Retinoic Acid and Polyriboinosinic Acid Act Synergistically to Enhance the Antibody Response to Tetanus Toxoid during Vitamin A Deficiency: Possible Involvement of Interleukin‐2 Receptor‐β, Signal Transducer and Activator of Transcription‐1, and Interferon Regulatory Factor‐1

Abstract

Antibody responses to T cell-dependent antigens are reduced during vitamin A (VA) deficiency and restored by retinoids. To test whether retinoic acid (RA) and polyinosinic:polycytidylic acid (PIC), an inducer of interferons, can increase specific antibody production, VA-deficient rats were treated with all-trans-RA, PIC, or both at the time of primary immunization with tetanus toxoid. VA-deficient rats produced low primary and secondary anti-tetanus IgG responses (P<.001 vs. VA-sufficient controls). Both responses were increased synergistically by RA plus PIC (P<.0001). In VA-deficient spleens, mRNAs were low for interleukin (IL)-2 receptor-beta, interferon regulatory factor-1, and signal transducer and activator of transcription 1. Each, however, was induced by RA plus PIC (P<.0001 vs. controls). Conversely, IL-12 and IL-10 mRNAs were elevated in VA deficiency and were induced by PIC and suppressed by RA. Thus, RA plus PIC appears to be a promising combination for stimulating antigen-specific immunity. Several molecular factors identified here may partially account for the observed enhancement.

Retinoic Acid and Polyriboinosinic:Polyribocytidylic Acid Stimulate Robust Anti-Tetanus Antibody Production while Differentially Regulating Type 1/Type 2 Cytokines and Lymphocyte Populations

“…However, the immunoregulatory effect of RA and IFNs combined has not yet been well characterized. DeCicco et al (25,30) reported that RA and PIC synergistically enhanced both primary and secondary anti-TT Ab responses in vitamin A-deficient rats, suggesting that RA and IFNs can interactively promote immune functions. However, whether RA and IFNs, especially in combination, can effectively modulate primary immune responses and promote long-term immunity in the healthy state had not been studied.…”

“…Sense and antisense primers were as reported previously (26,30) or were as follows: IL-4 (NM 021283), 5Ј-AGAGCTATTGATGGGTCTCA, 3Ј-GGCTTTCAAGGAAGTCTTTC, 401 bp; T-bet (AF241242), 5Ј-GATC GTCCTGCAGTCTCTCC, 3Ј-AACTGTGTTCCCGAGGTGTC, 413 bp; GATA-3 (NM008091), 5Ј-CTTATCAAGCCCAAGCGAAG, 3Ј-CAGGG ATGACATGTGTCTGG, 311 bp; IL-12R␤2 (NM008354), 5Ј-TGACA GCTGCTGGTGAAAGTCC, 3Ј-ATGATCAGGGGCTCAGGCTCTTCA, 269 bp; and 18S rRNA (M35283), 5Ј-AATGGTGCTACCGGTCATTC, 3Ј-ACCTCTCTTACCCGCTCTCC, 193 bp. The PCR products were separated on a nondenaturing polyacrylamide gel and then exposed to x-ray film.…”

Toll-Like Receptor 3 Ligand and Retinoic Acid Enhance Germinal Center Formation and Increase the Tetanus Toxoid Vaccine Response

“…Vitamin A deficiency causes low and dysregulated primary and memory antibody responses against several T-cell-dependent (TD) and polysaccharide antigens (47,57), including common vaccines, such as tetanus and diphtheria toxoids (46). These impairments are reversible, since providing vitamin A or RA to vitamin A-deficient animals resulted in significant rescue of the anti-tetanus antibody response (16,24). In humans, supplementation with vitamin A is recognized as an effective means of reducing morbidity and mortality among young children, a population at risk for vitamin A deficiency (53), and vitamin A supplementation has shown therapeutic benefits in infectious diseases, such as measles and diarrhea (53,57,60).…”

“…Recently, we have reviewed studies showing that RA augments the production of an antigen-specific B-cell response in vivo (48). RA has gained attention due to its multiple effects on innate and adaptive immunity, including its ability to modulate cytokine production (27), promote the development of Th2 cells (20), induce gut-homing T cells (22) and T regulatory cells (6), regulate Th17 cells (37), stimulate B-cell maturation (11,62), and increase primary and memory antibody responses (14,16,27). The potentiation of TD antigen-specific antibody production after treatment with RA could be due to a direct involvement in B-cell activation, as RA enhanced the production of IgM and IgG induced by both TD and T-cell-independent antigen in human peripheral blood mononuclear cells (61) and stimulated the plasmacytic maturation of isolated B cells in vitro (11).…”

Vitamin A and immune function: Retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells

“…Vitamin A deficiency is also associated with exacerbation of immunodeficiency (7), reduced or unbalanced numbers of lymphocytes (8), and dysregulated production of antibodies (9). Animal experiments have demonstrated that an adequate level of vitamin A is necessary to mount an efficient antibody response (10,11), whereas supplementation with vitamin A͞RA can stimulate the antibody response to vaccination even in normal animals (10,12,13). Despite these interesting functional properties of vitamin A and RA on antibody production, little is known about the underlying mechanisms, especially related to B lymphocyte activation and differentiation.…”