Transdifferentiation of polymorphonuclear neutrophils to dendritic-like cells at the site of inflammation in rheumatoid arthritis: evidence for activation by T cells

Abstract

Objectives: To investigate infiltrated cells in the synovial fluid (SF) of inflamed joints of patients with rheumatoid arthritis (RA), with special reference to polymorphonuclear neutrophils (PMN) and their interaction with T cells. Methods: Expression on PMN of activation associated receptors CD14, CD64, CD83, and major histocompatibility complex (MHC) class II was examined in the SF of 15 patients with RA, as were the infiltrated T cells. SF cytokines were determined by enzyme linked immunosorbent assay (ELISA). To mimic the in vivo situation, co-culture experiments were carried out using PMN and T cells of healthy donors. Results: The SF contained activated T lymphocytes and abundant PMN. SF PMN expression of CD14 and CD64 was enhanced compared with peripheral blood. Of special interest was the observation that only the SF PMN expressed MHC class II antigens and CD83. Exposure to SF, which contained considerable amounts of cytokines (for example, interferon c (IFNc), tumour necrosis factor a, and interleukin 2), induced a similar receptor pattern on blood derived PMN of healthy donors. Furthermore, PMN acquired MHC class II and CD83 within 24 to 48 hours, when co-cultured with autologous T cells or T cell lines. This effect was also achieved by T cell supernatants, was dependent on protein synthesis, and could be inhibited by antibodies against IFNc. Conclusions: SF PMN from patients with RA undergo major alterations, including transdifferentiation to cells with dendritic-like characteristics, probably induced by T cell derived cytokines. Because MHC class II positive PMN are known to activate T cells, the mutual activation of PMN and T cells might contribute to the perpetuation of the local inflammatory process, and eventually to the destructive process in RA.

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

“…We note a similar instance of inflammatory Functions of long-lived neutrophilsreprogramming in synovial fluid neutrophils, a percentage of which expressed functional HLA-DR. 50 Neutrophils from patients with vasculitis and systemic bacterial infections also acquire novel surface receptors and functions, such as expression of CD64, CD14 and neoexpression of HLA-DR and CD83. 51,52 In addition, we showed that, relative to freshly isolated neutrophils, long-lived neutrophils have increased cell surface ICAM-1, neoexpression of CD49d with concomitant diminution in expression of the traditional neutrophil adhesion integrins b 1 and b 2 . This unique pattern of expression of adhesion molecules might underlie the robust adhesion of this subset of long-lived neutrophils to stromal cells.…”

Reduction of cPLA2α overexpression: An efficient anti‐inflammatory therapy for collagen‐induced arthritis

“…Antisense treatment caused a significant reduction (po0.001) in LTB 4 levels in the peritoneal cavity (Fig. 3A), which was already detected 3 h after induction of peritonitis, indicating that even the first dose of antisense was effective in inhibiting LTB 4 . In correlation with the reduction in LTB 4 levels in the peritoneal cavity, there was a significant reduction (po0.001) in the number of recruited neutrophils, as was detected after 5 h of peritonitis induction (Fig.…”

“…To demonstrate that the inhibition of neutrophil recruitment is due to the specific effect of the antisense on cPLA 2, the levels of its metabolite, LTB 4 , were monitored in the peritoneal cavity during the first 24 h of peritonitis in control mice (treated with sense). As shown in Fig.…”

“…Furthermore, numerous studies have reported evidence of activation of neutrophils in synovial fluid. Since neutrophils have a reservoir of receptors and cytokines, and a propensity to generate and release cytotoxic and proteolytic entities, they may contribute to cartilage destruction [4].…”

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…It can be speculated that even though neutrophils may be less potent than DCs in processing and presenting antigenic peptides to T cells and be less relevant for the induction of primary T cell responses in the draining lymph nodes, the sheer quantity of neutrophils rapidly recruited to the site of infection will easily outnumber local DCs that are relatively sparse in peripheral tissues. Indirect evidence for the existence of APC-like neutrophils comes from studies in patients with various infectious and non-infectious inflammatory diseases [90][91][92][93][94][95][96], most notably in acute sepsis where circulating neutrophils possess a phenotype similar to Vc9/Vd2 T cell-primed neutrophils and are similarly capable of cross-presenting soluble proteins to antigen-specific CD8 + T cells [10]. These findings support the existence of an effective sentinel network comprised of Vc9/Vd2 T cells and their crosstalk with neighboring immune and non-immune cells [4], and identify a novel role for human unconventional T cells in shaping the transition of the innate to the adaptive phase of anti-microbial responses.…”