Human Intestinal B-Cell Blasts and Plasma Cells Express the Mucosal Homing Receptor Integrin α4β7

Interactions between homing receptors on circulating leucocytes and endothelial addressins regulate tissue-specific cellular extravasation. Although integrin á4β7 appears to be the main receptor for guthoming T lymphocytes, less is known about molecules mediating mucosal B cell homing. Expression of integrin α4β7 on B lymphocytes, B cell blasts, and plasma cells in human gut-associated lymphoid tissue (GALT; the Peyer's patches and appendix) and lamina propria was studied by multi-colour immunofluorescence applied on cryosections. Isolated mononuclear cells from the same tissue compartments were examined by flow cytometry and compared with peripheral blood B cells. Integrin α4β7 was expressed by IgA⁺ B cell blasts and plasma cells (CD38^high) in the lamina propria, B cell blasts in GALT, and sIgD⁺ B lymphocytes in peripheral blood. In contrast, GALT sIgD⁺ B lymphocytes were negative or only weakly positive for α4β7. These results suggested that B lymphocytes down-regulate αAβ7 upon extravasation in GALT but up-regulate this integrin after antigen-priming. Thus, α4β7 may be a homing receptor also for B cell blasts extravasating in the gut lamina propria, where this integrin is maintained on plasma cells, perhaps as a local retention factor.     

Distribution of beta 7 integrins in human intestinal mucosa and organized gut-associated lymphoid tissue.

Two alternative integrins involved in mucosal homing (alpha 4 beta 7) or epithelial retention (alpha E beta 7) of lymphocytes were examined in the human gut. The distribution of the beta 7 subunit [monoclonal antibody (mAb) M301] was bimodal in that it was strongly expressed by alpha E beta 7 + cells but weakly by alpha 4 beta 7 + cells. More than 90% of intraepithelial lymphocytes (IEL), including the minor subsets of CD4+, T-cell receptor (TCR) gamma/delta +, and CD3- cells, expressed alpha E beta 7 as did most lamina propria CD8+ (88%) and a fraction (36%) of CD4+ lymphocytes. Conversely, B-lineage cells (CD19+) and macrophages (CD68+) were negative. In gut-associated lymphoid tissue (GALT: Peyer's patches and appendix) only a few (< 5%) cells were positive for alpha E beta 7 (confined to CD8+ lymphocytes and CD11c+ putative dendritic cells). A relatively small fraction of IEL (30-50%) expressed alpha 4 beta 7 (mAb Act-1), while most (70%) lamina propria T and B lymphocytes, blasts, plasma cells and macrophages were positive. In GALT, T lymphocytes expressed similar levels of alpha 4 beta 7 as in the lamina propria whereas relatively few B lymphocytes (< 50%) were positive. Isolated lamina propria CD8+, CD4+, CD19+, and CD38+ cells contained mRNA for alpha 4 and the former three subsets as well as appendix CD8+ cells also for beta 7 while only lamina propria CD8+ cells had mRNA for alpha E. Together, the results suggested that alpha E beta 7 and alpha 4 beta 7 are differentially regulated in inductive sites and effector sites of the human gut. Because lymphoid cells at both sites expressed mainly alpha 4 beta 7, this integrin may be a homing receptor on memory and effector cells bound for lamina propria as well as on naive lymphocytes extravasating in GALT. Conversely, because alpha E beta 7 was mainly expressed by CD8+ cells in epithelium and lamina propria, it was probably induced after extravasation, in agreement with the observation that IEL and a fraction of lamina propria T lymphocytes (mainly CD8+ cells) generally expressed higher levels of beta 7 than most CD4+ and B cells. Also a subset of putative dendritic cells located near the follicle-associated epithelium of GALT expressed alpha E beta 7, perhaps reflecting epithelial interaction during primary immune responses.     

ONTOGENIC DEVELOPMENT OF GUT-ASSOCIATED LYMPHOID TISSUE IN THE RAT. An Immunohistochemical Study

The development of gut-associated lymphoid tissue (GALT) in the rat was investigated, with special reference to the behavior and ultrastructure of Ia(+) cells during the development of Peyer's patches (PP). At birth, Ia(+) cells were randomly scattered in the lamina propria. From three days, small aggregates of CD4(+), Ia(+), CD5(−) and IL-1(+) cells were observed in the lamina propria. Immunoelectron microscopically, these appeared as mixed populations of dendritic cells, capillary endothelial cells, flbroblast-like spindle cells and lymphocytes. In addition, CD8(+), CD4(–) and IL-1(−) cells were present in the interepithelial space. By seven days, lymphoid follicles were recognizable in the lamina propria, each with an aggregate of IgM-positive small lymphocytes at its center, surrounded by CD4(+) or CD8(+) lymphocytes. Between the 10th and 14th days, these follicles were covered with single-layered, specially differentiated epithelial cells, and structures resembling PP were formed. IgA plasma cells were identified in the lamina propria between the third and the fourth weeks. We speculate that the PP developed from aggregates of Ia(+), IL-1(+) spindle- or dendritic-shaped cells in the lamina propria. The PP were structurally complete by two weeks, although establishment of the characteristic distribution of GALT components evident in the adult took more than six weeks.     

Ontogenic development of gut-associated lymphoid tissue in the rat. An immunohistochemical study

The development of gut-associated lymphoid tissue (GALT) in the rat was investigated, with special reference to the behavior and ultrastructure of Ia(+) cells during the development of Peyer's patches (PP). At birth, Ia(+) cells were randomly scattered in the lamina propria. From three days, small aggregates of CD4(+), Ia(+), CD5(-) and IL-1(+) cells were observed in the lamina propria. Immunoelectron microscopically, these appeared as mixed populations of dendritic cells, capillary endothelial cells, fibroblast-like spindle cells and lymphocytes. In addition, CD8(+), CD4(-) and IL-1(-) cells were present in the interepithelial space. By seven days, lymphoid follicles were recognizable in the lamina propria, each with an aggregate of IgM-positive small lymphocytes at its center, surrounded by CD4(+) or CD8(+) lymphocytes. Between the 10th and 14th days, these follicles were covered with single-layered, specially differentiated epithelial cells, and structures resembling PP were formed. IgA plasma cells were identified in the lamina propria between the third and the fourth weeks. We speculate that the PP developed from aggregates of Ia(+), IL-1(+) spindle- or dendritic-shaped cells in the lamina propria. The PP were structurally complete by two weeks, although establishment of the characteristic distribution of GALT components evident in the adult took more than six weeks.     

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

The 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.     

Function of Mucosa-Associated Lymphoid Tissue in Antibody Formation

Abundant evidence supports the notion that human intestinal plasma cells are largely derived from B cells initially activated in gut-associated lymphoid tissue (GALT). Nevertheless, insufficient knowledge exists about the uptake, processing, and presentation of luminal antigens occurring in GALT to accomplish priming and sustained expansion of mucosal B cells. Also, it is unclear how the germinal center reaction so strikingly promotes class switch to IgA and expression of J chain, although the commensal microbiota appears to contribute to both diversification and memory. B-cell migration from GALT to the intestinal lamina propria is guided by rather well-defined adhesion molecules and chemokines/chemokine receptors, but the cues directing homing to secretory effector sites beyond the gut require better definition. In this respect, the role of human Waldeyer's ring (including adenoids and the palatine tonsils) as a regional mucosa-associated lymphoid tissue must be better defined, although the balance of evidence suggests that it functions as nasopharynx-associated lymphoid tissue (NALT) like the characteristic NALT structures in rodents. Altogether, data suggest a remarkable compartmentalization of the mucosal immune system that must be taken into account in the development of effective local vaccines to protect specifically the airways, small and large intestines, and the female genital tract.     

Cytotoxic reactivity of gut lamina propria CD4+ αβ T cells in SCID mice with colitis

Polyclonal, mucosa-seeking memory/effector CD4⁺ T cells containing a large fraction of blasts activated in situ accumulate in the gut lamina propria of severe-combined immunodeficient (SCID) mice developing colitis after CD4⁺ T cell transplantation. CD4⁺ T cells isolated from different repopulated lymphoid tissues of transplanted SCID mice proliferate in vitro in the presence of interleukin (IL)-2 + IL-7. CD3 ligation enhances this cytokine-supported proliferation in CD4⁺ T cells from the spleen and the mesenteric lymph node of transplanted SCID mice; CD3 ligation suppresses the cytokine-supported proliferation in CD4⁺ T cells from the gut lamina propria in a cell density- and dose-dependent manner. Almost all CD4⁺ T cells from repopulated lymphoid tissues of transplanted SCID mice express CD95 (Fas) on the cell surface, and a large fraction of CD4⁺ T cells from the gut lamina propria of transplanted SCID mice express the Fas ligand on the surface. Gut lamina propria CD4⁺ T cells show Fas-dependent cytotoxicity. A large fraction of gut lamina propria CD4⁺ T cells that infiltrate the inflamed colon in transplanted SCID mice are activated in situ and many CD4⁺ T cells are apoptotic. Hence, a large fraction of colitis-inducing CD4⁺ T cells undergo activation-induced cell death in situ and can damage other cells through Fas-dependent cytotoxicity.     

Gastric lesions and immune responses caused by long-term infection with Helicobacter heilmannii in C57BL/6 mice

Helicobacter heilmannii is a gastric micro-organism that can induce gastritis and B-cell MALT (mucosa-associated lymphoid tissue) lymphoma in mice, in a host-dependent manner. The present study was designed to examine gastric lesions and immune responses caused by intragastric H. heilmannii infection of an inbred mouse strain, C57BL/6. Long-term infection led to the formation of gastric nodules and increased mucosal thickness of the stomach, due to gastric epithelial proliferation. Infection also induced the formation of lymphoid follicles in the corpus mucosa and submucosa. The follicular cells were mainly CD45R+ cells that did not produce immunoglobulin. However, scattered in the lamina propria and corpus submucosa, numerous IgA+ cells were found in infected mice, but not in control mice. RT-PCR results showed that H. heilmannii infection led to increased mRNA expression for IFN-gamma (a Th1 cytokine) and IL-10 (a Th2 cytokine) in the mouse stomach, suggesting that both Th1 and Th2 responses are associated with H. heilmannii infection. The mRNA of other cytokines and chemokines (IL-1beta, IL-12p40, TNF-alpha, MCP-1, KC and MIP-2) was also increased by infection.     

Differential expression of adhesion molecules and chemokines between nasal and small intestinal mucosae: implications for T- and sIgA+ B-lymphocyte recruitment

Nasal and small intestinal mucosae are the first sites of contact with infectious agents and the sites of T-cell-mediated and secreted immunoglobulin A (IgA)-mediated defences against pathogens. We investigated the factors controlling the infiltration of CD3(+) T lymphocytes and surface IgA(+) (sIgA(+)) B lymphocytes into swine epithelium and lamina propria (LP) within and between these two mucosal effector sites. Vascular addressins, vascular cell adhesion molecule 1 and mucosal addressin cell adhesion molecule-1 were reciprocally expressed in both mucosae. Strong expression of alpha(4)beta(1) relative to alpha(4)beta(7) was characteristic of CD3(+) T cells in nasal mucosa LP and epithelium and of sIgA(+) cells in nasal mucosa epithelium. The same profile was observed on corresponding blood cells. Conversely, higher levels of integrins beta(7) and alpha(4)beta(7) than alpha(4)beta(1) were characteristic of CD3(+) T cells and sIgA(+) cells in the small intestine. However, about 40% of the LP-activated sIgA(+) cells displayed sIgA(high), integrin alpha(4) and integrin alpha(4) expression. Whereas CCL19, CXCL12, CCL21 and CCL28 messenger RNAs were similarly expressed in both mucosae, CCL25 messenger RNA was only expressed in the small intestine. Thus, the nasal and small intestine mucosae represent separate compartments for infiltration by CD3(+) T cells and sIgA(+) effector cells, with the exception of a population of small intestine activated sIgA(+) cells, which may gain access to both mucosae.     

痢疾杆菌口服免疫小鼠肠道相关淋巴组织中CD45R~+和CD45RB~+细胞动态变化的观察

为了解肠道相关淋巴组织（GALT）对痢疾杆菌口服免疫的应答状况,分离了Shigella fiexneri四次免疫后Balb/c 小鼠牌（SP）、肠系膜淋巴结（MLN）、Peyer’s结（PP）、固有膜（LP）和上皮内（IE）淋巴细胞,对末次免疫后1～13d内免疫组与对照组GALT中的CD45R~+和CD45RB~+细胞群作了FACS分析。结果免疫后起初7d IE和LPCD45R~+细胞增加而MLN和PP CD45R~+细胞减少。CD45RB~+LPL在起初4d增加,而CD45RB~+IEL总是低于对照。CD45RB~(lo)/CD45RB~(hi)比例在SP和MLN中几乎无变化,但在PP中先降至最低后上升并超过对照。LP中主要为CD45RBD~(lo),IE中主要为CD45RB~(hi)。这些结果在一定程度上反映了粘膜淋巴细胞CD45表达的组织特异性及在痢疾杆菌免疫后B细胞、记忆细胞和辅助细胞的功能状态和变化趋势。     

Enhancement of mucosal antibody responses to Salmonella typhimurium and the microbial hapten phosphorylcholine in mice with X-linked immunodeficiency by B-cell precursors from the peritoneal cavity.

The observation that approximately half of the B cells in the murine intestinal lamina propria are derived from peritoneal CD5 B-cell precursors raises the question of their contribution to mucosal protection. Using mice with X-linked immunodeficiency which are deficient in CD5+ B cells, we showed that they mount little serum and virtually no intestinal immunoglobulin M (IgM), IgG, and IgA antibody responses following oral inoculation with live Salmonella typhimurium. Nonresponsive Xid mice were reconstituted with responsive CBA/Ca donor cell preparations which were constitutively enriched or depleted of CD5 B-cell precursors. Reconstitution of irradiated Xid mice with CD5 B-cell-deficient bone marrow from CBA/Ca donors marginally improved IgM responses in the intestinal mucosa but had no effect on IgG or IgA in response to oral immunization with live S. typhimurium. Whenever Xid mice were reconstituted with donor cells from the peritoneal cavity, which are enriched for CD5 B-cell precursors, strong IgA and in some cases IgG responses in the intestinal mucosa were stimulated in response to oral immunization. When mucosal and serum antibody responses were compared, the peritoneal donor cells again reinstated maximal serum antibody responses to S. typhimurium. Serum and mucosal responses to the bacterial hapten phosphorylcholine could be induced in Xid mice after immunization with S. typhimurium or hapten-carrier conjugates but only following reconstitution with donor cells containing CD5 B-cell precursors. These observations suggest that different lymphoid compartments are enriched for regulatory or effector cells which vary in their contributions to the mucosal antibody response against epitopes on S. typhimurium.     

Terminal B cell development as seen in different human myelomas and related disorders.

Immunological surface marker analysis of the mature lymphoid and plasma cells of a range of human lymphoproliferative diseases is used to show that the surface immunoglobulin (sIg) phenotype of plasma cells depends upon the isotype being secreted. Using a sensitive rosette assay, the plasma cells of all IgG (eight), IgA (six) and IgE (one) myelomas studied and of one of two cases of IgD myeloma were negative for all classes of sIg. The plasma cells from the other case of IgD myeloma expressed only sIgD, while a proportion of plasma cells from two cases of IgM myeloma and one of BJ myeloma had both sIgM and sIgD at the cell surface. The mature lymphoid and plasma cells from the two patients with mixed lymphoid/plasmacytoid proliferations of IgA type (2) carried sIgA alone, while the mature bone marrow cells from a case of Waldenström''s macroglobulinaemia had only sIgM. In all the various types of immunoproliferative disease studied, a greater proportion of lymphoid cells than plasma cells possessed γFc receptors, and plasma cells were negative for receptors for EAC and μFc, and lacked the Ia-like p29, 34 antigen. These results are used to provide a scheme illustrating the terminal stages of B cell development.Examination of the peripheral blood from nineteen cases without morphological evidence of blood involvement demonstrated a monoclonal B cell proliferation in 40% of these cases. Immunological analysis of lymphocyte subpopulations showed that both E-rosette-forming cells and sIgM⁺ and sIgD⁺ normal B cells were depressed in most cases and that there was a corresponding increase in Fc⁺sIg⁻ and/or null (Fc⁻sIg⁻) cells.     

B-cell production and differentiation in adult rats.

The B-cell development in a group of rats was suppressed for the first 45 days of life by serial administration of rabbit anti-rat IgM and IgD antibody. Total or near total suppression of B lymphopoiesis was achieved. At 45 days, suppression was stopped by injection of IgM and IgD rat paraproteins. The sequence of B-cell and plasma cell development following suppression was assessed by immunohistological analysis of spleen lymph nodes and small intestinal lamina propria. The main findings are listed below. Complete reconstitution of B-cell numbers occurs within 8 days, at which stage germinal centres are also present. B lymphopoiesis in the red pulp of the spleen differs from that reported for bone marrow. Cells develop expressing surface sIgM and sIgM with IgA, but not sIgD. sIgD-positive cells first appear in splenic follicles 2 days after stopping suppression, but their appearance in lymph nodes is delayed until after 3 days. At this stage, sIgD-positive cells become apparent in the splenic red pulp. IgM plasma cells appear from day 4. IgA plasma cells in the gut appear in small numbers at day 6, and gradually increase to normal numbers by day 14. sIgG2c expression in the splenic marginal zone did not approach normal levels, even 2 weeks after suppression was stopped.     

The distribution of leucocyte subsets in the small intestine of healthy cats

The aim of this study was to investigate the distribution of leucocyte subsets in the small intestine of healthy adult cats (n=16). Immunohistochemical methods were used to identify leucocyte subsets within the mucosa of the duodenum, jejunum and ileum. Computer-aided morphometry was used to enumerate cells within the epithelial compartment, villous lamina propria and lamina propria adjacent to upper and lower crypt. Throughout the small intestine, IgA+ and IgM+ plasma cells were more prominent in the lamina propria adjacent to the lower crypt than in the villus, whereas IgG+ plasma cells were present in equal numbers in the crypt and villous regions. Overall, IgA+ plasma cells predominated and IgM+ plasma cells were higher in number than IgG+ plasma cells at each of the three anatomical locations. By contrast, T cells (CD3+) and T-cell subsets (CD4+ and CD8+) were present in greater numbers in the villous lamina propria than in the lamina adjacent to the crypts. Intraepithelial lymphocytes (IELs) were also characterized phenotypically, the majority being CD8+ T lymphocytes. Lamina propria macrophages and dendritic cells were characterized by expression of L1 and major histocompatibility complex (MHC) class II, and MHC class II expression by enterocytes overlying Peyer's patches, although rare, was also shown. The qualitative and quantitative data from this study provide a basis for comparison with cats with inflammatory enteropathies. Copyright Harcourt Publishers Ltd.     

Modulation of IgD and CD20 by ligation of CD5 on tonsillar B cells

The CD5 molecule, pan T cell marker, has been known to be expressed on a minor population of B cells, termed B-1 cells. However, the physiological function and pathological role of CD5+B (B-1) cells remain to be fully elucidated in humans. In the present study, we aimed to clarify the significance of CD5 expression on the B lymphocytes in human tonsil. Using flow cytometric analysis by three-colour immunofluorescence staining, we observed a majority of the cell surface CD5-positive (sCD5+) B cells among the sIgD+ B-cell population, as previously described. Contrary to our expectation, approximately half of the sIgD+/sCD5+ B cells expressed CD38 on their cell surface. Furthermore, a small number of sCD5+ were observed in the sIgD- B cell population. The addition of anti-CD5 monoclonal antibody (MoAb) to the culture induced downmodulation of sCD20 and sIgD of the tonsillar B cells, resulting in an increase of sCD38-/sIgD- (memory) B cells during the 10 day culture periods in the CD40/l cell culture system. Our findings suggest that ligation of CD5 might transduce the signal to regulate B cell maturation.     

Effects of the lpr/lpr mutation on T and B cell populations in the lamina propria of the small intestine, a mucosal effector site.

MRL mice, which develop a lymphoproliferative disease characterized by increased numbers of alpha/beta T cell receptor+ (TCR+) B220/6B2+CD4-CD8- T cells [lymphoproliferation (lpr) T cells], were studied for the effect of the lpr/lpr mutation on the mucosal immune system in the gastrointestinal (GI) tract. We analyzed the effect of the lpr gene mutation on T and B cell populations in the Peyer's patches (PP) and the lamina propria lymphocytes (LPLs), as examples of major IgA inductive and effector tissues in the GI tract respectively. Normal mouse PP contain B cells committed to IgA (surface IgA+) but only low numbers of B cells producing IgA. However, enhanced spontaneous IgA and IgG synthesis occurs in the PP of MRL mice. Further, we have now shown that PP of MRL mice are populated by lpr T cells. Interestingly, lpr T cells were not present in significant numbers in LPLs of MRL mice, even in older animals. Of interest was the finding that the ratio of CD4+ to CD8+ T cells in the lamina propria was lower in MRL when compared with control mice, and the CD8+ T cell subset actually predominates in LPLs of autoimmune mice. In addition, the number of gamma/delta TCR+ T cells in LPL of MRL lpr/lpr mice was significantly increased, especially in MRL lpr/lpr mice at 6 and 12 weeks of age. When the isotype distribution of B cells in LPLs was analyzed, no changes were noted in MRL lpr/lpr mice in comparison with MRL +/+ or normal control mice, and the pattern was IgA much greater than IgM greater than IgG. These results show that although increased numbers of CD8+ T cells and gamma/delta TCR+ cells occur in the LPLs of MRL mice, a normal distribution of plasma cell isotypes (IgA much greater than IgM greater than IgG) is found in this mucosal compartment. Further, Ipr T cells do not develop in the lamina propria compartment of the GI tract.     

Production of immunoglobulins by human sIgD+ and sIgD- human blood B lymphocytes in response to stimulation with activated T cells and agonistic antibodies; effect of IL-10, IL-2 and mode of activation of T cells.

Production of IgM, IgG and IgA was induced from human blood B lymphocytes by culturing with a CD40 MoAb and IL-2 for 9 days. Replacement of IL-2 by IL-10 markedly enhanced production of all three isotypes. High levels of immunoglobulin production also occurred when activated irradiated autologous T cells replaced the CD40 MoAb, and when IL-10 replaced IL-2 in these cultures a spectacular increase in IgG production occurred. The effectiveness of the T cell stimulus depended on the mode of purification of the T cells and the nature of the stimulant used to activate them. Differences in the kinetics and level of expression of CD40L on the various T cell preparations were observed, but did not account for variations in immunoglobulin-inducing efficiency. Immunoglobulin production from sIgD+ and sIgD- B cells was investigated. IgG and IgA were found in sIgD+ cultures, indicating that some isotype switching had occurred, but the major part of the IgG and IgA secreted was from cells already committed to these isotypes. Anti-IgD or anti-IgM MoAbs enhanced the proliferation of B cells induced by anti-CD40 antibody, but immunoglobulin production was not enhanced. Factors affecting the balance of proliferation and differentiation are discussed.     

肠道黏膜免疫

肠道免疫系统由大量弥散分布在肠黏膜上皮内和固有层的免疫细胞和免疫分子、以及诸如peyer’spatches(PP)等肠相关性淋巴组织等组成。小肠PP结为肠黏膜免疫主要诱导部位,肠黏膜上皮和固有层为主要效应部位。B细胞、T细胞在PP结诱导后,分化、成熟,并移行到黏膜效应部位,发挥免疫效应功能。     

Induction of Mucosal B-Cell Memory by Intranasal Immunization of Mice with Respiratory Syncytial Virus

The capacity of live or inactivated respiratory syncytial virus (RSV) to induce B-cell memory in respiratory-associated lymphoid tissues of mice was examined. Eight weeks after primary inoculation with either live or inactivated RSV, adult BALB/c mice were challenged with 4 × 10⁵ PFU of RSV. Protection from viral shedding and mucosal production of RSV-specific antibodies were examined at various time points after challenge. We found that primary immunization with live, but not inactivated, RSV induced complete and durable protection upon challenge within the upper and lower respiratory tract. Also, primary immunization with live, but not inactivated, RSV enhanced the production of mucosal RSV-specific immunoglobulin A (IgA) upon challenge. Secondary mucosal IgA responses were characterized by (i) the early production of mucosal IgA by B cells that reside in organized nasal-associated lymphoid tissues, cervical lymph nodes, and bronchial lymph nodes, and (ii) the subsequent production of RSV-specific IgA by mucosal effector tissues, such as the tracheal lamina propria and lung. These findings suggest that primary infection of mice with live RSV might induce mucosal IgA-committed memory B cells. A greater understanding of the characteristics of RSA-specific mucosal memory B cells may facilitate the development of an RSV vaccine.     

Transient secretory IgA deficiency in mice after cyclophosphamide treatment

Cyclophosphamide (Cy), an alkylating agent widely used in chemotherapy of leukemia and cancer, causes a well-documented toxicity on hematopoietic and lymphoid cells. Neutropenia is thought to be the main factor involved in infectious complications following antimitotic chemotherapy. Little is known on the effects of these therapies on the mucosal associated lymphoid system which is one of the main barriers against environmental pathogenic agents. The present study examined the effects of a single administration of Cy (200 mg/kg) on murine T and B cell populations of Peyer's patches (PPs), IgA secretion in the proximal part of the small intestine, and plasma cells of the lamina propria. Cy induced in mice a transient decrease in the T and B cell populations of the PPs with a drastic fall of B cell counts and a profound decrease of intestinal IgA secretion due to a reduction of lamina propria plasma cells. This transient secretory IgA deficiency may contribute to the infectious complications following antimitotic chemotherapy.