Modulation of B-cell immunoglobulin synthesis by retinoic acid

Retinoic acid (RA) and its parent compound retinol (ROH, vitamin A) have been recognized as important immunopotentiating agents since the early 1900s. We have focused our studies on the effects of retinoids on B-cell immune function in the newborn infant. The response of cord blood mononuclear cells (CBMC) to formalinized Cowan I strain Staphylococcus aureus (SAC), a T-cell-dependent factor for inducing the differentiation of B cells into immunoglobulin (Ig)-secreting cells, was used as a model system for studying whether RA could alter the immunoglobulin synthesis of newborn B lymphocytes. The addition of RA to SAC-stimulated CBMC cultures produced a 2- to 47-fold increase in IgM synthesis. An ELISA-spot assay showed that the RA-induced enhancement in Ig synthesis was due to the recruitment of more B cells to differentiate into Ig-secreting cells. Whereas RA enhanced IgM production of CBMC stimulated with SAC, RA augmented only IgG production of SAC-stimulated adult peripheral blood mononuclear cells (PBMC). To determine if the differences in dose-response characteristics between CBMC and adult PBMC resided within the target cell, i.e., the B cell, T-cell-enriched and T-cell-depleted (B-cell) fractions from CBMC and adult PBMC were cocultured in various combinations. The isotype, i.e., IgM vs IgG, and the dose-response curve characteristics were intrinsic to the responding B-cell source, i.e., newborn vs adult. Highly purified T cells from CBMC, when preincubated for 36 hr with RA, enhanced IgM synthesis of cord blood B cells. Supernatants from purified T cells generated a factor which could enhance B-cell synthesis. Although interleukin (IL)-2, IL-4, and IL-6 could not be detected by ELISA in the T-cell-derived supernatants, RA probably generates a cytokine/interleukin from T cells which modulates B-cell Ig secretion. RA can also act directly on B cells as evidenced by the augmentation in Ig synthesis of Epstein-Barr virus (EBV)-transformed B-cell lines. These data suggest that RA can have a direct effect on B cells. Since increased proliferation (numbers) of lymphoblastoid B cells was not responsible for the increased amounts of Ig in the supernatant fluids, we examined whether cytokines secreted by EBV-transformed B cells could be acting as an autocrine factor in increasing Ig synthesis. EBV-transformed B-cell clones incubated with RA for 6 days produced a 20- to 45-fold increase in IL-6. An understanding of the mechanisms by which RA enhances B-cell immune function may lead to the use of RA or its derivatives in patients with immune deficiencies and in preterm infants with immature immune systems.