Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia

Daridon, Capucine; Loddenkemper, Christoph; Spieckermann, Simone; Kühl, Anja A.; Salama, Abdulgabar; Burmester, Gerd R.; Lipsky, Peter E.; Dörner, Thomas

doi:10.1182/blood-2012-04-424648

Cited by 43 publications

(40 citation statements)

References 44 publications

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“…Most TFHs were proinflammatory cells, as only a few of them expressed Foxp3 1 in accordance with a previous report showing a decrease in splenic TFRegs in ITP. 29 We subsequently demonstrated that the described expansion of TFHs could be involved in B-cell differentiation in the spleen of ITP patients, contributing to the development of PCs producing antiplatelet autoantibodies. As a first line of evidence and in agreement with previous reports, 32,33 the increased number of TFHs was concomitant to an expansion of GC in ITP patients related to an increase in both GC B cells and PCs.…”

Section: Discussionmentioning

confidence: 99%

“…28 In the second report, TFHs were quantified in the spleens of 6 ITP patients and 6 controls by assessing PD-1 expression by immunochemistry. 29 PD-1-positive cells tended to be less frequent in ITP patients compared with controls. However, concomitant measurement of additional differentiation markers is usually required to identify TFHs because PD-1 is also expressed by activated non-TFH CD4…”

Section: Introductionmentioning

confidence: 95%

“…29 Taking advantage of splenectomy as part of the treatment of ITP, we quantified and localized TFHs within the spleen during a B-cell-mediated AID. Given the importance of TFHs in promoting B-cell differentiation, we assessed whether TFHs could participate in the increase in secondary follicles and GC usually observed in the spleen of ITP patients.…”

Section: Introductionmentioning

confidence: 99%

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Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

Audia

Rossato

Santegoets

et al. 2014

Blood

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Key Points• Human splenic TFH expansion during ITP participates in B-cell differentiation and antiplateletantibody production.• IL-21 and CD40 are key TFH molecules that could be promising targets in the treatment of ITP.Antiplatelet-antibody-producing B cells play a key role in immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand (CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

Audia

Rossato

Santegoets

et al. 2014

Blood

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“…Finally, the spleen has been considered as the major reservoir for mBCs, based on the following observations. First, cluster of differentiation (CD) 27 + mBCs are present in the spleen (16), usually organized around B cell follicles (17)(18)(19). Splenectomy greatly diminishes peripheral mBC numbers of both CD27 + IgM + IgD + preswitch mBCs and CD27 + IgD 2 postswitch mBCs (20)(21)(22).…”

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confidence: 99%

Tissue Distribution and Dependence of Responsiveness of Human Antigen-Specific Memory B Cells

Giesecke

Frölich

Reiter

et al. 2014

The Journal of Immunology

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Memory B cells (mBCs) are a key to immunologic memory, yet their distribution within lymphoid organs and the individual role of these for mBC functionality remain largely unknown. This study characterized the distribution and phenotype of human (Ag-specific) mBCs in peripheral blood (PB), spleen, tonsil, and bone marrow. We found that the spleen harbors most mBCs, followed by tonsils, BM, and PB, and we detected no major differences in expression of markers associated with higher maturity. Testing the distribution of tetanus toxoid–specific (TT+) mBCs revealed their presence in PB during steady state, yet absolute numbers suggested their largest reservoir in the spleen, followed by tonsils. To explore the role of both tissues in the maintenance of reactive B cell memory, we revaccinated controls and splenectomized and tonsillectomized individuals with TT. All donor groups exhibited comparable emergence of anti-TT IgG, TT+ plasma cells, and TT+ mBCs in the PB, together with similar molecular characteristics of TT+ plasma cells. In summary, human mBCs recirculate through PB and reside in different lymphoid organs that do not reflect different mBC maturity stages. The spleen and tonsil, although harboring the largest number of overall and TT+ mBCs, appear to be dispensable to preserve adequate responsiveness to secondary antigenic challenge.

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“…Proliferative lymphoid nodules in the spleen are reported to be the sites of autoantigen stimulation in patients with ITP [21]. Higher levels of B cells have been reported in the red pulp of spleens in patients with ITP [22].…”

Section: Ba N Discussionmentioning

confidence: 95%

Imbalance between CD205 and CD80/CD86 in dendritic cells in patients with immune thrombocytopenia

Zhang

et al. 2015

Thrombosis Research

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Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia

Abstract: To understand more specific abnormalities of humoral autoimmunity, we studied 31 spleens from immune thrombocytopenia (ITP) patients and 36 control spleens.

Cited by 43 publications

References 44 publications

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia

Tissue Distribution and Dependence of Responsiveness of Human Antigen-Specific Memory B Cells

Imbalance between CD205 and CD80/CD86 in dendritic cells in patients with immune thrombocytopenia

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