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 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 eight-fold, 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 (APCs), 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.

Figure 1. Therapeutic responsiveness distinguishes separate immune-inflammatory pathways in GCA

Supra-high doses of corticosteroids (>1 mg/kg) are necessary to suppress the IFN-γ pathway. Vice versa, even low doses of corticosteroids are sufficient to inhibit IL-17 mediated immunity. Aspirin has previously been described to lower IFN-γ-production. Differences in therapeutic responsiveness strongly suggest a contribution of two independent inflammatory networks to the disease process and emphasize the requirement for therapeutic cocktails to efficiently treat the vasculitis.

Figure 2. Two separable immune axes participate in GCA

Studies in untreated and treated GCA patient have indicated that two, separable cytokine networks contribute to the vasculitic immune pathology. Dendritic cells producing IL-1β, IL-6 and IL-23 coax T cells to differentiate into IL-17 producers that modulate the function of endothelia cells, vascular smooth muscle cells, fibroblasts and bone marrow stromal cells. In an independent immune pathway, dendritic cells release IL-12 to induce the differentiation of IFN-γ-producing T cells. The downstream, target cells are macrophages, endothelial cells and cytotoxic cells. The IL-17 axis is steroid responsive, whereas the IFN-γ axis is steroid resistant. The separability of both axes is strongly suggestive for distinct immune instigators.