Retinoic acid acts as a selective human IgA switch factor

Seo, Goo Young; Jang, Young Saeng; Kim, Jini; Choe, Jongseon; Han, Hye Ju; Lee, Jeong Min; Kang, Seong-Ho; Rhee, Ki Jong; Park, Seok‐Rae; Kim, Woan Sub; Kim, Pyeung Hyeun

doi:10.1016/j.humimm.2014.06.021

Cited by 33 publications

(34 citation statements)

References 30 publications

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“…It was previously reported that T cell-independent B cell class switch inducing factors such as APRIL and retinoic acid are potent inducers of IgA when co-stimulated with IL-10 [4,25]. Highly purified unstimulated total peripheral blood B cells (>98%, T cells <1%) did not produce IgA1 or IgA2 after exposure to APRIL, BAFF, IL-10 or RA (ß10 ± 1.5 ng/ml IgA1, 10 ± 2.1 ng/ml IgA2) ( Fig.…”

Section: R848 and Cpg-odn Stimulated Total Peripheral B Cells Producementioning

confidence: 99%

BAFF augments IgA2 and IL‐10 production by TLR7/8 stimulated total peripheral blood B cells

et al. 2017

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Class‐switching of B cells to IgA can be induced via both T‐cell‐dependent and T‐cell‐independent mechanisms. IgA is most predominantly produced mucosally and is important for combating infections and allergies. In contrast to mice, humans have two forms of IgA; IgA1 and IgA2 with diverse tissue distribution. In early life, IgA levels might be sub‐optimal especially during the fall season when bacterial and viral infections are more common. Therefore, we investigated using human B cells whether T‐cell‐independent factors ‐promoting cell survival, class switching and immunoglobulin secretion‐ BAFF, APRIL, IL‐10 and retinoic acid can boost IgA production in the context of viral or bacterial infection. To this end total and naive peripheral blood B cells were stimulated with these factors for 6 days in the presence or absence of TLR7/8 agonist R848 (mimicking viral infection) or TLR9 agonist CpG‐ODN (mimicking bacterial infection). We show that BAFF significantly augments IgA2 production in TLR7/8 stimulated mature, but not naïve B cells. In addition, BAFF augments IL‐10 production and viability in TLR7/8 and TLR9 stimulated mature B cells. These data warrant further investigation of its role in immune regulation both in the periphery and mucosal tissues in early life or during disease.

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Section: R848 and Cpg-odn Stimulated Total Peripheral B Cells Producementioning

confidence: 99%

BAFF augments IgA2 and IL‐10 production by TLR7/8 stimulated total peripheral blood B cells

et al. 2017

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“…The biological influences of vitamins and hormones are highly complex, because ligand and DNA-binding patterns of nuclear receptors are promiscuous (1,(4)(5)(6)(7)13,18). A common binding site for RAR-RXR heterodimers (retinoic acid response element [RARE]) is a direct repeat (DR) of two puG(G/T)TCA half-sites, but sequences, spacing, and half-site orientations are variable (15).The upregulation of cytokines is one method by which vitamins influence antibody isotype expression patterns (21,29,32,(35)(36)(37) …”

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confidence: 99%

Hotspots for Vitamin–Steroid–Thyroid Hormone Response Elements Within Switch Regions of Immunoglobulin Heavy Chain Loci Predict a Direct Influence of Vitamins and Hormones on B Cell Class Switch Recombination

Hurwitz

Penkert

et al. 2016

Viral Immunology

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Vitamin A deficiencies are common throughout the world and have a significant negative influence on immune protection against viral infections. Mouse models demonstrate that the production of IgA, a first line of defense against viruses at mucosal sites, is inhibited in the context of vitamin A deficiency. In vitro, the addition of vitamin A to activated B cells can enhance IgA expression, but downregulate IgE. Previous reports have demonstrated that vitamin A modifies cytokine patterns, and in so doing may influence antibody isotype expression by an indirect mechanism. However, we have now discovered hundreds of potential response elements among Sl, Se, and Sa switch sites within immunoglobulin heavy chain loci. These hotspots appear in both mouse and human loci and include targets for vitamin receptors and related proteins (e.g., estrogen receptors) in the nuclear receptor superfamily. Full response elements with direct repeats are relatively infrequent or absent in Sc regions although half-sites are present. Based on these results, we pose a hypothesis that nuclear receptors have a direct effect on the immunoglobulin heavy chain class switch recombination event. We propose that vitamin A may alter S site accessibility to activation-induced deaminase and nonhomologous endjoining machinery, thereby influencing the isotype switch, antibody production, and protection against viral infections at mucosal sites. V itamin A is a critical nutrient for the protection of humans from infectious disease (9,30,34,37). Functions of vitamin A include upregulation of IgA among activated B cells (29), and downregulation of IgE (41). This vitamin is well known for its capacity to bind nuclear receptors and modulate gene expression. Examples of receptors are the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), bound respectively by all-trans retinoic acid and 9-cis retinoic acid metabolites. RAR and RXR are members of the nuclear receptor superfamily, which is inclusive of retinoic acid, vitamin D, thyroid hormone, and steroid receptors. Typically, these receptor proteins have a central DNA-binding domain with which the protein is targeted to a particular DNA response element sequence. Receptors usually assemble as homodimers or heterodimers. The biological influences of vitamins and hormones are highly complex, because ligand and DNA-binding patterns of nuclear receptors are promiscuous (1,(4)(5)(6)(7)13,18). A common binding site for RAR-RXR heterodimers (retinoic acid response element [RARE]) is a direct repeat (DR) of two puG(G/T)TCA half-sites, but sequences, spacing, and half-site orientations are variable (15).The upregulation of cytokines is one method by which vitamins influence antibody isotype expression patterns (21,29,32,(35)(36)(37) MOTIFS IN IMMUNOGLOBULIN HEAVY CHAIN SWITCH REGIONS 133on the B cell heavy chain class switch recombination (CSR) event. The CSR involves deletion of intervening sequences within the immunoglobulin heavy chain locus between a target S (e.g., Sa) and an upstream S...

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“…Ten years ago researchers have found that ATRA upregulates the expression of the polymeric IgA receptor, which exports secretory IgA into the gut lumen [40] . In human B cells, RA increased IgA production and the expression of germ-line IgA1 and IgA2 transcripts (GLTa1 and GLTa2), and under the same conditions, RA did not increase IgM and IgG productions [41] . RA also plays a vital role together with TGF-β in the presence of Runx proteins on switching of different B cell subpopulations to IgA [42,43] .…”

Section: Discussionmentioning

confidence: 85%

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

Peng²,

Chen³

et al. 2016

Am J Nephrol

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Background: Immunoglobulin (Ig) A nephropathy (IgAN) is the ﬁnding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Increasing evidence suggested that retinoic acid (RA) signaling selectively induces IgA isotype switching and basic leucine zipper transcription factor, ATF-like (BATF) controls the global regulators of class switch recombination (CSR) in lymphocytes. Great effort has been paid to identify whether impaired immune regulation along the ‘mucosa-bone marrow (BM) axis' play an important role in the pathogenesis of IgAN. Methods: The aim of the study was to investigate the expression of all-trans-RA (ATRA) and BATF, and to identify their impact on IgA CSR in IgAN patients and rat animal models. Blood samples and tonsillar tissue specimens were obtained from 22 patients with IgAN and 24 patients with chronic tonsillitis as control. Results: Immunohistochemical, RT-PCR and western blotting examination revealed that RA signaling and BATF productions are activated in IgAN patients compared with controls. Lipopolysaccharide and α-hemolytic streptococcus stimulation upregulated RA receptor (RAR) and BATF expression, promote IgA CSR and ATRA productions in tonsil mononuclear cells. RAR alpha (RARα) or BATF siRNA decreases IgA expression. We also built IgAN rat models and found that RARα, BATF and activation-induced cytidine deaminase were upregulated in the peripheral blood, spleen and BM. With ATRA (500 μg/kg body weight) treatment for 8 weeks, IgA deposition on glomeruli and mesangial cells proliferation increased. It also revealed that ATRA activated BATF and IgA CSR in vivo. Conclusion: These data point toward the role of RA signaling together with BATF in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with neoantigen results in impaired mucosal and systemic IgA responses.

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Retinoic acid acts as a selective human IgA switch factor

Cited by 33 publications

References 30 publications

BAFF augments IgA2 and IL‐10 production by TLR7/8 stimulated total peripheral blood B cells

BAFF augments IgA2 and IL‐10 production by TLR7/8 stimulated total peripheral blood B cells

Hotspots for Vitamin–Steroid–Thyroid Hormone Response Elements Within Switch Regions of Immunoglobulin Heavy Chain Loci Predict a Direct Influence of Vitamins and Hormones on B Cell Class Switch Recombination

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

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