Pregnancy-induced effects on memory B-cell development in multiple sclerosis

Abstract

In MS, pathogenic memory B cells infiltrate the brain and develop into antibody-secreting cells. Chemokine receptors not only define their brain-infiltrating capacity, but also assist in their maturation in germinal centers. How this corresponds to pregnancy, as a naturally occurring modifier of MS, is underexplored. Here, we aimed to study the impact of pregnancy on both ex vivo and in vitro B-cell differentiation in MS. The composition and outgrowth of peripheral B cells were compared between 19 MS pregnant patients and 12 healthy controls during the third trimester of pregnancy (low relapse risk) and postpartum (high relapse risk). Transitional, and not naive mature, B-cell frequencies were found to drop in the third trimester, which was most prominent in patients who experienced a pre-pregnancy relapse. Early after delivery, these frequencies raised again, while memory B -cell frequencies modestly declined. CXCR4 was downregulated and CXCR5, CXCR3 and CCR6 were upregulated on postpartum memory B cells, implying enhanced recruitment into germinal center light zones for interaction with T follicular helper (TFH) cells. Postpartum memory B cells of MS patients expressed higher levels of CCR6 and preferentially developed into plasma cells under TFH-like in vitro conditions. These findings imply that memory B- cell differentiation contributes to postpartum relapse risk in MS.

Selective emergence of antibody-secreting cells in the multiple sclerosis brain

“…As described previously [35], IgM, IgA and IgG levels were determined in supernatants from in vitro B-cell cocultures using an ELISA. Plates were coated with goat anti-human IgM, IgG or IgA (1 mg/mL; Southern Biotech, Uithoorn, The Netherlands).…”

Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

“…This increase was found in B cells from both patients with RRMS and SPMS but not patients with PPMS, pointing to a direct relation with local inflammation rather than neurodegeneration. CNS-infiltrating CXCR3 + memory B cells are also poised to mature into ASCs in vitro ( 13 , 14 ), which seems to be a process that can be affected by evobrutinib (this study). Hence, the potential of next-generation BTK inhibitors to penetrate the CNS may provide an opportunity to not only prevent, but also target (clinically relevant) local antibody production in patients with MS ( 15 ), which should be investigated in the near future.…”

“…B cells from patients with MS are highly sensitive to both triggers ( 12 ), resulting in enhanced class switching ( 8 ). Moreover, CXCR3 + memory B cells are triggered by EBV ( 13 ) and show pronounced CNS-infiltrating ability and recall responses in vitro ( 8 , 13 , 14 ). This points to a tendency of these B cells to further mature into antibody-secreting cells (ASCs) after entering the CNS, a process associated with less favorable outcomes in MS ( 15 ).…”

The peripheral and decidual immune cell profiles in women with recurrent pregnancy loss

“…The peripheral NKT-like cells could modulate the immune response of innate and adaptive immune cells by secreting inflammatory cytokines ( 29 ), we observed a strong increase in the number of NKT-like cells in RPL patients, implying that higher level of NKT-like cells might disturb the balance of the immune system. B cells were reported to play an important role in maintaining a successful pregnancy by regulating the secretion of autobodies and cytokines ( 30 ). Our results showed that the abundance of B and CD62L + B cells was significantly higher in RPL patients, indicating that the alteration of immune effectors may be associated with RPL.…”