Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

Abstract

IntroductionMalaria caused by infection with protozoan parasites of Plasmodium spp. is one of the most serious infectious diseases of humans and causes about one million deaths annually. Plasmodium infection may induce multiple disease syndromes including severe anemia, metabolic acidosis, and neurological dysfunction, e.g. cerebral malaria (CM) [1]. Sequestration of the Correspondence: Dr. Zhong Su e-mail: su_zhong@gibh.ac.cn parasitized red blood cells (pRBCs) in brain microvessels is a characteristic histopathology feature observed in human and murine CM and is believed to be the primary cause of the neurological syndrome [2,3]. Evidence from more recent studies supports the notion that CM is an immune-driven pathology. The proinflammatory cytokines and mediators produced in the "cytokine storm" during malaria induce activation and recruitment of cytotoxic CD8 + cells in brain blood vessels and upregulate the expression of adhesion receptors by brain endothelial cells, leading to leukocyte accumulation and capillary obstruction, cerebral hemorrhage, and hypoxia in brain tissues [1,[4][5][6]. Therefore, the immune regulatory cells and cytokines may be critical in counteracting the inflammatory response and prevention of malaria-associated www.eji-journal.eu 2908 Yunfeng Liu et al. Eur. J. Immunol. 2013. 43: 2907-2918 neuropathology. The levels of anti-inflammatory cytokines such as IL-10 and TGF-β have been shown to be inversely associated with the occurrence of CM in murine malaria [7,8]. However, no consensus has been reached concerning the role of regulatory T (Treg) cells in regulation of CM pathogenesis [9][10][11].B cells have been traditionally considered antibody-producing cell and APC. Many studies in recent years showed the existence of a subset of B cells that exhibit the immune regulatory functions (reviewed in [12]). An early study by Fillatreau et al.[13] reported a subset of B cells that produce IL-10 and inhibit the immune pathology in murine EAE. Further studies revealed that these regulatory B (Breg) cells play important roles in control of immunopathology in autoimmune diseases [14], cancer [15], and organ transplantation [16]. Breg cells have also been shown to modulate immune responses and immunopathology in infectious diseases. Protective immunities against Salmonella typhimurium and Brucella abortus infections were inhibited by transfer of Breg cells in mouse models [17,18]. Transfer of CD1d + CD5 hi Breg cells rendered the BALB/c mice more susceptible to Leishmania major infection [19]. Adoptive transfer of IL-10-producing B cells isolated from helminth-infected mice inhibited the allergic responses and autoimmune inflammation in recipient mice [20]. Thus, Breg cells are an important component of immunoregulatory system and plays critical roles in immune homeostasis.The immunomodulatory roles of Breg cells have been studied in autoimmune and infectious disease settings, but little is known of its role in regulation of immune response and immunopathology of malaria. In this study, we i...

The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production

“…Adoptive transfer of IL-10 + B regs to P. berghei infected mice significantly reduced the accumulation of NK and CD8 + T cells and hemorrhage in brain tissue, and improved the survival of the mice compared with control groups without altering parasitemia. Treatment of B reg-cell recipient mice with anti-IL-10 receptor mAb blocked the protective effect of B reg cells [79]. As B regs can contribute to regulation of inflammation and prevent immunopathology, they may also suppress protective host responses and increase susceptibility for infections.…”

The Roles of Regulatory B Cells in Cancer

“…It has been demonstrated that Bregs were capable of suppressing the proliferation of CD4 +   CD25 −   T cells [31] and production of interferon gamma (IFN- γ ) and IL-17 by Th1 and T helper 17 (Th17) cells, respectively [32, 33]. In vitro studies in human had further postulated the potential ability of Breg cells to influence innate immunity by abrogating mitogen-stimulated secretion of TNF- α by monocytes, macrophages, and T cells.…”

The immunological balance between host and parasite in malaria

“…As such, IL-27 plays a dual role as it suppresses efficient parasitemia control in primary and secondary infections, while it also protects against severe inflammatory liver pathology (Findlay et al 2010;Gwyer et al 2014), illustrating the importance of this cytokine in steering the immunological balance of malaria toward equilibrium or imbalances. Besides T cells, regulatory B cells also produce IL-10 in murine malaria and may contribute to the suppression of CM (Liu et al 2013). With P. vivax also CD14 hi CD16/Fcγ RIIIA + 'inflammatory' monocytes seem to be a source of IL-10 production, which is produced in combination with TNF (Antonelli et al 2014).…”