Immunoglobulins at the interface of the gut mycobiota and anti-fungal immunity.

The dynamic and complex community of microbes that colonizes the intestines is composed of bacteria, fungi, and viruses. At the mucosal surfaces, immunoglobulins play a key role in protection against bacterial and fungal pathogens, and their toxins. Secretory immunoglobulin A (sIgA) is the most abundantly produced antibody at the mucosal surfaces, while Immunoglobulin G (IgG) isotypes play a critical role in systemic protection. IgA and IgG antibodies with reactivity to commensal fungi play an important role in shaping the mycobiota and host antifungal immunity. In this article, we review the latest evidence that establishes a connection between commensal fungi and B cell-mediated antifungal immunity as an additional layer of protection against fungal infections and inflammation.

Infectious virus shedding duration reflects secretory IgA antibody response latency after SARS-CoV-2 infection.

Infectious virus shedding from individuals infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is used to estimate human-to-human transmission risk. Control of SARS-CoV-2 transmission requires identifying the immune correlates that protect infectious virus shedding. Mucosal immunity prevents infection by SARS-CoV-2, which replicates in the respiratory epithelium and spreads rapidly to other hosts. However, whether mucosal immunity prevents the shedding of the infectious virus in SARS-CoV-2-infected individuals is unknown. We examined the relationship between viral RNA shedding dynamics, duration of infectious virus shedding, and mucosal antibody responses during SARS-CoV-2 infection. Anti-spike secretory IgA antibodies (S-IgA) reduced viral RNA load and infectivity more than anti-spike IgG/IgA antibodies in infected nasopharyngeal samples. Compared with the IgG/IgA response, the anti-spike S-IgA post-infection responses affected the viral RNA shedding dynamics and predicted the duration of infectious virus shedding regardless of the immune history. These findings highlight the importance of anti-spike S-IgA responses in individuals infected with SARS-CoV-2 for preventing infectious virus shedding and SARS-CoV-2 transmission. Developing medical countermeasures to shorten S-IgA response time may help control human-to-human transmission of SARS-CoV-2 infection and prevent future respiratory virus pandemics.

Recombinant neutralizing secretory IgA antibodies for preventing mucosal acquisition and transmission of SARS-CoV-2.

Passive delivery of antibodies to mucosal sites may be a valuable adjunct to COVID-19 vaccination to prevent infection, treat viral carriage, or block transmission. Neutralizing monoclonal IgG antibodies are already approved for systemic delivery, and several clinical trials have been reported for delivery to mucosal sites where SARS-CoV-2 resides and replicates in early infection. However, secretory IgA may be preferred because the polymeric complex is adapted for the harsh, unstable external mucosal environment. Here, we investigated the feasibility of producing neutralizing monoclonal IgA antibodies against SARS-CoV-2. We engineered two class-switched mAbs that express well as monomeric and secretory IgA (SIgA) variants with high antigen-binding affinities and increased stability in mucosal secretions compared to their IgG counterparts. SIgAs had stronger virus neutralization activities than IgG mAbs and were protective against SARS-CoV-2 infection in an in vivo murine model. Furthermore, SIgA1 can be aerosolized for topical delivery using a mesh nebulizer. Our findings provide a persuasive case for developing recombinant SIgAs for mucosal application as a new tool in the fight against COVID-19.

The Role of IgA in the Manifestation and Prevention of Allergic Immune Responses.

PURPOSE OF REVIEW: Immunoglobulin A (IgA) mediates immune exclusion of antigens in the gut. Notably, IgA plays also a role in the prevention of IgE-mediated allergies and induction of immune tolerance. The present review addresses the role of IgA in the manifestation of IgE-mediated allergies, including allergen-specific immunotherapy (AIT), the regulation of IgA production, and the mechanism of IgA in immune cell activation. RECENT FINDINGS: The majority of studies report an association of IgA with the induction of immune tolerance in IgE-mediated allergies. However, reports on the involvement of humoral and mucosal IgA, IgA subtypes, monomeric and polymeric IgA, and the mechanism of IgA-mediated immune cell activation are confounding. Effects by IgA are likely mediated by alteration of microbiota, IgE-blocking capacity, or activation of inhibitory signaling pathways. However, the precise mechanism of IgA-regulation, the contribution of serum and/or mucosal IgA, and IgA1/2 subtypes, on the manifestation of IgE-mediated allergies, and the underlying immune modulatory mechanism are still elusive.

Human salivary protein-derived peptides specific-salivary SIgA antibodies enhanced by nasal double DNA adjuvant in mice play an essential role in preventing Porphyromonas gingivalis colonization: an in-vitro study.

BACKGROUND: We previously showed that fimbriae-bore from Poryphyromonas gingivalis (Pg), one of the putative periodontopathogenic bacteria specifically bound to a peptide domain (stat23, prp21) shared on statherin or acidic proline-rich protein 1 (PRP1) molecule of human salivary proteins (HSPs). Here, we investigated whether the nasal administration of DNA plasmid expressing Flt3 ligand (pFL) and CpG oligodeoxynucleotide 1826 as double DNA adjuvant (dDA) with stat23 and prpr21 induces antigen (Ag)-specific salivary secretory IgA (SIgA) antibodies (Abs) in mice. Further, we examined that stat23- and prpr21-specific salivary SIgA Abs induced by dDA have an impact on Pg-binding to human whole saliva-coated hydroxyapatite beads (wsHAPs). MATERIAL AND METHODS: C57BL/6N mice were nasally immunized with dDA plus sta23 or/and prp21 peptide as Ag four times at weekly intervals. Saliva was collected one week after the final immunization and was subjected to Ag-specific ELISA. To examine the functional applicability of Ag-specific SIgA Abs, SIgA-enriched saliva samples were subjected to Pg binding inhibition assay to wsHAPs. RESULTS: Significantly elevated levels of salivary SIgA Ab to stat23 or prp21 were seen in mice given nasal stat23 or prp21 with dDA compared to those in mice given Ag alone. Of interest, mice nasally given the mixture of stat23 and prp21 as double Ags plus dDA, resulted in both stat23- and prp21-specific salivary SIgA Ab responses, which are mediated through significantly increased numbers of CD11c+ dendritic cell populations and markedly elevated Th1 and Th2 cytokines production by CD4+ T cells in the mucosal inductive and effector tissues. The SIgA Ab-enriched saliva showed significantly reduced numbers of live Pg cells binding to wsHAPs as compared with those in mice given double Ags without dDA or naïve mice. Additionally, saliva from IgA-deficient mice given nasal double Ags plus dDA indicated no decrease of live Pg binding to wsHAPs. CONCLUSION: These findings show that HSP-derived peptides-specific salivary SIgA Abs induced by nasal administration of stat23 and prp21 peptides plus dDA, play an essential role in preventing Pg attachment and colonization on the surface of teeth, suggesting a potency that the SIgA may interrupt and mask fimbriae-binding domains in HSPs on the teeth.

Secretory Cells Are the Primary Source of pIgR in Small Airways.

Loss of secretory IgA (SIgA) is common in chronic obstructive pulmonary disease (COPD) small airways and likely contributes to disease progression. We hypothesized that loss of SIgA results from reduced expression of pIgR (polymeric immunoglobulin receptor), a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium. pIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice used immunostaining, primary murine tracheal epithelial cell culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from nontypeable Haemophilus influenzae was evaluated in vitro. We found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and nontypeable H. influenzae-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD. Loss of the SIgA immunobarrier in small airways of patients with severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.

Colostrum IgA1 antibodies recognize antigens from Helicobacter pylori and prevent cytoskeletal changesin human epithelial cells.

Helicobacter pylori is a Gram-negative bacterium found on the luminal surface of the gastric mucosa in at least 50% of the world's human population. The protective effect of breastfeeding against H. pylori infection has been extensively reported; however, the mechanisms behind this protection remain poorly understood. Human IgA from colostrum has reactivity against H. pylori antigens. Despite that IgA1 and IgA2 display structural and functional differences, their reactivity against H. pylori had not been previously determined. We attested titers and reactivity of human colostrum-IgA subclasses by ELISA, immunoblot, and flow cytometry. Colostrum samples from healthy mothers had higher titers of IgA; and IgA1 mostly recognized H. pylori antigens. Moreover, we found a correlation between IgA1 reactivity and their neutralizing effect determined by inhibition of cytoskeletal changes in AGS cells infected with H. pylori. In conclusion, colostrum-IgA reduces H. pylori infection of epithelial gastric cells, suggesting an important role in preventing the bacteria establishment during the first months of life. As a whole, these results suggest that IgA1 from human colostrum provides protection that may help in the development of the mucosal immune system of newborn children.

A Randomized Controlled Trial of Dietary Rice Bran Intake on Microbiota Diversity, Enteric Dysfunction, and Fecal Secretory IgA in Malian and Nicaraguan Infants.

BACKGROUND: Malnutrition and diarrhea are leading causes of death in children aged <5 y. Rice bran is a nutrient-dense prebiotic available globally. OBJECTIVES: The objective of this secondary analysis was to evaluate the effects of daily rice bran supplementation on environmental enteric dysfunction (EED) markers, total fecal secretory IgA (sIgA), and microbiota in infants at high risk of malnutrition. METHODS: Six-month-old Malian and Nicaraguan infants were randomly assigned to control or daily rice bran supplementation cohorts (1 to 5 g/d). Feces were collected monthly for 6 mo to evaluate fecal sIgA, markers of EED, and microbiota diversity. Statistical methods included linear mixed models, generalized mixed models, Spearman correlation, and Wilcoxon rank-sum tests. RESULTS: Six-month-old Malian infants had significantly elevated sIgA (4.0× higher, P < 0.001), fecal myeloperoxidase (31.6× higher, P < 0.001), fecal α1-antitrypsin (1.8× higher, P = 0.006), and lower fecal neopterin (0.13× higher, P < 0.001) than the age-matched Nicaraguan infants. In the Nicaraguan rice bran cohort from 6 to 12 mo of age, there was a significant decrease in sIgA concentrations (0.4×, P < 0.05) and a correlation between sIgA and the EED marker α1-antitrypsin (0.523, P < 0.0001) at 12 mo of age. In Malian infants, daily rice bran ingestion resulted in decreased EED scores (0.71×, P = 0.02) and a stable sIgA concentration over time. The rice bran group of Malian infants also had correlation between sIgA and the EED marker neopterin (0.544, P < 0.001) at 12 mo of age and a significant (P < 0.05) increase in microbiota α-diversity at a younger age (9 mo with rice bran compared with 10 mo in control group), which supports earlier microbiota maturation. CONCLUSIONS: These results support rice bran as a functional food ingredient targeting gut mucosa in children at high-risk of malnutrition.

Low rate of asymptomatic carriage and salivary immunoglobulin A response to Group A Streptococci in the healthy adult population in Finland.

Streptococcus pyogenes, also called group A streptococcus (GAS), is a human pathogen causing a wide range of infections ranging from mild tonsillitis to severe, life threatening conditions such as bacteraemia, necrotizing fasciitis, and streptococcal toxic shock syndrome. GAS may also colonise the oropharynx without causing any signs of disease which is known as asymptomatic carriage. This study aims to investigate IgA responses against GAS and oral streptococci from saliva samples collected from healthy Finnish adults. In addition, asymptomatic throat GAS carriage was studied. The study participants consisted of healthy adult volunteers who provided one saliva sample, a throat swab, and a background questionnaire. Total salivary IgA, and GAS specific IgA were analysed from the saliva samples using enzyme-linked immunosorbent assays (ELISA) and the results were compared to oral streptococci specific IgA levels. Asymptomatic GAS throat carriers were identified by bacterial culture, and the isolates were emm typed. Samples from a total of 182 individuals were analysed. The median salivary IgA concentration was 62.9 µg/ml (range 17.3-649.9 µg/ml), and median GAS and oral streptococcal specific IgA concentrations 2.7 and 3.3 arbitrary units (AU, range 1.4-7.4 AU and 1.6-12.0 AU), respectively. Three individuals with asymptomatic GAS throat carriage were identified.

Intestinal polyparasitism and levels of mucosal anthelmintic SIgA in children from endemic areas in Northeastern Brazil.

Interactions between parasites during co-infections are often complex and can impact immunization and treatment programmes, as well as disease outcomes and morbidity. However, little is known about these interactions and the mechanisms involved. In this study, a coproparasitological survey was carried out in school-age children living in endemic areas of parasitic infection in the state of Sergipe, Northeastern Brazil. Anti-helminth-specific and total secretory immunoglobulin-A (SIgA) levels were measured in stool and saliva samples and were compared in children presenting monoparasitism, polyparasitism (helminths and/or intestinal protozoa) and no infections. The survey showed that protozoa were more prevalent than helminths, and that there was a high frequency of polyparasitism in the studied population, mainly from combinations of protozoan species. Although less frequent, combinations between species of protozoa and helminths were also observed. The levels of salivary SIgA in these co-infected individuals were lower than the average observed in infections with helminths alone. Although the children participating in this survey were asymptomatic, and it was, therefore, not possible to evaluate the impact of salivary SIgA reduction on the diseases, and the study highlights the need for further investigations of co-infections by intestinal parasites and the effects on immune response induced by the interactions between different parasites.

Prevalence of saliva immunoglobulin A antibodies reactive with severe acute respiratory syndrome coronavirus 2 among Japanese people unexposed to the virus.

While the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a threat to public health as the number of cases and COVID-19-related deaths are increasing worldwide, the incidence of the virus infection is extremely low in Japan compared with many other countries. To explain this uncommon phenomenon, we investigated the prevalence of naturally occurring ("natural") antibodies, focusing on those of the secretory immunoglobulin A (sIgA) form, reactive with SARS-CoV-2 among Japanese people. One hundred and eighty healthy Japanese volunteers of a wide range of age who had been considered to be unexposed to SARS-CoV-2 participated in this study. Saliva samples and blood samples were collected from all of the 180 participants and 139 adults (aged ≥ 20 years) included therein, respectively. The determination of saliva IgA antibodies, mostly comprising sIgA antibodies, as well as serum IgA and immunoglobulin G antibodies, reactive with the receptor binding domain of the SARS-CoV-2 spike-1 subunit proteins was conducted using an enzyme-linked immunosorbent assay. The major findings were that 52.78% (95% confidence interval, 45.21%-60.25%) of the individuals who had not been exposed to SARS-CoV-2 were positive for saliva IgA antibodies with a wide range of levels between 0.002 and 3.272 ng/mL, and that there may be a negative trend in positivity for the antibodies according to age. As we had expected, a frequent occurrence of assumable "natural" sIgA antibodies reactive with SARS-CoV-2 among the studied Japanese participant population was observed.

Induced Polyspecificity of Human Secretory Immunoglobulin A Antibodies: Is It Possible to Improve Their Ability to Bind Pathogens?

INTRODUCTION: As has been shown previously, various protein-modifying agents can change the antigen-binding properties of immunoglobulins. However, induced polyspecificity of human secretory immunoglobulin A (sIgA) has not been previously characterized in detail. METHODS: In the present study, human secretory immunoglobulin A (IgA) was exposed to buffers with acidic pH, to free heme, or to pro-oxidative ferrous ions, and the antigen-binding behavior of the native and modified IgA to viral and bacterial antigens was compared using Western blotting and enzyme-linked immunosorbent assay. The ability of these agents to modulate the antigen-binding properties of human sIgA toward a wide range of pathogen peptides was investigated using an epitope microarray. RESULTS: We have shown that acidic pH, heme, and pro-oxidative ferrous ions influenced the binding of secretory IgA in opposite directions (either increasing or decreasing); however, the strongest effect was observed when using buffers with low pH. This fraction had the highest number of affected reactivities; most of them were increased and most of the new ones were toward common pathogens. CONCLUSIONS: Thus, it was shown that all investigated treatments can alter to some degree the antigen-binding of secretory IgA, but acidic pH has the most potentially beneficial effect by increasing binding to a largest number of common pathogens' antigens.

Oral Immunotherapy With Human Secretory Immunoglobulin A Improves Survival in the Hamster Model of Clostridioides difficile Infection.

Coadministration of human secretory IgA (sIgA) together with subtherapeutic vancomycin enhanced survival in the Clostridioides difficile infection (CDI) hamster model. Vancomycin (5 or 10 mg/kg × 5 days) plus healthy donor plasma sIgA/monomeric IgA (TID × 21 days) or hyperimmune sIgA/monomeric IgA (BID × 13 days) enhanced survival. Survival was improved compared to vancomycin alone, P = .018 and .039 by log-rank Mantel-Cox, for healthy and hyperimmune sIgA, respectively. Passive immunization with sIgA (recombinant human secretory component plus IgA dimer/polymer from pooled human plasma) can be administered orally and prevents death in a partially treated CDI hamster model.

[Magnetic resonance and magnetoelectric therapy combined with Danhong Tongjing Prescription for the treatment of CP/CPPS and its effects on secretory IgA, vascular cell adhesion molecule-1 and interleukin-8].

OBJECTIVE: To investigate the therapeutic effect of magnetic resonance and magnetoelectric therapy (MRMT) combined with oral Danhong Tongjing Prescription (DTP) on chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS) and the changes in the levels of cytokine-secretory IgA (sIgA), vascular cell adhesion molecule-1 (VCAM-1) and interleukin-8 (IL-8) after treatment. METHODS: Totally 200 patients with CP/CPPS of the qi stagnation and blood stasis type were randomly divided into three groups to receive MRMT + DTP (n = 68), MRMT (n = 67) and DTP (n = 65), respectively, all for 12 weeks. After treatment, we compared the total effectiveness rate, patients' scores on NIH-CPSI and traditional Chinese medicine (TCM) syndrome, and the expressions of sIgA, VCAM-1 and IL-8 in the EPS among the three groups of the patients. RESULTS: After treatment, the patients in the MRMT + DTP group, compared with those in the MRMT and DTP groups, showed a significantly higher total effectiveness rate (86.76% vs 79.10% and 78.46%, P < 0.05 and P < 0.01) and lower scores on pain or discomfort (4.61 ± 2.37 vs 5.86 ± 3.26 and 6.94 ± 2.25 P < 0.01), abnormal urination symptoms (2.98 ± 1.75 vs 3.85 ± 2.01 and 3.94 ± 1.95) and quality of life (3.26 ± 1.87 vs 4.54 ± 2.13 and 4.69 ± 1.72). There were statistically significant differences in the total NIH-CPSI scores among the three groups (10.64 ± 5.91 vs 4.59 ± 6.87 vs 15.54 ± 5.76, P < 0.05). The MRMT + DTP group also exhibited a remarkably lower TCM syndrome score than the MRMT and DTP groups (5.56 ± 3.42 vs 7.37 ± 4.57 and 8.16 ± 3.65, P < 0.05). Compared with the baseline, the expressions sIgA, VCAM-1 and IL8 were all markedly decreased after treatment in the MRMT + DTP (Z = －7.170, Z = －7.182, Z = －7.18), MRMT (Z = －6.802, Z = －6.973, Z = －6.768) and DTP groups (Z = －5.963, Z = －6.990 Z = －5.618) (P < 0.05), even more significantly in the former than in the latter two groups (P < 0.05). CONCLUSION: Magnetic resonance and magnetoelectric therapy combined with Danhong Tongjing Prescription has a good therapeutic effect on CP/CPPS of the qi stagnation and blood stasis type, probably by regulating sIgA, VCAM-1, IL-8 and other cytokines, activating the function of the immune system, inhibiting inflammation, and promoting the absorption of local inflammatory substances.

Effect of Senecio scandens ethanol extract on gut microbiota composition in mice.

The gut microbiota inhabits the animal intestinal tract, and dysbiosis of the gut microbiota may result in disease. Senecio scandens has pharmaceutical antibacterial activities and is regarded as a broad-spectrum antibiotic in traditional Chinese medicine. Extracts of S. scandens are reported to show strong antimicrobial activity, and quercetin significantly decreases some species in the caecal microflora. However, the bactericidal effects of the extracts on the gut microbiota remain obscure. Here, we supplied ethanol extract of S. scandens, which might possibly be used as an alternative for chemical antibiotics, to mice to investigate the state of the intestinal microbiota. Our studies included a control group, low-, moderate-, and high-dose ethanol extract groups, and cefixime capsule group. The ethanol extract groups did not present reduced diversity or differences in the gut microbiota balance. There were significant differences between the ethanol extract and cefixime capsule groups in terms of the gut microbiota. The control and ethanol extract groups contained similar bacteria, which suggested that the ethanol extract has no inhibitory effect on the gut microbiota in vivo. Bifidobacteriales and Lactobacillus acidophilus were significantly increased in the high-dose group. Both secretory immunoglobulin A and mucin 2 concentrations increased as the dose of ethanol extract increased. The functional prediction differences between the control and ethanol extract groups decreased with increasing extract doses, which indicated that the low-dose and high-dose extract treatments might regulate different pathways and functions of the gut microbiota. The results also highlighted the prevention of bacterial drug resistance in the ethanol extract groups.

Impaired salivary SIgA antibodies elicit oral dysbiosis and subsequent induction of alveolar bone loss.

OBJECTIVE: Secreted IgA (SIgA) plays a central role in preventing bacterial and viral infections on mucosal surfaces by neutralizing toxins and viruses and inhibiting bacterial attachment to epithelial cells. However, the role of salivary SIgA antibodies (Abs) in regulating oral flora is still unknown. This study aimed to evaluate the association among oral bacteria, their metabolites and periodontitis in IgA-deficient (IgA KO) and wild-type (WT) control mice. METHODS: Microcomputed tomography (micro-CT) analysis was used to assess alveolar bone resorption as a development of periodontitis. The bacterial profiles of saliva were determined using the next-generation sequencing assays. Furthermore, the metabolites in saliva were measured and compared using CE-TOFMS. RESULTS: Salivary microbiota of IgA KO mice revealed a remarkably decreased frequency of Streptococcus, and increased percentages of Aggregatibacer, Actinobacillus, and Prevotella at the genus level when compared with those of WT. Compared to WT control mice of the same age, the level of alveolar bone loss was significantly increased in IgA KO mice, and infiltration of osteoclasts was found on the surface of the alveolar bone. The metabolome profile indicated that the metabolites of IgA KO mice had greater variability in carbon metabolic, urea cycle, and lipid pathways than WT mice. CONCLUSION: These results suggest that salivary SIgA plays an important role in regulating and maintaining normal oral microflora to prevent the development of periodontal disease.

Role of Human Mesangial-Tubular Crosstalk in Secretory IgA-Induced IgA Nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is characterized by the mesangial deposition of pathogenic IgA. We previously detected the deposition of pathogenic secretory IgA (SIgA) in the mesangium of about one-third of IgAN patients. Tubulointerstitial injury has an important role in the development of IgAN. However, the relationship between SIgA and tubulointerstitial damage is currently unclear. In this work, the role of the mesangial-tubular crosstalk was explored in the tubulointerstitial damage in SIgA-induced IgAN. METHODS: SIgA deposition in renal tissues of IgAN patients was detected by immunofluorescence. Flow cytometry was used to assess the binding of SIgA to human renal mesangial cells (HRMC) and human proximal tubule epithelial (HK-2) cells. HK-2 was co-cultured with HRMC added with SIgA isolated from patients or normal volunteers. Protein synthesis and gene expressions of TNF-α, TGF-ß1, and MCP-1 were determined by ELISA and PCR, respectively. The expressions of the above cytokines in renal tissues of patients and normal controls were detected by immunohistochemistry. RESULTS: Twenty-nine of 96 patients had SIgA deposition in the mesangium, but SIgA was rarely detected in the tubulointerstitium. The binding rate of SIgA to HK-2 (2.79%) was significantly lower than that of HRMC (81.6%) (p < 0.001). The expressions of TNF-α, TGF-ß1, and MCP-1 in HRMC were significantly higher than in SIgA-stimulated HK-2 (p < 0.05), and their expressions were significantly higher in the SIgA-stimulated co-culture group compared with SIgA-stimulated HRMC (p < 0.05). The expressions of the above cytokines were mainly detected in tubulointerstitium of IgAN patients with positive and negative SIgA deposition, without significant difference between the 2 groups, but to a significantly higher level than that in normal controls, and their expressions positively correlated with tubulointerstitial injury. CONCLUSION: Inflammatory factors released from the mesangium after SIgA deposition might mediate tubulointerstitial damage via mesangial-tubular crosstalk in IgAN.

[A prospective randomized comparative study of the efficacy and safety of a two-week bismuth-based quadrotherapy of Helicobacter pylori infection with the inclusion of the probiotic containing Bifidobacterium longum BB-46 and Enterococcus faecium ENCfa-68 ].

AIM: To study the efficacy and safety of a two-week bismuth-based quadruple of Helicobacter pylori (Hp) infection with the inclusion of a probiotic Bifiform. MATERIALS AND METHODS: An open prospective comparative randomized study included 68 Hp-positive patients: 22 with a confirmed diagnosis of peptic ulcer disease, 46 with chronic gastritis, gastroduodenitis and erosions in the pylorobulbar zone. The diagnosis and Hp infection were verified by the results of endoscopic and morphological studies, as well as using the 13C-urease breath test and determination of the Hp antigen in the feces. Depending on the therapy, the patients were randomized into 2 groups: the main group was taken 2 times a day for 14 days omeprazole 20 mg + amoxicillin 1000 mg + clarithromycin 500 mg + bismuth tripotassium dicitrate 240 mg + Bifiform 2 capsules 2 times a day; control similar therapy was carried out, but without the inclusion of Bifiform. Repeated testing for Нр was carried out one month after the termination of the course of treatment. RESULTS: When using bismuth-containing quadruple, a high frequency of Hp eradication was noted, which in the ITT analysis was 86.1 and 68.8% (p0.05) and in the PP analysis it was 93.9 and 95.7% (p0.05) in patients of the main and control groups, respectively. Side effects of drug therapy were detected in 16.7 and 43.8% (p0.05), which was the reason for the early termination of therapy as a result of their development in 5.6 and 28% (p0.05) in patients of the main and control groups, respectively. The inclusion of the probiotic Bifiform in the eradication triple therapy of Hp infection reduced the frequency of detection of colonic dysbiosis from 27.8 to 3.6% and had a positive effect on the indices of local immunity (increased content of plasma cells in the inflammatory infiltrate and a stable level of secretory immunoglobulin A in coprofiltrate). CONCLUSION: A prospective, comparative, randomized study has shown that when using a two-week bismuth-based quadruple the eradication rate exceeds 90%. The inclusion of Bifiform in the eradication scheme dramatically reduces the frequency of adverse events and increases patient compliance, and also maintains the protective factors of the gastrointestinal mucosa at a higher level.

Secretory IgA accumulated in the airspaces of idiopathic pulmonary fibrosis and promoted VEGF, TGF-ß and IL-8 production by A549 cells.

Secretory IgA (SIgA) is a well-known mucosal-surface molecule in first-line defense against extrinsic pathogens and antigens. Its immunomodulatory and pathological roles have also been emphasized, but it is unclear whether it plays a pathological role in lung diseases. In the present study, we aimed to determine the distribution of IgA in idiopathic pulmonary fibrosis (IPF) lungs and whether IgA affects the functions of airway epithelial cells. We performed immunohistochemical analysis of lung sections from patients with IPF and found that mucus accumulated in the airspaces adjacent to the hyperplastic epithelia contained abundant SIgA. This was not true in the lungs of non-IPF subjects. An in-vitro assay revealed that SIgA bound to the surface of A549 cells and significantly promoted production of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß and interleukin (IL)-8, important cytokines in the pathogenesis of IPF. Among the known receptors for IgA, A549 cells expressed high levels of transferrin receptor (TfR)/CD71. Transfection experiments with siRNA targeted against TfR/CD71 followed by stimulation with SIgA suggested that TfR/CD71 may be at least partially involved in the SIgA-induced cytokine production by A549 cells. These phenomena were specific for SIgA, distinct from IgG. SIgA may modulate the progression of IPF by enhancing synthesis of VEGF, TGF-ß and IL-8.

Distinct roles for Peyer's patch B cells for induction of antigen-specific IgA antibody responses in mice administered oral recombinant Salmonella.

Our previous study demonstrated an indispensable role of Peyer's patches (PPs) for the induction of antigen-specific secretory (S)IgA antibody responses after oral immunization with recombinant Salmonella expressing fragment C of tetanus toxin (rSalmonella-Tox C). In this study, we defined the PP lymphoid structures and immune cells required for the induction of mucosal SIgA antibody responses. Adoptive transfer of mononuclear cells (MNCs) from PPs into PP-deficient (PP-null) mice failed to elicit tetanus toxoid (TT)-specific mucosal immunity. However, when the same PP MNCs were transferred into lethally irradiated PP-normal recipient mice, PP MNCs preferentially emigrated to recipient PPs, leading to PP lymphoid structures and TT-specific SIgA antibody responses. Significantly reduced numbers of TT-specific IgA antibody-forming cells were detected in the mesenteric lymph nodes (MLNs) and intestinal lamina propria of mice when surface expression of the sphingosine 1-phosphate receptor on lymphocytes was inhibited by its agonist FTY720. However, FTY720 treatment did not alter dendritic cell migration or Salmonella dissemination into these tissues. When rSalmonella-Tox C-stimulated CD4+ T cells isolated from PPs, MLNs and the spleen were co-cultured with B cells from these tissues, significantly increased levels of TT-specific IgA antibody responses were exclusively induced in cultures containing PP B cells. Furthermore, surface IgA+ PP B cells produced TT-specific IgA antibody responses in vitro. These findings suggest that PP lymphoid structures and surface IgA+ PP B cells are essential elements for the induction of antigen-specific intestinal SIgA antibody responses to oral Salmonella.