Developmental changes in the rules for B cell selection

Abstract

The autoimmune checkpoint during B cell maturation eliminates self-antigen reactive specificities from the mature B cell repertoire. However, an exception to this rule is illustrated by B-1 cells, an innate-like self-reactive B cell subset that is positively selected into the mature B cell pool in a self-antigen-driven fashion. The mechanisms by which B-1 cells escape central tolerance have puzzled the field for decades. A key clue comes from their restricted developmental window during fetal and neonatal life. Here we use B-1 cells as a prototypic early life derived B cell subset to explore developmental changes in the constraints of B cell selection. We discuss recent advancements in the understanding of the molecular program, centered around the RNA binding protein Lin28b, that licenses self-reactive B-1 cell output during ontogeny. Finally, we speculate on the possible link between the unique rules of early life B cell tolerance and the establishment of B cell-microbial mutualism to propose an integrated model for how developmental and environmental cues come together to create a protective layer of B cell memory involved in neonatal immune imprinting.

Immunization of preterm infants: current evidence and future strategies to individualized approaches

“…B surface Ag Inact. Poliovirus Hib polysaccharide •CRI as a non-specific self-limiting stress reaction especially in most vulnerable infants [ 14 , 34 – 37 ] but no difference in CRI-rates in RCT between DTaP exposed and unexposed PIs [ 38 – 40 ] •post-immunization fever: 1.4%—33% [ 13 , 41 – 43 ] RCTs: [ 38 , 44 ] •excellent immunogenicity of most hexavalent components across all GA- and BW- groups [ 14 , 45 ] •inconclusive reports for pertussis and Hib vaccines [ 45 – 48 ] •Lower response of PIs to certain polio serotypes [ 14 , 49 - 51 ], Hib [ 52 – 54 ] and HBV [ 15 – 17 , 19 , 55 ] no RCTs •AAP/AGH/WHO/GOC: immunization of PIs according to chronological age without correction for prematurity •AGH: extra dose of Hib for ELGANs or VLBWI at 6 months of age depending on the vaccine used Pneumococcal vaccine (intramuscular) Conjugate vaccines (i.e., PCV13) Polysaccharide vaccines (i.e., PPSV23) •safe and well tolerated by PI [ 56 , 57 ] •comparable rate of AEs after immunization (compared to FTI) [ 58 , 59 ] •no serious, vaccine-related AEs reported RCTs: [ 56 ] •inconclusive results: GA-dependent specific IgG antibody titers [ 61 ] •reduced but protective responses to certain PCV serotypes [62,57,63,64 (importance of a booster dose [ 62 ]) •significant reduction in IPD in birth cohorts of PI [ 65 ] and up to 100% efficacy for PI and LBWI [ 59 , 60 ] RCTs: [ 56 ] •AGH/GOC: P...…”

“…•significant reduction in IPD in birth cohorts of PI [ 65 ] and up to 100% efficacy for PI and LBWI [ 59 , 60 ]…”

“…The differentiation of CD4 + T helper (Th) cells is skewed toward Th-2 cells, while the generation of T FH cells and GC B cell responses is hampered and antibody responses are often transient [ 57 , 58 ]. Recent studies, however, prompt a reinterpretation of B and T cell function in (preterm) neonates [ 59 , 60 ]. Instead of being impaired, neonatal T and B cells rather seem to be adapted for encountering distinct immune challenges present at the beginning of life.…”

“…•significant reduction in IPD in birth cohorts of PI [65] and up to 100% efficacy for PI and LBWI [59,60] RCTs: [56] •AGH/GOC: PIs •immunogenic in PIs [53,66,68]; similar immunogenicity between PI and FTI (> 99%) [66,68] •high importance of booster dose to ensure longterm protection [66,68] no RCTs…”

MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors

“…The Lin28B gene is negatively regulated by miRNAs (such as miR-26) and its overexpression is linked to the repression of let-7 miRNAs [44]. A previous publication also showed that Lin28b serves as a molecular switch for tuning the tolerance threshold during B cell receptor (BCR) repertoire selection early in life [45]. Therefore, it is enticing to speculate that this protein may contribute to the development of SSc, in which the appearance of autoantibodies is the first clinical phenomenon observed.…”