Increased IgA Production Research Articles

Regulatory T and B cells in pediatric Henoch–Schönlein purpura: friends or foes?

Background and objectivesHenoch–Schönlein purpura (HSP) is the most common immunoglobulin A-mediated systemic vasculitis in childhood. We studied immune dysregulation in HSP by analyzing regulatory T (Treg), T helper 3 (Th3), and regulatory B cell (Breg) subpopulations that might intervene in immune activation, IgA production, and HSP clinical manifestations.MethodsThis prospective study included 3 groups of children: 30 HSP on acute phase, 30 HSP on remission, and 40 healthy controls (HCs) matched on age. Treg, Breg, and Th3 were analyzed by flow cytometry. Serum immunoglobulin and cytokine levels were quantified by ELISA and Luminex.ResultsTreg frequencies were higher in acute HSP than in remitting HSP and HCs (6.53% [4.24; 9.21] vs. 4.33% [3.6; 5.66], p = 0.002, and vs. 4.45% [3.01; 6.6], p = 0.003, respectively). Activated Th3 cells (FoxP3 + Th3 cells) tend to be more abundant in HSP than in HCs (78.43% [50.62; 80.84] vs. 43.30% [40.20; 49.32], p = 0.135). Serum IgA, IL-17, and latency-associated peptide (a marker of the anti-inflammatory cytokine TGF-beta production) were significantly and inflammatory cytokines TNF-alpha, IL-1-beta, and IL-6 were non-significantly higher in HSP than HCs. Bregs were identical between the groups, but, in patients with renal impairment, Breg percentage was lower compared to those without. Treg removal in PBMC culture resulted in an increase in IgA production in HSP proving a negative regulatory role of Tregs on IgA production.ConclusionsIn pediatric HSP, immune activation persists in spite of an increase in Th3 and Tregs. Th3 could be involved in IgA hyperproduction, inefficiently downregulated by Tregs. Lack of Bregs appears linked to renal impairment.

Lrba participates in the differentiation of IgA+ B lymphocytes through TGFβR signaling.

Lrba is a cytoplasmic protein involved in vesicular trafficking. Lrba-deficient (Lrba-/-) mice exhibit substantially higher levels of IgA in both serum and feces than wild-type (WT) mice. Transforming growth factor β1 (TGFβ1) and its receptors (TGFβR I and II) is essential for differentiating IgA+ B cells. Furthermore, increased IgA production suggests a potential connection between Lrba and the TGFβR signaling pathway in IgA production. However, the specific function of Lrba in B cell biology remains unknown. Given the increased IgA levels in Lrba-/- mice, the goal in this work was to explore the lymph organs where the switch to IgA occurs, and if TGFβR function is affected. Non-immunized Lrba-/- mice were compared with Lrba+/+ mice. IgA levels in the serum and feces, as well as during peripheral B cell development, were determined. IgA+ B cells and plasma cells were assessed in the small intestine and secondary lymphoid organs, such as the spleen, mesenteric lymph nodes, and Peyer's patches. The TGFβR signaling pathway was evaluated by determining the expression of TGFβR on B cells. Additionally, SMAD2 phosphorylation was measured under basal conditions and in response to recombinant TGFβ. Finally, confocal microscopy was performed to investigate a possible interaction between Lrba and TGFβR in B cells. Lrba-/- mice exhibited significantly higher levels of circulating IgA, IgA+ B, and plasma cells than in peripheral lymphoid organs those in WT mice. TGFβR expression on the membrane of B cells was similar in both Lrba-/- and Lrba+/+ mice. However, intracellular TGFβR expression was reduced in Lrba-/- mice. SMAD2 phosphorylation showed increased levels under basal conditions; stimulation with recombinant TGFβ elicited a poorer response than in that in Lrba+/+ B cells. Finally, we found that Lrba colocalizes with TGFβR in B cells. Lrba is essential in controlling TGFβR signaling, subsequently regulating SMAD2 phosphorylation on B cells. This mechanism may explain the increased differentiation of IgA+ B cells and production of IgA-producing plasma cells.

Influence of IgA nephropathy on the progression of pulpitis and apical periodontitis in HIGA mice

ObjectivesImmunoglobulin (Ig)A nephropathy has been associated with oral infections such as periodontitis, but its pathogenesis is not fully understood; no treatments exist. This study analyzes the influence of IgA nephropathy, an autoimmune disease, on the pathogenesis of pulpitis and apical periodontitis. MethodsTwo groups of mice were used in pulp infection experiments: high serum IgA nephropathy model mice (HIGA) and control mice (BALB/c). Histologic analyses of the pulp and apical periodontal tissues were performed on days 3, 5, 7, 14, and 28 following oral bacterial infection. The dynamics of odontoblasts, apoptotic cells, and IgA expression were analyzed using anti-Nestin, TUNEL, and anti-IgA staining, respectively. ResultsInflammatory cells infiltrated the exposed pulp at day three in both groups and by 14 days, these cells had infiltrated from the pulp to the apical periodontal tissue. The area of necrotic pulp tissue increased significantly in the control group at seven days. Odontoblasts decreased from day three onwards and disappeared by 28 days in both groups. The number of apoptotic cells in the pulp and apical periodontal tissues was significantly higher in the experimental group at day 28. The experimental group exhibited a significant increase in IgA production in the pulp after 14 days. Bone resorption in the apical periodontal tissue was significantly decreased in the experimental group at day 28. ConclusionsThe results of this study suggest that IgA nephropathy may modulate the inflammatory response and sustain long-term biological defense responses in pulpitis and apical periodontitis in HIGA mice.

MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy

Multiple genome-wide association studies (GWASs) have reproducibly identified the MTMR3/HORMAD2/LIF/OSM locus to be associated with IgA nephropathy (IgAN). However, the causal variant(s), implicated gene(s), and altered mechanisms remain poorly understood. Here, we performed fine-mapping analyses based on GWAS datasets encompassing 2762 IgAN cases and 5803 control individuals, and identified rs4823074 as the candidate causal variant that intersects the MTMR3 promoter in B-lymphoblastoid cells. Mendelian randomization studies suggested the risk allele may modulate disease susceptibility by affecting serum IgA levels through increased MTMR3 expression. Consistently, elevated MTMR3 expression in peripheral blood mononuclear cells was observed in patients with IgAN. Further mechanistic studies invitro demonstrated that MTMR3 increased IgA production dependent upon its phosphatidylinositol 3-phosphate binding domain. Moreover, our study provided the invivo functional evidence that Mtmr3-/- mice exhibited defective Toll Like Receptor 9-induced IgA production, glomerular IgA deposition, as well as mesangial cell proliferation. RNA-seq and pathway analyses showed that MTMR3 deficiency resulted in an impaired intestinal immune network for IgA production. Thus, our results support the role of MTMR3 in IgAN pathogenesis by enhancing Toll Like Receptor 9-induced IgA immunity.

Стан неспецифічної резистентності ротової порожнини у працівників промислових виробництв із шкідливими чинниками

The purpose of the study was to investigate local resistance of the oral cavity in industrial workers with harmful factors, patients with generalized periodontitis. Materials and methods. For this study, 2 examination groups were formed. The main group (61 people) includes employees of three industrial productions of the Ivano-Frankivsk region: employees of chemical production, glass production and agro-industrial complex. The control group consisted of 30 conditionally healthy individuals with intact periodontium. The age of the examinees was 25–55 years. Work experience in production is from 0.5 to 15 years. In order to study the state of local resistance in generalized periodontitis under the influence of harmful factors of the production environment, individual indicators of the immunity of the capillary blood of the gums and oral fluid were studied: the total number of leukocytes and lymphocytes; to evaluate the T-system of immunity, calculation of subpopulations of lymphocytes was performed using monoclonal antibodies CD-3, CD-4, CD-8; the level of immunoglobulins IgA, IgG and sIA; circulating immune complexes; phagocytic index, spontaneous nitroblue tetrazolium test. Results and discussion. A comparative evaluation of the results of immunological research in 61 patients with generalized chronic periodontitis of the main group and 30 healthy individuals of the control group indicated certain changes in the quantitative data of cellular and humoral factors and deviations in the functional activity of individual parameters of non-specific protection in the capillary blood of the gums of patients compared to the indicators of individuals with intact periodontium. The total number of leukocytes and lymphocytes in workers with generalized periodontitis remained within the generally accepted norm and differed insignificantly from the similar indicators of the healthy group. At the same time, a difference in the subpopulation composition of T-lymphocytes was revealed. According to absolute indicators, the number of CD4+ lymphocytes in patients with generalized periodontitis was 0.57 ± 0.04109/l, which is by 1.2 times lower compared to 0.68 ± 0.03109/l in healthy individuals. The obtained indicators of CD4+ and CD8+ lymphocytes made it possible to state a decrease in the value of the immunoregulatory index in workers with generalized periodontitis by 19.31% from the value of healthy people (1.63 ± 0.04 versus 2.02 ± 0.02), which is characteristic of immunodepressive conditions. In patients of the main group, an increase in IgA production was recorded on average to 2.05 ± 0.06 g/l, which is by 11.41% higher compared to the indicator (1.84 ± 0.02 g/l) of the control group. In workers of industries with harmful factors, with a dystrophic-inflammatory process in the periodontium, the level of average globular circulating immune complexes exceeded the value of healthy people (0.10 ± 0.03 mg/ml) by 2.5 times. This may indicate exhaustion of the clearance function of the phagocytic system and the development of hyperimmune complex syndrome. Conclusion. Having studied individual indicators of the capillary blood of the gums and oral fluid, we can conclude that in chronic exogenous intoxication with industrial xenobiotics, phenomena of acquired combined immune deficiency were observed, which were manifested by a decrease in the immuno-regulatory index CD4+/CD8+; a violation in the humoral link of immunity – activation of IgA, IgG production and a decrease in sIgA secretion, disorders of the phagocytic system, manifested by a decrease in the phagocytic activity of neutrophils and activation of oxygen-dependent metabolism (nitroblue tetrazolium test), which indicated, on the one hand, the strengthening of redox processes in these cells and a certain antibacterial potential of them, but on the other hand – the deepening of the inflammatory process of autogenous origin. Exhaustion of the body's compensatory capabilities confirmed the increase in the level of medium-globular circulating immune complexes. Therefore, significant changes in the non-specific protection of the oral cavity were observed in industrial workers suffering from generalized periodontitis

Identification and Functional Evaluation of Polyphenols That Induce Regulatory T Cells.

Regulatory T cells (Tregs) and CD4+/CD25+ T cells play an important role in the suppression of excessive immune responses, homeostasis of immune function, and oral tolerance. In this study, we screened for food-derived polyphenols that induce Tregs in response to retinaldehyde dehydrogenase (RALDH2) activation using macrophage-like THP-1 cells. THP-1 cells were transfected with an EGFP reporter vector whose expression is regulated under the control of mouse Raldh2 promoter and named THP-1 (Raldh2p-EGFP) cells. The THP-1 (Raldh2p-EGFP) cells were treated with 33 polyphenols after inducing their differentiation into macrophage-like cells using phorbol 12-myristate 13-acetate. Of the 33 polyphenols, five (kaempferol, quercetin, morin, luteolin and fisetin) activated Raldh2 promoter activity, and both quercetin and luteolin activated the endogenous Raldh2 mRNA expression and enzymatic activity. Furthermore, these two polyphenols increased transforming growth factor beta 1 and forkhead box P3 mRNA expression, suggesting that they have Treg-inducing ability. Finally, we verified that these polyphenols could induce Tregs in vivo and consequently induce IgA production. Oral administration of quercetin and luteolin increased IgA production in feces of mice. Therefore, quercetin and luteolin can induce Tregs via RALDH2 activation and consequently increase IgA production, suggesting that they can enhance intestinal barrier function.

Distinct B cell subsets in Peyer\u2019s patches convey probiotic effects by Limosilactobacillus reuteri

BackgroundIntestinal Peyer’s patches (PPs) form unique niches for bacteria-immune cell interactions that direct host immunity and shape the microbiome. Here we investigate how peroral administration of probiotic bacterium Limosilactobacillus reuteri R2LC affects B lymphocytes and IgA induction in the PPs, as well as the downstream consequences on intestinal microbiota and susceptibility to inflammation.ResultsThe B cells of PPs were separated by size to circumvent activation-dependent cell identification biases due to dynamic expression of markers, which resulted in two phenotypically, transcriptionally, and spatially distinct subsets: small IgD+/GL7−/S1PR1+/Bcl6, CCR6-expressing pre-germinal center (GC)-like B cells with innate-like functions located subepithelially, and large GL7+/S1PR1−/Ki67+/Bcl6, CD69-expressing B cells with strong metabolic activity found in the GC. Peroral L. reuteri administration expanded both B cell subsets and enhanced the innate-like properties of pre-GC-like B cells while retaining them in the sub-epithelial compartment by increased sphingosine-1-phosphate/S1PR1 signaling. Furthermore, L. reuteri promoted GC-like B cell differentiation, which involved expansion of the GC area and autocrine TGFβ-1 activation. Consequently, PD-1-T follicular helper cell-dependent IgA induction and production was increased by L. reuteri, which shifted the intestinal microbiome and protected against dextran-sulfate-sodium induced colitis and dysbiosis.ConclusionsThe Peyer’s patches sense, enhance and transmit probiotic signals by increasing the numbers and effector functions of distinct B cell subsets, resulting in increased IgA production, altered intestinal microbiota, and protection against inflammation.3CbyP5PufHSWXKDo4r3t6tVideo abstract

Industrial applications of selected JFS articles

Industrial applications of selected <i>JFS</i> articles

Effect of long-term consumption of tea (Camellia sinensis L.) flower polysaccharides on maintaining intestinal health in BALB/c mice.

Polysaccharides have various health-promoting functions. However, dietary polysaccharides cannot be digested by the human alimentary tract, thus the gut is the most important location where polysaccharides play their role. The effect of polysaccharides from tea (Camellia sinensis L.) flower (TFPS) on intestinal health was investigated in the present study. TFPS with the molecular weight of 1,316.29kDa was prepared, and twenty 6-week-old BALB/c male mice were randomly allotted to a chow diet (normal control group, NC group) or with 200mg/kg (body weight)/day of TFPS for 13 weeks (n = 10 each). Histomorphology observation of jejunum and colons showed that TFPS maintained the adequate gut barrier. qPCR analysis revealed that the expression of colonic tight junction proteins of claudin1 (1.29±0.15compared with 1.00±0.13, P <0.05) and claudin5 (2.91±0.44compared with 1.00±0.27, P <0.01) at mRNA level with a significant difference between TFPS supplement or not, while the expression of TLR4 and TNF-α mRNA was not changed statistically. 16S rDNA amplicons sequencing was applied to measure the compositions of gut microbiota from feces of mice. TFPS treatment exhibited similar relative abundances in Bacteroidetes and Firmicutes; however, it decreased the relative abundance of Akkermansia and increased that of Lactobacillus compared with the NC group. The contents of short-chain fatty acids after TFPS supplementation, both in cecal contents and feces, were significantly higher than those of the NC group. Besides, TFPS significantly increased IgA production. These results suggest that TFPS is beneficial to intestinal health and can improve intestinal adaptive immune tolerance. PRACTICAL APPLICATION: Dietary polysaccharides improve human intestinal health. Understanding the effect of TFPS, safe and healthy food components, on gut health increases the likelihood that TFPS will be developed as a functional food.

Immune regulation features in workers engaged into underground mining of chromite ores

The study of immune regulation features in workers engaged into underground mining of chromite ores demonstrated that high serum chromium levels were associated with increased phagocytic activity, if compared to physiologic normal values, in 25.7% of the workers. Findings also are phagocytic activity reliably changed by phagocytic index criterion, and significantly (1.2–1.33 times) increased absolute and relative phagocytosis and phagocytic index vs. the reference group values. IgM levels appeared 1.2 times lower vs. the reference group values, in association with IgG deficiency and increased IgA production vs. the reference values. The authors also revealed changes in cellular subpopulations balance and T-cell receptors transformation, with depressed regulatory marker CD95 in 90.0% in the main group workers, and higher number of CD4+CD25+CD127 lymphocytes, increased CD3+ and CD4+ cells 1.5- and 1.2-fold respectively vs. the reference group values. Other findings are disordered launching and regulation of apoptosis via lower Fas-receptor expression and changed balance of regulatory proteins Bcl–2 and Bax vs. the normal value in 50.0–62.5% of the workers, with reliable 2.6-fold increase of Bax level vs. the reference group.

Humoral Immune Response Modulation by Aryl hydrocarbon Receptor Activation (AhR) in CD11c+ Cells: Exploring Gender-specific and Ligand-dependent Effects on Antibody Responses in Mice.

Abstract Modulation of antibody responses is often a summation of effects on B cells, helper T cells, and dendritic cells (DCs). All three of these immune cells express AhR, a ligand-activated transcription factor with endogenous and exogenous ligands known to modulate immune responses. Importantly, antibody responses are keenly sensitive to AhR activation by TCDD, its prototypical ligand and common environmental pollutant. However, the specific contribution of AhR activation in DCs has not yet been defined, particularly in the context of gender-specific and ligand-dependent effects. We aimed to determine the effects of AhR activation in DCs by endogenous and exogenous ligands on OVA-specific antibody responses in mice. Specifically, we hypothesized that AhR activation in DCs alone suppresses antigen-specific serum antibody production, selectively affecting different isotypes. To test this hypothesis, we used mice conditionally deficient of AhR in CD11c+ DCs (AHRCD11c). Control (AhRd) and AHRCD11c mice were treated with vehicle, ITE or TCDD via oral gavage, and subsequently immunized i.p. with whole OVA/adjuvant to induce a systemic, antigen-specific humoral response. One week later, AhRd mice showed significantly reduced OVA-specific IgM and IgG2a titers while IgA was significantly increased; effects that were ameliorated in AhRCD11c mice. Interestingly, TCDD-induced IgA increases were both AhR- and gender-dependent with female mice showing increased IgA production. Collectively, these results demonstrate that DCs contribute to, but are not wholly responsible for, AhR-mediated effects on antigen-specific serum antibody generation. Research supported by ES013784 (DMS) and AAI Careers in Immunology Fellowship (JMK).

Modeling primary immune regulatory disorders: Ferrari or Yugo?

Despite about 75 million years of evolutionary separation, mice have proven to be remarkably informative for understanding the human immune system. Many immune signaling and developmental pathways are nearly identical between mouse and man, and some pathways, such as NK cell sensing of self, display clear evolutionary convergence. In this issue, Burnett et al. and Gamez-Diaz et al. independently describe the phenotype of Lipopolysaccharide Responsive Beige-like Anchor (LRBA) deficient mice. LRBA-deficient humans have a striking and severe syndrome of varied autoimmunity, lymphoproliferation, gut inflammation and immune deficiency.1 In contrast, these two groups report that LRBA-deficient mice are generally quite well. Despite aging and/or challenge with infectious organisms, these animals display none of the pathologies seen in humans. Of note, LRBA knockout mice have decreased CTLA4 protein levels, as is seen in LRBA-deficient patients, and is thought to underlie disease development. Both groups also noted other subtle immune abnormalities not correlated in patients to date: a decrease of the innate-like B1 B cells, and evidence of increased IgA production. These abnormalities are not predicted by any known function of LRBA, but may provide additional clues to disease pathogenesis.

Effect of purine nucleosides on growth performance, gut morphology, digestive enzymes, serum profile and immune response in broiler chickens

ABSTRACT1. This study was conducted to evaluate the effects of purine nucleosides on performance, gut morphology, intestinal enzymes and immunity functions in broiler chickens from 0 to 21 d of age.2. A total of 360 1-d-old male chickens (Cobb 500) were randomly assigned to 4 treatments with 6 replications. Experimental diets consisted of a control without any additives and diets containing 0.1% pure adenosine, 0.1% pure guanosine and 0.1% equal aliquots of pure adenosine and guanosine. Two birds per cage (12 birds per treatment) were killed on d 11 and 21 in order to obtain serum samples for lipid profile, jejunal samples for morphology and mucosal immunity, digestive enzymes for epithelial maturation, and bursa and spleen samples for relative weight of immune organs to live body weight.3. Birds receiving adenosine in their diets showed a significant increase in body weight and average daily gain and a significantly lower feed conversion ratio compared to the control birds. Villus height and width in jejunal samples also increased significantly in birds supplemented with adenosine. Although maltase was not affected by the experimental diets, adenosine increased alkaline phosphatase and aminopeptidase. Adenosine and its combination with guanosine boosted mucosal immunity as a result of increased IgA production. While there was no significant difference among treatments regarding the relative weight of the spleen, adenosine increased the relative weight of the bursa of Fabricius. Present results also showed that adding guanosine to broiler diets had no significant effects on growth, gut morphology, enzymes activity and immunological indices.4. In conclusion, the improvement in growth performance, gut morphology and immunity in birds receiving adenosine demonstrated that pure adenosine could be a beneficial feed additive for the poultry industry, while guanosine showed no significant improvement.

Neonatal colonization of mice with LGG promotes intestinal development and decreases susceptibility to colitis in adulthood.

Development of the intestinal microbiota during early life serves a key regulatory stage in establishing the host-microbial relationship. This symbiotic relationship contributes to developing host immunity and maintaining health throughout the life span. This study was to develop an approach to colonize conventionally raised mice with a model probiotic bacterium, Lactobacillus rhamnosus GG (LGG), and determine the effects of LGG colonization on intestinal development and prevention of colitis in adulthood. LGG colonization in conventionally raised was established by administering LGG to pregnant mice starting at gestational day 18 and pups at postnatal day 1 to day 5. LGG colonization promoted bodyweight gain and increased diversity and richness of the colonic mucosa-associated microbiota prior to weaning. Intestinal epithelial cell proliferation, differentiation, tight junction formation and mucosal IgA production were all significantly enhanced in LGG colonized mice. Adult mice colonized with LGG showed increased IgA production and decreased susceptibility to intestinal injury and inflammation induced in the dextran sodium sulphate model of colitis. Thus, neonatal colonization of mice with LGG enhances intestinal functional maturation and IgA production and confers life long health consequences on protection from intestinal injury and inflammation. This strategy might be applied for benefiting health in the host.

In vitro and in vivo effects of polysaccharides isolated from Korean persimmon vinegar on intestinal immunity

The in vitro and in vivo effects of crude polysaccharide isolated from Korean persimmon vinegar (KPV-0) on the intestinal immunostimulation were examined. KPV-0 was not cytotoxic to intestinal epithelial Caco-2 cells and could be transported through a Caco-2 cell monolayer in an in vitro coculture system. For and in vitro experiment, KPV-0 treatment significantly increased IgA production by Peyer’s patch (PP) cells and triggered an increase in transforming growth factor (TGF)-β1 and interleukin (IL)-6 levels. To investigate the in vivo effects of KPV-0 treatment, KPV-0 was administered to mice orally at different doses for 20 days. Oral administration of KPV-0-induced IgA and cytokines (IL-6, granulocyte macrophage-colony-stimulating factor, and TGF-β) production by PP cells and significantly increased the IgA levels in intestinal fluids and feces. These results suggested that the polysaccharides isolated from persimmon vinegar appear to modulate the intestinal immune system and could be beneficial to human health.

Retinoic acid enhances lactoferrin-induced IgA responses by increasing betaglycan expression.

Lactoferrin (LF) and retinoic acid (RA) are enriched in colostrum, milk, and mucosal tissues. We recently showed that LF-induced IgA class switching through binding to betaglycan (transforming growth factor-beta receptor III, TβRIII) and activation of canonical TGF-β signaling. We investigated the combined effect of LF and RA on the overall IgA response. An increase in IgA production by LF was further augmented by RA. This combination effect was also evident in Ig germ-line α (GLα) transcription and GLα promoter activity, indicating that LF in cooperation with RA increased IgA isotype switching. We subsequently found that RA enhanced TβRIII expression and that this increase contributed to LF-stimulated IgA production. In addition to the IgA response, LF and RA in combination also enhanced the expression of the gut-homing molecules C-C chemokine receptor 9 (CCR9) and α4β7 on B cells. Finally, peroral administration of LF and RA enhanced the frequency of CCR9+IgA+ plasma cells in the lamina propria. Taken together, these results suggest that LF in cooperation with RA can contribute to the establishment of gut IgA responses.

Ginsenoside Rg1 and 20(S)-Rg3 Induce IgA Production by Mouse B Cells.

Ginsenosides are the major components of ginseng, which is known to modulate blood pressure, metabolism, and immune function, and has been used to treat various diseases. It has been reported that ginseng and several ginsenosides have immunoregulatory effects on the innate and T cell-mediated immune response. However, their effects on the humoral immune response have not been fully explored. The present study examined the direct effects of red ginseng extract (RGE) and ginsenosides on mouse B cell proliferation and on antibody production and the expression of germline transcripts (GLT) by mouse B cells in vitro. RGE slightly reduced B cell proliferation, but increased IgA production by LPS-stimulated B cells. Furthermore, ginsenoside Rg1 and 20(S)-Rg3 selectively induced IgA production and expression of GLTα transcripts by LPS-stimulated B cells. Collectively, these results suggest that ginsenoside Rg1 and 20(S)-Rg3 can drive the differentiation of B cells into IgA-producing cells through the selective induction of GLTα expression.

Lactoferrin Combined with Retinoic Acid Stimulates B1 Cells to Express IgA Isotype and Gut-homing Molecules.

It is well established that TGF-β1 and retinoic acid (RA) cause IgA isotype switching in mice. We recently found that lactoferrin (LF) also has an activity of IgA isotype switching in spleen B cells. The present study explored the effect of LF on the Ig production by mouse peritoneal B cells. LF, like TGF-β1, substantially increased IgA production in peritoneal B1 cells but little in peritoneal B2 cells. In contrast, LF increased IgG2b production in peritoneal B2 cells much more strongly than in peritoneal B1 cells. LF in combination with RA further enhanced the IgA production and, interestingly, this enhancement was restricted to IgA isotype and B1 cells. Similarly, the combination of the two molecules also led to expression of gut homing molecules α4β7 and CCR9 on peritoneal B1 cells, but not on peritoneal B2 cells. Thus, these results indicate that LF and RA can contribute to gut IgA response through stimulating IgA isotype switching and expression of gut-homing molecules in peritoneal B1 cells.

Retinoic acid acts as a selective human IgA switch factor

Retinoic acid (RA) is known to have several functions that lead to a potent mucosal IgA response. Nevertheless, its exact role in human IgA synthesis has yet to be elucidated. Thus, we investigated the role of RA in promoting IgA isotype switching in human B cells. We found that RA increased IgA production and the expression of germ-line IgA1 and IgA2 transcripts (GLTα1 and GLTα2). This induction occurred alongside an increase in the frequency of IgA1-secreting B cell clones, as assessed by limiting dilution analysis. Under the same conditions, RA did not increase IgM and IgG production. Am80, an agonist of RA receptor α (RARα), increased IgA production. In addition, RA activity was abrogated by LE540, an antagonist of RAR, suggesting that the RAR pathway is involved in RA-induced IgA production. Taken together, these results indicate that RA induces IgA isotype switching mainly through RARα in human B cells.

Oral Administration of Lactobacillus plantarum Strain AYA Enhances IgA Secretion and Provides Survival Protection against Influenza Virus Infection in Mice

The mucosal immune system provides the first line of defense against inhaled and ingested pathogenic microbacteria and viruses. This defense system, to a large extent, is mediated by the actions of secretory IgA. In this study, we screened 140 strains of lactic acid bacteria for induction of IgA production by murine Peyer’s patch cells. We selected one strain and named it Lactobacillus plantarum AYA. We found that L. plantarum AYA-induced production of IL-6 in Peyer’s patch dendritic cells, with this production promoting IgA+ B cells to differentiate into IgA-secreting plasma cells. We also observed that oral administration of L. plantarum AYA in mice caused an increase in IgA production in the small intestine and lung. This production of IgA correlated strongly with protective ability, with the treated mice surviving longer than the control mice after lethal influenza virus infection. Our data therefore reveals a novel immunoregulatory role of the L. plantarum AYA strain which enhances mucosal IgA production and provides protection against respiratory influenza virus infection.