Induction and Breaking of Peripheral Tolerance

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have unprecedentedly improved global prognosis in several types of cancers. However, they are associated with the occurrence of immune-related adverse events. Despite their low incidence, renal complications can interfere with the oncologic strategy. The breaking of peripheral tolerance and the emergence of auto- or drug-reactive T-cells are the main pathophysiological hypotheses to explain renal complications after ICI exposure. ICIs can induce a large spectrum of renal symptoms with variable severity (from isolated electrolyte disorders to dialysis-dependent acute kidney injury (AKI)) and presentation (acute tubule-interstitial nephritis in >90% of cases and a minority of glomerular diseases). In this review, the current trends in diagnosis and treatment strategies are summarized. The diagnosis of ICI-related renal complications requires special steps to avoid confounding factors, identify known risk factors (lower baseline estimated glomerular filtration rate, proton pump inhibitor use, and combination ICI therapy), and prove ICI causality, even after long-term exposure (weeks to months). A kidney biopsy should be performed as soon as possible. The treatment strategies rely on ICI discontinuation as well as co-medications, corticosteroids for 2 months, and tailored immunosuppressive drugs when renal response is not achieved.

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Potential Role of Trace Elements (Al, Cu, Zn, and Se) in Multiple Sclerosis Physiopathology

NeuroImmunoModulation ◽

10.1159/000511308 ◽

2020 ◽

Vol 27 (4) ◽

pp. 163-177

Author(s):

Mohammad Sadegh Hesamian ◽

Nahid Eskandari

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Trace Elements ◽

Plasma Cells ◽

Peripheral Tolerance ◽

The Central Nervous System ◽

Living Organisms ◽

Tolerance Breakdown ◽

Peripheral Immune Cells

Multiple sclerosis (MS) is an unpredictable disease of the central nervous system. The cause of MS is not known completely, and pathology is specified by involved demyelinated areas in the white and gray matter of the brain and spinal cord. Inflammation and peripheral tolerance breakdown due to Treg cell defects and/or effector cell resistance are present at all stages of the disease. Several invading peripheral immune cells are included in the process of the disease such as macrophages, CD8+ T cells, CD4+ T cells, B cells, and plasma cells. Trace elements are known as elements found in soil, plants, and living organisms in small quantities. Some of them (e.g., Al, Cu, Zn, Mn, and Se) are essential for the body’s functions like catalysts in enzyme systems, energy metabolism, etc. Al toxicity and Cu, Zn, and Se toxicity and deficiency can affect the immune system and following neuron inflammation and degeneration. These processes may result in MS pathology. Of course, factors such as lifestyle, environment, and industrialization can affect levels of trace elements in the human body.

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VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

Science ◽

10.1126/science.aay0524 ◽

2020 ◽

Vol 367 (6475) ◽

pp. eaay0524 ◽

Cited By ~ 22

Author(s):

Mohamed A. ElTanbouly ◽

Yanding Zhao ◽

Elizabeth Nowak ◽

Jiannan Li ◽

Evelien Schaafsma ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Subset ◽

Peripheral Tolerance ◽

Cell Immune Response ◽

Naive T Cells ◽

Naïve T Cells ◽

Naïve T Cell ◽

Naive T Cell

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

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