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Regional dichotomy of idiotypic expression on senescent B lymphocytes in systemic and mucosal immune systems: selective changes in NPb and T15 idiotypes with aging.

The age-associated changes in the expression of NPb and T15 idiotypes on antibody-secreting B cells in the spleen and bronchial lymph nodes (BLN) of mice following peritoneal immunization with (4-hydroxy-3-nitrophenylacetyl) acetic acid (NP) and phosphorylcholine (PC) as antigens were investigated. Changes in the NPb or T15 idiotype expressions were detected by the inhibition of anti-NP or anti-PC elispot-forming cells (SFC) with monoclonal (Mab) anti-idiotypic antibodies, Mabs Ac38 and Ac146, or AB1-2, respectively. We found that Mabs Ac38 and Ac146 significantly inhibited anti-NP IgM and IgG SFC responses in the spleen from 4-month old animals in a dose-dependent manner as opposed to a lack of effect on 24-month old splenic cells. There were no significant effects on anti-NP SFC responses in the BLN from either young or old mice. Similar results were obtained using Mab AB1-2 inhibition of T15 idiotype on anti-PC SFC responses in the spleen and BLN. No age-related changes in the gamma- and kappa-light chain contents of the secreted anti-NP antibodies by B cells in the spleen and BLN were observed. The kinetics of the appearance of endogenously auto-anti-idiotype blocked, hapten augmentable (HA) anti-NP IgM SFC responses revealed significantly higher percentages of HA SFC in the spleen and BLN, 14 days after immunization for both young and old mice. The findings suggest that the age-related changes in the idiotypic expression on antigen-specific antibody repertoires in the spleen and mucosa-associated tissues may be caused by the activation of subsets of B cells with different VH gene expressions.

Aging↗

Innervation of mucosal immune cells in the gastrointestinal tract.

There is mounting evidence for interactions between the immune and peripheral nervous systems. Many regulatory molecules are candidate mediators for communication between inflammatory cells and nerves; however, the extent of targeting of neurotransmitters (and interleukins) as intersystem messengers has been somewhat overlooked. Lymphoid tissues are well supplied by nerves and the gastrointestinal lamina propria, which is populated by a variety of immune cell types, is densely innervated. One-half to two-thirds of mast cells are closely apposed to nerves in the intestinal mucosa, in both rodents and humans, and nerve stimulation has been reported to cause mast cell activation. Although less extensively studied, both eosinophils and plasma cells in the gastrointestinal mucosa are also positioned for interaction with nerves, and intra-epithelial leukocytes may be subject to diffusible neurally-derived mediators. Peyer's patches are relatively sparsely innervated but appear to express neuropeptide receptors in inflammatory conditions. Although the nerves in the mucosa have traditionally been thought of as a static component, recent experiments suggest that these may undergo extensive remodelling during nematode-induced inflammation. Such data suggest a dynamic interplay between the immune and nervous systems during inflammatory episodes in the gut, although considerable work is still needed to determine the importance of neuro-immune interactions in gastrointestinal homeostasis and inflammation.

Animals↗

Oral administration of immunomodulators and the mucosal immune system.

Orally administered antigens reach the lymphoid tissue in Peyer's patches in the gut where they initiate an immune response with clonal expansion of antigen-specific T and B cells. Activated T cells migrate through lymph and blood to intestinal epithelium (intra-epithelial leukocytes) whereas activated B cells migrate to the lamina propria, other mucosae and exocrine glands where they differentiate into plasma cells secreting polymeric IgA1 or IgA2. These antibodies are transported across the epithelial cells after binding to a poly-Ig receptor, then excreted in the lumen as secretory IgA. Reciprocal interactions have been demonstrated between lymphoid and epithelial cells in the mucosae. Oral administration of antigens in different experimental models may induce the production of secretory antibodies and/or systemic unresponsiveness with suppression of delayed-type hypersensitivity or specific IgG and IgE antibody production or both. New strategies are currently being explored for the development of oral vaccines using recombinant antigens or viral vectors (e.g. pox-viruses, vaccinia virus, cholera toxin B subunit etc.). Conversely, immunomodulating compounds or procedures which could enhance specific oral tolerance in association with antigen would have considerable therapeutic applications in auto-immune diseases and allergy.

Adjuvants, Immunologic↗

[Mucosal immunization of recombinant Schistosoma japonicum ferritin].

OBJECTIVE: To subclone and express the gene encoding Schistosoma japonicum ferritin (SjFer) and study its immune protection against challenge infection in mice vaccinated intranasally. METHODS: The SjFer gene was amplified by PCR, and subcloned into the N-terminal of intein 2 of the pTWIN1 vector. The positive recombinant was screened by PCR, restriction enzyme digestion and sequence analysis. The positive recombinant was transformed into E. coli ER2566. The soluble recombinant fusion protein (rSjFer-intein 2) was expressed in E. coli by induction of low IPTG concentration under low temperature, and analyzed by SDS-PAGE and Western blotting. Mice were immunized intranasally with rSjFer, using chitosan as adjuvant. Two weeks after the third vaccination, challenge infection with S. japonicum cercariae was carried out. Worms and eggs collected from the livers of mice were counted at 42 days after the challenge. Levels of specific antibodies were detected by ELISA before infection. RESULTS: SjFer was successfully subcloned into pTWIN1 vector and expressed in E. coli. In mice vaccinated intranasally with rSjFer and adjuvant chitosan, the worm reduction rate was 35.51% and the reduction rate of eggs per gram liver tissue (LEPG) was 52.17%. As compared with the control groups, levels of IgG, IgA in sera and SIgA in saliva increased significantly. CONCLUSION: The expressed rSjFer can induce partial protective immunity against S. japonicum infection in mice when they were vaccinated intranasally, with chitosan as adjuvant.

Animals↗

Interactions between Helicobacter pylori and the local mucosal immune system.

The recognition that Helicobacter pylori is associated with an array of gastric disorders immediately raises several issues with regard to the role of the local immune system. The belief that the harsh gastric environment limits or prevents infection has perhaps dismissed studies into the immunology of the stomach as a low priority. Now, in combination with our understanding of local immune reactivity in pernicious anaemia, an interest in defining the contribution of the immune response in the pathogenesis of disease associated with H. pylori has fueled a great deal of interest. Furthermore, the evidence of local immunity to this bacteria has kindled interest that gastric immune/inflammatory responses may contribute to the treatment or prevention of a gastric infection.

Animals↗

A rabbit model for mucosal immunity in the bowel. II. Local cellular reactivity to virus infection.

An animal model was used to examine local and systemic cellular reactivity against virus infection of bowel mucosa. Firstly, existing techniques for extracting lymphoid cells from the dispersed populations of the bowel mucosa were adapted for use in rabbits and viable lymphocytes were isolated from the lapine ileal mucosa in numbers suitable for assay. Lamina propria lymphocytes (LPL) showed a strong blastogenic response to T-cell mitogens but intra-epithelial lymphocytes (IEL) responded poorly, even in the presence of splenic accessory cells. Next, chronically isolated ileal loops in rabbits were infected with parainfluenzavirus type 3 (PI-3) and isolates from the organized and dispersed lymphoid tissues associated with infected ileal mucosae and those from systemic lymphoid sites were used in in vitro assays of virus-specific lympho-proliferation. A T-cell-mediated immune response against PI-3 was mounted in lymphoid tissues associated with the infected loops, appearing first in loop Peyer's patches (PP) at Day 4 and in mesenteric lymph nodes (MLN) and lamina propriae at Day 7 after infection. The response in PP had waned by 21 days but was sustained in the other sites for at least 42 days. Epithelial lymphocytes were consistently anergic and there was no evidence of specific reactivity at systemic lymphoid sites or elsewhere in the bowel. Thus, a highly localized T-cell-mediated response was sustained, not only in organized lymphoid tissues but also in the bowel wall itself, following infection with a novel antigen.

Animals↗

Intraepithelial lymphocytes contain virus-specific, MHC-restricted cytotoxic cell precursors after gut mucosal immunization with reovirus serotype 1/Lang.

Reovirus 1 has been intraduodenally administered to mice to determine whether virus-specific cytotoxic cells can be elicited within the intestinal epithelium. We have found that reovirus-stimulated, but not control mice, generate virus-specific cytotoxic effector cells when isolated intraepithelial lymphocytes are restimulated in vitro. These effector cells are restricted by major histocompatibility complex (MHC) class I determinants and thus appear to utilize the T cell antigen receptor and to be of the T cell lineage. These results raise the possibility that cytotoxic T lymphocytes (CTL) may be an important component of the host immune response in the intestinal epithelium.

Animals↗

IgA nephropathy and mucosal immune system.

IgA-containing immune complexes may play a major role in IgA nephropathy, and the author emphasizes that impairment of their clearance and of hepatobiliary transport has etiological significance. In addition, an abnormality of the phagocytic system, such as mesangial cells, may lead to mesangial deposition of preformed circulating IgA-containing immune complexes. The IgA bound to the glomerular mesangium is polymeric IgA to microbial or dietary antigens in the mucosa. Mesangial cells and endothelial cells in the glomeruli may play an important immunoregulatory role in IgA nephropathy.

Glomerular Mesangium↗

Distribution of rotavirus antigen in intestinal lymphoid tissues: potential role in development of the mucosal immune response to rotavirus.

Groups of suckling BALB/c mice were inoculated with murine rotavirus (MRV) at 5 days of age and sequentially tested for the presence of MRV antigen (Ag) in intestinal villus epithelium (VE), Peyer's patch (PP), mesenteric lymph node (MLN), spleen, liver and lung, using indirect immunofluorescence techniques (IF). MRV Ag was first detected in VE 24 h after oral administration of the virus and remained in VE for as long as 10 days post-inoculation (pi). MRV Ag was observed in the epithelium overlying PP at 3-7 days pi and in subepithelial and interfollicular areas in the PP between 3 and 20 days pi. MRV Ag was also detected in MLN during the same period of time. Small numbers of MRV-Ag-containing cells were detected in the lamina propria (LP) of intestinal villi at 10 days pi. Most MRV-Ag-containing cells in PP and MLN were Ia-positive but negative for Lyt-1, Lyt-2 and MAC-1 cell surface markers. MRV-Ag-containing cells were negative for surface or cytoplasmic immunoglobulin. Intestinal antibody response to MRV indicated by the presence of MRV-specific IgA plasma cells in LP was first detectable 10 days pi. Highest density of MRV-specific plasma cells was observed in the duodenum, with a similar distribution to that of MRV-Ag-containing cells in PP. These observations suggest that MRV-Ag uptake is largely limited to the PP associated epithelium and the virus Ag is subsequently transported to the underlying lymphoid follicles and MLN. These findings suggest a close relationship between the availability of MRV Ag in the lymphoid follicles at different locations and the subsequent development of local antibody responses in different segments of small intestine.

Animals↗