UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors.

Type 1 Diabetes Mellitus (T1D) is an autoimmune disease caused by unremitting immune attack on pancreas insulin-producing beta cells. Persistence of the autoimmune response is mediated by TCF1+ Ly108+ progenitor CD8+ T (T) cells, a stem-like population that gives rise to exhausted effectors with limited cytolytic function in chronic virus infection and cancer. What paradoxically drives T conversion to highly cytolytic effectors in T1D, however, remains unclear.

Polyfunctional IL-21 IFNG T follicular helper cells contribute to checkpoint inhibitor diabetes mellitus and can be targeted by JAK inhibitor therapy.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic beta-islet cell destruction leading to hyperglycemia and life-long insulin dependence.

A pathologically expanded, clonal lineage of IL-21-producing CD4+ T cells drives inflammatory neuropathy.

Inflammatory neuropathies, which include chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain Barré syndrome (GBS), result from autoimmune destruction of the PNS and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood.

Cutting Edge: Hypoxia Sensing by the Histone Demethylase UTX (KDM6A) Limits Colitogenic CD4+ T Cells in Mucosal Inflammation.

Hypoxia is a hallmark of inflammatory conditions (e.g., inflammatory bowel disease [IBD]), and adaptive responses have consequently evolved to protect against hypoxia-associated tissue injury.

A pathologically expanded, clonal lineage of IL-21 producing CD4+ T cells drives Inflammatory neuropathy.

Inflammatory neuropathies, which include CIDP (chronic inflammatory demyelinating polyneuropathy) and GBS (Guillain Barre Syndrome), result from autoimmune destruction of the peripheral nervous system (PNS) and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood.

Hypoxia-sensing by the Histone Demethylase UTX ( ) Controls Colitogenic CD4 T cell Fate and Mucosal Inflammation.

Hypoxia is a feature of inflammatory conditions [e.g., inflammatory bowel disease (IBD)] and can exacerbate tissue damage in these diseases.

Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.

Introduction: Increased T cell infiltration and interferon gamma (IFNγ) pathway activation are seen in tumors of melanoma patients who respond to ICI (immune checkpoint inhibitor) or MAPK pathway inhibitor (MAPKi) therapies. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi, suggesting that additional mechanisms may be present in patients responding to ICI therapy that are beneficial for anti-tumor immunity.

Methods: We used transcriptional analysis and clinical outcomes from patients treated with ICI or MAPKi therapies to delineate immune mechanisms driving tumor response.

IL-11 induces NLRP3 inflammasome activation in monocytes and inflammatory cell migration to the central nervous system.

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11 monocytes, IL-11 and IL-11R CD4 lymphocytes, and IL-11R neutrophils in comparison to matched healthy controls.

Clonally expanded, thyrotoxic effector CD8 T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease.

Mild COVID-19 in an APECED Patient with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and High Titer of Type 1 IFN-Abs: A Case Report.

Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), caused by mutations in the Autoimmune Regulator (AIRE) gene, is an autosomal recessive multi-organ autoimmunity syndrome usually defined by high serum titers of type I Interferon Autoantibodies (Type 1 IFN-Abs). These antibodies have recently been found in individuals in the general population who develop life-threatening Coronavirus Disease 2019 (COVID-19), but the significance of pre-existing Type 1 IFN-Abs in APECED patients with COVID-19 remains unclear. Previous reports of COVID-19 outcomes in APECED patients have been divergent, and protective roles have been proposed for female sex, age <26 years, and immunomodulatory medications including intravenous immunoglobulin (IVIg).

The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences.

Viral infection outcomes are sex biased, with males generally more susceptible than females. Paradoxically, the numbers of antiviral natural killer (NK) cells are increased in males. We demonstrate that while numbers of NK cells are increased in male mice, they display decreased effector function compared to females in mice and humans.

Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor-Induced Hypophysitis.

Context: Hypophysitis is a known immune-related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors.

Objective: We aimed to determine clinical, imaging, and HLA characteristics of CPI-induced hypophysitis (CPI-hypophysitis).

Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary, and association with HLA type in patients with CPI-hypophysitis.

Inhibition of IL-17A Protects against Thyroid Immune-Related Adverse Events while Preserving Checkpoint Inhibitor Antitumor Efficacy.

Immune checkpoint inhibitor (ICI) immunotherapy leverages the body's own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune-related adverse events (IrAEs) may lead to treatment interruption, permanent organ dysfunction, hospitalization, and premature death. Thyroiditis is one of the most common IrAEs, but the cause of thyroid IrAEs remains unknown.

Polyendocrine Autoimmunity and Diabetic Ketoacidosis Following Anti-PD-1 and Interferon α.

Immune checkpoint inhibitor (ICI) therapies are now first-line therapy for many advanced malignancies in adults, with emerging use in children. With increasing ICI use, prompt recognition and optimal management of ICI-associated immune-related adverse events (IRAEs) are critical. Nearly 60% of ICI-treated adults develop IRAEs, which commonly manifest as autoimmune skin, gastrointestinal, and endocrine disease and can be life-threatening.

Pathogenic TNF-α drives peripheral nerve inflammation in an Aire-deficient model of autoimmunity.

Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g.

Sex Differences in Immunity.

Strong epidemiological evidence now exists that sex is an important biologic variable in immunity. Recent studies, for example, have revealed that sex differences are associated with the severity of symptoms and mortality due to coronavirus disease 2019 (COVID-19). Despite this evidence, much remains to be learned about the mechanisms underlying associations between sex differences and immune-mediated conditions.

COVID-19 Outcomes of Patients With Differentiated Thyroid Cancer: A Multicenter Los Angeles Cohort Study.

Objective: Cancer may be a risk factor for worse outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections. However, there is a significant variability across cancer types in the extent of disease burden and modalities of cancer treatment that may impact morbidity and mortality from coronavirus disease-19 (COVID-19). Therefore, we evaluated COVID-19 outcomes in patients with a differentiated thyroid cancer (DTC) history.

AIM2 in regulatory T cells restrains autoimmune diseases.

The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells. It consists of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells.

Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nerves that presents with either chronic progression or relapsing disease. Recent studies in samples from patients with CIDP and mouse models have delineated how defects in central (thymic) and peripheral (extrathymic) immune tolerance mechanisms can cause PNS autoimmunity. Notably, nerve parenchymal cells actively contribute to local autoimmunity and also control disease outcome.

The dysfunction of BP180/collagen XVII in keratinocytes promotes melanoma progression.

BP180, also termed collagen XVII, is a hemidesmosomal transmembrane glycoprotein expressed in basal keratinocytes, and functions as a cell-matrix adhesion molecule in the dermal-epidermal junction of the skin. Its function, other than cell-matrix adhesion, remains unclear. We generated a mouse strain with BP180 dysfunction (termed ∆NC16A), which develops spontaneous skin inflammation accompanied by an influx of myeloid derived suppressor cells (MDSCs).

Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy.

A major breakthrough in cancer treatment occurred with the development of strategies that overcome T-cell tolerance toward tumor cells. These approaches enhance antitumor immunity by overcoming mechanisms that are normally in place to prevent autoimmunity but simultaneously prevent rejection of tumor cells. Although tolerance mechanisms that restrict antitumor immunity take place both in the thymus and periphery, only immunotherapies that target peripheral tolerance mechanisms occurring outside of the thymus are currently available.

An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses.

Epidemiologic data demonstrate sex differences in autoimmune diseases, immune responses against infection, and antitumor immunity, and accumulating evidence suggests a major role for sex hormones in mediating these differences. In this study, we review recent advances in understanding how sex hormones regulate T cell responses to alter susceptibility to autoimmunity. Although sex hormones can directly alter gene transcriptional programs of T cells, we focus in this study on how sex hormones alter T cell development and function through their effects on thymic stromal cells and innate cell types.

Correction: Dynamic metrics-based biomarkers to predict responders to anti-PD-1 immunotherapy.

Since the publication of this paper, the authors noticed that the funding information for Maureen A. Su was not included. Therefore the authors would like to add the following information to the Acknowledgements section.