, and antiviral and antibacterial responses. LTα, known for some time as TNFβ, has pleiotropic functions including control of lymphoid tissue development and homeostasis cross talk between lymphocytes and their environment, as well as lymphoid tissue neogenesis with formation of lymphoid follicles outside the lymph nodes. Along with their homeostatic functions, deregulation of these two cytokines may be associated with initiation and progression of chronic inflammation, autoimmunity, and tumorigenesis. In this review, we summarize the current state of knowledge concerning TNF/LTα functions in tumor promotion and suppression, with the focus on the recently uncovered significance of host–microbiota interplay in cancer development that may explain some earlier controversial results.

Role of Interleukin-6 in Vascular Health and Disease.

IL-6 is usually described as a pleiotropic cytokine produced in response to tissue injury or infection. As a pro-inflammatory cytokine, IL-6 activates innate and adaptative immune responses. IL-6 is released in the innate immune response by leukocytes as well as stromal cells upon pattern recognition receptor activation. IL-6 then recruits immune cells and triggers B and T cell response. Dysregulated IL-6 activity is associated with pathologies involving chronic inflammation and autoimmunity, including atherosclerosis. However, IL-6 is also produced and released under beneficial conditions, such as exercise, where IL-6 is associated with the anti-inflammatory and metabolic effects coupled with physical adaptation to intense training. Exercise-associated IL-6 acts on adipose tissue to induce lipogenesis and on arteries to induce adaptative vascular remodeling. These divergent actions could be explained by complex signaling networks. Classical IL-6 signaling involves a membrane-bound IL-6 receptor and glycoprotein 130 (gp130), while trans-signaling relies on a soluble version of IL-6R (sIL-6R) and membrane-bound gp130. Trans-signaling, but not the classical pathway, is regulated by soluble gp130. In this review, we discuss the similarities and differences in IL-6 cytokine and myokine signaling to explain the differential and opposite effects of this protein during inflammation and exercise, with a special focus on the vascular system.

APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas. Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH. APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.