Antibody class switching occurs in mature B cells in response to antigen stimulation and costimulatory signals. It occurs by a unique type of intrachromosomal deletional recombination within special G-rich tandem repeated DNA sequences [called switch, or S, regions located upstream of each of the heavy chain constant (C(H)) region genes, except Cdelta]. The recombination is initiated by the B cell-specific activation-induced cytidine deaminase (AID), which deaminates cytosines in both the donor and acceptor S regions. AID activity converts several dC bases to dU bases in each S region, and the dU bases are then excised by the uracil DNA glycosylase UNG; the resulting abasic sites are nicked by apurinic/apyrimidinic endonuclease (APE). AID attacks both strands of transcriptionally active S regions, but how transcription promotes AID targeting is not entirely clear. Mismatch repair proteins are then involved in converting the resulting single-strand DNA breaks to double-strand breaks with DNA ends appropriate for end-joining recombination. Proteins required for the subsequent S-S recombination include DNA-PK, ATM, Mre11-Rad50-Nbs1, gammaH2AX, 53BP1, Mdc1, and XRCC4-ligase IV. These proteins are important for faithful joining of S regions, and in their absence aberrant recombination and chromosomal translocations involving S regions occur.

/pdf/mechanism-and-regulation-of-class-switch-recombination-577q56612t.pdf

Mechanism and regulation of class switch recombination.

The immune system can remember a previously experienced pathogen and can evoke an enhanced response to reinfection that depends on memory lymphocyte populations. Recent advances in tracking antigen-experienced memory B cells have revealed the existence of distinct classes of cells that have considerable functional differences. Some of these differences seem to be determined by the stimulation history during memory cell formation. To induce rapid recall antibody responses, the contributions of other types of cells, such as memory T follicular helper cells, have also now begun to be appreciated. In this Review, we discuss these and other recent advances in our understanding of memory B cells, focusing on the underlying mechanisms that are required for rapid and effective recall antibody responses.

Memory B cells.

Memory B cells are at the center of longstanding controversies regarding the presence of antigen for their survival and their re-engagement in germinal centers after secondary challenge. Using a new mouse model of memory B cell labeling dependent on the cytidine deaminase AID, we show that after immunization with a particulate antigen, B cell memory appeared in several subsets, comprising clusters of immunoglobulin M-positive (IgM(+)) and IgG1(+) B cells in germinal center-like structures that persisted up to 8 months after immunization, as well as IgM(+) and IgG1(+) B cells with a memory phenotype outside of B cell follicles. After challenge, the IgG subset differentiated into plasmocytes, whereas the IgM subset reinitiated a germinal center reaction. This model, in which B cell memory appears in several layers with different functions, reconciles previous conflicting propositions.

Multiple layers of B cell memory with different effector functions

The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information - resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes - has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming.

/pdf/molecular-programming-of-b-cell-memory-4h63adb0qv.pdf

Molecular programming of B cell memory.

This paper synthesizes recent progress toward understanding the integrated control systems and fail-safes that guide the quality and quantity of antibody produced by B cells. We focus on four key decisions: (1) the choice between proliferation or death in perifollicular B cells in the first 3 days after antigen encounter; (2) differentiation of proliferating perifollicular B cells into extrafollicular plasma cells or germinal center B cells; (3) positive selection of B cell antigen receptor (BCR) affinity for foreign antigen versus negative selection of BCR affinity for self antigen in germinal center B cells; and (4) survival versus death of antibody-secreting plasma cells. Understanding the engineering of these control systems represents a challenging future step for treating disorders of antibody production in autoimmunity, allergy and immunodeficiency.

Control systems and decision making for antibody production

The basis of immune memory leading to heightened secondary antibody responses is a longstanding unanswered issue. Here we show that a single irreversible molecular change in the B cell antigen receptor, which is brought about by immunoglobulin M (IgM) to IgG isotype switching, is sufficient to greatly increase the extrafollicular proliferative burst of antigen-specific B cells. The unique membrane-spanning regions of IgG do not alter the T cell–dependent activation and proliferation of antigen-specific B cells in vivo, but markedly increase the number of progeny cells and plasmablasts that accumulate. These results establish a key molecular determinant of immunological memory and define an unexpected cellular basis by which it enhances the magnitude of secondary antibody responses.

Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory

Immunological memory is characterized by heightened immunoglobulin (Ig) G antibody production caused in part by enhanced plasma cell formation conferred by conserved transmembrane and cytoplasmic segments in isotype-switched IgG B cell receptors. We tested the hypothesis that the IgG tail enhances intracellular B cell antigen receptor (BCR) signaling responses to antigen by analyzing B cells from Ig transgenic mice with IgM receptors or chimeric IgMG receptors containing the IgG tail segment. The IgG tail segment enhanced intracellular calcium responses but not tyrosine or extracellular signal–related kinase (ERK) phosphorylation. Biochemical analysis and crosses to CD22-deficient mice established that IgG tail enhancement of calcium and antibody responses, as well as marginal zone B cell formation, was not due to diminished CD22 phosphorylation or inhibitory function. Microarray profiling showed no evidence for enhanced signaling by the IgG tail for calcium/calcineurin, ERK, or nuclear factor κB response genes and little evidence for any enhanced gene induction. Instead, almost half of the antigen-induced gene response in IgM B cells was diminished 50–90% by the IgG tail segment. These findings suggest a novel “less-is-more” hypothesis to explain how switching to IgG enhances B cell memory responses, whereby decreased BCR signaling to genes that oppose marginal zone and plasma cell differentiation enhances the formation of these key cell types.

/pdf/enhancement-and-suppression-of-signaling-by-the-conserved-au3dsgcgig.pdf

Enhancement and suppression of signaling by the conserved tail of IgG memory–type B cell antigen receptors

Introduction Previous attempts to enhance medical nutrition education have typically focussed on students’ acquiring nutrition knowledge or skills. Given that medical training uses an apprenticeship model of training, surprisingly few studies have explored the ‘hidden curriculum’ that students experience regarding expectations of behaviour, roles and responsibilities regarding nutrition. This study explored medical students’ perceptions and experiences regarding medical nutrition education, focussing on the context in which nutrition teaching has been provided, the presented place of nutrition within medicine and their subsequent views on their role in providing nutrition care. Methods Individual semi-structured qualitative interviews were conducted with 14 postgraduate medical students at different stages of their medical degree in Australia. The interviews were conducted using case studies followed by interview questions. Data were audio recorded, transcribed, coded and then underwent inductive thematic analysis. Results Three themes were discovered (i) Valuing nutrition in the medical management of patients whereby students perceived nutrition to be a foundational and central component of ideal medical management for patients, particularly those with chronic disease; (ii) Fluctuating emphasis on nutrition which showed that students experienced diversity in the importance placed on nutrition by others and (iii) Working with others whereby students expressed their understanding of their role in nutrition and the roles of team members such as dietitians. Conclusion To enhance medical nutrition education, consideration needs to extend beyond counting dedicated teaching hours and mapping nutrition content, to a more contextual understanding of the situated learning that occurs for medical students.

https://nutrition.bmj.com/content/bmjnph/3/1/18.full.pdf

Hidden curriculum within nutrition education in medical schools

Immune ‘memory’ is the body’s ability to remember a disease attack and respond swiftly to reinfection. One view is that such memory requires the intermittent re-stimulation of the cells concerned, B cells; another that it does not. New work supports the second possibility.

Immunology. Memory needs no reminders.

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Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory

Enhancement and suppression of signaling by the conserved tail of IgG memory–type B cell antigen receptors

Hidden curriculum within nutrition education in medical schools

Immunology. Memory needs no reminders.