Th17 Cells Promote Autoimmune Anti-Myeloperoxidase Glomerulonephritis(1)
The primary antigenic targets of Anti-neutrophil cytoplasmic antibody (ANCA) are found abundantly in azurophilic granules of neutrophils and comprise proteinase 3, lysosomal-associated membrane protein 2 and myeloperoxidase (MPO). Neutrophils are important targets and mediators in these diseases. In addition, CD4+ T helper (Th) cells play an important role both in the generation of ANCA and as effectors of tissue injury. Th1 cells predominantly produce IFN-γ, whereas Th2 cells produce IL-4 and IL-5. The most recently defined Th cell subset, Th17, is characterized by the production of IL-17A and other cytokines, including IL-17F, IL-21, and IL-22. Several immunologically mediated disease models, including encephalitis, arthritis, and uveitis, that have classically been thought to be caused by a Th1 response are directed by Th17 cells. A study of experimental colitis found a protective role for IL-17A via suppression of Th1 responses. Thus, the role of the Th17 subsets might differ depending on the type of disease and target organ. IL-17A stimulates resident tissue cells to produce neutrophil-attracting chemokines. IL-17A induces the release of proinflammatory mediators (e.g., TNF, IL-1β) from macrophages. IL-17A therefore mediates both innate and adaptive immunity as a key regulator and initiator of inflammation.
An ANCA-associated disease model involves three steps. First, autoimmunity to MPO was established in mice by injecting murine MPO. Second, disease was triggered by injecting sheep anti-mouse GBM globulin. Anti-MPO ANCA titers (OVA immunized control mice did not develop autoantibodies) were shown in WT mice but IL-17A deficiency did not alter autoantibody titer. Compared with OVA-immunized mice, MPO-immunized mice produced significant amounts of IL-17A (but IL-17A−/− mice did not, and no significant IFN-γ production was observed. MPO-specific dermal footpad delayed-type hypersensitivity (DTH) was demonstrated in MPO-immunized WT mice and was absent in IL-17A−/− mice.
MPO-immunized WT mice developed significant glomerular disease with abnormal glomeruli, fibrin deposition, and cellular proliferation. Histologic injury in MPO-immunized WT mice was associated with functional damage, measured by pathologic albuminuria
The prominence of neutrophils in this disease, as well as its autoimmune pathogenesis, suggests that the Th17 subset is injurious. IL-17A plays pathogenic roles in experimental autoimmune anti-MPO focal necrotizing GN in two ways. The first mechanism involves its effects on mobilizing and directing neutrophils. These neutrophils localize to vulnerable vascular beds, including the glomerulus, where they release MPO, which is important both for inducing injury itself and as a planted autoantigen. The second mechanism by which IL-17A is important is via promoting recruitment of injurious effector macrophages to the target organ in a DTH-like manner in response to MPO as an autoantigen.