GLYCOSYLATION REGULATES PLASMA CELLS AND SECRETORY IgA FUNCTION IN GUT INFLAMMATION

CUTINE, ANABELA M.; MOROSI, LUCIANO; CAGNONI, ALEJANDRO J.; MERLO, JOAQUÍN; MANSELLE COCCO, MONTANA; MAHMOUD, YAMIL; MARTINEZ ALLO, VERONICA; MORALES, ROSA; GATTO, SABRINA; MAY, MARÍA; GIROTTI, MARÍA ROMINA; RABINOVICH, GABRIEL A.; TOSCANO, MARTA A; MARIÑO, KARINA V.

CABA

Congreso; Reuníon Biociencias SAI-SAIC-SAFIS 2020; 2020

SAIC/SAI/SAFIS

Inflammatory bowel diseases (IBD) are characterized by inflammation of the digestive tract resulting in severe damage to the tissues involved. Secretory IgA (SIgA) is a heavily glycosylated protein complex that plays a key role in maintaining gut immune homeostasis. However, functional consequences of an altered SIgA glycosylation during gut inflammation have not been addressed yet. Our goal was to evaluate a potentially aberrant glycosylation of plasma cells (PCs) and SIgA, focusinginto its pathological relevance. Analysis from single cell RNA seq databases on PCs from IBD patients showed an altered N-glycosylation machinery. Considering that DSS-induced colitis showed decreased α2,6 sialylation (α2,6sia) specifically on IgA+ PCs (p < 0,05) and SIgA in vivo, we investigated the functionality of B cells deficient in ST6Gal1, an enzyme that adds α2,6sia to N-glycans. ST6Gal1-/- B cells are impaired in their ability to suppress T cell driven colitis in Rag2-/- mice, resulting in greater histologic scores than their wild type counterparts (p < 0,05).To unravel the mechanisms involved in the defective regulation of inflammation, we focused in analyzing the functionality of α2,6sia-deficient SIgA. Notably, desialylated SIgA showed higher binding to fecal bacteria (p < 0,05) and human monocytes (p < 0,05) in vitro and potentiates the activation of LPS-stimulated monocytes, upregulating HLA-DR and IL-1β (p < 0,05). Moreover, binding ofdesialylated SIgA to THP-1 monocytic cells is inhibited by EGTA and Lewis X (p < 0,05), suggesting that these interactions are mediated by a C-type lectin. The evidence provided here postulates a novel immune circuit where gut inflammation may promote transcriptional changes inPCs resulting in decreased α2,6sia. In turn, desialylated SIgA promotes colitis through a newly gained proinflammatory activity. This work contributes to the construction of a new paradigm where aberrant glycosylation modulates the immunoregulatory activity of SIgA.