Secretory Immunity Research Articles

Nonspecific secretory immunity in HIV-infected patients with oral candidiasis.

Buccal and digestive tract opportunistic infections occur frequently in patients infected by HIV. In this study, we measured lysozyme (Lz), lactoferrin (Lf), total IgA (T-IgA), and secretory IgA (S-IgA) levels to investigate nonspecific secretory immunity in HIV-infected patients with oral candidiasis. Serum, saliva, and stool samples were analyzed by time-resolved immunofluorometric assay for Lz and Lf levels and by enzyme-linked immunosorbent assay for T-IgA and S-IgA levels. Mean salivary Lf and T-IgA levels (66.50 mg/L and 0.10 g/L, respectively) and mean fecal Lf, T-IgA, and S-IgA outputs (0.87, 54.0, and 43.6 mg/d, respectively) were significantly higher in HIV-infected patients with oropharyngeal candidiasis than in HIV-infected patients without oropharyngeal candidiasis and healthy subjects. There was a modification in the molecular form rate, with a high increase in S-IgA and monomeric IgA transudation from the plasmatic compartment into salivary and digestive fluids and an increase in salivary Lf local synthesis by polymorphonuclear neutrophils. HIV infection appears to be associated with dysregulation of some of the nonspecific immune factors at the mucosal surface. Despite high saliva concentrations and high intestinal output, innate immunity was not able to stop yeast expansion in HIV-infected patients.

Stress and secretory immunity

Publisher Summary This chapter focuses on the relationship between stress and saliva secretory immunity in humans. Salivary gland function is largely under autonomic control; the parasympathetic nerves mainly govern salivary fluid secretion, whereas the sympathetic nerves regulate protein secretion. The primary salivary centers in the brain stem receive inhibitory and excitatory inputs from neural structures in the forebrain and brain stem. As well as governing typical salivary functions, these structures are also involved in generating bodily changes associated with stress. It is, therefore, reasonable to assume that salivary changes during stress are an integral part of a centrally coordinated stress response that encompasses many other bodily functions. The autonomic receptors in the salivary glands can be divided into two main groups: the classic autonomic receptor types, which respond to either noradrenaline or acetylcholine, and the nonadrenergic–noncholinergic (NANC) receptors that respond to other autonomic messenger substances, such as peptides, nitric oxide, and purines. Differential activation of these receptor types can cause additive, synergistic, or antagonistic intracellular responses, ultimately resulting in a protein release that is capable of being differentially regulated among glands.

Differential effects of active versus passive coping on secretory immunity

This study examined the acute immunological effects of two laboratory stressors, expected to evoke distinct patterns of cardiac autonomic activity; namely an "active coping" time-paced memory test, and a "passive coping" stressful video showing surgical operations. We measured salivary S-IgA, IgA-subclasses (IgA1, IgA2), and secretory component (SC). SC is responsible for the transport of S-IgA across the epithelium, and thus a rate-determining step in S-IgA secretion. Thirty-two male undergraduates were subjected to both stressors and a control video (a didactic television program). The memory test induced a typical "fight-flight" response, characterized by increases in heart rate and blood pressure in association with a decrease in cardiac preejection period (PEP) and vagal tone. The surgical video produced a "conservation-withdrawal"-like response, characterized by an enhanced vagal tone, a decrease in heart rate, and a moderate sympathetic coactivation (as indicated by a shortened PEP and an increased systolic pressure). The memory test induced an increase in the concentration and, to a lesser extent, in the output of S-IgA, IgA], and SC. The output of IgA2 was not significantly affected. For the surgical video, a different pattern emerged: During stressor exposure S-IgA remained unaffected, against the background of a small increase in SC output. However, 10 min after the surgical video S-IgA levels had decreased. This decrease in S-IgA was paralleled by a decrease in IgA1, but not IgA2. We conclude that acute stress can have both enhancing and suppressive effects on secretory immunity, the IgA1 subclass in particular. The mechanisms that underlie these divergent responses may include stressor-specific patterns of autonomic activation.

Differential effects of active versus passive coping on secretory immunity

Differential effects of active versus passive coping on secretory immunity

Long-Term Behavior of Secretory Immunity in Ileocecal and Ileal Orthotopic Neobladders

Objective: To compare secretory immunity in cecal and ileal orthotopic neobladders, and to detect its permanence over time. Patients and Methods: IgA was studied in the urine of 33 patients with ileocecourethrostomy (ICUS) and 13 patients with ileal reservoir (IR). The mean follow-up was 55 months. Results were compared in terms of the type of operation, a healthy control group, and the time since surgery. Results: Urinary IgA levels were significantly higher in ICUS and IR patients than in normal controls. No significant differences in IgA concentrations were detected in patients with different reservoirs and with regard to time. Conclusion: Both the reservoirs maintain the function of producing IgA. In particular no differences were detected over time and urine could be a permanent antigenic stimulus. IgA could be considered an adjunctive factor for upper urinary tract protection. For this reason we prefer to use a simple, indirect antireflux mechanism, thus avoiding direct manipulation of the uretero-intestinal anastomosis.

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.

Development and Function of Intestinal B and T Cells

The gastrointestinal immune system has evolved under the dual evolutionary pressure of preventing bacterial invasion along its extensive epithelial surfaces, while permitting absorption of nutrients. Accordingly, the development, selection and function of mucosal immune cells differ from comparable characteristics of lymphoid cells in other peripheral tissues. In the normal state, intestinal immune responses are aiming at exclusion of antigens – that is, preventing translocation of intestinal microorganisms and dangerous immunogenic substances such as bacterial toxins into the lamina propria. Furthermore, presentation of soluble food proteins and components of the autologous intestinal microora to mucosal T and B cells, apparently results in immunological downregulation as well as active suppression of systemic immune responses, a phenomenon termed mucosal or ‘oral’ tolerance. The normal microbial flora has a major impact on the pool size, composition, antigen recognition repertoire, and effector function of mucosal immune cells. Local antibody responses are characterized by differentiation of B lymphocytes to lamina propria plasma cells which produce polymeric immunoglobulins, a process strictly regulated by mucosal T cells. Polymeric immunoglobulins (e.g., dimeric IgA and pentameric IgM) are actively transported by a specific receptor across the epithelial barrier into the gut lumen where they can bind bacteria and soluble antigens, thereby preventing them from adhering to, and penetrating, the mucosal surface. A major population of intestinal T cells is located in the surface epithelium, thus being strategically situated at the interface between the gut lumen and the interior of the body. However, their precise role in microbial defence has not yet been established. It is remarkable how the immune system normally maintains the balance between exclusion of (but coexistence with) the commensal gut bacteria, while protecting against (and eventually eliminating) intestinal pathogens. This immune balance appears to be tightly regulated by intestinal T cells. Recent findings in various genetically manipulated mouse models suggest that a dysregulated T-cell response against the normal intestinal microflora may lead to progressive inflammatory disease in the gut. This adverse development appears to reflect abrogation of oral tolerance and may be a central mechanism in the pathogenesis of inflammatory bowel disease. Also the development of atopic allergy appears to be influenced by immunoregulatory mechanisms on which the intestinal microflora exerts a substantial impact in terms of both mucosal barrier maintenance, oral tolerance and a balanced cytokine profile. Keywords: intestinal microflora, secretory immunity, oral tolerance, intraepithelial lymphocytes, gut disease.

Immunoglobulins in nasal secretions of healthy humans: structural integrity of secretory immunoglobulin A1 (IgA1) and occurrence of neutralizing antibodies to IgA1 proteases of nasal bacteria.

Certain bacteria, including overt pathogens as well as commensals, produce immunoglobulin A1 (IgA1) proteases. By cleaving IgA1, including secretory IgA1, in the hinge region, these enzymes may interfere with the barrier functions of mucosal IgA antibodies, as indicated by experiments in vitro. Previous studies have suggested that cleavage of IgA1 in nasal secretions may be associated with the development and perpetuation of atopic disease. To clarify the potential effect of IgA1 protease-producing bacteria in the nasal cavity, we have analyzed immunoglobulin isotypes in nasal secretions of 11 healthy humans, with a focus on IgA, and at the same time have characterized and quantified IgA1 protease-producing bacteria in the nasal flora of the subjects. Samples in the form of nasal wash were collected by using a washing liquid that contained lithium as an internal reference. Dilution factors and, subsequently, concentrations in undiluted secretions could thereby be calculated. IgA, mainly in the secretory form, was found by enzyme-linked immunosorbent assay to be the dominant isotype in all subjects, and the vast majority of IgA (median, 91%) was of the A1 subclass, corroborating results of previous analyses at the level of immunoglobulin-producing cells. Levels of serum-type immunoglobulins were low, except for four subjects in whom levels of IgG corresponded to 20 to 66% of total IgA. Cumulative levels of IgA, IgG, and IgM in undiluted secretions ranged from 260 to 2,494 (median, 777) microg ml(-1). IgA1 protease-producing bacteria (Haemophilus influenzae, Streptococcus pneumoniae, or Streptococcus mitis biovar 1) were isolated from the nasal cavities of seven subjects at 2.1 x 10(3) to 7.2 x 10(6) CFU per ml of undiluted secretion, corresponding to 0.2 to 99.6% of the flora. Nevertheless, alpha-chain fragments characteristic of IgA1 protease activity were not detected in secretions from any subject by immunoblotting. Neutralizing antibodies to IgA1 proteases of autologous isolates were detected in secretions from five of the seven subjects but not in those from two subjects harboring IgA1 protease-producing S. mitis biovar 1. alpha-chain fragments different from Fc(alpha) and Fd(alpha) were detected in some samples, possibly reflecting nonspecific proteolytic activity of microbial or host origin. These results add to previous evidence for a role of secretory immunity in the defense of the nasal mucosa but do not help identify conditions under which bacterial IgA1 proteases may interfere with this defense.

Humoral intestinal immunity in systemic lupus erythematosus.

Forty-five patients with systemic lupus erythematosus (SLE) underwent a cross-sectional study to evaluate intestinal secretory immunity. Peroral jejunal biopsy with histologic and immunohistochemical assessment of the mucosa were carried out in the patients and in 12 healthy volunteers. It was observed that an altered pattern of immunoglobulin-bearing plasma cells distributed in the lamina propria and complementary components were invariably present, mainly in the patients with active disease. The basement membrane of the intestinal crypt epithelium exhibited immunoglobulin and complementary deposits, similar to the lupus band test. None of the immunologic findings correlated with the medical treatment and with the peripheral blood analysis. The local changes in humoral immunity in patients with SLE did not correlate with gastrointestinal symptoms and may reflect the systemic effects of the disease.

Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice.

Mucosal surfaces are protected specifically by secretory immunoglobulin A (SIgA) and SIgM generated through external translocation of locally produced dimeric IgA and pentameric IgM. Their active transport is mediated by the epithelial polymeric Ig receptor (pIgR), also called the transmembrane secretory component. Paracellular passive external transfer of systemic and locally produced antibodies also provides mucosal protection, making the biological importance of secretory immunity difficult to assess. Here we report complete lack of active external IgA and IgM translocation in pIgR knockout mice, indicating no redundancy in epithelial transport mechanisms. The knockout mice were of normal size and fertility but had increased serum IgG levels, including antibodies to Escherichia coli, suggesting undue triggering of systemic immunity. Deterioration of their epithelial barrier function in the absence of SIgA (and SIgM) was further attested to by elevated levels of albumin in their saliva and feces, reflecting leakage of serum proteins. Thus, SIgA did not appear to be essential for health under the antigen exposure conditions of these experimental animals. Nevertheless, our results showed that SIgA contributes to maintenance of mucosal homeostasis. Production of SIgA might therefore be a variable in the initiation of human immunopathology such as inflammatory bowel disease or gluten-sensitive enteropathy.

Impaired secretory immunity in dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa is a congenital disorder characterized by blistering of the skin and oral mucosa. This study investigated the hypothesis that children with dystrophic epidermolysis bullosa have impaired oral secretory immunity. Immunoglobulin A (IgA), secretory IgA and IgG concentrations, and IgA and secretory IgA antibody levels to Candida albicans, Lactobacillus casei and Streptococcus mutans were measured in whole saliva from 22 children with dystrophic epidermolysis bullosa and 22 matched controls. Salivary total IgA and total IgG concentrations were significantly raised in dystrophic epidermolysis bullosa due to serum leakage from oral blistering, but the converse was seen with secretory IgA. This suggestion of a mucosal immune defect was supported by decreased secretory IgA antibody responses to all three microorganisms tested. This apparent defect in secretory immunity in dystrophic epidermolysis bullosa may be due to mucosal involvement and damage resulting in impaired antigen sampling in mucosal associated lymphoid tissue or to impaired transport of secretory IgA across the salivary gland mucosa.

Study of the possible mechanisms involved in the mucosal immune system activation by lactic acid bacteria.

The induction of a mucosal immune response is not easy due to the development of oral tolerance, but under some conditions, bacteria can activate this immune system. Antigens administered orally can interact with M cells of Peyer's patches or bind to the epithelial cells. We have demonstrated that certain lactic acid bacteria are able to induce specific secretory immunity, and others will enhance the gut inflammatory immune response. The aim of this work was to establish the reason for these different behaviors and to define possible mechanisms involved in the interaction of lactic acid bacteria at the intestinal level. We studied IgA+ and IgM+ B cells comparatively in bronchus and intestine and CD4+ T cells and IgA anti-lactic acid bacteria antibodies in the intestinal fluid, induced by oral administration of Lactobacillus casei, Lb. delbrueckii ssp. bulgaricus, Lb. acidophilus, Lb. plantarum, Lb. rhamnosus, Lactococcus lactis, and Streptococcus salivarius ssp. thermophilus. The increase in the IgA+ B cells in the bronchus means that these lactic acid bacteria were able to induce the IgA cycle by interaction with M cells from Peyer's patches or intestinal epithelial cells. The IgM+ cells increased when the stimulus did not induce the switch from IgM+ to IgA+. The increase in the CD4+ cells suggests interaction of Peyer's patches and enhancement of the B- and T-cell migration. The anti-lactic acid bacteria antibody is related to the processing and presentation of the microorganisms to the immune cells. We demonstrated that Lb. casei and Lb. plantarum were able to interact with Peyer's patch cells and showed an increase in IgA-, CD4+ cells, and antibodies specific for the stimulating strain. Lactobacillus acidophilus induced gut mucosal activation by interaction with the epithelial cells without increase in the immune cells associated with the bronchus. Although Lb. rhamnosus and Strep. salivarius ssp. thermophilus interact with epithelial cells, they also induced an immune response against their epitopes. Lactococcus lactis and Lb. delbrueckii ssp. bulgaricus induced an increase of IgA+ cells entering the IgA cycle but not CD4+ cells; thus, these bacteria would have been bound to epithelial cells that activated B lymphocytes without processing and presenting of their epitopes. We did not determine specific antibodies against Lc. lactis or Lb. bulgaricus.

Diversity of antibody-mediated immunity at the mucosal barrier.

Although over 90% of all human infections begin at a mucosal site (respiratory, gastrointestinal, urogenital, or ocular), the total number of infections occurring in the population is relatively low. This is in part the result of the secretion of a complex array of local and systemically produced immunoglobulins (Igs). Since the time of Pasteur (37), when immunization by the oral route was first described, and the identification of a special mucosal immune system by Besredka (7), considerable progress in understanding secretory immunity in humans has been achieved. Mechanisms of induction, synthesis, translocation, and activity of secretory immunoglobulin A (S-IgA) antibodies are now well established, as extensively reviewed in a recent book (46). However, while it would be more effective to block infections at the mucosa by using specific mucosal vaccines, the only such vaccine commercialized for human use is the oral polio vaccine (53). This delay in commercialization is due to the necessity of optimizing safety and efficacy which are related to a number of factors such as the requirements for persistent antigens (Ags) which linger on mucosal surfaces, for highly effective mucosal adjuvants, and for live mucosal vaccine vectors with harmless colonizing properties. Present efforts have focused on the study of both mucosal adjuvants, mainly cholera toxin and its derivatives, and immunogens such as encapsulated molecules, DNA, and recombinant microorganisms. Alternatively, an understanding of additional aspects of antibody-mediated immunity in secretions may enable us to develop new methods of local protection against pathogens. We present here those immune mechanisms known to be used by the host to block infection at the mucosal surface and discuss their respective importance and limitations.

Production and characterization of recombinant IgA

Existence of secretory immunity at the mucosal surfaces was first postulated in 1919. Since then experimental and clinical studies have indicated that it is immunoglobulin A (IgA) that provides the first line of immune defense at the mucosal surfaces. While a number of expression systems—including viral, plant and mammalian cells—have been used to produce recombinant IgA, we used the mammalian expression system to produce IgA1 and the three allotypes of IgA2. By introducing the gene coding for human secretory component (SC) into transfectants producing IgA1, we have generated a single mammalian cell system that produces covalently assembled secretory IgA (sIgA). Using pulse-chase analysis, we determined the covalent assembly pathways of IgA1, IgA2 and sIgA and identified some of the structural differences leading to the different assembly patterns. Using affinity purified proteins, we have shown that neither IgA1 nor any of the allotypes of IgA2 activate either the classical or the alternative complement pathways, but modulate the complement activity of IgG or IgM. The two N-linked glycosylation sites in IgA1 are not required for its binding to the polymeric Ig receptor (pIgR). Finally, we have shown that sIgA1 was more stable than dIgA1 in the gastrointestinal tract of mice, suggesting that SC provides resistance to IgA in the gastrointestinal tract.

IgA/IgM and Secretory Immunity

The mucosal wall is equipped with a highly developed defence system. The concept of local or mucosal immunity has expanded dramatically during the past decades. The bronchus-associated lymphoid tissue (BALT) and the gut-associated lymphoid tissue (GALT) belong to the common mucosal immune system (CMIS), which also includes mucosal sites in the genital tract, the salivary glands, ocular tissues and the mammary glands. These systems not only communicate with each other, they also communicate with the external environment. The intestinal mucosa contains more than 80% of all immunoglobulin producing cells in the human body. GALT and BALT are primary inductive sites for secretory immunoglobulin isotypes of which sIgA are the dominant molecules. Responses are directed against ingested and inhaled antigens. Therapeutic IgM- and IgA-containing immunoglobulin concentrates can modify mucosal immunity. The progress in the field of molecular biology and genetics offers new strategies and tools for the improvement and further development of conventional vaccines for mucosal immunization.

Secretory Immunity in HIV Infection

Secretory IgA plays a crucial role in the defense of pathogens at mucosal surfaces. As CD4+ T cells are lost early in the mucosa of human immunodeficiency virus (HIV)-infected patients and as CD4+ T cells play an essential role in the regulation of specific IgA responses to pathogenic agents at mucosal sides, it could be expected that this first line of defense is impaired in HIV-infected patients. Therefore, several studies were undertaken to characterize the humoral immune response at mucosal surfaces. However, the results obtained so far are in part contradictory. For intestinal IgA, reduced, increased and no changes compared to controls were described. The different results may be due to different methods applied. In most studies an abnormal predominance of HIV-specific IgG over IgA response was found in the intestine of HIV-infected patients. Studies on cytomegalovirus-specific intestinal antibodies indicate a complete lack of a specific intestinal IgA response. However, in cryptosporidiosis of HIV-infected patients, diarrhea persists despite a secretory IgA response indicating that other factors are also important for the clearance of this pathogen.

Increased immunoglobulin G production by short term cultured duodenal biopsy samples from HIV infected patients

Background—Secretory immunity is a major defence mechanism against infections at mucosal surfaces which are common in HIV infected patients.Aims—To analyse intestinal immunoglobulin production in HIV infection in comparison with that...

TAC-TIC therapy: a non-pharmacological stroking intervention for premature infants.

This paper describes a non-pharmacological stroking intervention which has been used with premature infants. This intervention is referred to as Touching and Caressing, Tender in Caring (TAC-TIC) therapy. Some of the beneficial outcomes resulting from TAC-TIC in healthy preterms are outlined, along with some of the initial findings from research using the therapy with the high-risk ventilated premature neonate. Current research has been conducted using a psychoneuroimmunological framework and preliminary findings have indicated stabilized cardiovascular responses, enhanced secretory immunity and increased frequency of occurrence of comfort behaviours as a result of TAC-TIC therapy.

Mucosal immunity in the female genital tract

Immunoglobulin (Ig)-producing cells in mucosal tissues represent quantitatively the most important humoral immune system of the body. All exocrine tissue sites contain immunocytes (B-cell blasts and plasma cells) that mainly synthesize dimers and larger polymers of IgA (collectively called pIgA) with incorporated J chain. Such pIgA is actively transported to external secretions as secretory IgA (SIgA) by the polymeric Ig receptor (pIgR), a transmembrane epithelial glycoprotein also called the secretory component (SC). The same transport mechanism includes pentameric IgM to generate SIgM. Although the most active SIgA system occurs in the gut, secretory immunity also operates in the female genital tract, with considerable pIgA production in the cervical mucosa and fallopian tubes. The origin of these local IgA immunocytes remains undefined. In mice, both lymphoid tissue in the large bowel (GALT) and nasopharynx (NALT) have been suggested as inductive sites for B cells homing to the urogenital tract. It is well established that integrin α4 β7 is used by primed lymphoid cells to enter the intestinal lamina propria through interactions with mucosal addressin cell adhesion molecule (MAdCAM)-1 expressed on venule endothelium. However, α4 β7 does not appear to be an important homing molecule in the airways, and the same might be true for the urogenital tract; this could explain that high levels of IgA antibodies occur in cervicovaginal secretions of mice after nasal immunization. The endometrium can likewise perform pIgR-mediated external translocation of pIgA that in this tissue appears to be mainly derived from serum, partly under hormonal regulation. In addition, paracellular diffusion of serum-derived and locally produced IgG through epithelia is an important part of humoral immunity in the female genital tract.

Small intestine in lymphocytic and collagenous colitis: mucosal morphology, permeability, and secretory immunity to gliadin.

There is a recognised association between the "microscopic" forms of colitis and coeliac disease. There are a variety of subtle small intestinal changes in patients with "latent" gluten sensitivity, namely...