Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T‐lymphocyte antigen‐4

Yang, Min; Klocke, K.; Marquina, Clara; Xu, Bingze; Gjertsson, Inger; Wing, Kajsa; Holmdahl, Rikard

doi:10.1111/imm.12983

Cited by 4 publications

(2 citation statements)

References 30 publications

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“…This apparent discrepancy is likely due to contextual differences. Many studies investigating the regulatory roles of T Reg cells are in the context of autoimmune pathologies (Chen et al, 2005;Yang et al, 2018a;Mohr et al, 2019). In a SCI setting that typically causes an overall loss of lymphocytes, T Reg cells may function differently to increase/protect this important population.…”

Section: Discussionmentioning

confidence: 99%

Attenuating Neurogenic Sympathetic Hyperreflexia Robustly Improves Antibacterial Immunity After Chronic Spinal Cord Injury

et al. 2019

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Spinal cord injury (SCI) disrupts critical physiological systems, including the cardiovascular and immune system. Plasticity of spinal circuits below the injury results in abnormal, heightened sympathetic responses, such as extreme, sudden hypertension that hallmarks life-threatening autonomic dysreflexia. Moreover, such sympathetic hyperreflexia detrimentally impacts other effector organs, including the spleen, resulting in spinal cord injury-induced immunodeficiency. Consequently, infection is a leading cause of mortality after SCI. Unfortunately, there are no current treatments that prophylactically limit sympathetic hyperreflexia to prevent subsequent effector organ dysfunction. The cytokine soluble tumor necrosis factor ␣ (sTNF␣) is upregulated in the CNS within minutes after SCI and remains elevated. Here, we report that commencing intrathecal administration of XPro1595, an inhibitor of sTNF␣, at a clinically feasible, postinjury time point (i.e., 3 d after complete SCI) sufficiently diminishes maladaptive plasticity within the spinal sympathetic reflex circuit. This results in less severe autonomic dysreflexia, a real-time gauge of sympathetic hyperreflexia, for months postinjury. Remarkably, delayed delivery of the sTNF␣ inhibitor prevents sympathetic hyperreflexia-associated splenic atrophy and loss of leukocytes to dramatically improve the endogenous ability of chronic SCI rats to fight off pneumonia, a common cause of hospitalization after injury. The improved immune function with XPro1595 correlates with less noradrenergic fiber sprouting and normalized norepinephrine levels in the spleen, indicating that heightened, central sTNF␣ signaling drives peripheral, norepinephrine-mediated organ dysfunction, a novel mechanism of action. Thus, our preclinical study supports intrathecally targeting sTNF␣ as a viable strategy to broadly attenuate sympathetic dysregulation, thereby improving cardiovascular regulation and immunity long after SCI.

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Section: Discussionmentioning

confidence: 99%

Attenuating Neurogenic Sympathetic Hyperreflexia Robustly Improves Antibacterial Immunity After Chronic Spinal Cord Injury

et al. 2019

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“…Treg cells may control bystander T cells and epitope spreading through interaction with cross-presenting DCs. In a rheumatoid arthritis mouse model Treg cell depletion promoted the expansion of pathogenic autoreactive T cells, an increase in inflammatory cytokines, and B-cell epitope spreading (92).…”

Section: Loss Of Immune Tolerancementioning

confidence: 99%

Potential for Antigen-Specific Tolerizing Immunotherapy in Systematic Lupus Erythematosus

Thomas

2021

Front. Immunol.

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Systemic lupus erythematosus (SLE) is a chronic complex systemic autoimmune disease characterized by multiple autoantibodies and clinical manifestations, with the potential to affect nearly every organ. SLE treatments, including corticosteroids and immunosuppressive drugs, have greatly increased survival rates, but there is no curative therapy and SLE management is limited by drug complications and toxicities. There is an obvious clinical need for safe, effective SLE treatments. A promising treatment avenue is to restore immunological tolerance to reduce inflammatory clinical manifestations of SLE. Indeed, recent clinical trials of low-dose IL-2 supplementation in SLE patients showed that in vivo expansion of regulatory T cells (Treg cells) is associated with dramatic but transient improvement in SLE disease markers and clinical manifestations. However, the Treg cells that expanded were short-lived and unstable. Alternatively, antigen-specific tolerance (ASIT) approaches that establish long-lived immunological tolerance could be deployed in the context of SLE. In this review, we discuss the potential benefits and challenges of nanoparticle ASIT approaches to induce prolonged immunological tolerance in SLE.

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Epitope Spreading in Autoimmune Diseases

Venkatesha,

Durai,

Moudgil

2024

Infection and Autoimmunity

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Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T‐lymphocyte antigen‐4

Cited by 4 publications

References 30 publications

Attenuating Neurogenic Sympathetic Hyperreflexia Robustly Improves Antibacterial Immunity After Chronic Spinal Cord Injury

Attenuating Neurogenic Sympathetic Hyperreflexia Robustly Improves Antibacterial Immunity After Chronic Spinal Cord Injury

Potential for Antigen-Specific Tolerizing Immunotherapy in Systematic Lupus Erythematosus

Epitope Spreading in Autoimmune Diseases

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