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PubMed2003

The role of mucosal immunity in prevention of HIV transmission.

Vaccines designed to prevent mucosal transmission of HIV should establish multiple immune effectors in vaccine recipients, including antibodies which are capable of blocking HIV entry at mucosal epithelial barriers and of preventing initial infection of target cells in the mucosa. Immunological analyses of HIV-resistant humans and data obtained in nonhuman primate vaccine studies indicate that both secretory and serum antibodies may play an important role in protection against mucosal transmission of HIV or SIV, whereas cytotoxic T cells are required for clearance of mucosal infection and prevention of systemic spread. This review summarizes the roles of IgA and IgG antibodies in preventing mucosal infection by other viral and bacterial pathogens, and then discusses the various mechanisms by which antibodies might contribute to protection against HIV at mucosal surfaces. These include prevention of mucosal contact, blocking attachment of virus or infected cells to epithelial cells, interception of virus during transepithelial transport, neutralization of virus in the mucosa, and elimination of locally infected cells through antibody-dependent cell-mediated cytotoxic reactions. The regional nature of mucosal immune responses is reviewed in light of its relevance to HIV vaccine development. We conclude that mucosal immunization should be considered a component of vaccine strategies against HIV.

AIDS Vaccines↗
PubMed2004

Co-immunization with an HIV-1 Tat transduction peptide-rotavirus enterotoxin fusion protein stimulates a Th1 mucosal immune response in mice.

The cholera toxin B subunit (CTB) and a 12 aa HIV-1 Tat transduction peptide were genetically linked to a 90 aa peptide from the murine rotavirus non-structural enterotoxin protein (NSP4) for comparison of receptor directed and transduction peptide mediated antigen targeting to the gut associated lymphoid tissues for enhanced protection against rotavirus infection. Oral immunization with Tat-NSP4(90) fusion protein isolated from Escherichia coli generated detectable anti-NSP4(90) IgG titers in mice. CTB-NSP4(90) fusion protein stimulated higher serum IgG titers than CTB fused to a 22 aa immunodominant epitope NSP4(22) indicating the presence of additional immunogenic epitopes in the NSP4(90) peptide. Mice immunized with CTB-NSP4(22) stimulated high IgG2a antibody levels suggesting a dominant Th1 lymphocyte response. However, mice immunized with CTB-NSP4(90) generated similar levels of IgG1 and IgG2a suggesting equal stimulation of Th1 and Th2 responses. Mice co-immunized with CTB-NSP4(90) and Tat-NSP4(90) fusion proteins generated dominant IgG2a levels indicating that the two ligands co-operate to generate an increased Th1 response.

Adjuvants, Immunologic↗
PubMed1987

IgA antibody-producing cells in peripheral blood after antigen ingestion: evidence for a common mucosal immune system in humans.

The finding that ingestion of antigens results in the selection induction of IgA antibodies in external secretions suggests that antigen sensitizes Peyer's patch lymphoid cells, which migrate to mucosal sites and generate local secretory IgA (S-IgA) antibody responses. Evidence for a common mucosal immune system in humans has been scanty because of the difficulty in demonstrating migratory behavior of Peyer's patch cells. In the present study, peripheral blood mononuclear cells (PBMC) from human volunteers who had ingested capsules containing killed Streptococcus mutans were assayed for spontaneous antibody-producing cells. Four of five volunteers exhibited circulating IgA-producing cells within 7 days and reached maximum responses by days 10-12. One IgA-deficient subject exhibited IgM responses with identical kinetics. Pokeweed-mitogen-stimulated PBMC produced anti-S. mutans antibodies predominantly of the IgA isotype. Significant S-IgA anti-S. mutans antibodies were detected in saliva and tears by day 14, and the antibodies reached maximum titers by 3 weeks. No changes in serum anti-S. mutans antibodies were noted. The IgA-deficient subject produced salivary secretory IgM antibodies. These results suggest that, after antigen ingestion, peripheral blood contains antigen-specific precursors of IgA plasma cells and that their presence precedes the appearance of S-IgA antibodies in external secretions. Therefore, these experiments provide further support for the existence of a common mucosal immune system in humans.

Adult↗
PubMed2004

Oral opportunistic infections in HIV-positive individuals: review and role of mucosal immunity.

Oral opportunistic infections in the HIV-positive individual have been documented since the first reports of the epidemic, with many lesions associated with reduced CD4(+) T lymphocyte cell count. The most common oral lesions seen in HIV disease prior to the advent of highly active antiretroviral therapy (HAART) were oropharyngeal candidiasis and oral hairy leukoplakia. However, since the advent of HAART while many oral lesions have decreased significantly the incidence of oral warts has surprisingly increased. Despite the correlation of diminished CD4(+) T lymphocyte count to the occurrence of these lesions, it is rare for the lesions to occur concurrently suggesting that each pathologic lesion type is associated with distinct host immune dysfunctions. To date, the oral opportunistic infection most frequently investigated is oropharyngeal candidiasis, where data suggests that both systemic and local immunity is important for protection against infection. In contrast, recent investigations into the host responses associated with oral hairy leukoplakia and oral warts show little to no evidence of systemic or mucosal immune responsiveness despite the presumed competence of several types of leukocytes other than CD4(+) T cells. Together these data are suggesting that susceptibility to oropharyngeal candidasis in HIV-positive persons is predominantly immune-based, whereas protection or susceptibility to oral hairy leukoplakia and oral warts may be more associated with factors other than mucosal immune function.

AIDS-Related Opportunistic Infections↗
PubMed2003

The role of dendritic cells in regulating mucosal immunity and tolerance.

The intestinal immune system discriminates between invasive pathogens and antigens that are harmless, such as food proteins and commensal bacteria. The latter groups of antigens normally induce tolerance and a breakdown in this homeostatic process can lead to diseases such as coeliac disease or Crohn's disease. The nature ofthe intestinal immune response depends on how antigen is presented to CD4+ T cells by dendritic cells (DCs). Both oral tolerance and priming are influenced by the numbers and activation status of DCs in the gut and its draining lymphoid tissues, and our current work indicates that dietary proteins are taken up preferentially by DCs in the lamina propria of the small intestine. These then migrate to interact with antigen-specific CD4+ T cells in the mesenteric lymph node. In vivo and in vitro studies using purified lamina propria DCs suggest these may play a unique role in the regulation of intestinal immune responses. We propose that local DCs are the gatekeepers of the mucosal immune system, inducing tolerance under physiological conditions, but being sufficiently responsive to inflammatory stimuli to allow T cell priming and protective immunity when necessary. In addition, we will discuss evidence that adjuvant vectors such as ISCOMS may be effective mucosal vaccines due to an ability to activate intestinal DCs.

Animals↗
PubMed2001

Induction of mucosal immune response after intranasal or oral inoculation of mice with Lactococcus lactis producing bovine beta-lactoglobulin.

The bovine beta-lactoglobulin (BLG) is a major cow's milk allergen. Here, we evaluated the immune response against BLG induced in mice, using the organism Lactococcus lactis, which has GRAS ("generally regarded as safe") status, as a delivery vehicle. The cDNA of the blg gene, encoding BLG, was expressed and engineered for either intra- or extracellular expression in L. lactis. Using a constitutive promoter, the yield of intracellular recombinant BLG (rBLG) was about 20 ng per ml of culture. To increase the quantity of rBLG, the nisin-inducible expression system was used to produce rBLG in the cytoplasmic and extracellular locations. Although the majority of rBLG remained in the cytoplasm, the highest yield (2 microg per ml of culture) was obtained with a secreting strain that encodes a fusion between a lactococcal signal peptide and rBLG. Whatever the expression system, the rBLG is produced mostly in a soluble, intracellular, and denatured form. The BLG-producing strains were then administered either orally or intranasally to mice, and the immune response to BLG was examined. Specific anti-BLG immunoglobulin A (IgA) antibodies were detected 3 weeks after the immunization protocol in the feces of mice immunized with the secreting lactococcal strain. Specific anti-BLG IgA detected in mice immunized with lactococci was higher than that obtained in mice immunized with the same quantity of pure BLG. No specific anti-BLG IgE, IgA, IgG1, or IgG2a was detected in sera of mice. These recombinant lactococcal strains constitute good vehicles to induce a mucosal immune response to a model allergen and to better understand the mechanism of allergy induced by BLG.

Administration, Intranasal↗
PubMed2003

ICOS+ Th cells produce distinct cytokines in different mucosal immune responses.

T cell activation, differentiation and effector functions depend on signals delivered through the antigen-specific TCR and non-clonal costimulatory receptors on the T cell. Activated T cells express the inducible costimulator (ICOS). We examined the co-expression of ICOS with Th cytokines in mucosal immune responses. ICOS+CD4+ Th cells expressed strikingly different cytokines depending on the type of infection encountered and the cells' anatomical localization. In the Th2-dominated response to Schistosoma mansoni, ICOS expression of CD4+ cells isolated from the liver was strongly associated with the expression of IL-5, IL-10, IL-13, and T1/ST2, but not with the chemokine receptor CXCR5, a pattern consistent with Th2 effector cells. In the secondary lymphatic organs of schistosome-infected mice, ICOS expression was randomly correlated with Th2 effector-cytokines, but positively correlated with CXCR5 expression; a pattern consistent with follicular Th cells. In Th cells isolated from gut or liver of mice infected with Toxoplasma gondii, ICOS expression was positively correlated with IFN-gamma production. Finally, in the severe combined immunodeficiency transfer colitis model, ICOS expression was strongly positively associated with IFN-gamma and IL-2. Thus, ICOS appears to costimulate distinct effector functions in different immune responses, depending on factors such as the nature of the antigen encountered and localization and chronicity of the immune response.

Animals↗
PubMedDate not supplied

Impact of microbicides and sexually transmitted infections on mucosal immunity in the female genital tract.

Human immunodeficiency virus, genital herpes, and other sexually transmitted infections are a critical national and global health priority requiring the rapid development of safe and effective control methods. Topical microbicides, self-administered agents designed for vaginal use, that block transmission at the mucosal surface may provide a realistic method of intervention that could be distributed worldwide. An optimal microbicide should protect against infection but must also be safe, without adversely affecting the mucosal environment, including mediators of host defense. Thus, a critical component in microbicides development is to identify optimal assays that could serve as surrogate markers to predict safety of microbicides prior to embarking on large-scale clinical trials. This will require a greater understanding of the mediators of mucosal immunity in the female genital tract.

Animals↗
PubMed1997

Mucosal immunity in the urinary tract: changes in sIgA, FSC and total IgA with age and in urinary tract infection.

The incidence of primary urinary tract infection (UTI) is greatest in the first month of life and decreases with age throughout childhood. Secretory immunoglobulin A (sIgA) is an important component of mucosal immunity. The changes in secretory IgA, IgA and free secretory component (FSC) during the first year of life were examined in relation to age, sex and in infants, feeding practice. These constituents were further compared between healthy children and those with acute and recurrent UTI. Urine was collected from 41 healthy infants (16 female: 25 male) at intervals (mean age 1.4, 9.1, 44, 91, 210 and 412 days), 139 healthy children (75 female: 64 male), 29 children with histories of recurrent UTI (25 female: 4 male) and 10 with acute UTI (8 female: 2 male). sIgA, IgA and FSC were measured by enzyme linked immunoassay. In the majority of children sIgA and IgA were undetectable at birth. SIgA and IgA rose significantly during the first year then levelled off throughout childhood. FSC was detectable from birth (geometric mean [mean of logged values]-GOM at day 1.4, 362.2 ng/ml). No sex differences were apparent for any of the three constituents at any age. Breast feeding was associated with higher levels of sIgA and IgA than bottle feeding. This was highly significant at 9.1 days when sIgA and IgA levels of breast fed compared with bottle fed infants were 64.6 ng/ml vs 21.2 and 56.2 ng/ml vs 18.7 ng/ml respectively, giving a GOM ratio of 3.04 for sIgA and 3.0 for IgA (p < 0.001 for both). No significant difference in the three parameters were demonstrable when children with recurrent UTI-with normal or abnormal renal tracts-were compared with controls. Acute UTI resulted in raised sIgA, IgA and FSC compared with controls (GOM ratio of 4.9 [p < 0.002], 4.2 [p < 0.005] and 2.7 [p < 0.001] respectively). The proportion of total IgA present as sIgA (sIgA/total IgA) was not significantly different in the acute vs control groups. Urinary sIgA and IgA may be important for the observed variation with age in infant UTI and the reduced incidence in breast fed infants but does not appear to contribute to the sex associated difference in susceptibility to infection at any age.

Acute Disease↗
PubMed1999

Induction of systemic and mucosal immune response in mice immunised with porins of Salmonella typhi.

Porins, purified from Salmonella typhi strain 0901 provided 90% protection to BALB/c mice against a lethal dose (300 x LD50) of S. typhi Ty2 when given intraperitoneally. To measure the porin-induced cellular immune responses, macrophages and lymphocytes were isolated from spleen and lamina propria (LP) of porin immunised-challenge mice and of infected and control mice; T-cell phenotypes, lymphocyte proliferation and cytokine production were studied. The secretory IgA (sIgA) antibody level in the intestinal fluid was also measured to study mucosal immune response. After immunisation, the splenic lymphocytes exhibited a significant increase in total T-cell count and CD4+/CD8+ ratio, while the LP lymphocytes (LPL) exhibited an increase in CD4+/CD8+ ratio only. They also exhibited a significant increase in porin-specific proliferative response and cytokine levels (IL-1, IL-2, IFN-gamma and IL-4). After immunisation, sIgA antibody was also found to be increased. These results suggest that porins given intraperitoneally induce cellular and humoral immune responses both at systemic and mucosal levels.

Animals↗
PubMed2003

Mucosal immunization of BALB/c mice using enterotoxigenic Escherichia coli colonization factors CFA/I and CS6 administered with and without a mutant heat-labile enterotoxin.

Mice (BALB/c) were intranasally (IN) and intragastrically (IG) administered the ETEC colonization factors (CF), CFA/I and CS6, with and without the R192G mutant heat-labile enterotoxin (mLT), and immunogenicity and efficacy measured. The IN administration of CFA/I to mice induced strong serum and fecal IgG and IgA responses. The IG administration of CFA/I to mice induced serum IgG and fecal IgA responses, but only when mLT was co-administered with CFA/I were serum IgA titers detected. The IN administration of CS6 to mice induced serum IgG antibodies, and mLT, when co-administered with CS6, enhanced the serum IgG response. Only when the mLT was co-administered with CS6, were serum and fecal IgA responses detected. The IG administration of CS6 plus mLT induced serum IgG and fecal IgA responses. Partial protection against lethal challenge with ETEC strain H10407 was seen in the mice IN administered the CFA/I plus mLT (P<0.01), and H10407 was cleared from the lungs of CFA/I plus mLT-immunized mice at a significantly greater rate than from the control mice (P<0.05). CFA/I and CS6 administered IN and IG induced mixed Th1/Th2 immune responses with the Th2 type being predominant as evidenced by IgG1>IgG2a. The administration of colonization factors to mice, particularly by the IN route, potentially serves as a useful way to measure the serum and mucosal immune responses to these antigens prior to their use in volunteers.

Animals↗
PubMed2000

Therapeutic oral vaccination induces mucosal immune response sufficient to eliminate long-term Helicobacter pylori infection.

We examined the efficacy of therapeutic oral vaccination using Helicobacter pylori-whole cell sonicate and cholera toxin (CT) in mice persistently infected with H. pylori. Efficacy was determined by bacterial culture and microscopic examination of gastric tissues for the persistence of bacteria at 6 weeks after the last vaccination. Vaccination of H. pylori-whole cell sonicate combined with CT eradicated bacteria in 10/16 mice (62.5%). Interestingly, oral vaccination with CT alone also eliminated the bacteria in 8/17 mice (47.1%). However, a therapeutic intraperitoneally administered vaccine failed to eradicate H. pylori from the stomach (1/17 mice, 5.9%). Identification of the type of immunity involved in the eradication process showed that oral vaccination enhanced the antigen-specific IgA in the feces and saliva. The efficacy of eradication of H. pylori correlated well with increases in IgA secretion in mucosal tissue and a higher labeling index of IgA-positive lumina of pyloric glands. Moreover, the expression of IL-4 mRNA in the stomach of mice with eradicated bacteria was higher than in the uneradicated group. Our results suggest that the efficacy of vaccination depends on the mucosal IgA response in the gastrointestinal tract against H. pylori via Th2 cell activation and that therapeutic oral vaccination induces a mucosal immune response sufficient to eradicate long-term infection with H. pylori.

Administration, Oral↗
PubMed2002

Taming the mucosal immune response in Crohn's disease.

New effective therapeutic strategies for inflammatory bowel disease are based on recent knowledge of the regulation of the immune response. Specific defects of innate immunity, such as the NOD2 mutation in a subset of patients with Crohn's disease, have been associated with inflammatory bowel disease and provide new therapeutic targets. The ultimate therapeutic goal is the complete restoration of the mucosal immune balance and healing of all intestinal lesions. This may require repair of the underlying genetic mutation, restoration of defects of apoptosis, or generation of regulatory T-lymphocytes.

Animals↗
PubMed2004

Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases.

Commensal microflora (normal microflora, indigenous microbiota) consists of those micro-organisms, which are present on body surfaces covered by epithelial cells and are exposed to the external environment (gastrointestinal and respiratory tract, vagina, skin, etc.). The number of bacteria colonising mucosal and skin surfaces exceeds the number of cells forming human body. Commensal bacteria co-evolved with their hosts, however, under specific conditions they are able to overcome protective host responses and exert pathologic effects. Resident bacteria form complex ecosystems, whose diversity is enormous. The most abundant microflora is present in the distal parts of the gut; the majority of the intestinal bacteria are Gram-negative anaerobes. More than 50% of intestinal bacteria cannot be cultured by conventional microbiological techniques. Molecular biological methods help in analysing the structural and functional complexity of the microflora and in identifying its components. Resident microflora contains a number of components able to activate innate and adaptive immunity. Unlimited immune activation in response to signals from commensal bacteria could pose the risk of inflammation; immune responses to mucosal microbiota therefore require a precise regulatory control. The mucosal immune system has developed specialised regulatory, anti-inflammatory mechanisms for eliminating or tolerating non-dangerous, food and airborne antigens and commensal micro-organisms (oral, mucosal tolerance). However, at the same time the mucosal immune system must provide local defense mechanisms against environmental threats (e.g. invading pathogens). This important requirement is fulfilled by several mechanisms of mucosal immunity: strongly developed innate defense mechanisms ensuring appropriate function of the mucosal barrier, existence of unique types of lymphocytes and their products, transport of polymeric immunoglobulins through epithelial cells into secretions (sIgA) and migration and homing of cells originating from the mucosal organised tissues in mucosae and exocrine glands. The important role of commensal bacteria in development of optimally functioning mucosal immune system was demonstrated in germ-free animals (using gnotobiological techniques). Involvement of commensal microflora and its components with strong immunoactivating properties (e.g. LPS, peptidoglycans, superantigens, bacterial DNA, Hsp) in etiopathogenetic mechanism of various complex, multifactorial and multigenic diseases, including inflammatory bowel diseases, periodontal disease, rheumatoid arthritis, atherosclerosis, allergy, multiorgan failure, colon cancer has been recently suggested. Animal models of human diseases reared in defined gnotobiotic conditions are helping to elucidate the aetiology of these frequent disorders. An improved understanding of commensal bacteria-host interactions employing germ-free animal models with selective colonisation strategies combined with modern molecular techniques could bring new insights into the mechanisms of mucosal immunity and also into pathogenetic mechanisms of several infectious, inflammatory, autoimmune and neoplastic diseases. Regulation of microflora composition (e.g. by probiotics and prebiotics) offers the possibility to influence the development of mucosal and systemic immunity but it can play a role also in prevention and treatment of some diseases.

Autoimmune Diseases↗
PubMed2000

Effects of bombesin on gut mucosal immunity in rats after thermal injury.

BACKGROUND AND PURPOSE: Severe burns induce a disruption in gastrointestinal mucosal integrity and facilitate bacterial translocation (BT). Bombesin (BBS), a tetradecapeptide analogous to mammalian gastrin-releasing peptide, can induce the release of all gut hormones except secretin. This study examined the effects of BBS on mucosal immunity in rats after thermal injury. METHODS: Forty-two Sprague-Dawley rats were divided into one sham control group and six burn groups. Burn groups were subjected to 35% total body surface area burn injury. One to 6 days after the injury, six animals (one from each group) were killed every 24 hours. Biliary secretory immunoglobulin A (SIgA), jejunal mucosal height, intestinal permeability, and BT to the mesenteric lymph nodes (MLNs), liver, and spleen were examined. In a second experiment, three groups of rats (6 in each) received either sham treatment and saline injection, or thermal injury and saline injection, or thermal injury and BBS injection. Twenty-four hours after burns or sham treatment, six animals (1 from each group) were killed. The biliary SIgA, jejunal mucosal height, and BT to the MLNs, liver, and spleen were examined. RESULTS: The biliary SIgA decreased to one-seventh of normal levels 1 day after burn injury, and increased thereafter. The jejunal mucosal height decreased significantly to two-thirds of the normal value 1 day after burn injury. The intestinal mucosal permeability increased significantly to three times the normal level 2 days after the burn injury, and decreased thereafter. BBA significantly reduced the BT incidence and significantly increased the biliary SIgA and jejunal mucosal height 1 day after burn injury. CONCLUSIONS: The results of this study show that, in rats, the intestinal permeability increased, the gut mucosal barrier failed, and the gut immunity deteriorated in the first few days after burn injury. BBS therapy helped to restore the postburn gut mucosal barrier in rats, by increasing biliary SIgA levels and the jejunal mucosal height.

Animals↗
PubMed2005

Defects in mucosal immunity leading to Crohn's disease.

Crohn's disease (CD) is characterized by patchy transmural inflammation involving any part of the intestinal tract. Animal models have provided a great deal of insight into the pathogenesis of CD, but no animal model has recapitulated the full spectrum of manifestations witnessed in human disease. The defects in mucosal immunity in CD can be divided into those that involve the epithelial barrier, those that involve the innate immune response, and finally, defects in the adaptive immune response. Defects in the epithelial barrier in CD include an increase in intestinal permeability, increased adherence of bacteria, and decreased expression of defensins. Murine and human studies have demonstrated an increased expression of T-helper 1 (Th1) cytokines by lamina propria lymphocytes. This increased Th1 cytokine expression is driven by interleukin-12 (IL-12)/IL-23 and tumor necrosis factor-like 1A (TL1A) production by antigen-presenting cells, resulting in Tbet expression by CD4+ T cells. Another dimension of the inappropriate immune response in CD is T-cell and B-cell reactivity to luminal microbes. With the identification of the nucleotide-binding oligomerization domain 2 (NOD2) gene as a susceptibility gene, defects in the innate immune response are beginning to be explored. One may consider a model in which defective innate immune clearance of pathogens or commensal bacteria in CD leads to an inappropriate adaptive immune response to the commensal flora.

Animals↗
PubMedDate not supplied

[Mucosal immune response development: breastfeeding and environmental influence].

A review of the current knowledge of mucosal immune response development indicates that migration of immunocytes to mucosal surfaces is an early event during fetal life. The morphologic development of gut-associated lymphoid tissues (lymphoid follicles, Peyer's patches and tonsils) occurs from 11-20 weeks' gestation upwards. But they are active only after birth, when usually antigenic challenge takes place. The complete development of secretory immunity is a postnatal achievement. In infancy, some environmental factors such as feeding and oral antigenic challenge seems to modulate immune response development. Breastfeeding, by means of antiinfectious, antiinflammatory and immunomodulating properties, besides completing infant secretory immunity, also stimulates immunological maturation on mucosal surfaces.

English Abstract↗