Per Brandtzaeg

The impact of perinatal immune development on mucosal homeostasis and chronic inflammation

The mucosal surfaces of the gut and airways have important barrier functions and regulate the induction of immunological tolerance. The rapidly increasing incidence of chronic inflammatory disorders of these surfaces, such as inflammatory bowel disease and asthma, indicates that the immune functions of these mucosae are becoming disrupted in humans. Recent data indicate that events in prenatal and neonatal life orchestrate mucosal homeostasis. Several environmental factors promote the perinatal programming of the immune system, including colonization of the gut and airways by commensal microorganisms. These complex microbial–host interactions operate in a delicate temporal and spatial manner and have an important role in the induction of homeostatic mechanisms.

Gene-environment interactions in chronic inflammatory disease

Chronic inflammatory diseases represent a major challenge for both clinical research and patient care, and evidence indicates that these disorders develop as a result of complex gene-environment interactions. Better understanding of their cause-and-effect relationship is the basis for emerging proposals for therapy and prevention.

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 Waldeyers 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.

Food allergy: separating the science from the mythology

Numerous genes are involved in innate and adaptive immunity and these have been modified over millions of years. During this evolution, the mucosal immune system has developed two anti-inflammatory strategies: immune exclusion by the use of secretory antibodies to control epithelial colonization of microorganisms and to inhibit the penetration of potentially harmful agents; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens, such as food proteins. The latter strategy is called oral tolerance when induced via the gut. Homeostatic mechanisms also dampen immune responses to commensal bacteria. The mucosal epithelial barrier and immunoregulatory network are poorly developed in newborns. The perinatal period is, therefore, critical with regard to the induction of food allergy. The development of immune homeostasis depends on windows of opportunity during which innate and adaptive immunity are coordinated by antigen-presenting cells. The function of these cells is not only orchestrated by microbial products but also by dietary constituents, including vitamin A and lipids, such as polyunsaturated omega-3 fatty acids. These factors may in various ways exert beneficial effects on the immunophenotype of the infant. The same is true for breast milk, which provides immune-inducing factors and secretory immunoglobulin A, which reinforces the gut epithelial barrier. It is not easy to dissect the immunoregulatory network and identify variables that lead to food allergy. This Review discusses efforts to this end and outlines the scientific basis for future food allergy prevention.

Secretory IgA: Designed for Anti-Microbial Defense.

Prevention of infections by vaccination remains a compelling goal to improve public health. Mucosal vaccines would make immunization procedures easier, be better suited for mass administration, and most efficiently induce immune exclusion – a term coined for non-inflammatory antibody shielding of internal body surfaces, mediated principally by secretory immunoglobulin A (SIgA). The exported antibodies are polymeric, mainly IgA dimers (pIgA), produced by local plasma cells (PCs) stimulated by antigens that target the mucose. SIgA was early shown to be complexed with an epithelial glycoprotein – the secretory component (SC). A common SC-dependent transport mechanism for pIgA and pentameric IgM was then proposed, implying that membrane SC acts as a receptor, now usually called the polymeric Ig receptor (pIgR). From the basolateral surface, pIg-pIgR complexes are taken up by endocytosis and then extruded into the lumen after apical cleavage of the receptor – bound SC having stabilizing and innate functions in the secretory antibodies. Mice deficient for pIgR show that this is the only receptor responsible for epithelial export of IgA and IgM. These knockout mice show a variety of defects in their mucosal defense and changes in their intestinal microbiota. In the gut, induction of B-cells occurs in gut-associated lymphoid tissue, particularly the Peyer’s patches and isolated lymphoid follicles, but also in mesenteric lymph nodes. PC differentiation is accomplished in the lamina propria to which the activated memory/effector B-cells home. The airways also receive such cells from nasopharynx-associated lymphoid tissue but by different homing receptors. This compartmentalization is a challenge for mucosal vaccination, as are the mechanisms used by the mucosal immune system to discriminate between commensal symbionts (mutualism), pathobionts, and overt pathogens (elimination).

Update on mucosal immunoglobulin A in gastrointestinal disease

Purpose of review To review recent findings dealing with the involvement of mucosal immunoglobulin A (IgA) in the gut barrier function and various gastrointestinal diseases. New information will be discussed in the context of previous knowledge in this field. Recent findings The epithelial barrier function seems to be central in many mucosal disorders because it is decisive for host–microbial interactions and penetration of soluble antigens into the lamina propria. Secretory IgA contributes to the barrier function and recent evidence strongly supports the notion that such antibodies are involved in immunological homeostasis. Summary Inflammatory bowel disease involves a break of tolerance to the commensal microbiota. Aberrations in the mucosal IgA system may, therefore, be part of the inflammatory bowel disease pathogenesis. In gluten-induced enteropathy, however, it has been suggested that a mucosal IgA response may promote the progression of celiac disease and dermatitis herpetiformis by enhancing the uptake of gluten peptides and inhibiting the enzyme activity of tissue transglutaminase. A mucosal IgA response may also promote gastritis by protecting Helicobacter pylori from complement attack. In food allergy, several facets of the epithelial barrier function may show deficiency, including secretory IgA.

Gene-environment interaction in chronic disease: a European Science Foundation Forward Look.

Over the last half century, a dramatic increase in the incidence of chronic inflammatory diseases, such as asthma, allergy, and irritable bowel syndrome, has rightfully led to concern about how the modern lifestyle might inappropriately trigger innate physiologic defense mechanisms. Health care research in the Western world is faced with a significant challenge if it is to meet the needs of its populations in the decades ahead. The tools with which we hope to advance our understanding of the intrinsic and extrinsic mechanisms of chronic inflammatory diseases must therefore be adequately exploited and further developed to identify treatment and prevention strategies. There is an urgent need to prioritize resources and identify the most efficient scientific and societal initiatives to be adopted within this area. In this context national collaboration within Europe and beyond to establish state-of-the-art practices with an interdisciplinary perspective and promote an efficient exchange of best practices is essential. Such an approach likely represents the most efficient manner in which strategies for amelioration of the increase of chronic inflammatory diseases in the Western world can be achieved. The present report is based on a Forward Look initiative conducted by the European Medical Research Councils under the European Science Foundation. Experts from industry and academia, as well as relevant interest organizations, have been consulted in the process of conducting this initiative and have, based on this work, developed a set of final recommendations that target academic research, science funders, and policy makers.

Binding of human milk to pathogen receptor DC-SIGN varies with bile salt-stimulated lipase (BSSL) gene polymorphism

Objective Dendritic cells bind an array of antigens and DC-SIGN has been postulated to act as a receptor for mucosal pathogen transmission. Bile salt-stimulated lipase (BSSL) from human milk potently binds DC-SIGN and blocks DC-SIGN mediated trans-infection of CD4+ T-lymphocytes with HIV-1. Objective was to study variation in DC-SIGN binding properties and the relation between DC-SIGN binding capacity of milk and BSSL gene polymorphisms. Study Design ELISA and PCR were used to study DC-SIGN binding properties and BSSL exon 11 size variation for human milk derived from 269 different mothers distributed over 4 geographical regions. Results DC-SIGN binding properties were highly variable for milks derived from different mothers and between samplings from different geographical regions. Differences in DC-SIGN binding were correlated with a genetic polymorphism in BSSL which is related to the number of 11 amino acid repeats at the C-terminus of the protein. Conclusion The observed variation in DC-SIGN binding properties among milk samples may have implications for the risk of mucosal transmission of pathogens during breastfeeding.

Increased number and activation of colonic macrophages in pediatric patients with untreated Crohn's disease

Background: Pediatric inflammatory bowel disease (IBD) may be phenotypically different from adult IBD. In IBD lesions, macrophages are overactivated, suggesting involvement of innate immunity in the pathogenesis. Here, mucosal macrophages were studied in selected untreated pediatric patients compared with adults from a population‐based Norwegian cohort of IBD patients. Age‐matched non‐IBD controls were also included. Methods: Untreated children (<18 years) and adults (≥18 years) were included at diagnosis with colonic and ileal biopsies. Controls were symptomatic non‐IBD patients with histologically normal gut. Frozen mucosal sections were examined by immunohistochemistry for cellular expression of the pan‐macrophage marker CD68 and the costimulatory molecule CD40. Two‐color immunofluorescence staining in situ was performed to identify CD40+ macrophages. Results: Non‐IBD adults had significantly higher mucosal density of colonic CD68+ macrophages than non‐IBD children. In pediatric Crohns disease (CD), macrophages were significantly increased in the colon (but not in the ileum) compared with controls. Their mucosal density in pediatric CD was significantly higher than in pediatric ulcerative colitis. The number of CD40+ (activated) macrophages was significantly elevated in both histologically inflamed and uninflamed colon and ileum of IBD children. Conclusions: Histologically normal colon mucosa contains fewer macrophages in children than in adults. However, in colon of children with untreated CD the mucosal macrophage density is increased. Activated mucosal macrophages are increased in untreated pediatric IBD regardless of inflammatory grade. Such upregulated innate mucosal immune activation may contribute to the colonic phenotype of childhood CD. (Inflamm Bowel Dis 2009)

Intraepithelial γδ T Cells Remain Increased in the Duodenum of AIDS Patients Despite Antiretroviral Treatment

Intraepithelial lymphocytes (IELs) bearing the γδ T-cell receptor are a unique intestinal subset whose function remains elusive. Here, we examine how they behave in AIDS and during various regimens of antiretroviral treatment in order to obtain mechanistic insight into their adaptive or innate functional in vivo properties. IELs were studied by multimarker two-colour immunofluorescence in situ staining. Consecutive duodenal biopsies were obtained from advanced infection-prone HIV+ patients (n = 30). The systemic adaptive immune status was monitored by determining T-cell subsets and immunoglobulins in peripheral blood. The γδ IEL ratio (median 14.5%, range 1.5–56.3%) was significantly increased (p<0.02) compared with that in clinically healthy HIV− control subjects (n = 11, median 2.8%; range 0.3–38%), although the number of γδ IELs per mucosal length unit (U) only tended to be increased (4.0/U in HIV+ versus 3.2/U in HIV−subjects). Notably, the total number of CD3+ IELs was significantly reduced in AIDS (p<0.0001, 39.6/U in HIV+ versus 86.4/U in HIV− subjects). Almost 100% of the γδ IELs were CD8− and they often expressed the Vδ1/Jδ1-encoded epitope (median 65.2%). HIV+ patients on highly active antiretroviral therapy only tended to have a lower ratio of γδ IELs (median 12.8%) than those receiving no treatment (median 14.3%) or 1 nucleoside analogue (NA) (median 23.5%) or 2 NAs (median 13.0%). This minimal variation among therapy groups, contrasting the treatment response of systemic and local adaptive immunity, harmonizes with the novel idea derived from animal experiments that γδ T cells are largely innate cells in first-line microbial defence.