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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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Related in: MedlinePlus

The elevated mortality of B cells in active SLE patients. Scatter plots represent the percentages of these B cell-subsets in 21 healthy controls (closed circles) and 14 SLE patients (closed squares). The mean of each set of values is shown as a horizontal line. (a–c) The percentage of CD86+ CD19+, CD80+CD19+ and CD40+CD19+ B cells. (d) The percentage of CD19− cells and CD19− Annexin V+ cells. (e) The percentage of CD19+ cells and CD19+Annexin V+ cells. (f) The percentage of CD27+CD19+ cells and CD27+ CD19+Annexin V+ cells. (g) The percentage of CD27−CD19+ cells and CD27− CD19+ Annexin V+ cells. (h) The percentage of IgM+CD19+ cells and IgM+CD19+ Annexin V+ cells. (i) The percentage of IgM−CD19+ cells and IgM− CD19+Annexin V+ cells. P-values (Students t-test) were calculated for the difference between SLE group and the control group. *P<0.05, **P<0.01 and ***P<0.001
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fig1: The elevated mortality of B cells in active SLE patients. Scatter plots represent the percentages of these B cell-subsets in 21 healthy controls (closed circles) and 14 SLE patients (closed squares). The mean of each set of values is shown as a horizontal line. (a–c) The percentage of CD86+ CD19+, CD80+CD19+ and CD40+CD19+ B cells. (d) The percentage of CD19− cells and CD19− Annexin V+ cells. (e) The percentage of CD19+ cells and CD19+Annexin V+ cells. (f) The percentage of CD27+CD19+ cells and CD27+ CD19+Annexin V+ cells. (g) The percentage of CD27−CD19+ cells and CD27− CD19+ Annexin V+ cells. (h) The percentage of IgM+CD19+ cells and IgM+CD19+ Annexin V+ cells. (i) The percentage of IgM−CD19+ cells and IgM− CD19+Annexin V+ cells. P-values (Students t-test) were calculated for the difference between SLE group and the control group. *P<0.05, **P<0.01 and ***P<0.001

Mentions: A total of 14 active SLE patients and 21 healthy donors were recruited and peripheral blood mononuclear cells (PBMCs) were obtained. We first evaluated the activation status of SLE CD19+B cells in PBMCs. The results revealed that the activation marker CD86 was significantly upregulated in active SLE B cells compared with healthy donors (4.8±0.4% versus 7.8±1.0% Figure 1a), whereas the expression of CD40 and CD80 was unchanged (Figures 1b and c).


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)

The elevated mortality of B cells in active SLE patients. Scatter plots represent the percentages of these B cell-subsets in 21 healthy controls (closed circles) and 14 SLE patients (closed squares). The mean of each set of values is shown as a horizontal line. (a–c) The percentage of CD86+ CD19+, CD80+CD19+ and CD40+CD19+ B cells. (d) The percentage of CD19− cells and CD19− Annexin V+ cells. (e) The percentage of CD19+ cells and CD19+Annexin V+ cells. (f) The percentage of CD27+CD19+ cells and CD27+ CD19+Annexin V+ cells. (g) The percentage of CD27−CD19+ cells and CD27− CD19+ Annexin V+ cells. (h) The percentage of IgM+CD19+ cells and IgM+CD19+ Annexin V+ cells. (i) The percentage of IgM−CD19+ cells and IgM− CD19+Annexin V+ cells. P-values (Students t-test) were calculated for the difference between SLE group and the control group. *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

fig1: The elevated mortality of B cells in active SLE patients. Scatter plots represent the percentages of these B cell-subsets in 21 healthy controls (closed circles) and 14 SLE patients (closed squares). The mean of each set of values is shown as a horizontal line. (a–c) The percentage of CD86+ CD19+, CD80+CD19+ and CD40+CD19+ B cells. (d) The percentage of CD19− cells and CD19− Annexin V+ cells. (e) The percentage of CD19+ cells and CD19+Annexin V+ cells. (f) The percentage of CD27+CD19+ cells and CD27+ CD19+Annexin V+ cells. (g) The percentage of CD27−CD19+ cells and CD27− CD19+ Annexin V+ cells. (h) The percentage of IgM+CD19+ cells and IgM+CD19+ Annexin V+ cells. (i) The percentage of IgM−CD19+ cells and IgM− CD19+Annexin V+ cells. P-values (Students t-test) were calculated for the difference between SLE group and the control group. *P<0.05, **P<0.01 and ***P<0.001
Mentions: A total of 14 active SLE patients and 21 healthy donors were recruited and peripheral blood mononuclear cells (PBMCs) were obtained. We first evaluated the activation status of SLE CD19+B cells in PBMCs. The results revealed that the activation marker CD86 was significantly upregulated in active SLE B cells compared with healthy donors (4.8±0.4% versus 7.8±1.0% Figure 1a), whereas the expression of CD40 and CD80 was unchanged (Figures 1b and c).

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