Cutting Edge: B Cells Promote CD8+ T Cell Activation in MRL-Fas<i>lpr</i>Mice Independently of MHC Class I Antigen Presentation

Chan, Owen; Shlomchik, Mark J.

doi:10.4049/jimmunol.164.4.1658

Cited by 35 publications

(21 citation statements)

References 34 publications

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“…Future examination of corresponding B-cell subsets and BAFF levels in emerging murine models possessing phenotypic changes that closely mirror those of cGVHD patients will yield important information. 54 Identification of immune targets in cGVHD in further investigations is also required to determine whether IgG produced by activated B cells contributes to end organ damage by aiding in cross-presentation to T cells, 55,56 forming immune complexes that deposit in tissue, 57 or through binding to functional receptors. 18 Naive B lymphopenia in patients with active cGVHD appeared to begin during the first year after HSCT.…”

Section: Discussionmentioning

confidence: 99%

Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease

Sarantopoulos¹,

Stevenson

Kim

et al. 2009

Blood

286

353

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Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of alloantibodies and high plasma B cell–activating factor (BAFF) levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF/B-cell ratios compared with patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre–germinal center (GC) B cells and post-GC “plasmablast-like” cells, suggesting in vivo BAFF dependence of these 2 CD27+ B-cell subsets. Circulating CD27+ B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27+ B cells in the first year after HSCT. These studies delineate specific abnormalities of B-cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease.

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Section: Discussionmentioning

confidence: 99%

Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease

Sarantopoulos¹,

Stevenson

Kim

et al. 2009

Blood

286

353

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“…Notably, our MRL-Fas lpr mice that were IL-10 deficient had expansion of conventional CD3 ϩ CD4 ϩ B220 Ϫ and CD3 ϩ CD8 ϩ B220 Ϫ T cells, also suggesting a regulatory role of this cytokine in controlling the number of conventional T cells, including those that promote autoantibody production and renal disease. Indeed, recent studies with B cell-deficient or autoantibody-deficient MRL-Fas lpr mice (39,40) have suggested that disease can occur in the absence of B cells and autoantibodies; i.e., T cells presumably can promote disease independently of B cell help. However, the finding that MRL-Fas lpr IL-10 Ϫ/Ϫ mice had T cell expansion suggests that IL-10 can regulate T cell expansion apart from Fas-Fas ligand interactions.…”

Section: Discussionmentioning

confidence: 99%

IL-10 Regulates Murine Lupus

Yin

Bahtiyar

Zhang

et al. 2002

The Journal of Immunology

210

175

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MRL/MpJ-Tnfrsf6lpr (MRL/MpJ-Faslpr; MRL-Faslpr) mice develop a spontaneous lupus syndrome closely resembling human systemic lupus erythematosus. To define the role of IL-10 in the regulation of murine lupus, IL-10 gene-deficient (IL-10−/−) MRL-Faslpr (MRL-Faslpr IL-10−/−) mice were generated and their disease phenotype was compared with littermates with one or two copies of an intact IL-10 locus (MRL-Faslpr IL-10+/− and MRL-Faslpr IL-10+/+ mice, respectively). MRL-Faslpr IL-10−/− mice developed severe lupus, with earlier appearance of skin lesions, increased lymphadenopathy, more severe glomerulonephritis, and higher mortality than their IL-10-intact littermate controls. The increased severity of lupus in MRL-Faslpr IL-10−/− mice was closely associated with enhanced IFN-γ production by both CD4+ and CD8+ cells and increased serum concentration of IgG2a anti-dsDNA autoantibodies. The protective effect of IL-10 in this lupus model was further supported by the observation that administration of rIL-10 reduced IgG2a anti-dsDNA autoantibody production in wild-type MRL-Faslpr animals. In summary, our results provide evidence that IL-10 can down-modulate murine lupus through inhibition of pathogenic Th1 cytokine responses. Modulation of the level of IL-10 may be of potential therapeutic benefit for human lupus.

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“…The presence of anti-dsDNA antibodies identifies patients at risk of lupus nephritis, consistent with experimental evidence that these antibodies have a causative role in GN when deposited as immune complexes in the kidney. However, B cell-deficient but not antibody-deficient mice are protected from lupus nephritis, indicating that cellular functions of B cells also contribute to disease pathogenesis (149,150). In addition to glomerular lesions, lupus nephritis is characterized by inflammation and scarring of the renal interstitium, which predicts progression to renal failure.…”

Section: Role In Gnmentioning

confidence: 99%

B Cells, Antibodies, and More

Hoffman¹,

Lakkis

Chalasani

2016

Clinical Journal of the American Society of Nephrology

382

268

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B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation.

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Cutting Edge: B Cells Promote CD8+ T Cell Activation in MRL-FaslprMice Independently of MHC Class I Antigen Presentation

Cited by 35 publications

References 34 publications

Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease

Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease

IL-10 Regulates Murine Lupus

B Cells, Antibodies, and More

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