Jack for critical discussion and help in the preparation of the manuscript

Jack for critical discussion and help in the preparation of the manuscript. the major organized lymphoid tissue of the gut C the Peyer’s patches (PP). Surprisingly, however, lack of eosinophils abolishes efficient class\switching of B cells to immunoglobulin (Ig)A in the germinal centres of PP. Thus, eosinophils are required to generate and to maintain mucosal IgA plasma cells, and as a consequence their absence leads to a marked reduction of IgA both in serum and in the gut\associated lymphoid tissues (GALT). Eosinophils thus have an essential part in long\term humoral immune protection, as they are crucial for the longevity of antibody\producing plasma cells in the bone marrow and, in addition, for gut immune homeostasis. pulse\chase labelling with the thymidine analogue 5\ethynyl\2\deoxyuridine (EdU) has shown that this eosinophil survival time is very much shorter than that of plasma cells 35. This implies that this plasma cell survival niche in the bone marrow is usually a dynamic niche, where dying eosinophils are replaced constantly with newly generated ones 36. Eosinophils are the main source of plasma cell survival factors Stromal cells in the bone marrow secrete the chemokine CXCL12, which attracts both CXCR4\expressing plasma cells and eosinophils. cultures have shown that while the chemokine CXCL12 helps to support the maintenance of plasma cells 38, the crucial survival factor for the long\term maintenance of plasma cells is usually APRIL 39. In the lymph node and the spleen, plasma cell survival is usually supported by macrophages expressing APRIL 36, 40. However, in the bone marrow, where the vast majority of plasma cells reside, macrophages alone are not sufficient, as CNT2 inhibitor-1 depletion of eosinophils by injection of Siglec F\specific Rab25 antibody induces a rapid loss both of eosinophils and of CNT2 inhibitor-1 plasma cells 25. Furthermore, at constant state only a few plasma cells are found in the bone CNT2 inhibitor-1 marrow of eosinophil\deficient mice, and when these animals are immunized with a T cell\dependent antigen almost no plasma cells home to the bone marrow and practically no long\lived plasma cells are detected 25. Thus, eosinophils are essential for the maintenance of long\lived plasma cells in the bone marrow. Eosinophils are required for the maintenance of plasma cells in the lamina propria At constant state large numbers of eosinophils are found in the lamina propria, in particular in the small intestine and the caecum. As in the bone marrow, intestinal eosinophils express high levels of the plasma cell survival factors APRIL and IL\6 26. Co\staining of tissue sections with antibodies specific for APRIL showed that epithelial cells are the main producers within the lamina propria, followed by eosinophils, while dendritic cells (DC) express much less. Neutrophils, which were shown to express APRIL and B cell\activating factor (BAFF) and thus support the differentiation of marginal zone B cells 23, do not seem to have an important function in mucosal B cell activation at constant state. A significant influx of neutrophils is usually induced only under inflammatory conditions. When animals are injected with Siglec F\specific antibodies, which induce apoptosis in eosinophils, a rapid loss of plasma cells follows. As soon as the eosinophils are replenished, plasma cells, which are being generated constantly in the intestinal immune tissue, also reappear 26. Thus, both in the bone marrow and in the lamina propria, plasma cell survival is dependent upon the presence of eosinophils. In the lamina propria of eosinophil\deficient mice the overall level of the plasma cell survival factors APRIL and IL\6 is not reduced significantly 27, most probably because epithelial cells express these cytokines abundantly. Nevertheless, abundant though this epithelial cell expression of APRIL and IL\6 is usually, it is not sufficient for the maintenance of plasma cells. It is well possible that the effective promotion of plasma cell maintenance requires close contact with the source of survival factors. Alternatively, the eosinophils in the intestinal mucosa may provide additional signals through direct cell contact with plasma cells, as has also been proposed for the survival niche in the bone marrow 36. Normally, IgA is the most abundant antibody class in CNT2 inhibitor-1 the mucosa and has a crucial function in the maintenance of immune homeostasis of the gut\associated tissues. Deficiencies in IgA production also have a strong effect in shaping the microbial community in the gut lumen 41, 42. Because, in eosinophil\deficient mice, the amount of IgA\secreting plasma is strongly reduced, there is a dramatic effect on the levels of IgA both in the circulation and at mucosal sites. It is therefore not surprising that in the absence of eosinophils there.

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