Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the <i>Yaa</i> mutation promotes only anti‐DNA production

Kuroki, Aki; Moll, Thomas; López-Hoyos, Marcos; Fossati-Jimack, Liliane; Ibnou-Zekri, Nabila; Kikuchi, Shuichi; Merino, Jesús; Merino, Ramón; Izui, Shozo

doi:10.1002/eji.200424859

Cited by 7 publications

(9 citation statements)

References 44 publications

(52 reference statements)

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“…Furthermore, Fc␥RIIB expressed on follicular dendritic cells may also contribute to the elimination of RF-specific B cells generated during the germinal center reaction, as it has been proposed that preferential interaction of IC present on follicular dendritic cells with Fc␥RIIB over BCR could result in B cell apoptosis (22). This is consistent with our recent observation that an abnormality in B cell apoptosis plays an important role in the induction of RF autoimmune responses (8).…”

Section: Discussionsupporting

confidence: 91%

“…Notably, activated B cells in the germinal center are particularly sensitive to apoptosis because of their down-regulated Bcl-2 and up-regulated Fas expression (7). This is consistent with our recent finding that autoimmune-prone mice overexpressing a Bcl-2 transgene in B cells are able to produce substantial titers of RF (8).…”

Section: R Heumatoid Factors (Rf)supporting

confidence: 90%

“…We have recently shown a synergistic interaction between the Yaa mutation and Bcl-2 overexpression on IgG anti-DNA production, but not on RF production (8). We interpreted these results as follows: unlike anti-DNA-specific B cells, the activation of RF-specific B cells is negatively regulated through corecognition of IC by Fc␥RIIB, and the Yaa mutation may be unable to counteract the potent negative signal triggered by Fc␥RIIB engagement in B cells expressing normal levels of Fc␥RIIB.…”

Section: Discussionmentioning

confidence: 95%

“…In addition, our previous study has shown that the Y-linked autoimmune acceleration (Yaa) mutation enhanced anti-DNA production, but failed to promote RF responses in mice overexpressing Bcl-2 in B cells (8). Therefore, the effect of the Yaa mutation on the induction of RF production was also investigated in mice partially deficient in Fc␥RIIB.…”

Section: R Heumatoid Factors (Rf)mentioning

confidence: 99%

“…We have recently shown that the Yaa mutation promotes the production of IgG anti-DNA autoantibodies, but hardly that of RF in B6 mice (8). In view of a possible key role for Fc␥RIIB in RF autoimmune responses, we determined whether the Yaa mutation is able to promote RF production in B6 mice if their expression of Fc␥RIIB is diminished to a heterozygous level.…”

Section: Induction Of Rf and Anti-dna Production In Fc␥riib Haploinsumentioning

confidence: 99%

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A Critical Role for FcγRIIB in the Induction of Rheumatoid Factors

Moll¹,

Nitschke

Carroll

et al. 2004

The Journal of Immunology

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Rheumatoid factors (RF) are autoantibodies with specificity for the Fc portion of IgG, and IgG-containing immune complexes are likely to be the major source of RF autoantigens. Therefore, the activation of RF-producing B cells could be controlled specifically through recognition of IgG immune complexes by the low-affinity IgG FcR, FcγRIIB, a potent negative regulator of the BCR. To test this possibility, we determined the development of RF in C57BL/6 (B6) mice lacking FcγRIIB, in relation to the H2 haplotype, complement C3, and the Y-linked autoimmune acceleration (Yaa) mutation. FcγRIIB-null B6 mice displayed substantial anti-IgG2a RF activities in their sera, in addition to anti-DNA autoantibodies. Their RF and anti-DNA responses were linked to the H2b haplotype, but were suppressed almost completely by the H2d haplotype. Strikingly, the absence of C3 failed to modulate RF production, but strongly inhibited anti-DNA production. Furthermore, we observed that partial FcγRIIB deficiency (i.e., heterozygous level of FcγRIIB expression) was sufficient to induce the production of RF and anti-DNA autoantibodies in the presence of the Yaa mutation. In contrast to FcγRIIB, the deficiency in another BCR negative regulator, CD22, was unable to promote RF and anti-DNA autoimmune responses in B6 mice. Our results indicate that RF autoimmune responses are critically controlled by FcγRIIB, together with the H2b and Yaa gene, while C3 regulates positively and specifically anti-DNA, but not RF autoimmune responses.

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Section: Discussionsupporting

confidence: 91%

Section: R Heumatoid Factors (Rf)supporting

confidence: 90%

Section: Discussionmentioning

confidence: 95%

Section: R Heumatoid Factors (Rf)mentioning

confidence: 99%

Section: Induction Of Rf and Anti-dna Production In Fc␥riib Haploinsumentioning

confidence: 99%

See 3 more Smart Citations

A Critical Role for FcγRIIB in the Induction of Rheumatoid Factors

Moll¹,

Nitschke

Carroll

et al. 2004

The Journal of Immunology

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A female preponderance for chemically induced lupus in SJL/J mice

Smith

Dong

et al. 2007

Clinical Immunology

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Both spontaneous and chemically induced rodent models of autoimmune nephritis and autoantibody production have been explored to understand mechanisms involved in human systemic lupus erythematosus (SLE). While it has been known for decades that women are more susceptible than men to SLE, mechanisms underlying this female preponderance remain unclear. One chemically induced model involves injection of hydrocarbon oils such as pristane into otherwise normal mouse strains, which results in the development of autoantibodies and inflammation in organs such as kidney and liver. It is unknown whether lupus-like disease induced by chemicals would exhibit a sex bias in disease susceptibility. Here, we show that SJL/J female mice injected with pristane display greater mortality, kidney disease, serum anti-nuclear and anti-dsDNA antibodies than their male siblings. This is the first evidence that a female sex bias exists in a chemically induced lupus model.

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Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice

Kobayashi

Takahashi

Nagai

et al. 2008

International Immunology

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Toll-like receptors (TLRs) have a crucial role in sensing microbial products and triggering immune responses. Recent reports have indicated that TLR7 and TLR9 have an important role in activating autoreactive B cells. In addition to TLR7 and TLR9, mouse B cells express TLR2, TLR4 and structurally related Radioprotective105 (RP105). We have previously shown that RP105 works in concert with TLR2/4 in antibody response to TLR2/4 ligands. We here report that B cells are constitutively activated by TLR2/4 and RP105. Such B cell activation was revealed by the gamma3 germ line transcript and serum IgG3 production, both of which were impaired by the lack of RP105 or TLR2/4. Serum IgG3 was not altered in germ-free or antibiotics-treated mice, suggesting that the microbial flora hardly contributes to the continuous activation of B cells. The lack of RP105-dependent B cell activation ameliorated disease progression in lupus-prone MRL/lpr mice. RP105(-/-) MRL/lpr mice showed less lymphoadenopathy/splenomegaly and longer survival than MRL/lpr mice. Whereas glomerulonephritis and auto-antibody production were not altered, improvement in blood urea nitrogen and lower incidence of renal arteritis indicated that renal function was ameliorated in the absence of RP105. Our results suggest that RP105-dependent tonic B cell activation has a pathogenic role in MRL/lpr mice.

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Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production

Cited by 7 publications

References 44 publications

A Critical Role for FcγRIIB in the Induction of Rheumatoid Factors

A Critical Role for FcγRIIB in the Induction of Rheumatoid Factors

A female preponderance for chemically induced lupus in SJL/J mice

Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice

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