Soy Gly m 8 sIgE Has Limited Value in the Diagnosis of Soy Allergy in Peanut Ara h 2-Sensitized Adults.

INTRODUCTION: Recently, specific IgE (sIgE) sensitization against Gly m 8 (soy 2S albumin) has been described as a good diagnostic marker for soy allergy (SA). The aim of this study was to evaluate the diagnostic value of Gly m 8 by determining the sensitization profiles based on the homologues soy allergens Bet v 1, Ara h 1, Ara h 2, and Ara h 3. METHODS: Thirty soy-allergic adults were included; sIgE to total soy extract, Gly m 8, Gly m 4, Gly m 5, Gly m 6, Bet v 1, Ara h 1, Ara h 2, and Ara h 3 were determined. Sensitization patterns were analyzed and determined. The clinical relevance of sIgE of Gly m 8 sensitization was measured by assessing its capacity to degranulate basophils in Gly m8-sensitized patients by an indirect basophil activation test (iBAT). RESULTS: Based on the sIgE patterns of sensitization, two groups of SA patients were identified: (i) peanut-associated SA group (all patients were sensitized to one or more of the peanut compounds) and (ii) non-peanut/PR-10-associated SA group (22 patients were sensitized to Gly m 4 and Bet v 1 but not to any of the peanut compounds). A high and significant correlation between total soy extract and Gly m 6 (R2 = 0.97), Gly m 5 (R2 = 0.85), and Gly m 8 (R2 = 0.78) was observed. A nonsignificant correlation was observed between the levels of sIgE of Gly m 8 versus Ara h2. The iBAT results showed that Gly m 8 did not induce basophil degranulation in any of the peanut-associated patients, indicating that the Gly m8 sensitizations were not clinically relevant. CONCLUSIONS: Gly m 8 was not a major allergen in the selected soy-allergic population. The iBAT results indicated that Gly m 8 was not able to induce basophil degranulation in sIgE Gly m 8-sensitized soy-allergic patients. Thus, Gly m 8 would have no added value in the diagnosis of SA in the present study population.

Fcα Receptor-1-Activated Monocytes Promote B Lymphocyte Migration and IgA Isotype Switching.

Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy.

Enhanced IgA coating of bacteria in women with Lactobacillus crispatus-dominated vaginal microbiota.

BACKGROUND: Immunoglobulin A (IgA) plays an important role in maintaining a healthy intestinal microbiome, but little is known about the interaction between local immunoglobulins and the vaginal microbiome. We assessed immunoglobulins (unbound and bound to bacteria), their association with vaginal microbiota composition and the changes over time in 25 healthy women of reproductive age. RESULTS: In both Lactobacillus crispatus-dominated and non-L. crispatus-dominated microbiota, IgA and IgG (unbound and bound to bacteria) were higher during menses (T = 1) compared to day 7­11 (T = 2) and day 17­25 (T = 3) after menses onset. The majority of vaginal bacteria are coated with IgA and/or IgG. Women with L. crispatus-dominated microbiota have increased IgA coating of vaginal bacteria compared to women with other microbiota compositions, but contained less IgA per bacterium. Presence of a dominantly IgA-coated population at T = 2 and/or T = 3 was also strongly associated with L. crispatus-dominated microbiota. In women with non-L. crispatus-dominated microbiota, more bacteria were uncoated. Unbound IgA, unbound IgG, and bound IgG levels were not associated with microbiota composition. CONCLUSIONS: In conclusion, L. crispatus-dominated vaginal microbiota have higher levels of bacterial IgA coating compared to non-L. crispatus-dominated vaginal microbiota. Similar to its regulating function in the intestinal tract, we hypothesize that IgA is involved in maintaining L. crispatus-dominated microbiota in the female genital tract. This may play a role in L. crispatus-associated health benefits. Video abstract.

IgA Immune Complexes Induce Osteoclast-Mediated Bone Resorption.

Objective: Autoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption. Methods: Anti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption. Results: NET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts. Conclusion: IgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.

IgA and FcαRI: Pathological Roles and Therapeutic Opportunities.

Immunoglobulin A (IgA) is the most abundant antibody class present at mucosal surfaces. The production of IgA exceeds the production of all other antibodies combined, supporting its prominent role in host-pathogen defense. IgA closely interacts with the intestinal microbiota to enhance its diversity, and IgA has a passive protective role via immune exclusion. Additionally, inhibitory ITAMi signaling via the IgA Fc receptor (FcαRI; CD89) by monomeric IgA may play a role in maintaining homeostatic conditions. By contrast, IgA immune complexes (e.g., opsonized pathogens) potently activate immune cells via cross-linking FcαRI, thereby inducing pro-inflammatory responses resulting in elimination of pathogens. The importance of IgA in removal of pathogens is emphasized by the fact that several pathogens developed mechanisms to break down IgA or evade FcαRI-mediated activation of immune cells. Augmented or aberrant presence of IgA immune complexes can result in excessive neutrophil activation, potentially leading to severe tissue damage in multiple inflammatory, or autoimmune diseases. Influencing IgA or FcαRI-mediated functions therefore provides several therapeutic possibilities. On the one hand (passive) IgA vaccination strategies can be developed for protection against infections. Furthermore, IgA monoclonal antibodies that are directed against tumor antigens may be effective as cancer treatment. On the other hand, induction of ITAMi signaling via FcαRI may reduce allergy or inflammation, whereas blocking FcαRI with monoclonal antibodies, or peptides may resolve IgA-induced tissue damage. In this review both (patho)physiological roles as well as therapeutic possibilities of the IgA-FcαRI axis are addressed.

Granulocytes as modulators of dendritic cell function.

Effector T cell development is directly driven by APCs, in particular, by antigen-primed dendritic cells (DCs). Depending on the pathogenic stimulus and the microenvironment, DCs induce proliferation and polarization of naive CD4+ T cells into different effector subsets, such as Th1, Th2, Th17, or regulatory T cells (Tregs). During inflammation, DCs are found in close proximity to other innate immune cells, including all granulocyte subtypes, which potentially influence the immunomodulatory capacities of DCs. Neutrophils, eosinophils, and basophils are rapidly recruited into infected tissues where their main function is to eliminate invading pathogens. Mast cells are tissue-resident granulocytes that also contribute to host defense against pathogens but have, thus far, primarily been associated with their detrimental roles in allergic diseases. Although granulocytes have always been considered essential in innate immunity, their ability to influence the development of adaptive immunity has long been overlooked. This view is now changing, as multiple studies showed significant modulating effects of granulocytes on key players of adaptive immunity, including DCs and lymphocytes. Neutrophils, eosinophils, basophils, and mast cells regulate recruitment and activation of DCs through the release of mediators or via direct cell-cell contact, thereby influencing antigen-specific T cell responses. In this review, we will summarize the current knowledge on the impact of granulocytes on DC functioning and the subsequent putative consequences of this cross-talk on T cell proliferation and polarization. Together, this overview underscores the importance of granulocyte-DC communication to establish optimal immune responses.