Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts

Abstract

Rapid production of neutralizing antibody can be critical for limiting the spread of infection. Such early antibody results when B-cell blasts mature directly to plasmablasts without forming germinal centers. These extrafollicular responses can involve Ig class switch recombination (CSR), producing antibody that can readily disseminate through infected tissues. The present study identifies the differentiation stage where CSR occurs in an extrafollicular response induced by 4-hydroxy-3-nitrophenyl acetyl (NP) conjugated to Ficoll (NP-Ficoll). To do this, we took advantage of the antigen dose dependency of CSR in this response. Thus, while both 30 and 1 lg NP-Ficoll induce plasmablasts, only the higher antigen dose induces CSR. Activation-induce cytidine deaminase (AID) is critical for CSR and in keeping with this a proportion of NP-specific B-cell blasts induced by 30 lg NP-Ficoll express AID. None of the B blasts responding to the non-CSR-inducing 1 lg dose of NP-Ficoll express AID. We confirmed that CSR occurs in B blasts by demonstrating the presence of rearranged heavy-chain transcripts in B blasts in the 30 lg response. CSR in this extrafollicular response is confined to B blasts, because NP-specific plasmablasts, identified by expressing CD138 and Blimp-1, no longer express AID and cannot undergo CSR.

Salmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation

“…This strategy would not only provide a measure of immediately effective pathogen protection, it also would generate a large number of clones that can subsequently be optimized. As we and others (Marshall et al, 2011; Toellner et al, 1996) show, plasmablasts and B blasts can quickly undergo isotype switch, a process independent of GCs and even to some degree of T cells; thus, a variety of effector functions aside from IgM are rapidly engaged. Isotype switching is a process that requires AID activity, which is also necessary and sufficient for SHM (Muramatsu et al, 2000).…”

“…The mutational process itself could occur in plasmablasts, as well as in B blasts, both of which were shown in other contexts to express AID (Marshall et al, 2011; Odegard et al, 2008; Toellner et al, 1996). Clearly, isotype switching, mainly to IgG2c, another AID-dependent process, was also occurring at these sites.…”

“…The fact that extensive isotype switching takes place in the EF response thus unequivocally indicates that functional AID is being expressed. It has further been established that AID is expressed in EF responses, at least in some models (Marshall et al, 2011; Odegard et al, 2008). Indeed, a second important finding is the unexpected discovery that the EF plasmablast response is permissive for SHM and in fact affinity-based selection.…”

HIV-derived lentiviral particles promote T-cell independent activation and differentiation of naïve cognate conventional B2-cells in vitro

“…4C). Together with low surface expression of CD38 and CD138 (not shown) these cells have rather an active GC plasmablast rather than a mature plasma cell phenotype [31].…”

B1b Cells Recognize Protective Antigens after Natural Infection and Vaccination

“…In mice, responses to model TI-2 and TD alum-precipitated antigens such as NP-chicken gamma globulin or ovalbumin, the kinetics of the immune response has been well characterized for both primary and recall responses and below is a short synopsis based on this non-exhaustive list of references (1, 2, 63–69) (Figure 1). It is likely most of the core features of this response reflect what happens in human beings.…”