Myelin-reactive B cells exacerbate CD4 T cell-driven CNS autoimmunity in an IL-23-dependent manner.

B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG, IgH mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH meninges and by CD4 T helper 17 (Th17) cells in the CNS.

Atypical B Cells Promote Cancer Progression and Poor Response to Bacillus Calmette-Guérin in Non-Muscle Invasive Bladder Cancer.

Poor response to Bacillus Calmette-Guérin (BCG) immunotherapy remains a major barrier in the management of patients with non-muscle invasive bladder cancer (NMIBC). Multiple factors are associated with poor outcomes, including biological aging and female sex. More recently, it has emerged that a B-cell-infiltrated pretreatment immune microenvironment of NMIBC tumors can influence the response to intravesically administered BCG.

Cutting Edge: Serpine1 Negatively Regulates Th1 Cell Responses in Experimental Autoimmune Encephalomyelitis.

Th1 cells are critical in experimental autoimmune encephalomyelitis (EAE). Serine protease inhibitor clade E1 (Serpine1) has been posited as an inhibitor of IFN-γ from T cells, although its role in autoimmunity remains unclear. In this study, we show that Serpine1 knockout (KO) mice develop EAE of enhanced severity relative to wild-type (WT) controls.

The X-linked histone demethylases KDM5C and KDM6A as regulators of T cell-driven autoimmunity in the central nervous system.

T cell-driven autoimmune responses are subject to striking sex-dependent effects. While the contributions of sex hormones are well-understood, those of sex chromosomes are meeting with increased appreciation. Here, we outline what is known about the contribution of sex chromosome-linked factors to experimental autoimmune encephalomyelitis (EAE), a mouse model that recapitulates many of the T cell-driven mechanisms of multiple sclerosis (MS) pathology.

Nociceptor neurons affect cancer immunosurveillance.

Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release.

SARS-CoV-2 and Multiple Sclerosis: Potential for Disease Exacerbation.

While the respiratory tract is the primary route of entry for SARS-CoV-2, evidence shows that the virus also impacts the central nervous system. Intriguingly, case reports have documented SARS-CoV-2 patients presenting with demyelinating lesions in the brain, spinal cord, and optic nerve, suggesting possible implications in neuroimmune disorders such as multiple sclerosis (MS) and other related neuroimmune disorders. However, the cellular mechanisms underpinning these observations remain poorly defined.

The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation.

Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes.

Biological Sex As a Critical Variable in CD4 Effector T Cell Function in Preclinical Models of Multiple Sclerosis.

T cells play a pivotal role in maintaining adaptive immune responses against pathogens. However, misdirected T cell responses against self-tissues may lead to autoimmune disease. Biological sex has profound effects on T cell function and is an important determinant of disease incidence and severity in autoimmune diseases such as multiple sclerosis (MS).

Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion.

T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells.

Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity.

Sex differences in multiple sclerosis (MS) incidence and severity have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive disease remain poorly defined. Using a T cell adoptive transfer model of chronic experimental autoimmune encephalomyelitis (EAE), we find that male Th17 cells induce disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients.

Selective Immunomodulatory and Neuroprotective Effects of a NOD2 Receptor Agonist on Mouse Models of Multiple Sclerosis.

The significance of monocytes has been demonstrated in multiple sclerosis (MS). One of the therapeutic challenges is developing medications that induce mild immunomodulation that is solely targeting specific monocyte subsets without affecting microglia. Muramyl dipeptide (MDP) activates the NOD2 receptor, and systemic MDP administrations convert Ly6C into Ly6C monocytes.

Protein translocation and retro-translocation across the endoplasmic reticulum are crucial to inflammatory effector CD4 T cell function.

Effector CD4 T cells can be classified by the cytokines they secrete, with T helper 1 (Th1) cells generating interferon (IFN)γ and Th17 cells secreting interleukin (IL)-17. Both Th1 and Th17 cells are strongly implicated in the initiation and chronicity of autoimmune diseases such as multiple sclerosis. The endoplasmic reticulum (ER) has been implicated as a potentially crucial site in regulating CD4 T cell function.

Endogenous T Cell Receptor Rearrangement Represses Aggressive Central Nervous System Autoimmunity in a TcR-Transgenic Model on the Non-Obese Diabetic Background.

The T cell response to central nervous system (CNS) antigen in experimental autoimmune encephalomyelitis (EAE) permits one to model the immune aspects of multiple sclerosis. 1C6 transgenic mice on the non-obese diabetic (NOD) background possess a class II-restricted T cell receptor (TcR; Vα5-Vβ7) specific for the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG). It remains to be determined what role is played by allelic inclusion in shaping the TcR repertoire of these mice.

Tim-3: A co-receptor with diverse roles in T cell exhaustion and tolerance.

T cell inhibitory co-receptors play a crucial role in maintaining the balance between physiologic immune responses and maladaptive ones. T cell immunoglobulin and mucin domain-containing-3 (Tim-3) is a unique inhibitory co-receptor in that its expression is chiefly restricted to interferon (IFN)γ-producing CD4 and CD8 T cells. Early reports firmly established its importance in maintaining peripheral tolerance in transplantation and autoimmunity.

Publisher Correction: The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Peripheral adaptive immunity of the triple transgenic mouse model of Alzheimer's disease.

Background: Immunologic abnormalities have been described in peripheral blood and central nervous system of patients suffering from Alzheimer's disease (AD), yet their role in the pathogenesis still remains poorly defined.

Aim And Methods: We used the triple transgenic mouse model (3xTg-AD) to reproduce Aβ (amyloid plaques) and tau (neurofibrillary tangles) neuropathologies. We analyzed important features of the adaptive immune system in serum, primary (bone marrow) as well as secondary (spleen) lymphoid organs of 12-month-old 3xTg-AD mice using flow cytometry and ELISPOT.

The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.

Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology.

Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling.

Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia.

IL-1β enables CNS access to CCR2 monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells.

Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1β-knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1β/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs).

Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes.

Multiple sclerosis (MS) is a chronic central nervous system disease that is associated with progressive loss of myelin and subsequent axonal degeneration. Cholesterol is an essential component of mammalian cellular and myelin membranes. In this systematic review, we examined the relationship between levels of cholesterol and markers of cholesterol turnover in circulation and/or cerebrospinal fluid (CSF) and disease outcomes in adults with clinically isolated syndrome (CIS) or confirmed MS.

The Non-Obese Diabetic Mouse Strain as a Model to Study CD8(+) T Cell Function in Relapsing and Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on central nervous system (CNS) myelin. Although CD4(+) T cell function in MS pathology has been extensively studied, there is also strong evidence that CD8(+) T lymphocytes play a key role. Intriguingly, CD8(+) T cells accumulate in great numbers in the CNS in progressive MS, a form of the disease that is refractory to current disease-modifying therapies that target the CD4(+) T cell response.