Intestinal IgA Plasma Cells Research Articles

Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo.

Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T-cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti-viral immunity and T-cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T-cell-independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short-term nor long-term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T-cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T-cell-dependent or T-cell-independent Ags, and are not required for proliferation and IgA switch of Ag-specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses.

Microbe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice

Intestinal plasma cells predominantly produce immunoglobulin (Ig) A, however, their functional diversity remains poorly characterized. Here we show that murine intestinal IgA plasma cells can be newly classified into two populations on the basis of CD11b expression, which cannot be discriminated by currently known criteria such as general plasma cell markers, B cell origin and T cell dependence. CD11b+ IgA+ plasma cells require the lymphoid structure of Peyer’s patches, produce more IgA than CD11b− IgA+ plasma cells, proliferate vigorously, and require microbial stimulation and IL-10 for their development and maintenance. These features allow CD11b+ IgA+ plasma cells to mediate early-phase antigen-specific intestinal IgA responses induced by oral immunization with protein antigen. These findings reveal the functional diversity of IgA+ plasma cells in the murine intestine.

Lambda Light Chain Revision in the Human Intestinal IgA Response

Revision of Ab L chains by secondary rearrangement in mature B cells has the potential to change the specific target of the immune response. In this study, we show for the first time that L chain revision is normal and widespread in the largest Ab producing population in man: intestinal IgA plasma cells (PC). Biases in the productive and non-productive repertoire of lambda L chains, identification of the circular products of rearrangement that have the characteristic biases of revision, and identification of RAG genes and protein all reflect revision during normal intestinal IgA PC development. We saw no evidence of IgH revision, probably due to inappropriately orientated recombination signal sequences, and little evidence of kappa-chain revision, probably due to locus inactivation by the kappa-deleting element. We propose that the lambda L chain locus is available and a principal modifier and diversifier of Ab specificity in intestinal IgA PCs.

IgA production in MHC class II-deficient mice is primarily a function of B-1a cells.

Mice deficient in MHC class II expression (C2d mice) do not make antibody to protein antigens administered systemically, but their ability to produce IgA antibody to antigen administered at mucosal sites has not been described. We investigated IgA production by C2d mice and their IgA antibody response to antigen given orally. Young C2d mice had normal amounts of serum IgA, intestinal-secreted IgA and normal numbers of intestinal IgA plasma cells, compared to control C57BL/6 mice. IgA production by C2d mice increased with age. Following oral immunization with cholera toxin, C57BL/6 mice responded with IgA and IgG antibody, and had increased numbers of IgA plasma cells, but C2d mice gave no response. The Peyer's patch and mesenteric lymph node tissues of C2d mice contained very few CD4-expressing T cells. Thus, C2d mice have no typical mucosal CD4 Th cells and cannot respond to a strong oral immunogen, yet they still produced and secreted IgA. We hypothesized that B-1 lymphocytes could provide a source of IgA independent of antigen-specific T cell help. Young C2d mice had normal numbers of peritoneal B-1a cells and their frequency increased with age. To test the role of these B-1a cells, we bred C2d mice to obtain mice that had no MHC class II expression and expressed the Xid gene that confers deficiency in B-1a cells. These double-deficient mice had 10-fold less serum and secreted IgA than all other F2 littermates. We conclude that B-1a cells are essential for the majority of IgA production in C2d mice. Thus, the C2d mouse may provide a useful tool for analysis of the role of intestinal IgA provided by B-1a cells.

Contribution of B-1 Cells to Intestinal IgA Production in the Mouse

In this paper we review the existing evidence that peritoneally derived B-1 cells may contribute significantly to the generation of IgA-secreting plasma cells in the murine intestinal lamina propria. The evidence is based upon a variety of experimental approaches performed in our laboratory and others and include (i) transfer studies of (sorted) B-1 cells into B-cell-depleted mice either experimentally (X-irradiation, anti-μ treatment) or genetically (SCID), (ii) analysis of genetically modified or manipulated mice (motheaten mice, CBA/N Xid mice, μ,k transgenic mice), and (iii) transplantation studies of fetal omentum. The data thus support the view that in addition to conventional B cells (B-2 cells) located in the Peyer′s patches (PP), B-1 cells contribute to the pool of IgA containing cells in the gut. Indeed, cotransfer of PP cells and peritoneal cells (PerC), which contain largely B-1 cells, into SCID recipients demonstrates that both PP and PerC contribute in a balanced fashion to the pool of IgA-containing cells in the gut lamina propria over long periods. Most likely IgA-positive (memory) B cells in PP are responsible for the long-term generation of IgA-producing cells derived from the PP inoculum. The potency of B-1 cells to contribute to mucosal IgA responses is also illustrated in adoptive transfer experiments in which PerC B-1 cells (or sorted B-1 cells) are adoptively transferred into untreated, Ig allotype congenic, SCID mice. These studies show that 6 months after injection of a few million PerC, almost all B cells in spleen and the recipient′s peritoneal cavity have the B-1 cell phenotype, while approximately 40 million PerC donor-derived IgA-producing cells can be detected in the gut lamina propria by allotype-specific ELISA spot assays. In conclusion, the data presented here show that, in principle, B-1 cells located in the peritoneal cavity may be an important source of precursors for intestinal IgA plasma cells in the mouse. However, the experiments performed so far do not allow us to draw definitive conclusions yet on the physiological contribution (in terms of numbers) and function (in terms of their specificity repertoire) of both B-1 cells and Peyer′s patch-derived B-2 cells to the pool of IgA-containing cells in the gut lamina propria in normal, unmanipulated animals.

A dual origin for IgA plasma cells in the murine small intestine.

More than two decades ago, Craig and Cebra1 showed that Peyer’s patches are an important source of progenitor cells for intestinal IgA plasma cells. The vast majority of B cells in Peyer’s patches are conventional B cells, which are produced throughout the life of the animal and which are responsible for high-affinity antibody responses to a variety of antigens. More recently, we provided evidence that probably also B-l cells (previously called Ly-1 or CD5 B cells2) also contribute significantly to the population of IgA plasma cells in the gut, at least in B lineage chimeras.3,4 B-l cells are almost absent from Peyer’s patches and are enriched in the peritoneal cavity. These cells are largely self-replenishing and have a selected antibody repertoire with specificities frequently directed towards “natural antigens”, autoantigens and bacteria-related antigens.5,6 In studies presented here we provide additional data, both from transfer studies with sorted B-l cells and from analysis of JLI,K transgenic mice, to support our hypothesis that B-l cells can contribute to the IgA response of the gut.KeywordsLamina PropriaAdult Bone MarrowAllelic ExclusionSyngeneic Bone MarrowTransgenie MouseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Evidence that intestinal IgA plasma cells in μ,ϰ transgenic mice are derived from B-1 (Ly-1 B) cells

B6-Sp6 transgenic mice carry fully rearranged (BALB/c-derived, Igh-Ca allotype) mu heavy chain and kappa light chain transgenes, specific for trinitrophenyl, on a C57BL background (Igh-Cb allotype). FACS analyses show that the majority of B cells in peripheral lymphoid organs and bone marrow (BM) express transgenic IgM exclusively. A small proportion of the B cells, however, express endogenous IgM, usually concomitant with transgenic IgM. Three criteria establish that the endogenous IgM expressing B cells belong to the B-1 cell lineage. (i) Endogenous IgM expressing B cells in B6-Sp6 mice have the same localization pattern as B-1 cells from normal animals: they are enriched in the peritoneal cavity. (ii) The endogenous IgM+ B cells have the phenotype of B-1 cells: the endogenous IgM+ peritoneal B cells express Mac-1 (CD11b) and low levels of IgD, and most also express CD5 (Ly-1). (iii) B6-Sp6 BM poorly reconstitutes endogenous IgM+ B cells, just as adult BM from normal mice poorly reconstitutes B-1 cells. In contrast, B cells which only express the transgene are readily reconstituted by B6-Sp6 BM. The few endogenous IgM+ cells in the B6-Sp6 BM recipients are located in the peritoneal cavity and have the phenotype of B-1b cells (previously the Ly-1 B sister population), which are known to be reconstituted by adult BM. Two-color immunofluorescence staining of tissue sections from the gut and from isolated gut lamina propria cells shows the presence of many IgA containing cells, about one-third of which simultaneously express cytoplasmic (transgenic) IgM. The C-region of this IgA is produced by endogenous C alpha genes, because the transgene encodes only for C mu. Furthermore, the majority of gut IgA containing cells do not express the idiotype of the transgene, indicating that most of the gut IgA cells are encoded by endogenous VH genes and thus the result of an isotype switch from endogenous IgM expressing B cells. Since the endogenous IgM+ cells are B-1 cells (both B-1a and B-1b), the data strongly indicate that the intestinal IgA plasma cells also belong to the B-1 cell lineage.

Peyer's Patches, Gut IgA Plasma Cells and Thymic Function: Study in Nude Mice Bearing Thymic Grafts

Nude mice have poorly developed Peyer's patches with very small or no germinal centers and little lymphoid cell proliferation, and a marked decrease in the number of gut-IgA plasma cells. Thymus grafts, which restore the T lymphocyte population of their lymphoid organs to nearly normal levels, lead to a considerable development of the Peyer's patches and of their germinal centers, assocaited with a considerable increase in gut IgA plasma cells, and in the serum IgA level. These findings are consistent with the postulated relationship between the Peyer's patches germinal center cells and the gut IgA plasma cells, and might help to explain the association of thymic defects, low serum IgA, and lack of intestinal IgA plasma cells observed in some immunodeficiency syndromes of man. Nude mice also have marked decrease in the number of lymphocytes present within the intestinal epithelium. These intraepithelial lymphocytes lymphocytes, which have been shown to be of T nature, are restored to normal numbers after thymus grafting.

The gut-associated lymphoid system: nature and properties of the large dividing cells.

AbstractThe nature of the lymphoid cells and blasts (i.e. cells labeled in vitro with [3H]‐thymidine) of the Peyer's patches (PP), mesenteric lymph nodes (MLN) and thoracic duct lymph (TDL) has been studied by combined immunofluorescence and radioautography, using antisera directed against T (MSLA) or B (MBLA) cell antigenic determinants, or against various Ig chains. The migration pattern of these various cell populations after transfer to syngeneic mice or rats was determined by radioactivity counting and radioautography and the nature of the homed cells was studied by combined immunofluorescence and radioautography. B and T blasts from MLN and TDL have, in contrast to blasts from the peripheral lymph nodes, a marked tendancy to home in the gut, and migrate as well in a graft of fetal intestine as in the recipient's own gut, indicating that this selective accumulation is not the result of a mechanism recognizing antigen absorbed from the gut lumen.The gut‐homing B blasts are cells bearing surface IgA (sIgA) and containing intracellular IgA, which transform into IgA plasam cells in the lamina propria. Evidence is discussed that the progenitors of the intestinal IgA plasma cells are proliferating sIgA cells from the PP geerminal centers, which migrate via lymphatics to MLN and TDL and mature during this migration, acquiring intracellular IgA chains as well as a gut‐homing mechanism which might be related to this increased IgA synthesis.The gut‐homing T blasts migrate both in the lamina propria and the intestinal epithelium. Most, if not all, the intraepithelial lymphocytes of the gut mucosa appear to be T lymphocytes derived from rapidly dividing cells. Evidence is presented for the existence in the lymphoid system of two types of T blasts, one that is circulating and has a marked tendancy to home to the gut, and a second that does not home to the gut and may be sessile.

Gut-associated lymphoblasts and intestinal IgA plasma cells.

The term “gut-associated lymphoid system” (GALS) can he applied, in the mouse and in the rat, to the lymphoid cells present in 1) the Peyers’ patches (PP) ; 2) the intestinal mucosa, where these cells consist of disseminated lymphocytes and IgA secreting plasma cells; 3) the mesenteric lymph nodes (MLN), into which the lymphatic system of the gut drains, and 4) the thoracic duct lymph (TDL), which receives the efferent MLN lymph. It has been shown in the rat that the TDL and MLN “lymphoblasts” (i.e. large dividing cells which are labeled after in vitro incubation with 3H thymidine) display, after transfer into syngeneic recipients, a strong tendency to migrate to the intestinal mucosa (1,2,3), the PP, and to some extent the MLN (2). This migration pattern is not observed with the blasts obtained from immunized peripheral lymph nodes (PLN); these blasts do not migrate to the gut and home more in the PLN than in the MLN (2). Preferential migration is characteristic of only the GALS blasts, since it is not found in transfer experiments when the total lymphoid population from TDL or MLN is labeled (2). Since these observations indicate that some of the GALS blasts have special properties, it was decided to investigate further the nature and properties of the various GALS cells in the mouse and in the rat.

The life span of IgA plasma cells from the mouse intestine.

Tritiated thymidine was injected during the neonatal period into conventional CBA mice. The disappearance rate of tritium-labeled IgA plasma cells was followed by a technique combining immunofluorescence with autoradiography which permitted the identification of the immunoglobulin class of plasma cells with labeled nuclei. In this way, it was possible to calculate that the major population of intestinal IgA plasma cells have a half-life of 4.7 days under physiological conditions of stimulation. It was also found that the maximum life span of both intestinal IgA plasma cells and the IgA, IgG, and IgM plasma cells from the spleen is of the order of 7-8 wk.