Increased peripheral T cell reactivity to microbial antigens and collagen type II in rheumatoid arthritis after treatment with soluble TNFα receptors

Abstract

Objective-Peripheral T cells from patients with rheumatoid arthritis (RA) are hyporesponsive when stimulated with antigen or mitogen in vitro, possibly owing to increased production of proinflammatory cytokines such as tumour necrosis factor (TNF ). This study sought to find out if and how RA T cell reactivity is aVected during treatment with etanercept (Enbrel), a soluble TNF receptor. Methods-Heparinised blood was collected from patients with RA at baseline, after four and eight weeks of etanercept treatment, and from healthy controls. After density separation spontaneous production of interferon (IFN ), TNF , interleukin 6 (IL6), and IL10 by peripheral blood mononuclear cells (PBMC) was detected by ELISPOT. For detection of T cell reactivity, PBMC were stimulated in vitro with mitogen (phytohaemagglutinin (PHA)), microbial antigens (purified protein derivative (PPD), influenza), or an autoantigen, collagen type II (CII). Supernatants were analysed for IFN and IL2 content by enzyme linked immunosorbent assay (ELISA). Results-In RA the number of cells spontaneously producing IFN was significantly increased after four, but not eight weeks' treatment with etanercept. T cell reactivity, as measured by IFN production to PPD, influenza, and CII was significantly increased after four and sustained after eight weeks' treatment, whereas IFN production induced by PHA remained unchanged. TNF production was significantly higher in patients with RA than in controls and did not change during etanercept treatment. Conclusion-Treatment of patients with RA with etanercept may lead to increased peripheral T cell reactivity both to microbial antigens and to self antigens such as CII. These findings indicate that TNF blockade may not only suppress but also stimulate certain aspects of antimicrobial immune defence and autoimmunity.

Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma

“…Instead, many of them had an untreated, longstanding, active and destructive RA disease associated with a persistent stimulation of the immune system rather than with a state of immunosuppression. An interesting possible explanation, and one that supports the notion of a role for inflammatory activity in the development of lymphomas, was found in a study by Wahl et al (40) and subsequently confirmed by many groups, including our own (41). In these studies, it has been shown that apart from being associated with a stimulation of certain immune functions, RA may also cause suppression of other functions.…”

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

“…Overall, our study thus lends strong support to the recent emerging conviction that TNF-␣ is a double-edged sword, and besides its proinflammatory properties, it plays an important immunoregulatory function in the host response to a number of intracellular infections and autoimmunogens. 21,22,[32][33][34][35][36][37][38][39][40] In our current study, we have found TNF-␣ regulation of MCP-1 responses to be an important molecular mechanism by which TNF-␣ negatively controls the level of influenza immunopathology. MCP-1 has previously been reported to be a major profibrotic chemokine involved in various fibrotic processes, including recruitment of fibrocytes, induction of collagen synthesis, and up-regulation of TGF-␤1 expression in various models.…”

“…[3][4][5][6][7][8][9][10][11] TNF-␣, a classical proinflammatory cytokine, has recently been shown to play anti-inflammatory and antifibrotic roles in various models. [32][33][34][35][36][37][38][39][40][41][42][43] However, whether TNF-␣ plays an immunoregulatory role during influenza infection remains unclear. Using a mouse model of respiratory influenza infection, we investigated this issue.…”

“…21,36 -39 Of interest, treatment of rheumatoid arthritis patients with etanercept, a soluble TNF-␣ receptor, led to increased peripheral T-cell reactivity both to microbial antigens such as influenza and to tissue antigens such as collagen type II. 40 Recent evidence has also implicated an antifibrotic activity of TNF-␣ in models of idiopathic pulmonary fibrosis, ureteral obstruction, and scleroderma. [41][42][43] However, whether TNF-␣ plays an immunoregulatory role in host defense and immunopathology during influenza infection still remains poorly understood.…”

New Treatment Alternatives in the Management of Non-İnfectious İntraocular İnflammations: Biologic Agents

“…Immun-mekanizma sebepli tablolar›n ortaya ç›kmas›, TNF'in yok edilmesi s›ras›nda artm›fl T ve B hücre aktivasyonunun, otoantijenler ve yabanc› antijenler ile reaksiyonlar›na ba¤lanm›flt›r. [125][126][127][128] TNF antagonistleri ile tedavi sonras›nda baflta anti-nukleer antikor ve antidsDNA antikor olmak üzere çeflitli otoantikorlar›n artt›¤› bilinmektedir. 129,130 Bu konuda yap›lan bir araflt›rmada 7700 infliksimab ve 3800 etanersept kullanan hasta grubunda lupus-benzeri tablo geliflen olgu say›s› yaln›z 22 (15 infliksimab ve 7 etanersept) olarak bildirilmifltir.…”