Reduced Surrogate Light Chain in Old B Cell Precursors Compromises B Lymphopoiesis and Increases B Cell Reactivity to Common Self Antigens

In murine bone marrow, old age (>2 yrs.) is characterized by low production of pre-B and immature B cells, alterations in the “read-out” of the B cell repertoire and increased autoreactivity within mature B cell populations. In addition, there are changes in the composition of B cell subsets: in the bone marrow early CD23 expression on immature B cells is linked to an activated phenotype, while in the periphery there is increased representation of “antigen experienced” B cells, exemplified by Age-associated B cells. I propose that: 1) Old age-associated reductions in expression of the surrogate light chain not only contribute to reduced pre-B and immature B cells in old mice, but also alter the "read-out” of the antibody repertoire. 2) Immature B cells in old mice are often phenotypically more activated, anergic, and display altered light chain usage. Changes in immature B cell reactivity to antigen associated with reduced surrogate light chain are also seen in the peripheral B cell populations. 3) Age-associated B cells represent “self-reactive” antigen experienced B cells, provide “feed-back” inhibition of B lymphopoiesis, and promote a “preBCR-deficient” pathway of new B cell production. This in turn alters “read-out” of the mature B cell repertoire.</p

Inflammatory immune cells may impair the preBCR checkpoint, reduce new B cell production, and alter the antibody repertoire in old age

Aging impairs development of new B cells and diminishes the expression of protective antibodies. Reduced numbers of B cell precursors generally occur in old (~2 yrs.) mice. At the pro-B to pre-B cell transition, the pre-B cell receptor (preBCR) checkpoint directs pre-B cell expansion and selection of the pre-B cell immunoglobulin (Ig) μ heavy chain variable region repertoire. The preBCR is comprised of Ig μ heavy chain + surrogate light chains (SLC; λ5/VpreB). In old B cell precursors, SLC is decreased and fewer pre-B cells form the preBCR. In pro-B cells, SLC is complexed with cadherin 17 to form a "pro-B cell receptor" whose signaling is postulated to increase apoptotic sensitivity. We propose that inflammation in old mice, in part mediated by the age-associated B cells (ABC), promotes apoptosis among pro-B cells, particularly those relatively high in SLC. The remaining pro-B cells, with lower SLC, now generate pre-B cells with limited capacity to form the preBCR. Ig μ heavy chains vary in their capacity to associate with SLC and form the preBCR. We speculate that limited SLC restricts formation of the preBCR to a subset of Ig μ heavy chains. This likely impacts the composition of the antibody repertoire among B cells

PubData: search engine for bioinformatics databases worldwide

Abstract We propose a search engine and file retrieval system for all bioinformatics databases worldwide. PubData searches biomedical data in a user-friendly fashion similar to how PubMed searches biomedical literature. PubData is built on novel network programming, natural language processing, and artificial intelligence algorithms that can patch into the file transfer protocol servers of any user-specified bioinformatics database, query its contents, retrieve files for download, and adapt to the user’s search preferences. PubData is hosted as a user-friendly, cross-platform graphical user interface program developed using PyQt: http://www.pubdata.bio . The methods are implemented in Python, and are available as part of the PubData project at: https://github.com/Bohdan-Khomtchouk/PubData

Age-associated B cells (ABC) inhibit B lymphopoiesis and alter antibody repertoires in old age

With old age (∼2y old), mice show substantial differences in B cell composition within the lymphoid tissues. In particular, a novel subset of IgM CD21/35 CD23 mature B cells, the age-associated B cells or ABC, increases numerically and proportionately. This occurs at the expense of other B cell subsets, including B2 follicular B cells in spleen and recirculating primary B cells in bone marrow. Our studies suggest that ABC have a distinctive antibody repertoire, as evidenced by relatively high reactivity to the self-antigens phosphorylcholine (PC) and malondialdehyde (MDA). While PC and MDA are found on apoptotic cells and oxidized lipoproteins, antibodies to these antigens are also cross-reactive with epitopes on bacterial species. In old mice, ABC express TNFα and are pro-inflammatory. ABC can inhibit growth and/or survival in pro-B cells as well as common lymphoid progenitors (CLP). In particular, ABC cause apoptosis in pro-B cells with relatively high levels of the surrogate light chain (SLC) and, consequently, promote an "SLC low" pathway of B cell differentiation in old mice. SLC together with μ heavy chain comprises the pre-B cell receptor (preBCR) critical for pre-B cell expansion and selection of the μ heavy chain Vh repertoire. The low level of SLC likely impairs normal preBCR driven proliferation and alters μ heavy chain Vh selection thereby affecting the antibody specificities of new B cells. In this manner, ABC may contribute to both qualitative and quantitative disruptions of normal B lymphopoiesis in old age

In old BALB/c mice, bone marrow pre-B cell and surrogate light chain reduction is associated with increased B cell reactivity to phosphorylcholine, but reduced T15 idiotype dominance

In young adult BALB/c mice, antibodies to phosphorylcholine (PC) bearing the T15 (TEPC 15) idiotype confer protection against pneumococcal infections. In old age, even though PC reactive B cells are often increased, the proportion of T15(+) antibodies declines. We hypothesize that limited surrogate light chain (SLC) and compromise of the pre-B cell receptor checkpoint in old mice contribute to both reduced new B cell generation and changes in the anti-PC antibodies seen in old age. In old mice: 1) early pre-B cell loss is most pronounced at the preBCR checkpoint; however, the reduced pool of early pre-B cells continues to proliferate consistent with preBCR signaling; 2) increased PC reactivity is seen in bone marrow immature B cells; 3) deficient SLC promotes increased B cell PC reactivity and diminished T15 idiotype within a subset of young adult mice; and 4) in old mice, as pre-B cell losses and reduced SLC become progressively more severe, increased T15 negative PC reactive B cells occur. These results associate a reduction in pre-B cells, imposed at the preBCR checkpoint, with increased reactivity to PC, but more limited expression of the protective T15 idiotype among PC reactive antibodies in old age