Baseline and Interferon-Enhanced Natural Killer Cell Activity in Rheumatoid Arthritis (original) (raw)
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Arthritis & Rheumatism, 1991
The role of natural killer (NK) cells in rheumatoid arthritis (RA) remains unclear. A pathogenetic function of rheumatoid factors (RF) also has not been defined. In the present studies, natural killer (NK) cells were examined as a model for Fcy receptor type IIIpositive (Fcy RIII+) cells, with regard to their interaction with RF. NK cell antigen CD16 (FcyRIII) and CD56 expression and functional NK and antibodydependent cell-mediated cytotoxicity (ADCC) activity were compared in peripheral blood lymphocytes and autologous synovial fluid lymphocytes (SFL) of RA patients. Peripheral blood lymphocytes and SFL showed normal CD56 expression. In contrast, both the frequency and the density of CD16 antigen were decreased in SFL. Furthermore, diminished NK cytotoxicity and a significant decrease in ADCC were observed in SF NK cells. In subsequent in vitro studies with normal fresh NK cells, it was demonstrated that IgG-containing RF complexes from RA patients induced a modulation of FCyRIII structure from the NK cell surface, a decrease in NK activity, and a complete loss of ADCC. When purified RF was incubated with NK-enriched cell lines From the
Mobilization of natural killer cells inhibits development of collagen-induced arthritis
Proceedings of the National Academy of Sciences of the United States of America, 2011
Although natural killer (NK) cells have been implicated in regulating immune responses, their ability to modulate disease development in autoimmune arthritis has not been analyzed. Here we investigate the contribution of NK cells to regulating collagen-induced arthritis, a well-characterized preclinical model of human rheumatoid arthritis. We find that the disease is induced by the combined action of two CD4(+) T helper (T(H)) subsets: follicular T(H) cells and T(H)17 cells. Both CD4(+) T(H) subsets are highly susceptible to lysis by NK cells after activation. Administration of antibody that activates NK cells through blockade of its inhibitory CD94/NKG2A receptor allows enhanced elimination of pathogenic follicular T(H) and T(H)17 cells and arrest of disease progression. These results suggest that antibody-dependent enhancement of NK activity may yield effective, previously undescribed therapeutic approaches to this autoimmune disorder.
Arthritis & Rheumatology, 2016
Objective. Systemic juvenile idiopathic arthritis (JIA) is an immunoinflammatory disease characterized by arthritis and systemic manifestations. The role of natural killer (NK) cells in the pathogenesis of systemic JIA remains unclear. The purpose of this study was to perform a comprehensive analysis of NK cell phenotype and functionality in patients with systemic JIA. Methods. Transcriptional alterations specific to NK cells were investigated by RNA sequencing of highly purified NK cells from 6 patients with active systemic JIA and 6 age-matched healthy controls. Cytokines (NK cellstimulating and others) were quantified in plasma samples (n 5 18). NK cell phenotype and cytotoxic activity against tumor cells were determined (n 5 10), together with their interferon-g (IFNg)-producing function (n 5 8). Results. NK cells from the systemic JIA patients showed an altered gene expression profile compared to cells from the healthy controls, with enrichment of immunoinflammatory pathways, increased expression of innate genes including TLR4 and S100A9, and decreased expression of immune-regulating genes such as IL10RA and GZMK. In the patients' plasma, interleukin-18 (IL-18) levels were increased, and a decreased ratio of IFNg to IL-18 was observed. NK cells from the patients exhibited specific alterations in the balance of inhibitory and activating receptors, with decreased killer cell lectin-like receptor G1 and increased NKp44 expression. Although NK cells from the patients showed increased granzyme B expression, consistent with intact cytotoxicity and degranulation against a tumor cell line, decreased granzyme K expression in CD56 bright NK cells and defective IL-18-induced IFNg production and signaling were demonstrated. Conclusion. NK cells are active players in the inflammatory environment typical of systemic JIA. Although their cytotoxic function is globally intact, subtle defects in NK-related pathways, such as granzyme K expression and IL-18-driven IFNg production, may contribute to the immunoinflammatory dysregulation in this disease. Systemic juvenile idiopathic arthritis (JIA) is a chronic immunoinflammatory childhood disorder of unknown etiology that is characterized by arthritis and systemic features such as quotidian fever, rash, lymphadenopathy, and serositis (1,2). An interplay of environmental factors and genetic predisposition is considered to underlie the pathogenesis (1). About 10% of systemic JIA patients develop
PLoS ONE, 2011
Objective: TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor + T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal. Methods: Patients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = 215); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3 + CD56 2), NK-(CD3 2 CD56 +) and NKT-(CD3 + CD56 +) cells was determined by flow cytometry. Results: Following TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3 + CD56-T cells from patients in remission compared to active RA (p,0.05). CD3 + CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p,0.05), with no differences observed for CD161 and CD57. CD3 + CD56 2 cell expression of NKG2A was inversely related to DAS28 (r = 20.612, p,0.005). Conclusion: High CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy.
Scientific Reports, 2019
Rheumatoid Arthritis (RA) causes chronic inflammation of joints. The cytokines TNFα and IFNγ are central players in RA, however their source has not been fully elucidated. Natural Killer (NK) cells are best known for their role in elimination of viral-infected and transformed cells, and they secrete pro-inflammatory cytokines. NK cells are present in the synovial fluids (SFs) of RA patients and are considered to be important in bone destruction. However, the phenotype and function of NK cells in the SFs of patients with erosive deformative RA (DRA) versus non-deformative RA (NDRA) is poorly characterized. Here we characterize the NK cell populations present in the blood and SFs of DRA and NDRA patients. We demonstrate that a distinct population of activated synovial fluid NK (sfNK) cells constitutes a large proportion of immune cells found in the SFs of DRA patients. We discovered that although sfNK cells in both DRA and NDRA patients have similar phenotypes, they function different...
Immunology, 2007
Natural killer (NK) cells are activated early during inflammatory events and contribute to the shaping of the ensuing adaptive immune response. To further understand the role for NK cells in inflammation, we investigated the phenotype and function of synovial fluid (SF) NK cells from patients with chronic joint inflammation, as well as from patients with transient inflammation of the knee following trauma. We confirm that synovial NK cells are similar to the well-characterized CD56 bright peripheral blood (PB) NK-cell subset present in healthy individuals. However, compared to this PB subset the synovial NK cells express a higher degree of activation markers including CD69 and NKp44, the latter being upregulated also on CD56 bright NK cells in the PB of patients. Activated synovial NK cells produced interferon-c and tumour necrosis factor, and the production was further up-regulated by antibody masking of CD94/ NKG2A, and down-regulated by target cells expressing human leucocyte antigen-E in complex with peptides known to engage CD94/NKG2A. We conclude that synovial NK cells have an activated phenotype and that CD94/NKG2A is a key regulator of synovial NK-cell cytokine synthesis.
Biologics : targets & therapy, 2012
The relationship between antiCD20 therapy with rituximab and the lymphocytes phenotype in patients with rheumatoid arthritis was investigated, with an attempt to establish a relationship between commonly used clinical activity indices and variations in leukocyte count, in particular natural killer (NK) lymphocytes. Patients with seropositive (cyclic citrullinated peptides and rheumatoid factor positive) rheumatoid arthritis (according to the American College of Rheumatology 1987 criteria) refractory to conventional and antitumor necrosis factor-alpha agents who were subsequently treated with rituximab, a chimeric monoclonal antibody directed against CD20, were enrolled between January 2009 and September 2009. All subjects were treated with rituximab standard rheumatologic dose of 1.0 g on days 1 and 15 every 6 months for at least 2 years. A clinical evaluation was performed at baseline and subsequently every 3 months thereafter. At each assessment activated NK (CD56+/CD16+/CD54brigh...