Deviation of the B Cell Pathway in Senescent Mice Is Associated with Reduced Surrogate Light Chain Expression and Altered Immature B Cell Generation, Phenotype, and Light Chain Expression

Alter-Wolf, Sarah; Blomberg, Bonnie B.; Riley, Richard L.

doi:10.4049/jimmunol.182.1.138

Cited by 45 publications

(52 citation statements)

References 39 publications

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“…Moreover, experiments using young and old donors to reconstitute immune-deficit SCID mice, suggest that these differences arise from B cell intrinsic factors, although the cytokine environment might also play a role (Shriner et al, 2006). In murine models it has also been reported the impaired expression of the surrogate chain and the increased usage of the VhS107 family that can also have consequences in the formation of the B cell repertoire (Alter-Wolf et al, 2009a). Some reports on B cell repertoire indicated that older mice showed evidence of non-malignant clonal expansion (LeMaoult et al, 1997), which in view of the homeostatic mechanisms that maintain the total numbers of B lymphocytes would lead to a decrease in diversity.…”

Section: B Lymphocytesmentioning

confidence: 99%

B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

Bulati¹,

Buffa²,

Candore³

et al. 2011

Ageing Research Reviews

101

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a b s t r a c tImmunosenescence contributes to the decreased ability of the elderly to control infectious diseases, which is also reflected in their generally poor response to new antigens and vaccination. It is known that the T cell branch of the immune system is impaired in the elderly mainly due to expansion of memory/effector cells that renders the immune system less able to respond to new antigens. B lymphocytes are also impaired in the elderly in terms of their response to new antigens. In this paper we review recent work on B cell immunosenescence focusing our attention on memory B cells and a subset of memory B cells (namely IgG + IgD − CD27 − ) that we have demonstrated is increased in healthy elderly.

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Section: B Lymphocytesmentioning

confidence: 99%

B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

Bulati¹,

Buffa²,

Candore³

et al. 2011

Ageing Research Reviews

101

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“…Optimal CD43/S7 expression on immature B cells, like CD23, requires Btk, and consequently BCR signaling 38 . We have previously reported that CD43/S7 is more prevalent on immature B cells from old mice and that new B cells with CD43/S7 expression are generated more readily from B cell precursors in old mice 19,33 . Together with the finding that CD23 expression is more prevalent on immature B cells from old mice, increased CD43/S7 expression on new B cells in old mice likely represents increased activation of these B cells 19,33 .…”

Section: Resultsmentioning

confidence: 95%

“…This early expression of CD23 by bone marrow immature B cells is a likely consequence of activation, possibly driven via the BCR and antigen selection, and is dependent upon Bruton’s tyrosine kinase (Btk) 35 . We have also described subsets of immature B cells based on differential expression of CD43/S7, which is also associated with activation and Btk expression, and described changes in this population in old age 19,33 .…”

Section: Resultsmentioning

confidence: 99%

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

Khomtchouk

Alter

Ratliff

et al. 2017

Mechanisms of Ageing and Development

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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.

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Section: Aging Alters Humoral Immune Responsesmentioning

confidence: 99%

“…For example, truncation of the responsive repertoire is partly explained by so-called B cell clonal expansions that emerge at the expense of more diverse naïve B cell populations [28,29]. Furthermore, shifts in key features of developing B cells and their production rates (discussed below) may yield skewed generation or selection of naïve B cell clonotypes [30][31][32].In addition to changes in the composition of naïve B cell pools per se, a substantial literature indicates that B lineageextrinsic components act in concert to yield overall dulled humoral responses. For example, both CD4+ and CD8+ T cells in aged mice display reduced responsiveness to encounters with novel Ag [33], and the effectiveness with which CD4+ T cells provide cognate help diminishes with age…”

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confidence: 99%

New Cells in Old Mice: The ABCs of Humoral Immunosenescence

Hao¹,

Oropallo²,

Scholz³

et al. 2012

TOLSJ

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Dampened humoral immune responses and increased propensity for autoimmune and inflammatory diseases are hallmarks of aging. Here, we summarize recent progress in understanding how aging affects humoral immunity, focusing on the discovery of a phenotypically and functionally unique B cell subset in aged mice, its potential role in immunosenescence, and its relationship to increased inflammation and autoimmunity.Keywords: Age, B cell homeostasis, function. OVERVIEWAging is a complex process characterized by functional declines in multiple physiologic systems. Age-related alterations in the immune system, a spectrum of changes that are in toto termed "immunosenescence," yield enhanced susceptibility to infectious diseases, increased propensity for inflammatory responses and autoantibody production, and consequently, increased morbidity and mortality [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Understanding the mechanisms through which age-associated phenomena yield the overall immunosenescent phenotype presents a fundamental and challenging biological problem. Multiple factors contribute to this general deterioration of immune activity, encompassing both cell-intrinsic changes and alterations in lymphoid organ microenvironments. In particular, determining how age-associated changes result in modified homeostatic relationships among steady-state lymphocyte pools, and how this in turn impacts the initiation and quality of adaptive immune responses, may provide the keys to effective prophylaxis and intervention. In this review, we briefly summarize global shifts in humoral immune responsiveness that emerge with age, followed by a detailed consideration of changes in the genesis and homeostasis of B lymphocyte populations. Finally, we focus on a recently described B lineage subset that emerges with age [15,16], and discuss how the shifting palette of functional B cell subsets may contribute to the global landscape of immunosenescence. AGING ALTERS HUMORAL IMMUNE RESPONSESProtective humoral immunity requires maintaining both naïve and antigen-experienced B cell subsets that respond robustly to pathogens, yet maintain self-tolerance. Multiple studies have revealed that, in contrast to healthy young adults, aged individuals display blunted humoral responses to both new and previously encountered antigens, as well as increases in autoantibody levels [4,7,11,13,[17][18][19]. Accordingly, studies over the last several decades have interrogated the basis for this array of features. Table I summarizes some of the changes in B cell development, dynamics and function that have been revealed by these efforts.Early work focused primarily upon whether the frequency or clonal composition of responsive B cells changes in aged individuals, as well as whether hallmarks of effective humoral immune responses are altered. Examinations of how aging influences responding B cell frequencies, using model antigens in mice, have yielded mixed results. For example, aged mice have decreased frequencies of B cells responsive to some...

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Deviation of the B Cell Pathway in Senescent Mice Is Associated with Reduced Surrogate Light Chain Expression and Altered Immature B Cell Generation, Phenotype, and Light Chain Expression

Cited by 45 publications

References 39 publications

B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

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

New Cells in Old Mice: The ABCs of Humoral Immunosenescence

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