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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(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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