Vitamin A Deficiency Disrupts Vaccine-Induced Antibody-Forming Cells and the Balance of IgA/IgG Isotypes in the Upper and Lower Respiratory Tract

Surman, Sherri L.; Rudraraju, Rajeev; Sealy, Robert E.; Jones, Bart G.; Hurwitz, Julia L.

doi:10.1089/vim.2012.0023

Cited by 37 publications

(51 citation statements)

References 15 publications

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“…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).…”

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confidence: 99%

“…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%

“…The upregulation of cytokines is one method by which vitamins influence antibody isotype expression patterns (21,29,32,(35)(36)(37). For example, vitamin A can upregulate interleukin 6 (IL-6), a cytokine that supports maturation and stabilization of IgA-producing cells (29).…”

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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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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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“…In the context of vitamin A deficiencies, mucosal IgA responses toward viruses and viral vaccines are impaired both in the gut and in the upper respiratory tract (URT) (4)(5)(6). IgG responses are relatively resistant to VAD compared to IgA responses, yielding an increase in IgG/IgA ratios at the mucosal surface.…”

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“…IgG responses are relatively resistant to VAD compared to IgA responses, yielding an increase in IgG/IgA ratios at the mucosal surface. Serum antibody responses, being predominantly of the IgG isotype, are essentially unchanged in VAD mice compared to control mice (4,5). Given that respiratory tract mucosal IgA serves as a correlate of protection against respiratory virus infections and lends to the protection conferred by respiratory virus vaccines (7)(8)(9)(10)(11), the lack of healthy IgA responses may render VAD individuals particularly susceptible to the diseases responsible for one-fifth of all deaths among children under the age of five years (2,12).…”

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confidence: 99%