Origins and Functions of B-1 Cells with Notes on the Role of CD5

Berland, Robert; Wortis, Henry H.

doi:10.1146/annurev.immunol.20.100301.064833

Cited by 676 publications

(704 citation statements)

References 299 publications

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“…This is also consistent with our observation that TLR signaling via MyD88 is not necessary for establishment of the primary mature B cell repertoire [34]. The peritoneal cavity B1 cell population (B220 low IgM ++ IgD low FSC high Mac1 + ), which is associated with the production of natural IgM autoAb [35], was also comparable between lyn -/-and DKO mice (data not shown). lyn -/-mice is unexplained.…”

Section: Myd88 Deficiency Prevents Splenomegaly But Does Not Affect Bsupporting

confidence: 91%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

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Section: Myd88 Deficiency Prevents Splenomegaly But Does Not Affect Bsupporting

confidence: 91%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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“…CD5+ B220+ cells represent B1 cells which have been shown to be positively selected on self-antigen [33]. Self-antigen has been shown to promote accumulation of B-1 cells and serum autoantibody [34]. Although it remains unknown how self-antigen becomes available in this model, the data presented here suggest both T and B cell activation in response to self-antigen.…”

Section: Discussionmentioning

confidence: 73%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

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Most individuals have viral infections at some point in their life, however, only few develop autoreactivity to cardiac myosin following infection resulting in myocarditis suggesting a genetic predisposition. Most mouse models of myocarditis are induced by viral infection or by immunization with cardiac myosin. We generated HLA-DR3.Aβo and HLA-DQ8.Aβo transgenic mice in NOD and HLA-DQ8.Aβo in B10 background to study spontaneous autoimmunity. A high mortality was observed in NOD.DQ8 female mice 16 weeks or older. Echocardiography showed marked systolic dysfunction. Histopathology of various organs revealed an enlarged heart with mononuclear infiltrate consisting of CD4 and Mac-1+ cells and myocyte necrosis. The autoimmunity was associated with the presence of spontaneous autoreactive T cells and antibodies to cardiac myosin. Serologically, mice were negative for all known mouse viruses. NOD.DR3.Aβo, the transgene negative littermates, NOD, and B10.DQ8 Aβo mice had no gross or microscopic cardiac pathology. Spontaneous cellular and humoral response to cardiac myosin suggest that NOD.DQ8 may harbor autoreative cells that can lead to spontaneous myocarditis and dilated cardiomyopathy. HLA-DQ8 is required for predisposition to the spontaneous autoreactivity while NOD background influences onset and progression of disease. This model of myocarditis occurs predominantly in female mice and may provide insight into the pathogenesis of heart disease in women.

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“…This may reflect the ability of peritoneal B-2 cells to directly differentiate into B-1 cells as has been postulated by several investigators [38,39]. Alternatively, it may simply reflect the acquisition of similar phenotypes by different cell types that reside in the same physiological niche.…”

Section: Discussionmentioning

confidence: 80%

Peritoneal B‐2 cells comprise a distinct B‐2 cell population with B‐1b‐like characteristics

et al. 2006

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B‐1 and B‐2 cells are lymphocyte populations that differ in development, surface marker expression, tissue localization, and function. Though mainly found in the spleen, lymph nodes, and circulation of mice, small numbers of B‐2 cells are found in the peritoneal cavity, a site predominantly populated by B‐1 cells. Here, we characterized peritoneal B‐2 cells, and determined their relationship to B‐1 cells. We found that peritoneal B‐2 cells appear to be intermediate between splenic B‐2 and peritoneal B‐1 cells in terms of surface marker expression of B220, CD80, and CD43, expression of several marker genes, and in vitro viability and IgM secretion. Adoptive transfer of peritoneal B‐2 cells into severe combined immunodeficiency mice resulted in the acquisition of a phenotype reminiscent of B‐1b cells, as shown by up‐regulation of Mac‐1 and CD43, and down‐regulation of CD23. Moreover, adoptively transferred peritoneal B‐2 cells recapitulated B‐1 cell function by producing natural IgM in recipient mice. These data suggest that peritoneal B‐2 cells express some characteristics of B‐1b cells and that this similarity increases with additional time in the peritoneal cavity.

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Origins and Functions of B-1 Cells with Notes on the Role of CD5

Cited by 676 publications

References 299 publications

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Peritoneal B‐2 cells comprise a distinct B‐2 cell population with B‐1b‐like characteristics

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