Notch2 Haploinsufficiency Results in Diminished B1 B Cells and a Severe Reduction in Marginal Zone B Cells

Witt, Colleen M.; Won, Woong-Jai; Hurez, Vincent; Klug, Christopher A.

doi:10.4049/jimmunol.171.6.2783

Cited by 106 publications

(95 citation statements)

References 45 publications

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“…5 A modulation of CD5 expression according to the involved compartment could account for these discordant results between blood and spleen, since CD5 expression can depend on the micro-environment, as a possible result of the response to the local cytokine network, especially Tcell-derived lymphokine, interleukin-4, chemokine and Bcell receptor signaling via the notch2 pathway. [22][23][24] However in the present series, CD5 appears to be almost always uniformly expressed whatever the anatomical site. Indeed a very good correlation of CD5 expression was observed in both compartments, given that all the cases studied by flow cytometry except one were CD5-positive in spleen suspensions as well as in blood.…”

Section: Discussionmentioning

confidence: 48%

CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases

Baseggio¹,

Traverse-Gléhen²,

Petinataud³

et al. 2009

Haematologica

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The online version of this article has a Supplementary Appendix BackgroundClassically, splenic marginal zone B-cell lymphoma is characterized by the absence of CD5 expression. Cases of apparent splenic marginal zone B-cell lymphoma showing CD5 expression, as diagnosed by blood studies, have been described; however, in the absence of histological evidence, the correct diagnosis of these cases is controversial because of possible confusion with other CD5-positive small B-cell neoplasms. Design and MethodsWe report a series of 24 CD5-positive, t(11;14)-negative cases of splenic marginal zone B-cell lymphoma diagnosed by flow cytometry studies of blood and histologically proven on spleen sections. Clinical data as well as morphological, immunological, cytogenetic and molecular characteristics were assessed to evaluate the similarities and differences of these cases with those of classical CD5-negative splenic marginal zone B-cell lymphoma. ResultsThe CD5 expression detected in blood by flow cytometry was confirmed in most cases by immunohistochemistry on spleen sections. In general, cases of CD5-positive and CD5-negative splenic marginal zone B-cell lymphoma did not appear different and, in particular, they showed similar karyotypic changes such as 7q deletion, trisomy 3, trisomy 18 and biased IGHV usage (i.e. VH1-2). The main differences were a higher lymphocyte count at diagnosis (8.15×10 9 /L versus 3.90×10 9 /L; P=0.005) and more frequent diffuse bone marrow infiltration (34% versus 8%; P=0.03) in the CD5-positive group. A tendency to a more mutated IGHV status in the CD5 positive cases was observed (80% versus 54.5%; (P=0.11). No significant differences in outcome were found in relation to CD5 expression. ConclusionsThis study confirms the existence of cases of CD5-positive splenic marginal zone B-cell lymphoma and shows that these cases are closely related to classical splenic marginal zone lymphoma. Whether or not CD5-positive splenic marginal zone B-cell lymphoma constitutes a true subset obviously requires the study of more cases. Citation: Baseggio L, Petinataud F, Berger F, Ffrench M, Couris CM, Thieblemont C, Morel D, Coiffier B, Salles G, and Felman P. CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases. Haematologica. 2010;95:604-612 doi:10.3324/haematol.2009 This is an open-access paper.CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases © F e r r a t a S t o r t i F o u n d a t i o n

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Section: Discussionmentioning

confidence: 48%

CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases

Baseggio¹,

Traverse-Gléhen²,

Petinataud³

et al. 2009

Haematologica

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“…Loss of these interactions led to loss of MZB cells in many mouse strains 21,25,26,33 . Secondly, Notch2 ligation by Dll1 expressed on stromal cells is required for MZB development [2][3][4][5][6][7][8][9][10][11][12][13] , and maintenance of MZB identity 12,34 . Thirdly, the quality and the strength of the BCR repertoire determine whether positive selection of immature B cells by self ligands or microbiome derived ligands leads to deletion, FoB cell or MZB development [14][15][16]35 .…”

Section: Discussionmentioning

confidence: 99%

“…B1 cells derive from fetal progenitors and react to a restricted set of microbial ligands in a T cell-independent (TI) manner in serosal cavities and spleen 1 NF-B signaling emanating from the BAFF receptor [2][3][4][5][6][7][8][9][10][11][12][13] . The quality of B cell antigen receptor (BCR) signals during positive selection of B cell precursors in the spleen is equally important in B cell fate decisions [14][15][16] , and it was proposed that weak or strong BCR signals might render cells receptive or resistant to Notch instruction 17,18 .…”

Section: Introductionmentioning

confidence: 99%

Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

et al. 2017

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2 Notch2 and B cell antigen receptor (BCR) signaling determine if transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it isunknown how these pathways are related. We generated Taok3 equally important in B cell fate decisions [14][15][16] , and it was proposed that weak or strong BCR signals might render cells receptive or resistant to Notch instruction 17,18 . Yet how BCR repertoire or signaling controls Notch responsiveness is currently poorly understood.The Ste20 family kinases are serine-threonine kinases that participate in a variety of signaling pathways triggered by cellular stress 19,20 . The Tao kinase subfamily has three members in mammals (TAOK1, also known as proteins MAP3K16, PSK2 or MARKK; TAOK2 (MAP3K17, PSK1) and TAOK3 (MAP3K18, JIK or DPK)), whose function is largely unknown. Here, we generated Taok3 -/-mice and found that these mice lacked MZB cells, whereas FoB cells were intact. By carefully unraveling the molecular mechanism of this deficiency we have discovered how BCR signaling intersects with Notch signaling in immature transitional B cells undergoing positive selection. RESULTS 4 Taok3 -/-mice lack MZB cellsIn wild-type mice, the expression of mRNA for Taok3 was predominantly found in bone marrow and immune tissues like spleen, thymus and lymph nodes, but also in lung and gut (Fig. 1a). To gain insight into the biology of Taok3, we generated Taok3 -/-mice ( Supplementary Fig. 1a-e). Overall there was no difference in the cellularity of the various lymphoid organs in 6-12 week old mice (Supplementary Fig. 1f). In the spleen, there were no gross differences in the percentage of eosinophils, monocytes, natural killer (NK) cells and NKT cells between Taok3 -/-and wild-type mice, yet there was a consistent reduction in the amount of CD11c + dendritic cells in Taok3 -/-mice (Fig. 1b).There was a small yet consistent increase in the percentage of Ly6G + granulocytes in the spleen of Taok3 -/-mice. The distribution of CD3 + T cells and CD19 + B cells was comparable, yet there was a 25-30% reduction in the amount of CD8 + T cells (Fig. 1c). (Fig. 1d-f).Histological examination of the spleen revealed that the characteristic rim of IgM + CD1d + MZB cells separated from the IgM lo B cell follicles by the marginal sinus was absent in Taok3 -/-mice (Fig. 1g). Resident marginal zone metallophillic macrophages (MMM, expressing CD169) that line the marginal sinus were present and correctly localized in Taok3 -/-mice (Fig. 1h) (Fig. 1h). Collectively, Taok3 -/-mice lack MZB cells without compensatory alterations in other B cell subsets. Humoral immune response of Taok3 -/-miceThe baseline serum concentration of immunoglobulins (Ig) was comparable to wild-type, with a tendency for increased IgG3 in Taok3 -/-mice (Supplementary Fig 2) Fig. 1i and Supplementary Fig 2 ). The intact TNPspecific Ig response as not due to compensatory increase in recirculating MZB cells outside the spleen (data not shown). B1 B cells can also respond to TNP-Ficoll antigen, in the com...

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“…Notch2 is the family member preferentially expressed in mature B cells, 13 and plays a determining role for the development of B1 and marginal zone B cells. 14,15 Importantly, activation of Notch proteins has been demonstrated to inhibit apoptosis in different cellular contexts. [16][17][18][19][20] Notch1 expression provides significant protection to thymocytes and T-cell lines from glucocorticoid and TCRmediated apoptosis, respectively.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2

et al. 2004

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Notch2 Haploinsufficiency Results in Diminished B1 B Cells and a Severe Reduction in Marginal Zone B Cells

Cited by 106 publications

References 45 publications

CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases

CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases

Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2

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