The secretory IgA system

The secretory IgA system is common to all mucosal membranes and is presumably of great importance for their defense. In addition to the secretory IgA antibodies produced in a mucosa in response to a local antigenic stimulus there is a spread of this type of IgA response via committed lymphocytes. They originate from central lymphoid organs in the intestinal (Peyer's patches) and bronchial mucosa (bronchus-associated lymphoid tissue, BALT) which they leave after antigenic exposure. They migrate, or "home", to exocrine glands such as the lacrimal, salivary, mammary and prostatic glands and mucosal membranes of the respiratory, gastrointestinal and genito-urinary tract. Almost half of all lymphocytes may be involved in the production of IgA antibodies. The secretory IgA antibodies are the dominating immunoglobulins in exocrine secretions on mucous membranes. They function primarily by preventing contact between the microbe and the host tissue most commonly attacked in infections, the mucous membrane. The fact that breast-feeding protects the infant against intestinal infections is one good example of the clinical significance of secretory IgA antibodies. This mode of protection can be enhanced by vaccination.     

黏膜免疫反应与呼吸道过敏性疾病

黏膜免疫是近年来倍受关注的免疫学新理论之一,促使人们对黏膜免疫有了新认识。黏膜免疫系统是由黏膜相关淋巴样组织（MALT）组成。黏膜上皮细胞持续不断地接触外环境中微生物及过敏原等刺激物,发挥着黏膜免疫屏障保护性防御功能,作为机体对抗外来刺激物的第一道防线,以保障机体内环境的稳定。     

Ontogeny of the intestinal immune system in the premature infant

A variety of variables influence the development of secretory immunity and oral tolerance, two immune mechanisms that are of paramount importance for the mucosal barrier function. Epithelial permeability is likely a significant primary or secondary event in the pathogenesis of several intestinal diseases, including adverse immune reactions to foods. This variable is determined by the individual's age (e.g., preterm versus term infant), concurrent infections, and the shielding effect of secretory IgA (SIgA) antibodies provided by breast milk. The clinical consequences will depend on how fast “closure” of the epithelial barrier can be attained or re-established, which is influenced both by the age of the infant and by its successful mounting of adaptive intestinal SIgA responses as well as generation of oral tolerance towards innocuous antigens from the diet and from the normal indigenous microbiota. SIgA is the best defined effector component of the mucosal immune system; its enhancement, and the homeostatic mucosal immune regulation in general, induced by probiotic commensal bacteria is of considerable clinical interest. Importantly, the feeding and treatment regimen (e.g., antibiotics) to which the newborn is subjected, may disturb the balance of the developing mucosal immune system.     

Nutritional regulation of immunity and risk of illness

Nutrition is a critical determinant of immunocompetence and risk of illness. Young children with protein-energy malnutrition exhibit increased mortality and morbidity, largely due to infectious disease. Recent work has demonstrated that, undernourished individuals have impaired immune responses. The most consistent abnormalities are seen in cellmediated immunity, complement system, phagocytes, mucosal secretory antibody response, and antibody affinity. These changes, together with other handicapping factors observed in underprivileged societies, lead to more infections, which in turn produce physiological changes that worsen nutritional status. It is now established that deficiencies of single nutrients also impair immune responses. The best studied are zinc, iron vitamin B6, vitamin A, copper and selenium. If malnutrition occurs during fetal life, as epitomized by small-forgestational age infants, the effects on cell-mediated immunity are very significant and long lasting. These interactions on nutrition and immunity have several practical applications.     

Immunocompetence Is a Sensitive and Functional Barometer of Nutritional Status

Nutrition is a critical determinant of immunocompetence and risk of illness. Young children with protein-energy malnutrition exhibit increased mortality and morbidity, due largely to infectious disease. Recent work has demonstrated that undernourished individuals have impaired immune responses. The most consistent abnormalities are seen in cell-mediated immunity, complement system, phagocytes, mucosal secretory antibody response, and antibody affinity. Many of these immunologic changes occur early in the course of nutritional depletion and therefore can serve as sensitive functional indices of nutritional status.     

Mucosal immunity and strategies for novel microbial vaccines

Infectious diseases continue to be the leading cause of morbidity and mortality worldwide. Increased awareness of the fact that mucosal membranes are the most frequent portals of entry of pathogenic microorganisms has prompted studies aimed at the development of vaccination protocols and antigen delivery systems that would lead to an increased protection of mucosae. Although systemic and strictly local immunizations are of limited effectiveness in the induction of mucosal protection, ingestion or inhalation of antigens results in a generalized immune response manifested by the appearance of specific antibodies of the secretory immunoglobulin (Ig) isotype in external secretions due to the dissemination of IgA precursor cells from IgA-inductive lymphoid tissues. Furthermore, additional inductive sites strategically positioned at the opening of the respiratory and digestive tracts may also be suitable targets for induction of immune responses at desired effector sites. To prevent degradation and the increase of ingested antigens absorption, novel strategies including enclosure of antigens into biodegradable microspheres, liposomes or their expression in viral and bacterial vectors and plants are currently being considered. Forthcoming technological advances in antigen preparation and routes of delivery will undoubtedly have a profound impact on immunization practices in the future.     

Development of specific immunity in prenatal life]

The various defense mechanisms of specific immunity, which involves the T and B lymphocytes and the antigen presenting cells, are gradually developed during intra-uterine life. The first hematopoietic organ is the yolk sac which appears at the 4th week of development. Thereafter, the hematopoiesis takes place in the fetal liver (from the 6th week) followed by the bone-marrow during the 3rd trimester. The differentiation of the T lymphocytes begins around the 10th week. The thymic epithelial rudiments appear during the 7th week and the thymus migrates to its definitive place at ten weeks. It is then colonized by the T cell precursors, which there undergo their maturation process. From the 12th week of development, mature T cells are readily detectable in lymphoid organs and fetal blood. The maturation of B cells, which occurs firstly in fetal lever, and thereafter in bone marrow begins also early in fetal life (12th week). The antigen presenting cells, the precursors of which are detected in the yolk sac as soon as 4-6 weeks, are normally present and functional in secondary lymphoid organs as soon as 12 weeks. Thus, the specific immune response appears possible by the end of the 1st trimester. However, the naive nature of T and B lymphocytes is responsible for a delayed, slow and relatively ineffective primary response. This observation explains the particular susceptibility of neonates, especially premature neonates to bacterial and viral infections. The various antigenic stimulations and T/B cell cooperations allow a complete maturation of the immune system during the first years of life.     

Breast feeding increases concentrations of IgA in infants' urine.

To investigate the influence of breast feeding on mucosal immunity the concentrations and daily outputs of IgA and lactoferrin in urine were measured in 10 breast fed and 12 infants fed on formula milk at 6 and 12 weeks of age. The concentrations and outputs of secretory IgA in urine were significantly higher in the breast fed group by a factor of three. The secretion of IgA in urine by the breast fed infants was characteristic of the baby and was not related to the intake of IgA from breast milk. Lactoferrin concentrations were similar in the two groups at both ages. In addition to secretory IgA, two thirds of all samples contained proteins with alpha chain but no secretory component antigenic determinants. Breast feeding seems to increase the local production of secretory IgA into the urinary tract during early childhood, thus providing enhanced protection from infection.     

Development of mucosal immune function in man: potential for Gl disease states

The human mucosal immune system is structurally mature and has all the necessary cellular components to generate an immune response at birth. However, in the absence of dietary antigens and bacterial flora, there are no secondary follicles in the Peyer's patches and virtually no immunoglobulin A plasma cells in the lamina propria. Reactive follicle centers develop after birth but it takes 2 years for mucosal IgA plasma cell density to reach adult levels. T cells are present in the epithelium and lamina propria at birth, albeit at a lower frequency than later in life and there are major differences in phenotype between T cells in fetal intestine and postnatal intestine. There is no information on the impact of the massive antigenic challenge at birth on the mucosal immune system. Well-documented deficiencies in the ability of the blood T cells of the neonate to produce interleukin-4 and interferon-gamma may also occur in the intestine. It is still an open question whether it is better to try to prevent immunological sensitization of the newborn by avoiding potential allergens (i.e. cow's milk), or whether early exposure (as happens when premature infants are given formula feeds) might tolerize the infant. Hydrolysed cow's milk formulae are probably less antigenic than whole cow's milk and have been widely used in the treatment of cow's milk allergy. Some thought is now being given as to whether the prophylactic use of hydrolysates can reduce cow's milk allergy in ‘at-risk’ infants.     

Innate immunity of the gut: mucosal defense in health and disease

The intestine is an important immune organ consisting of a complex cellular network, secreted peptides and proteins and other host defenses. Innate immunity plays a central role in intestinal immune defense against invading pathogens. It also serves as a bridge to the activation of the adaptive immune system. Pattern recognition molecules of microorganisms are an essential component for identifying invading pathogens. Toll-like receptors (TLRs), CARD15/NOD2 and scavenger receptors all serve as the pattern recognition receptors in the innate immune defense system. Secreted bactericidal peptides or defensins produced by the intestinal epithelia represent another crucial element of innate mucosal immune defense. Mutations in pattern recognition receptors and dysfunction of secretory bactericidal peptides may impair host immune defenses leading to an invasion of pathogens resulting in chronic inflammation of the gut. This review updates our current understanding of innate immunity of the gastrointestinal tract.     

Congenital pernicious anemia: report of seven patients, with studies of the extended family

Unstimulated whole saliva was collected from 203 uninfected individuals at various ages from birth until adulthood. Levels of specific antibodies against Escherichia coli O antigens of secretory IgA, secretory IgM and IgG, as well as total amounts of SIgA, were determined using ELISA. Levels of SIgA antibodies found in adults were approached by the age of 12 months, but high levels could be attained earlier, presumably in response to antigenic exposure at the mucosal level. During the first few months of life, secretory IgM antibodies appeared in the saliva, possibly compensating for the relative lack of IgA.     

Immunoprophylaxis of viral infections in childhood

Conclusion It appears that an ideal vaccine would be the one which closely simulates the immunologic events occurring during the course of natural infection. Natural infection through the natural portal of entry seems to induce serum as well as secretory antibody response. Live attenuated vaccine administered orally most closely resembles natural infection in eliciting a balanced immunologic response. However, parenteral immunization with inactivated vaccine may be complicated by unbalanced immune response stimulating the humoral system without any secretory antibody production. Current approaches in immunoprophylaxis of viral disease are thus directed at immune mechanisms which lead to uniform stimulation of only certain components of the immune system. Hopefully, this approach would lead to balanced immunologic responses rather than a situation of altered immunity and hypersensitivity. Further, the success which has been attained with the use of live attenuated vaccine, suggests that the development of local immunity at the primary portal of entry may eventually provide an effective means of eradication of pathogenic virus flora in any community. From the Department of Pediatrics, School of Medicine, State University of New York at Buffalo, and the Virology Laboratory, Children's Hospital, Buffalo, N. Y.     

肺炎链球菌的感染与免疫研究进展

肺炎链球菌是儿童侵袭性细菌感染的主要病原菌,可以引起肺炎、脑膜炎和脓毒症等危及生命的疾病。作为上呼吸道常见定植菌,了解其感染过程中机体的免疫反应对于疾病的治疗至关重要。该文综述肺炎链球菌抗原结构、肺炎链球菌结合疫苗及主要毒力因子,并重点描述肺炎链球菌感染后机体的免疫反应,包括固有免疫、巨噬细胞、中性粒细胞和T细胞的作用。     

Immunology of malaria

Infection with parasites and exposure to their complex antigens, generates a diverse immune response. The levels of antibody activity or cellular sensitization may be measured using a variety of immunological tests but these provide little or no correlation with the degree of protective immunity that the host may possess. Acquired immunity depends upon specific inhibitory antibody as well as imprecisely defined cell-mediated and non-specific mechanisms. Survival of parasites is promoted by their capacity for antigenic variation and their intracellular location and by processes which may interfere with host immunity including production of lymphocyte mitogens and soluble antigens and generation of immunosuppressor cells.     

Protection of the neonate by the innate immune system of developing gut and of human milk

The neonatal adaptive immune system, relatively na?ve to foreign antigens, requires synergy with the innate immune system to protect the intestine. Goblet cells provide mucins, Paneth cells produce antimicrobial peptides, and dendritic cells (DCs) present luminal antigens. Intracellular signaling by Toll-like receptors (TLRs) elicits chemokines and cytokines that modulate inflammation. Enteric neurons and lymphocytes provide paracrine and endocrine signaling. However, full protection requires human milk. Breast-feeding reduces enteric infection and may reduce chronic disease in later life. Although human milk contains significant secretory immunoglobulin A (sIgA), most of its protective factors are constitutively expressed. Multifunctional milk components are nutrients whose partial digestion products inhibit pathogens. Cytokines, cytokine receptors, TLR agonists and antagonists, hormones, anti-inflammatory agents, and nucleotides in milk modulate inflammation. Human milk is rich in glycans (complex carbohydrates): As prebiotics, indigestible glycans stimulate colonization by probiotic organisms, modulating mucosal immunity and protecting against pathogens. Through structural homology to intestinal cell surface receptors, glycans inhibit pathogen binding, the essential first step of pathogenesis. Bioactive milk components comprise an innate immune system of human milk whereby the mother protects her nursing infant. Interactions between human milk glycans, intestinal microflora, and intestinal mucosa surface glycans underlie ontogeny of innate mucosal immunity, pathobiology of enteric infection, and inflammatory bowel diseases.     

Allogeneic hematopoietic stem‐cell engraftment and graft failure

Abstract: Two immunologically mediated reactions, the graft‐versus‐host (GvH) and host‐versus‐graft (HvG) responses, form primary and opposing barriers to successful transplantation of allogeneic hematopoietic stem‐cells (HSC). The HvG barrier is set by the strength of the allogeneic immune response, which is determined by antigenic stimulation provided by donor cells, owing to differences in histocompatibility antigens, and the capacity of host immune cells to generate a response. Risk of graft failure must be viewed as the interplay of multiple factors, including degree of human leukocyte antigen and minor histocompatibility antigen disparity, capacity of host immune response, and the capacity of donor hematopoietic and immunologic cells for overcoming residual host immunity.     

Alterations of the intestinal mucosal block in ulcerative colitis and Crohn's disease--immunological and ultrastructural findings, and considerations of the pathogenesis

The intestinal mucosa is the very site of the chronic inflammatory lesion in ulcerative colitis (UC) and in Crohn's disease (CD). The lamina mucosa together with its own and associated cellular and humoral protective properties can be described as the mucosal block which is functionally related to the intestinal and systemic immune system. Deteriorations of this mucosal block probably are of pathogenetic significance in UC and CD. This paper will summarize observations on the systemic immune system and local immune phenomena and their possible relations to the tissue injury in the gut. An immunopathogenetic concept intends to explain the chronicity of the diseases: epithelial insufficiencies of the mucosal block are followed by strong antigenic intrusion and stimulation of the local immune system with disturbance of the local immune homeostasis and the formation of immune complexes. The interactions of phagocytes with immune complexes cause the release of degrading lysosomal enzymes, which leads to continuous injury of the mucosal block and therefore to a perpetuation of the disease.     

加快我国儿童临床免疫学科之过敏免疫风湿病等亚专科的协调发展

儿童临床免疫专科为我国一个重要的儿内科领域分支学科，是一个覆盖儿童变态反应性疾病、免疫缺 陷病、风湿免疫性疾病、炎症性疾病、疫苗接种咨询、围器官移植免疫、危重病及系统器官免疫、感染与免疫及黏膜免疫学等多方面，涉及多个儿内科三级学科的交叉前沿学科，学科建设源远流长，近年来，在我国得到了重视及快速发展，但如何推动各亚专科的协调发展是我们当前面临的重要任务。该文对其历史、发展现状、如何加快儿童临床免疫专科及各亚专科的协调发展进行述评。     

Milk proteins,cytokines and intestinal epithelial functions in children

This paper discusses the relationship between food antigens, lymphocytes and the epithelial properties of the jejunum in children with cow's milk allergy. Experimental results indicate that increased protein permeability is not the primary cause of cow's milk allergy. Rather, results are interpreted as a secondary effect of an abnormal immunological response leading to mucosal inflammation and impairment of the endocytic process by the intestinal epithelial cells. Stimulation by cow's milk proteins caused the lymphocytes from infants with cow's milk allergy to release more tumor necrosis factor-α TNFα than those from control infants. After appropriate antigenic stimulation, the cytokines released by the activated lymphocytes from these infants perturbed epithelial function, in particular its barrier capacity. Tumor necrosis factor a, together with gamma interferon are involved in these adverse effects. It is thought that bovine β-lactoglobulin present in the intestinal lumen may be responsible for the secretory diarrhea observed in children with cow's milk allergy, as a consequence of stimulation of electrogenic chloride secretion. In addition, luminal foreign protein may stimulate the submucosal cells. As a consequence, the submucosal release of mediators, including lymphokines, might alter the intestinal epithelial barrier. In conclusion, in physiological conditions, the subepithelial tissue that comprises the immune system and many other systemic systems receive information on the antigenic content within the intestinal lumen via the intestinal epithelium.     

Nutrition and immunology

Since at least 350 million children on our earth suffer from severe caloric and especially protein deficiency it is of utmost importance to know its relation to host defense. In the first part of this paper the already known facts about nutrition and immune response are summarized. Especially the negative effects on the humoral and cellular immune mechanism are critically reviewed. Another chapter deals with the trophogenic immunity; especially the significance of secretory IgA of lactoferrin and lactoperoxydase is pointed out. Recent scientific work disclosed some anti-bacterial, anti-viral, and anti-mycotic properties of certain fatty acids.