Alterations in splenic architecture and the localization of anti-double-stranded DNA B cells in aged mice

Eaton-Bassiri, Ashlyn; Mandik-Nayak, Laura; Seo, Su Jean; Madaio, Michael P.; Cancro, Michael P.; Erikson, Jan

doi:10.1093/intimm/12.6.915

Cited by 26 publications

(28 citation statements)

References 60 publications

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“…9, lower left panel). This is consistent with the findings of Eaton-Bassiri et al (60), who investigated aged BALB/c mice. IgG anti-dsDNA Abs are widely accepted as pathogenic in lupus-like disease (42,44); however, sera from 7-mo-old (New Zealand Black ϫ New Zealand White)F 1 mice assayed in parallel had a median value of 6.24 U/ml.…”

Section: Autoantibody Production Is Increased In Aged 3-83␦ Micesupporting

confidence: 93%

Aging-Dependent Exclusion of Antigen-Inexperienced Cells from the Peripheral B Cell Repertoire

Johnson

Rozzo

Cambier

2002

The Journal of Immunology

121

111

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Aging is accompanied by greatly reduced B cell production in the bone marrow, yet peripheral B cell numbers do not decline. We hypothesize that this may reflect filling of the peripheral pool with B cells that are long-lived as a consequence of specificity for, and chronic stimulation by, environmental Ags. To begin to explore this possibility, we analyzed the effects of aging on B cell population dynamics in the anti-H2k/b 3-83μδ Ig-transgenic mouse. We predicted that, because they presumably do not bind environmental Ags, B cells bearing the transgenic receptor may be lost in aged animals. As seen in nontransgenic animals, total splenic B cell numbers remained constant with age in the Ig-transgenic animals despite reduced B cell production. Importantly, although the few newly produced B cells in the bone marrow of aged mice are 3-83 positive, the peripheral compartment of these mice is dominated by B cells that express endogenous Ig genes rather than the transgenes. This population includes large numbers of marginal zone-like and CD21low/−CD23low/−IgMlow B cells, as well as elevated numbers of CD5+ B cells. Many of these cells express only non-B220 CD45 isoforms, suggesting that they may be memory cells. A significant proportion of aged transgenic animals produce autoantibodies that are reactive with ssDNA, dsDNA, or histones. Results support the hypothesis that, in the face of severely reduced production with age, B cells are selected based on reactivity to environmental Ags, accumulate, and display activated phenotypes. Cells bearing 3-83-transgenic receptors are excluded from this population due to their specificity. Beyond their importance in aging, these findings define a novel form of receptor revision in which B cells are selected rather than deleted based on Ag reactivity.

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Section: Autoantibody Production Is Increased In Aged 3-83␦ Micesupporting

confidence: 93%

Aging-Dependent Exclusion of Antigen-Inexperienced Cells from the Peripheral B Cell Repertoire

Johnson

Rozzo

Cambier

2002

The Journal of Immunology

121

111

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“…2A), a phenotype that we and others have attributed to continual Ag encounter (17,18,30,(35)(36)(37)(38)(39)(40)(41)(42). At all ages examined, anti-dsDNA B cells from VH3H9 BALB-lpr/lpr mice had increased levels of B220, as compared with Fas-sufficient VH3H9 BALB/c mice (Fig.…”

Section: Altered Localization and Cell Surface Phenotype Of Anti-dsdnmentioning

confidence: 65%

“…The presence of ANAs and anti-dsDNA Abs in the serum was detected using the ANA and C. luciliae assays, respectively, as previously described (18,30). Binding was detected using either anti-IgM ϩ IgG FITC (together, to detect total Ig) or anti-Ig FITC (all from Southern Biotechnology Associates, Birmingham, AL).…”

Section: Anti-nuclear Ab (Ana) and Crithidia Luciliae Assaysmentioning

confidence: 99%

“…Kidneys were sectioned to 4-m thickness and stained with H&E. The presence of renal pathology was determined as described (30,32) by a single investigator (M. P. Madaio) without knowledge of age or genotype of the mice. Kidneys were graded for severity of disease in three areas (vascular, interstitial, and glomerular) in a range of 0 (for no pathology evident) to 4 ϩ (most severe pathology, end stage disease) (33), and cumulative scores were determined.…”

Section: Kidney Pathologymentioning

confidence: 99%

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Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Fields

Sokol

Eaton-Bassiri

et al. 2001

The Journal of Immunology

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Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.

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“…Decreased mature B cell turnover, hence increased lifespan [87,112] Increased number and proportion of ABCs [15,16] Immune responses Fewer GCs and PCs following T-dependent immunization [108,[113][114][115] Defects in T helper function [33][34][35] No change in PCs following T-independent immunization [116] Increased prevalence of chronically activated B cells [117] Increased prevalence of PCs secreting autoantibodies [117][118][119][120] Impaired class switching [109,121] [59]. During TR selection, sustained or strong BCR signals yield death or inactivation [55,[60][61][62][63][64].…”

Section: Constant Mature B Cell Numbersmentioning

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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Alterations in splenic architecture and the localization of anti-double-stranded DNA B cells in aged mice

Cited by 26 publications

References 60 publications

Aging-Dependent Exclusion of Antigen-Inexperienced Cells from the Peripheral B Cell Repertoire

Aging-Dependent Exclusion of Antigen-Inexperienced Cells from the Peripheral B Cell Repertoire

Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

New Cells in Old Mice: The ABCs of Humoral Immunosenescence

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