Mucosal Immune Function Research Articles

Lack of enteral nutrition—effects on the intestinal immune system

Total parenteral nutrition (TPN) results in a loss of mucosal immune function by alterations in both phenotype and function of intraepithelial lymphocytes (IEL). We hypothesized that the observed changes with TPN administration are caused by the lack of enteral feeding, and not to the TPN solution itself. Mice received oral feeding (Control), TPN alone (TPN), or TPN plus oral feeding (TPN+Food). Mice were killed after 7 days, and bacteriological cultures from spleen, liver, and mesenteric lymph nodes obtained, with bacterial translocation (BT) being defined as a positive culture. IEL phenotype was analyzed by flow cytometry. IEL messenger RNA (mRNA) cytokine expression used reverse transcriptase polymerase chain reaction (RT-PCR). Apoptosis was detected by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining. BT significantly (P < 0.05, with analysis of variance [ANOVA]) increased in the TPN group (53%) compared with Control (9%) and TPN+Food (14%) groups. TPN also resulted in a significant (P < 0.01) increase in epithelial cell apoptosis: TPN 7.6 +/- 1.1% versus Control 2.9 +/- 1.1% and TPN+Food 2.1 +/- 0.3% (mean +/- SD). Height of the villus-crypt complex was significantly decreased in TPN mice (315 +/- 16 microm) compared with Control (431 +/- 27 microm) and TPN+Food (421 +/- 26 microm) groups. IEL phenotypes significantly changed with TPN administration: CD4+ CD8- as well as CD4+ CD8+ subpopulations were reduced compared with Control or TPN+Food mice; as were the CD8alphabeta+ thymus-dependent, and CD8+ CD44+ mature IEL. IEL cytokine mRNA expression was also significantly altered with TPN: IL-2 and IL-10 expression declined, and IL-4 IL-6, interferon gamma (IFN-gamma), transforming growth factor beta-1 (TGF-beta1), and tumor necrosis factor-alpha (TNF-alpha) were increased, when compared with Control or TPN+Food mice. This study demonstrates that the major factor responsible for TPN-induced BT and IEL-changes is the lack of enteral feeding and not the administration of the TPN solution itself.

ROLE OF APPENDECTOMY IN THE CLINICAL COURSE OF CROHNʼS DISEASE

Purpose: History of appendectomy is associated with an increased risk of Crohn's disease (CD). Recently, the appendix has been noted for its significant role in mucosal immune function. The impact of prior appendectomy among CD patients on disease severity has not been studied. Therefore, we are evaluating this relationship. Methods: We reviewed a cohort of 1500 patients with Inflammatory Bowel Disease and identified 40 patients with CD who underwent appendectomy prior to being diagnosed with CD. These patients were compared to an age and gender matched control group of 40 CD patients without a history of appendectomy. Comparisons were made on demographic characteristics as well as on disease location, behavior, and severity (CD related hospitalizations, surgeries, and relapses) using either parametric or nonparametric tests accordingly. Results: Each group was comprised of 30% males and 70% females with CD. The distribution of professional status and medical insurance were similar (p = 0.78, p = 0.63, respectively). There was no difference in age of symptom onset (34 vs. 33 years, p = 0.58) and lag time to diagnosis (26 vs. 13 months, p = 0.15) in CD patients with and without previous appendectomy. Since the duration of patient follow-up between the appendectomy and control group was significantly different (152 (6–438) vs. 217 (8–680) months, p = 0.03), the number of hospitalizations, surgeries, and relapses were calculated as rates (number of events/follow up time) to correct for this difference. Table 1 shows the results on rate of hospitalizations, surgeries, and relapses between groups. Disease location (p = 0.57) and behavior (p = 0.37) did not differ between groups. However, there was a trend for the control group to have disease localized to the colon (p = 0.057).Table 1: Disease SeverityConclusions: The appendectomy group had significantly more CD related hospitalizations and surgeries. Based on these preliminary data, it appears that the appendix may have an immune modulating effect in the pathogenesis of CD.

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.

The vermiform appendix: not a useless organ.

The appendix has often been seen more as a nuisance rather than an important part of the human anatomy. Early misconceptions have led to the indiscriminate removal of the appendix from the body. Long thought to be an evolutionary remnant of little significance to normal physiology, the appendix has more recently been identified as an important component of mammalian mucosal immune function, particularly B-lymphocyte-mediated immune responses and extrathymically derived T-lymphocytes. This structure helps in the proper movement and removal of waste matter in the digestive system, contains lymphatic vessels that regulate pathogens, and lastly, might even produce early defences that prevent deadly diseases. The appendix is one of the guardians of the internal environment of the body from the hostile external environment.

Odor from Industrial Hog Farming Operations and Mucosal Immune Function in Neighbors

The authors evaluated whether exposure to malodor from industrial hog farming operations has a psychophysiologically mediated immunosuppressive effect on secretory immunoglobulin A (sIgA) in neighbors. Fifteen adults living within 2.4 km (1.5 mi) of at least one hog farming operation rated odor intensity on a 9-point scale and provided saliva samples twice daily for two weeks. The authors used hierarchical regression to model the association between reported odor and sIgA; study participants were their own controls. The natural log of slgA concentration and secretion rate declined, on average, 0.058 (0.032) and 0.116 (0.103), respectively, for each incremental 1-unit increase in reported odor from 4 to 9, adjusted for time of day, suggesting reduced levels of sIgA in response to moderate or high odor. Findings support the hypothesized immunosuppressive effect of malodor on mucosal immunity and provide preliminary data useful in understanding health effects related to malodor from industrial hog farming operations.

Bacterial colonization and the development of intestinal defences.

In humans, intestinal defences develop during gestation and, at full term, have the capacity to respond in an appropriate manner to infectious agents and foreign antigens. Before an active protective response can occur, however, the gut must first be exposed to colonizing bacteria. Colonization with diverse intestinal microbes is necessary for the development of important gut defenses such as the synthesis and secretion of polymeric immunoglobulin A and the generation of a balanced T helper (Th) cell response. Insights into normal immune physiological development of the gut have been made by studying the germ-free animal and intestinal defenses. These studies have provided insights into the physiology of immune responses. Two important immunological functions are the secretion of polymeric immunoglobulin A to protect the intestinal surface against harmful stimuli and inhibition of the systemic response to commensal bacteria and food proteins (eg, oral tolerance) to prevent chronic inflammation. Neither function exists in the germ-free state, but rapidly develops after conventionalization (colonization) of the germ-free animal. In the present review, the importance of bacterial colonization on the appearance of normal mucosal immune function and to the clinical consequences of inadequate colonization to the development of disease will be discussed. For example, excessive Th2 activity can lead to atopy, whereas Th1 predominance is found in conditions such as Helicobacter pylori gastritis and Crohn's disease. With the eradication of infectious diseases in developed countries in the past three decades, the incidence of atopic and autoimmune diseases has increased. This epidemiological observation has been explained by the 'hygiene hypothesis', which suggests that a reduction in microbial burden by public health measures has contributed to an immunological imbalance in the intestine. A family of pattern recognition receptors (Toll-like receptors) on gut lymphoid and epithelial cells mediates innate immune responses to bacterial molecular patterns and, thereby, orchestrates acquired immunity. As the role of bacterial communication within the gut (bacterial-epithelial cross-talk) is clarified, physicians should be able to modulate gut immune responses, for example, by the use of probiotics.

Short-term dietary adjustment with a hydrolyzed casein–based diet postpones diabetes development in the diabetes-prone BB rat

From earlier studies it appears that weaning associated changes in the animal's physiology and that of the pancreas in particular, render diabetes-prone Bio-Breeding (DP-BB) rats susceptible to the induction and development of insulin-dependent diabetes mellitus (IDDM). In this study we tested whether a short-term dietary adjustment at weaning would influence the development of diabetes later in life. For this purpose a diet in which the protein source was replaced with hydrolyzed casein (HC) was given to the rats from weaning to 60 days of age and from weaning to 130 days of age. The control group received the cereal-based standard diet throughout the experiment. The short-term dietary adjustment resulted in a significant delay of diabetes development. The rats fed the HC diet from weaning to 130 days of age showed a lower incidence of diabetes at 130 days of age. No differences were seen in the histological insulitis scores between the rats of the different treatment groups. Interestingly, when testing (mucosal) immune functions of short-term HC-fed rats, their mesenteric lymph node cells (MLNC) showed increased interferon-gamma (IFN-γ) and reduced interleukin-10 (IL-10) production after in vitro stimulation. These results demonstrate that short-term dietary adjustments at a young age can influence the course of diabetes later in life. The shift in cytokine profile of MLNC of the HC-fed rats suggests that mechanisms involved can be at the level of both the (mucosal) immune system and the β cell. Copyright 2003, Elsevier Science (USA). All rights reserved.

Effects of 12 months of exercise training on salivary secretory IgA levels in elderly subjects

Background: The immune system declines in efficiency with advancing age, making the elderly less resistant to pathogenic microorganisms. Upper respiratory tract infection (URTI) is a common illness. Recent studies have...

Immunonutrients and the Critically Ill Neonate

After completing this article, readers should be able to: 1. List the otherwise “nonessential” nutrients that may be required by the critically ill neonate. 2. Explain why omega-3 fatty acids do not cause as much inflammation as their omega-6 counterparts. 3. Define pre- and probiotics and describe how they can prevent colonization of the intestine by pathogenic organisms. 4. Describe the potential protective effects of lactoferrin on the neonatal gastrointestinal tract. In a critically ill individual, the intestinal barrier becomes compromised because of stress, lack of enteral feedings, and ischemic-reperfusion injury. In the preterm neonate, the mucosal barrier is not fully functional (see article on innate immunity in this issue of NeoReviews ). The combination of a damaged and immature gut barrier may lead to increased intestinal permeability, aberrant antigen transfer, and immune response, which can explain the vulnerability to infection, inflammation, and hypersensitivity at an early age. In patients dying of sepsis, there is clear evidence of an imbalance in pro- and anti-inflammatory cytokine production, a failure to maintain antioxidant defenses, and high levels of activation of nuclear factor- kappa-B (NF-kappa-B). Over the past several years, it has become more evident that the proinflammatory cytokine response, as part of an uncontrolled systemic inflammatory response syndrome (SIRS), plays an integral role in premature labor, chronic lung disease, cerebral palsy, necrotizing enterocolitis (NEC), and sepsis. Because the gut is a primary origin of SIRS, it is reasonable to suggest that nutritional agents might stabilize the intestinal mocosal barrier, alter the balance of pro- and anti- inflammatory cytokines, and prevent excessive activation of NF-kappa-B or other signaling pathways. Some nutrients, such as glutamine, arginine, omega-3 fatty acids, nucleotides, and probiotics, have been shown to have a considerable influence on immune function (eg, delayed hypersensitivity, lymphocyte subpopulation counts, immunologic test) and improve metabolic and nutritional indices such as …

Research agenda for pediatric gastroenterology, hepatology and nutrition: allergy and immunology. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Research agenda for pediatric gastroenterology, hepatology and nutrition: allergy and immunology. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

HIV disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

HIV disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Role for mucosal immune responses and cell‐mediated immune functions in protection from airborne challenge with Venezuelan equine encephalitis virus*

Venezuelan equine encephalitis virus (VEEV) replicates in lymphoid tissues following peripheral inoculation and a high titre viraemia develops. Encephalitis develops after the virus enters the central nervous system from the blood, with the earliest neuronal involvement being via the olfactory nerve. Following aerosol challenge with virulent VEEV, the virus is thought to replicate in the nasal mucosa and there could be direct entry into the olfactory nerve via infected neuroepithelial cells. Protection from VEEV infection is believed to be primarily mediated by virus specific antibody. The correlation between protection and neutralising serum antibody titres is, however, inconsistent when the virulent virus is administered by the airborne route. This study demonstrates a link between antibody in serum and the nasal mucosa and protection by means of passive immunisation studies. Intra-nasal administration of antibody increased protection against airborne virus in Balb/c mice. Vaccination of mu MT strain mice that do not have functional B cells and cannot produce antibody revealed normal proliferation of spleen cells in vitro and robust cytokine production. Aerosol challenge of mu MT mice demonstrated that complete protection was only achieved when passive immunisation with antibody was supplemented with active immunisation with the TC-83 vaccine strain of the virus. This implies that cell-mediated immune functions are required for protection against airborne challenge with virulent VEEV.

Immunological effects of yogurt addition to a re-nutrition diet in a malnutrition experimental model.

The therapeutic and preventive effects of yogurt and lactic acid bacteria on diseases such as cancer, infection and gastrointestinal disorders are well ocumented. The aim of this research was to study the effects of different doses of yogurt addition after milk re-nutrition diet, on the recovery of the intestinal barrier and mucosal immune function. Experiments were performed on groups of mice, malnourished and re-nourished with milk during 7 d, and mice with diet supplemented with yogurt for 2, 5 and 7 consecutive d. Nutritional parameters such as weight gain, serum total protein, and the number of IgA, IgM and IgG B cells of the small intestine were determined. We also quantified intraepithelial leukocytes, mastocytes and goblet cells, and performed structural and ultrastructural studies on the small intestine. We observed that 5 d of yogurt feeding was the optimal dose for improving gut barrier function and mucosal immune system in a malnutrition model. This effect was not observed with milk re-nutrition. Although the results were better for 5 d of yogurt, addition for 7 d also showed beneficial effects. Yogurt feeding in our model did not impair any gut functions. These results suggest that yogurt addition after a re-nutrition diet gives better recovery of intestinal function than the re-nutrition diet usually recommended. Although these results were obtained in an animal model, they indicate that consumption of yogurt by malnourished children might accelerate the restoration of gut function.

Changes in the number of gut mucosal T-lymphocytes and macrophages in patients treated by external biliary drainage.

To examine the changes in the number of T cells and macrophages in the mucosal lamina propria in the presence or absence of bile in the gastrointestinal tract. Clinical study. University hospital, Japan. 6 patients with obstructive jaundice who had external biliary drainage (drainage group) and 6 patients with no signs of obstructive jaundice (control group). Gastrointestinal specimens were taken at the time of operation. The number of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the lamina propria mucosae in each group measured immunohistochemically. The numbers of CD8 T cells and CD68+ macrophages in the lamina propria of the patients treated by external drainage were significantly less than in the control group (p < 0.01). However, there was no difference in the number of CD4+ T cells between the groups (p = 0.45). In the absence of bile, mucosal immune function fails as a result of reduced numbers of CD8+ T cells and macrophages.

Sequential Changes in Mucosal Immunity after Hemorrhagic Shock

Immunoinflammatory responses after shock and major trauma are characterized by an early hyperinflammatory response and later by compensatory anti-inflammatory host mediator production. This late phase is associated with depressed immune function that has been causally linked with post-traumatic infectious complications and late organ failure. Gut barrier failure is noted in this setting and may be an important source of nosocomial infections and organ failure. Secretory immunoglobulin A (sIgA) is the predominant immunoglobin at mucosal surfaces and is difficult to quantify in luminal secretions. Attempts to normalize sIgA concentrations may not be accurate and/or may not be applicable in vivo. A method using mucosal immunization with cholera toxin (ChT) to normalize gut sIgA levels was used to assess serial changes in sIgA after hemorrhagic shock (HS) in rodents. Total and anti-ChT sIgA levels were highly variable in both HS and sham animals. However, when normalized using the specific anti-ChT/total sIgA ratio, differences were clearly evident. This ratio was depressed between 3 and 10 days post-HS. The specific anti-ChT/total sIgA ratio is a reliable index of secretory antibody at gut luminal surfaces. Impaired mucosal immune function occurred in a time frame consistent with development of late nosocomial infections. This may be important mechanistically in the development of these infectious complications.

Vitamin A, infection, and immune function.

In populations where vitamin A availability from food is low, infectious diseases can precipitate vitamin A deficiency by decreasing intake, decreasing absorption, and increasing excretion. Infectious diseases that induce the acute-phase response also impair the assessment of vitamin A status by transiently depressing serum retinol concentrations. Vitamin A deficiency impairs innate immunity by impeding normal regeneration of mucosal barriers damaged by infection, and by diminishing the function of neutrophils, macrophages, and natural killer cells. Vitamin A is also required for adaptive immunity and plays a role in the development of T both-helper (Th) cells and B-cells. In particular, vitamin A deficiency diminishes antibody-mediated responses directed by Th2 cells, although some aspects of Th1-mediated immunity are also diminished. These changes in mucosal epithelial regeneration and immune function presumably account for the increased mortality seen in vitamin A-deficient infants, young children, and pregnant women in many areas of the world today.

Clinical evaluation of an operation planning system in the field of cranio–maxillo-facial surgery

Intestinal epithelial cells from the mouse small intestine were immortalized by SV40 large T gene transfer through a murine ecotropic virus. The resulting cell lines expressed the SV40 large T mRNA and exhibited morphological and phenotypic characteristics of normal enterocytes, including intercellular junctions, and expression of cytokeratin, villin, poly-Ig receptor (i.e., secretory component) and vasoactive intestinal peptide receptors. All expressed cell surface major histocompatibility complex class I molecules, but cell surface class II antigens were undetectable. Functional studies on antigen presentation were carried out using the MODE-K cell line established from the mouse duodenum. Interferon-γ treatment of MODE-K cells resulted in a high level of class II molecule expression, and the ability to process and present native protein antigens to specific CD4+ T-cell hybridomas, via functional class II molecules. These data suggest that the MODE-K cell line is a suitable model for the analysis of intestinal epithelial cell function in mucosal immunity.

Environmental triggers of type 1 diabetes

High risk HLA class II alleles account for 40% of the genetic susceptibility to type 1 diabetes in Caucasians, but the majority of the genetically predisposed do not develop the disease. This supports some environmental modification of the autoimmune destruction of beta cells that precedes type 1 diabetes. Identical twin studies and geographical variation in incidence also argue for a critical role of environmental factors. Attention has been directed to the possible harmful effect of cow's milk protein (or protective effect of breast-feeding) and enteric infections in early life. Natural history studies that follow children at increased risk of type 1 diabetes provide the best opportunity to study environmental triggers. The Australian Baby Diab Study has followed approximately 500 babies from birth who have a first-degree relative with type 1 diabetes. No prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity was found. The same Australian cohort demonstrated a relationship between rotavirus infection and the first appearance or increase in islet antibodies. Enteroviral infection is seen more frequently in prediabetic children and prior to the onset of islet autoimmunity in Finnish cohorts. Environmental factors may interact. Breast milk protects against enteric infections; enteric infections in turn could increase immunity to dietary antigens by increasing intestinal permeability. It is also possible that an alteration in gut mucosal immune function in genetically susceptible individuals underlies any effect of dietary or viral proteins on the development of islet autoimmunity in early life.

Prospects for research in inflammatory bowel disease.

Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract that manifests as ulcerative colitis and Crohn disease. Both these clinical entities result from interrelated genetic and environmental factors that may be channeled through an abnormality in mucosal immune function, possibly due to dysregulated or excessive T helper cell (T(H))1 (Crohn disease) or T(H)2 (ulcerative colitis) responses. This article reviews current knowledge of the role of immune factors in inflammatory bowel disease and the potential therapeutic strategies that target the pathways of T(H)1- or T(H)2-induced inflammation.

Characterization of CD1d in mucosal immune function: an immunotherapeutic target for inflammatory bowel disease.

In addition to the classical MHC class I and class II molecules, human intestinal epithelial cells also express nonclassical MHC class I-like molecules on their cell surface. CD1d is a non-polymorphic MHC-like molecule whose expression is mainly localized to the epithelial cells of the gastrointestinal tract. The biochemical structure of CD1d on intestinal epithelial cells (IECs) exists in two forms: a 37-kD nonglycosylated, beta 2-microglobulin (beta 2M) independent and a 48-kD glycosylated, beta 2M dependent form. Immunolocalization studies suggest that the 37-kD nonglycosylated form of CD1d is limited to the apical cell surface whereas the 48-50-kD glycosylated, beta 2M dependent form of CD1d is expressed both on the apical and the basolateral surfaces. The beta 2M association with CD1d seems to be important in regulating the pattern of glycosylation and the localization of CD1d within the cell based upon studies of the structure of CD1d in a transfected model cell line and in polarized epithelial cell monolayers. The functional role of intestinal CD1d remains unknown. However, based upon in vitro studies of the antigens presented by human CD1d and mouse CD1d, CD1d expressed on IECs likely presents a very hydrophobic glycolipid molecule possibly from the cell wall of bacteria or host cells. The processed-lipid antigen presented by CD1d may then involve a yet-to-be-identified subpopulation of the resident, oligoclonal alpha beta TCR CD8+ intestinal intraepithelial lymphocyte (iIEL) T cells. Subsequently, these T cells would be very important in regulating the local immune response by producing cytokines and recruiting other immune modulating cells to destroy infected cells, regenerate normal IECs, and possibly downregulate activated T cells to maintain mucosal integrity.