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Interleukin-4 Receptor Alpha Expressing B Cells Are Essential to Down-Modulate Host Granulomatous Inflammation During Schistosomasis.

ABSTRACT: Schistosomiasis (bilharzia) is a parasitic helminth disease that can cause severe inflammatory pathology leading to organ damage in humans. Failure of the host to regulate egg-driven granulomatous inflammation causes host morbidity during chronic infection with Schistosoma mansoni. Although the importance of B cells in regulating pathology during chronic infection has been well defined, the specific contribution of IL-4R?-expressing B cells is still unknown. To address this, we examined B cell-specific IL-4R?-deficient (mb1^creIL-4R?^-/lox) mice in three experimental models of schistosomiasis: high-dose (100 cercariae), low dose (30 cercariae), and a synchronous egg challenge. In the high dose model, we found that mice deficient in IL-4R?-expressing B cells were more susceptible to acute schistosomiasis than B cell-deficient (?MT) mice, succumbing to infection at the acute stage whereas ?MT mice survived until the chronic stage. An S. mansoni egg challenge model demonstrated that deleting IL-4R? expression specifically on B cells resulted in increased lung granulomatous pathology, suggesting a role for this B cell subset in controlling granulomatous pathology. In agreement with this, a low dose model of schistosomiasis-which mimics the course of clinical chronic disease-demonstrated that depleting IL-4R?-expressing B cells in mb1^creIL-4R?^-/lox mice considerably impaired the host ability to down-modulate granulomatous inflammation in the liver and gut during chronic schistosomiasis. Taken together, our findings indicate that within the B cell compartment, IL-4R?-expressing B cells in particular down-modulate the deleterious egg-driven tissue granulomatous inflammation to enable host survival during schistosomiasis in mice.

SUBMITTER: Ndlovu H

PROVIDER: S-EPMC6305417 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:RationaleThe critical innate immune mechanisms that regulate granulomatous inflammation in sarcoidosis are unknown. Because the granuloma-inducing component of sarcoidosis tissues has physicochemical properties similar to those of amyloid fibrils, we hypothesized that host proteins capable of forming poorly soluble aggregates or amyloid regulate inflammation in sarcoidosis.ObjectivesTo determine the role of the amyloid precursor protein, serum amyloid A, as an innate regulator of granulomatous inflammation in sarcoidosis.MethodsSerum amyloid A expression was determined by immunohistochemistry in sarcoidosis and control tissues and by ELISA. The effect of serum amyloid A on nuclear factor (NF)-kappaB induction, cytokine expression, and Toll-like receptor-2 stimulation was determined with transformed human cell lines and bronchoalveolar lavage cells from patients with sarcoidosis. The effects of serum amyloid A on regulating helper T cell type 1 (Th1) granulomatous inflammation were determined in experimental models of sarcoidosis, using Mycobacterium tuberculosis catalase-peroxidase.Measurements and main resultsWe found that the intensity of expression and distribution of serum amyloid A within sarcoidosis granulomas was unlike that in many other granulomatous diseases. Serum amyloid A localized to macrophages and giant cells within sarcoidosis granulomas but correlated with CD3(+) lymphocytes, linking expression to local Th1 responses. Serum amyloid A activated NF-kappaB in Toll-like receptor-2-expressing human cell lines; regulated experimental Th1-mediated granulomatous inflammation through IFN-gamma, tumor necrosis factor, IL-10, and Toll-like receptor-2; and stimulated production of tumor necrosis factor, IL-10, and IL-18 in lung cells from patients with sarcoidosis, effects inhibited by blocking Toll-like receptor-2.ConclusionsSerum amyloid A is a constituent and innate regulator of granulomatous inflammation in sarcoidosis through Toll-like receptor-2, providing a mechanism for chronic disease and new therapeutic targets.

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Interleukin-4 Receptor Alpha Expressing B Cells Are Essential to Down-Modulate Host Granulomatous Inflammation During Schistosomasis.

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