“…However, we did not notice any significant difference in the percentages of CD8 + CD45RO − CD28 − effectors, CD8 + CD45RO + CD28 − effector memory, CD8 + CD45RO + CD28 + central memory or CD8 + CD45RO − CD28 + naïve T cells (Fig. 3c) among RA patients and the healthy donors 18 . Thus we may conclude that in the present cohort the CD8 + T cell subpopulation is not variable.Figure 3Inflammatory mediators profiling of CD8 + T cell in RA patients.…”
Section: Resultsmentioning
confidence: 64%
“…Most studies evaluating the balance of T effector subsets have examined CD4 + T cells exclusively and less attention has been given to understand the role of CD8 + T cells in RA. A few recent studies have begun to address the contribution of CD8 + T cells to disease initiation, progression or severity 18 . CD8 + T cells are conventionally acknowledged for their significant role in defense against intracellular pathogens.…”
Aberrant immune responses characterize autoimmune disorders like Rheumatoid Arthritis (RA) wherein lymphocytes are recognized as key players. Role of CD8+ T cells in RA has been less defined however we found that these cells are activated in RA patients with increased expression of cytolytic granules and inflammatory mediators thereby modulating immune responses contributing to disease severity. Though unconventional expression of different Toll Like Receptors (TLRs) on CD8+ T cells has been proposed but their expression and role in T cell activation and differentiation in RA still remains obscure. Herein we report, for the first time, an increased expression of TLR4 on peripheral CD8+ T cells of RA patients and its role in skewing CD8+ T cells towards activated and inflammatory phenotype thereby playing a significant role in pathogenesis and progression of RA. We found that the surface expression of TLR4 on CD8+ T cells directly correlates with disease severity. Moreover, these CD8+ T cells respond to the TLR4 ligand LPS and express robust amounts of cytotolytic and inflammatory molecules including TNFα and IFNγ. Our study hence identifies an important role for CD8+ T cells in orchestrating RA through TLR4 mediated activation and differentiation.
“…However, we did not notice any significant difference in the percentages of CD8 + CD45RO − CD28 − effectors, CD8 + CD45RO + CD28 − effector memory, CD8 + CD45RO + CD28 + central memory or CD8 + CD45RO − CD28 + naïve T cells (Fig. 3c) among RA patients and the healthy donors 18 . Thus we may conclude that in the present cohort the CD8 + T cell subpopulation is not variable.Figure 3Inflammatory mediators profiling of CD8 + T cell in RA patients.…”
Section: Resultsmentioning
confidence: 64%
“…Most studies evaluating the balance of T effector subsets have examined CD4 + T cells exclusively and less attention has been given to understand the role of CD8 + T cells in RA. A few recent studies have begun to address the contribution of CD8 + T cells to disease initiation, progression or severity 18 . CD8 + T cells are conventionally acknowledged for their significant role in defense against intracellular pathogens.…”
Aberrant immune responses characterize autoimmune disorders like Rheumatoid Arthritis (RA) wherein lymphocytes are recognized as key players. Role of CD8+ T cells in RA has been less defined however we found that these cells are activated in RA patients with increased expression of cytolytic granules and inflammatory mediators thereby modulating immune responses contributing to disease severity. Though unconventional expression of different Toll Like Receptors (TLRs) on CD8+ T cells has been proposed but their expression and role in T cell activation and differentiation in RA still remains obscure. Herein we report, for the first time, an increased expression of TLR4 on peripheral CD8+ T cells of RA patients and its role in skewing CD8+ T cells towards activated and inflammatory phenotype thereby playing a significant role in pathogenesis and progression of RA. We found that the surface expression of TLR4 on CD8+ T cells directly correlates with disease severity. Moreover, these CD8+ T cells respond to the TLR4 ligand LPS and express robust amounts of cytotolytic and inflammatory molecules including TNFα and IFNγ. Our study hence identifies an important role for CD8+ T cells in orchestrating RA through TLR4 mediated activation and differentiation.
“…As mentioned above, a regulatory role for CD8+ T cells is now appreciated in several autoimmune diseases including, inflammatory bowel disease [15], Type I diabetes (T1D) [25], rheumatoid arthritis (RA) [26], and multiple sclerosis [7–9, 11, 27]. These CD8+ T cells come in a variety of flavors and can potentially target both pathogenic CD4+ T cells and APCs.…”
Section: Regulatory Cd8+ T Cells In Autoimmune Diseases: Emphasis On mentioning
The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) with an underlying T-cell-mediated immunopathology. CD8+ T cells are the predominant T cells in human MS lesions, showing oligoclonal expansion at the site of pathology. It is still unclear whether these cells represent pathogenic immune responses or disease-regulating elements. Through studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), we have discovered two novel CD8+ T cell populations that play an essential immunoregulatory role in disease: (1) MHC class Ia-restricted neuroantigen-specific “autoregulatory” CD8+ T cells and (2) glatiramer acetate (GA/Copaxone®) therapy-induced Qa-1/HLA-E-restricted GA-specific CD8+ T cells. These CD8 Tregs suppress proliferation of pathogenic CD4+CD25- T-cells when stimulated by their cognate antigens. Similarly, CD8+ Tregs significantly suppress EAE when transferred either pre-disease induction or during peak disease. The mechanism of disease inhibition depends, at least in part, on an antigen-specific, contact-dependent process and works through modulation of CD4+ T cell responses as well as antigen presenting cells (APC) through a combination of cytotoxicity and cytokine-mediated modulation. This review provides an overview of our understanding of CD8+ T cells in immune-mediated disease, focusing particularly on our findings about regulatory CD8+ T cells both in MS and EAE. Clinical relevance of these novel CD8-regulatory populations is discussed, providing insights into a potentially intriguing, novel therapeutic strategy for these diseases.
“…Recently, de Hair and colleagues45 emphasized the importance of CD8+ T cells in early RA through detection of perforin and granzyme-producing CD8+ T cells in the synovium of patients with preclinical RA. Carvalheiro et al46 similarly demonstrated abundant perforin/granzyme+ CD8+ T effector cells in the peripheral blood and SF from active RA patients. They showed that this effector T cell phenotype persisted in disease remission, thus maintaining the potential for disease relapse.…”
Section: Cd8+ T Cell Mediated Pmn-directed Cytotoxicity As a Potentimentioning
Anti-citrullinated protein antibodies (ACPAs) are highly specific serologic markers for rheumatoid arthritis (RA) and can pre-date clinical disease onset by up to 10 years, also predicting erosive disease. The process of citrullination, the post-translational conversion of arginine to citrulline residues, is mediated by peptidylarginine deiminase (PAD) enzymes present in polymorphonuclear cells (PMNs). Calcium ions (Ca2+) are required for PAD activation, but the intracellular Ca2+ concentration in normal cells is much lower than the optimal Ca2+ concentration needed for PAD activation. For this reason, it has been proposed that PAD activation, and thus citrullination, occurs only during PMN cell death when PAD enzymes leak out of the cells into the extracellular matrix, or extracellular Ca2+ enters the cells, with the high Ca2+ concentration activating PAD. Recently, using artificial in vitro systems to corroborate their hypothesis, Romero et al. demonstrated that “hypercitrullination,” citrullination of multiple intracellular proteins, occurs within synovial fluid (SF) cells of RA patients, and that only modes of death leading to membranolysis such as perforin-granzyme pathway or complement membrane attack complex activation cause hypercitrullination. In order for Romero’s hypothesis to hold, it is reasonable to surmise that PMN-directed lysis should occur in the rheumatoid joint or the circulation of RA patients. Research conducted thus far has shown that immunoglobulin G (IgG) targeting PMNs are present in RA SF and mediate PMN activation. However, the role of anti-PMN IgG in mediating complement activation and subsequent PMN lysis and hypercitrullination has not been fully evaluated.
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