TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases

Abstract

TNFα is a principal pro-inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNFα inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNFα causes its effects by binding to either or both of two membrane-bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNFα and depending on whether the cytokine is membrane-bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNFα and T cell signalling proteins can significantly impact the outcome of TNFα receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNFα. However, recent evidence indicates that the relationship between TNFα and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNFα on different T cell subsets. This review will summarise knowledge on how TNFα modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNFα inhibitors.

Response to Treatment with TNFα Inhibitors in Rheumatoid Arthritis Is Associated with High Levels of GM-CSF and GM-CSF+ T Lymphocytes

“…Although the molecular basis and the physiological and therapeutic implications remain to be determined, these findings indicate that TNFα/TNFα blockade have significant impacts on the function and frequency of T cell subsets [ 13 ]. This suggestion is consistent with the association between T cell responses and signalling generated by TNFα through its two receptors in T cells [reviewed in [ 14 ]].…”

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

“…TNFα is considered the most prominent cytokine involved in the RA inflammatory response, as it in turn stimulates further monocyte and macrophage activity and proinflammatory cytokine release. [189][190][191] TNFα has been demonstrated to be increased by 62% in RA patient sera compared with controls. 192 The suggested importance of TNFα in RA pathogenesis has been highlighted by the relative efficacy of TNFα inhibitor (infliximab) treatment in the attenuation of disease symptoms and synovial inflammation.…”

“…197 The chronic exposure of synovial T-cells to TNFα leads to decreased immune tolerance and unresponsiveness to TNFα inhibitor treatment (prevalent in 30-40% of RA patients). 191…”

Treg und Th17-Zellen: Verwandtschaft mit Folgen

“…Das Wiedererreichen einer T-Zell-Kontrolle durch suppressive Treg-Zellen konnte bereits für eine Inhibition von TNF-α und von IL-6 bei der rheumatoiden Arthritis gezeigt werden [19][20][21][22][23]. Etanercept, ein Anti-TNF-α-Rezeptormolekül, führte zu einer Erhöhung der Th17-und Th17/Th1-transitorischen T-Zell-Subpopulation und reduzierte die CD161+-nicht-klassischen Th1-Zellen, ohne die Proportion der CD161-negativen klassischen Th1-Zellen zu beeinflussen [10].…”