IFN-γ and IL-17: the two faces of T-cell pathology in giant cell arteritis

Abstract

Purpose of review Granuloma formation in giant cell arteritis (GCA) emphasizes the role of the adaptive immunity and highlights the role of antigen-specific T cells. Recent data demonstrate that at least two separate lineages of CD4 T-cells participate in vascular inflammation, providing an important clue that multiple disease instigators may initiate pathogenic immunity. Recent finding IFN-γ-producing Th1 cells and IL-17-producing Th17 cells have been implicated in GCA. Patients with biopsy-positive GCA underwent two consecutive temporal artery biopsies, one prior to therapy and one while on corticosteroids. In untreated patients, Th1 and Th17 cells co-existed in the vascular lesions. Following therapy, Th17 cells were essentially lost, whereas Th1 cells persisted almost unaffected. In the peripheral blood of untreated patients Th17 frequencies were increased eightfold, but normalized with therapy. Blood Th1 cells were doubled in frequency, independent of therapy. Corticosteroids functioned by selectively suppressing IL-1β, IL-6 and IL-23-releasing antigen-presenting cells (APC), disrupting induction of Th17 cells. Summary At least two distinct CD4 T-cell subsets promote vascular inflammation in GCA. In early disease, APCs promote differentiation of Th17 as well as Th1 cells. Chronic disease is characterized by persistent Th1-inducing signals, independent of IL-17-mediated inflammation. More than one disease instigator may trigger APCs to induce multiple T cell lineages. Cocktails of therapies will be needed for appropriate disease control.

New insights into the pathogenesis of giant cell arteritis

“…Recent data suggest that changes in the composition of the T-cell infiltrate allow the distinction of the arteritis into early and late GCA [75,76]. Th1 cells and Th17 cells seem in fact to predominate in early phases of GCA [76]. Interestingly, a stronger IL-17A expression in GCA patients has been demonstrated to be associated with less relapses, also requiring significantly shorter treatment periods [79].…”

“…The receptor for IL-9 activates endothelial cells, induces the expression of mast cell proteases and activates neutrophils [77]. Recent data suggest that changes in the composition of the T-cell infiltrate allow the distinction of the arteritis into early and late GCA [75,76]. Th1 cells and Th17 cells seem in fact to predominate in early phases of GCA [76].…”

“…These pleiotropic functions are achieved through the differentiation of naive CD4 + T cells in effector and/or memory cells of specialized phenotypes such as TH1, Th2, Th9 and Th17 cells [74]. In particular, compared with control subjects, patients with GCA show a massive artery infiltration by IFN-γ-secreting Th1 [75,76], IL-9-secreting Th9 [77] and IL-17-secreting Th17 lymphocytes [75][76][77]. IFN-γ levels in the GCA arteries are correlated with neo-angiogenesis and the outgrowth of the hyperplastic intima [78].…”

Giant Cell Arteritis which Developed after the Administration of Granulocyte-colony Stimulating Factor for Cyclic Neutropenia

“…In a mouse model, lupus-prone MRL-lpr/lpr mice receiving low doses of G-CSF showed an increased glomerular deposition of immunoglobulins and exacerbated lupus disease (8). The implicated Th17 T cells and the increased IL-17 production are together considered to contribute to the pathogenesis of GCA (2). It has been reported that activated neutrophils can also produce IL-17 (9).…”

“…The activation of dendritic cells (DC) caused by microorganisms has been suggested to play a role in the pathogenesis of GCA (1). T helper 1 (Th1)-inducing signals and interleukin 17 (IL-17) have also been reported to be involved in this condition (2). However, the precise mechanism remains poorly understood.…”