Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK

Ertesvag, Aase; Aasheim, Hans Christian; Naderi, Soheil; Blomhoff, Heidi Kiil

doi:10.1182/blood-2006-09-046748

Cited by 56 publications

(55 citation statements)

References 71 publications

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“…All-trans retinoic acid (RA) is the main vitamin A metabolite involved in immune regulation (6), where its primary function is to regulate gene transcription via binding to the nuclear receptors retinoic acid receptors (RARs) and retinoic X receptors (7). Although it is well established that vitamin A is crucial for an optimal immune defense, its effects on different cells of the immune system vary, depending on the type of costimulation involved (8,9). Our group demonstrated previously that, although RA inhibits B cells stimulated via the BCR (9)(10)(11), it can enhance immunologic responses in B cells when the cells are stimulated through TLR9 alone (9) or in combination with the TLR RP105 (12).…”

Section: Ommon Variable Immunodeficiency (Cvid) Is the Most Commonlmentioning

confidence: 99%

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Indrevær

Holm

Aukrust

et al. 2013

The Journal of Immunology

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Common variable immunodeficiency (CVID) is a disease that is characterized primarily by low levels of serum Igs, resulting in a high incidence of infections. It also has been associated with impaired B cell signaling via TLR9 and reduced serum levels of vitamin A. Given the established link between vitamin A deficiency and increased susceptibility to infections, we investigated the ability of the vitamin A metabolite all-trans retinoic acid (RA) to restore the defective immune responses in CVID-derived B cells activated through the TLRs TLR9 and RP105. We demonstrate that RA almost normalizes proliferation and IL-10 secretion in patient-derived B cells. IgG secretion is also partially restored, but to a more moderate extent. This can be explained by impaired RA-mediated isotype switching in TLR9/RP105-stimulated CVID-derived B cells owing to reduced induction of activation-induced deaminase. Accordingly, these B cells secreted higher levels of IgM than did normal B cells, and RA augmented IgM secretion. The ability of RA to improve critical immune parameters in CVID-derived B cells stimulated through TLR9 and RP105 support the possibility of combining RA with TLR stimulation for the treatment of CVID.

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Section: Ommon Variable Immunodeficiency (Cvid) Is the Most Commonlmentioning

confidence: 99%

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Indrevær

Holm

Aukrust

et al. 2013

The Journal of Immunology

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“…17,18 We have previously shown that RA enhances proliferation and Ig-production in B cells stimulated via TLRs. 23,24,31 In the present study we provide a novel mechanism whereby vitamin A may stimulate the immune system, by demonstrating that RA-induced secretion of IgG from TLR9-and CD180-stimulated human B cells involves ULK1-mediated autophagy. Hence, RA promoted both the formation of LC3B-II and the expression of ULK1, whereas blocking autophagy by knockdown of ULK1 reduced the RA-mediated production of IgG.…”

Section: Discussionmentioning

confidence: 76%

“…8,9 Having previously demonstrated the stimulatory effect of RA on IgG-production in normal human B cells activated via TLR9 alone or in combination with CD180, 23,24,31 we here investigated the possible involvement of autophagy in this process. The MAP1LC3/LC3 (microtubuleassociated protein 1 light chain 3) protein is a widely used and accepted marker of phagophores and autophagosomes, 32 and is commonly used to monitor the levels of autophagy.…”

Section: Resultsmentioning

confidence: 99%

“…Given the recently acknowledged importance of autophagy in plasma cell formation and Ig secretion, 8,9 and having previously shown that RA potentiates IgG secretion in human peripheral B cells stimulated via TLRs, 23,24,31 we next asked whether autophagy was involved in RA-mediated induction of IgG. To this end, B cells were transfected with siRNA against ULK1 or with a control siRNA, and as shown in Figure 6A, knocking down ULK1 reversed the RA-induced formation of LC3B-II.…”

Section: Ra-mediated Secretion Of Igg Involves Autophagymentioning

confidence: 99%

“…17,29,30 We have previously shown that the vitamin A metabolite RA is able to potentiate the interplay between innate and adaptive B cell responses by enhancing TLR9-mediated and TLR9-and CD180-mediated activation of human B cells 23,31 with a particularly strong impact on TLR9-and CD180-mediated differentiation of B cells into Ig-secreting plasma cells. 23 Given the recent awareness of the importance of autophagy for the generation and maintenance of plasma cells, 8,9 we here explored the involvement of autophagy in RA-mediated differentiation of B cells into Ig-secreting cells.…”

Section: Introductionmentioning

confidence: 99%

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Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy

et al. 2015

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(2015) Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy, Autophagy, 11:3, 460-471, DOI: 10.1080/15548627.2015 Keywords: antibody secretion, autophagy, B lymphocytes, CD180, plasma cell differentiation, retinoic acid, RP105, TLR9, ULK1Abbreviations: ATG, autophagy-related; BDS, bright detail similarity; CD180, CD180 molecule; CVID, common variable immune deficiency; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin; IL, interleukin; MAP1LC3B/LC3B, microtubuleassociated protein 1 light chain 3 b; MTOR, mechanistic target of rapamycin (serine/threonine kinase); PAMP, pathogen-associated molecular pattern, PML/RARA, promyelocytic leukemia/ retinoic acid receptor a; RA, all-trans retinoic acid; RAR, retinoic acid receptor; SQSTM1, sequestosome 1; TLR, toll-like receptor; ULK1, unc-51 like autophagy activating kinase 1.In the present study we have established a vital role of autophagy in retinoic acid (RA)-induced differentiation of tolllike receptor (TLR)-stimulated human B cells into Ig-secreting cells. Thus, RA enhanced autophagy in TLR9-and CD180-stimulated peripheral blood B cells, as revealed by increased levels of the autophagosomal marker LC3B-II, enhanced colocalization between LC3B and the lysosomal marker Lyso-ID, by a larger percentage of cells with more than 5 characteristic LC3B puncta, and by the concomitant reduction in the level of SQSTM1/p62. Furthermore, RA induced expression of the autophagy-inducing protein ULK1 at the transcriptional level, in a process that required the retinoic acid receptor RAR. By inhibiting autophagy with specific inhibitors or by knocking down ULK1 by siRNA, the RAstimulated IgG production in TLR9-and CD180-mediated cells was markedly reduced. We propose that the identified prominent role of autophagy in RA-mediated IgG-production in normal human B cells provides a novel mechanism whereby vitamin A exerts its important functions in the immune system.

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Retinoic Acid and Immunity

Larangé¹

2017

Encyclopedia of Life Sciences

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Vitamin A and its active metabolite retinoic acid (RA) are key players in the regulation of the immune response, especially at the mucosal borders, where RA is particularly abundant. Retinoic acid receptors (RARs), via their transcriptional activity, modulate the expression of many genes in many types of immune cells, such as T cells, B cells, macrophages or dendritic cells. Among the pleiotropic effects on immune cells, the ability of RA and RARs to confer gut tropism and to promote the generation of regulatory T cells (Tregs) are undoubtedly the most prominent. However, depending on the physiopathological context, RA can also promote inflammation. These multiple and sometimes paradoxical properties of RA reflect the importance of this nutrient‐derived molecule in the fine‐tuning of the immune system. Key Concepts Retinoic acid is the active metabolite of Vitamin A, a nutrient essential for many biological processes. Retinoic acid receptors act as transcription factors to regulate the expression of several genes. Retinoic acid induces the expression of gut homing receptors on several immune cells. Retinoic acid induces the generation of regulatory T cells that control the immune and inflammatory response. In certain physiopathological contexts, retinoic acid can act as an adjuvant to promote inflammation.

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Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK

Cited by 56 publications

References 71 publications

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy

Retinoic Acid and Immunity

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