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Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus.

Fan H, Liu F, Dong G, Ren D, Xu Y, Dou J, Wang T, Sun L, Hou Y - Cell Death Dis (2014)

Bottom Line: We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days.Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors.These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.

ABSTRACT
B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19(+)CD27(-) and CD19(+)IgM(+) B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19(+) B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients.

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Hierarchical cluster dendrogram and verifications of SLE B-cell transcriptomes. (a) The differentially expressed genes are displayed significantly between CD19+ B cells isolated from the peripheral blood of SLE patients and healthy controls. The bars in the left indicate the associativity of SLE B-cell transcriptomes, and the bars on the top present clusters of differential expressed genes. Color changes indicate the expression level relative to the average (log2 scale). Red is increased expression, black is unchanged and green is decreased expression. The entire list of transcripts in the order as they appeared on the dendrogram is in Supplementary Table S1. (b–g) Selective verification of SLE B-cell differentially expressed genes. The mRNA was extracted from CD19+ B cells, and real-time PCR was performed. Bar graphs represent the fold change of mRNA levels in B cells between healthy controls (N) and SLE patients (S). The data are presented as relative mRNA levels following normalization. *P<0.05, **P<0.01 and ***P<0.001
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fig2: Hierarchical cluster dendrogram and verifications of SLE B-cell transcriptomes. (a) The differentially expressed genes are displayed significantly between CD19+ B cells isolated from the peripheral blood of SLE patients and healthy controls. The bars in the left indicate the associativity of SLE B-cell transcriptomes, and the bars on the top present clusters of differential expressed genes. Color changes indicate the expression level relative to the average (log2 scale). Red is increased expression, black is unchanged and green is decreased expression. The entire list of transcripts in the order as they appeared on the dendrogram is in Supplementary Table S1. (b–g) Selective verification of SLE B-cell differentially expressed genes. The mRNA was extracted from CD19+ B cells, and real-time PCR was performed. Bar graphs represent the fold change of mRNA levels in B cells between healthy controls (N) and SLE patients (S). The data are presented as relative mRNA levels following normalization. *P<0.05, **P<0.01 and ***P<0.001

Mentions: To elucidate the molecular pathology feature of B cells in SLE, the differential gene expression profiles of CD19+ B cells between six active SLE patients and six healthy donors were assessed by gene microarrays. Hierarchical cluster analysis was performed for the changed genes with a ≥1.4-fold difference (P<0.05, Welch's t-test, BH-FDR). The results showed that 1017 genes were upregulated and 459 genes were downregulated in the active SLE B cells (Figure 2a).


Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus.

Fan H, Liu F, Dong G, Ren D, Xu Y, Dou J, Wang T, Sun L, Hou Y - Cell Death Dis (2014)

Hierarchical cluster dendrogram and verifications of SLE B-cell transcriptomes. (a) The differentially expressed genes are displayed significantly between CD19+ B cells isolated from the peripheral blood of SLE patients and healthy controls. The bars in the left indicate the associativity of SLE B-cell transcriptomes, and the bars on the top present clusters of differential expressed genes. Color changes indicate the expression level relative to the average (log2 scale). Red is increased expression, black is unchanged and green is decreased expression. The entire list of transcripts in the order as they appeared on the dendrogram is in Supplementary Table S1. (b–g) Selective verification of SLE B-cell differentially expressed genes. The mRNA was extracted from CD19+ B cells, and real-time PCR was performed. Bar graphs represent the fold change of mRNA levels in B cells between healthy controls (N) and SLE patients (S). The data are presented as relative mRNA levels following normalization. *P<0.05, **P<0.01 and ***P<0.001
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4225223&req=5

fig2: Hierarchical cluster dendrogram and verifications of SLE B-cell transcriptomes. (a) The differentially expressed genes are displayed significantly between CD19+ B cells isolated from the peripheral blood of SLE patients and healthy controls. The bars in the left indicate the associativity of SLE B-cell transcriptomes, and the bars on the top present clusters of differential expressed genes. Color changes indicate the expression level relative to the average (log2 scale). Red is increased expression, black is unchanged and green is decreased expression. The entire list of transcripts in the order as they appeared on the dendrogram is in Supplementary Table S1. (b–g) Selective verification of SLE B-cell differentially expressed genes. The mRNA was extracted from CD19+ B cells, and real-time PCR was performed. Bar graphs represent the fold change of mRNA levels in B cells between healthy controls (N) and SLE patients (S). The data are presented as relative mRNA levels following normalization. *P<0.05, **P<0.01 and ***P<0.001
Mentions: To elucidate the molecular pathology feature of B cells in SLE, the differential gene expression profiles of CD19+ B cells between six active SLE patients and six healthy donors were assessed by gene microarrays. Hierarchical cluster analysis was performed for the changed genes with a ≥1.4-fold difference (P<0.05, Welch's t-test, BH-FDR). The results showed that 1017 genes were upregulated and 459 genes were downregulated in the active SLE B cells (Figure 2a).

Bottom Line: We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days.Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors.These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.

ABSTRACT
B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19(+)CD27(-) and CD19(+)IgM(+) B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19(+) B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients.

Show MeSH
Related in: MedlinePlus