Evidence for Local Expansion of IgA Plasma Cell Precursors in Human Ileum (original) (raw)
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Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut
Nature, 2012
The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated wit...
The Secretory Immunoglobulin A Response in the Gut
Biochemical Society Transactions, 1977
Humoral immunity manifest in the mammalian gut is often due to the presence there of sIgA (secretory immunoglobulin A) antibodies. A considerable proportion of antibodies of this immunoglobulin isotype are synthesized locally by plasma cells, which are abundant in intestinal lamina propria. B-lymphocyte precursors for IgAsecreting plasma cells ('IgA plasma cells') appear to derive from the Peyer's patches (aggregated lymphatic follicles) of the small intestine. The Peyer's patches of rabbits contain a subpopulation of B-lymphocytes that can repopulate the spleen and lamina propria of irradiated allogeneic recipients with IgA plasma cells (Craig & Cebra, 1971). Pokeweed mitogen stimulates this subpopulation in vitro to generate IgA plasma cells (Jones et al., 1974). The immediate precursors for IgA plasma cells have been isolated in the subpopulation of Peyer's-patch cells bearing membrane Fab, and lacking membrane IgM by fluorescence-activated cell-sorting (Jones et al., 1974; Jones & Cebra, 1974). In addition to supplying precursors for IgA plasma cells, an 'antigen-sampling' role has been ascribed to Peyer's patches (Bockman & Cooper, 1973). Whole protein molecules may pass intact across their specialized dome epithelial cells and arrive in the midst of B-lymphocyte follicles. Thus IgA precursors may have their first encounter with antigen in the Peyer's patches, be stimulated to divide, and migrate in lymph/blood to intestinal lamina propria and generate plasma cells. We have devised an adoptive transfer system to compare the antigen-sensitivity of Peyer's-patch cells with cells from peripheral lymph nodes and spleen (Cebra et al., 1977a,b). Syngeneic or congeneic (CB20+Balb/c) cells were transferred into sublethally irradiated (600rad) recipients which were then challenged 1 day later with 5 x lo8 sheep erythrocytes. Antibody-forming cells in the recipients' spleens were enumerated at various times thereafter by the Jerne plaque assay and by facilitating antisera to distinguish cells making IgM, IgGl, IgG2 and IgA isotopes. Fluorochrome-labelled alloantisera, which distinguished IgA from CB20 (Ig-2*) and Balb/c (Ig-2") congeneic mice, were used to determine the origin of IgA plasma cells in recipient mice. The Peyer's-patch cells were as effective in adoptively transferring IgM and IgG responses as cells from peripheral lymph nodes or spleen. However, only Peyer's-patch cells transferred a significant IgA response, which began at about day 10 after transfer and reached a maximum of IgA Vol. 5
Gastroenterology, 2011
IgA contributes to homeostatic balance between host and intestinal microbiota. Mechanisms that initiate the IgA response are unclear and likely to differ between humans and animal models. We used multiple experimental approaches to investigate the origin of human intestinal plasma cells that produce IgA in the gastrointestinal tract. METH-ODS: Complexity of IgA-producing plasma cell populations in human gastrointestinal mucosa and bone marrow and the specific response to oral cholera vaccine were compared by analysis of immunoglobulin genes. Flow cytometry, gene expression analysis, and immunohistochemistry were used to analyze signaling pathways induced by B-cell receptor engagement in human gut-associated lymphoid tissue (GALT) and involvement of innate immunity in B-cell activation in GALT compared with nonintestinal sites. RESULTS: Human intestinal IgA-producing plasma cells appeared to be of germinal center origin; there was no evidence for the population complexity that accompanies multiple pathways of derivation observed in bone marrow. In germinal center B cells of human GALT, Btk and Erk are phosphorylated, CD22 is down-regulated, Lyn is translocated to the cell membrane, and Fos and Jun are up-regulated; these features indicate B-cell receptor ligation during germinal center evolution. No differences in innate activation of B cells were observed in GALT, compared with peripheral immune compartments. CONCLUSIONS: IgA-producing plasma cells appear to be derived from GALT germinal centers in humans. B-cell receptor engagement promotes formation of germinal centers of GALT, with no more evidence for innate immune receptor activation in the mucosa than nonintestinal immune compartments. Germinal centers in GALT should be targets of mucosal vaccinations because they are the source of human intestinal IgA response.
European Journal of Immunology, 1999
In pigs the lymphocytes emigrating from the intestinal wall were collected by cannulating the lymphatics, labeled in vitro using a fluorescent dye and retransfused. The injection of 6.6 ± 4.2 × 10 8 cells resulted in a labeling index between 1.5 % in intestinal lymph, 0.2 % in the spleen and lymph nodes,˚0.1 % in the intestinal lamina propria and 0.003 % in intraepithelial lymphocytes. About 25 % of the injected cells were present in the blood and 1 % was recovered in the lymph. T cells were found in similar proportions in the injected and the recovered cells in the organs (70-80 %). The proportion of IgA + cells among the immigrated cells in the intestinal lamina propria ranged from 5 to 8 %, which in absolute numbers was up to 60 % of the injected IgA + cells. T and IgM + cells did not show a higher accumulation in any organ. These experiments in conventional, unrestrained animals revealed that (1) T cells immigrate into the intestinal lamina propria, (2) preferential migration of IgA + cells from gut lymph to the intestinal lamina propria is obvious under in vivo conditions and (3) the immigrated IgA + cells represent a very small population which is difficult to detect when analyzed in relative numbers.