| 1. |
- Aranburu, Alaitz, et al.
(författare)
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Age-associatedBcells expanded in autoimmune mice are memory cells sharing H-CDR3-selected repertoires
- 2018
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 48:3, s. 509-521
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Tidskriftsartikel (refereegranskat)abstract
- Age-associated Bcells (ABCs) represent a distinct cell population expressing low levels of CD21 (CD21 −/low ). The Ig repertoire expressed by ABCs in aged mice is diverse and exhib its signs of somatic hypermutation (SHM). A CD21 −/low B-cell population is expanded in autoimmune diseases, e.g. systemic lupus erythematosus, as well as in lupus-prone NZB/W mice and in mice lacking a pre-Bcell receptor (SLC −/− ). However, the nature of the CD21 −/low Bcells (hereafter ABCs) in autoimmunity is not well understood. Here we show that in young SLC −/− mice, the vast majority of the ABCs express memory B-cell (MBC) markers in contrast to wild-type controls. A similar population is present in lupus-prone MRL mice before and at disease onset. In SLC −/− mice, a majority of the ABCs are IgM + , their V H genes have undergone SHM, show clonal diversification and clonal restriction at the H-CDR3 level. ABC hybridomas, established from SLC −/− mice, secrete typical lupus autoantibodies, e.g. anti-Smith antigen, and some of those that bind to DNA comprise a H-CDR3 that is identical to previously described IgM anti-DNA antibodies from lupus-prone mice. Together, these results reveal that ABCs in autoimmune mice are comprised of autoreactive MBCs expressing highly restricted H-CDR3 repertoires.
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| 2. |
- Camponeschi, Alessandro, et al.
(författare)
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Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.
- 2019
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we use an autoimmune mouse model, where MBCs are abundant, to show that the highest levels of LFA-1 and VLA-4 amongst B cells are found on MBCs. In vivo blockade of VLA-4 alone or in combination with LFA-1, but not LFA-1 alone, causes a release of MBCs from the spleen into the blood stream. In humans, we find that in peripheral blood, spleens, and tonsils from healthy donors the highest expression levels of the integrins LFA-1 and VLA-4 are also found on MBCs. Consistent with this, we found MBCs to have a higher capacity to adhere to ICAM-1 and VCAM-1 than naïve B cells. In patients with the autoimmune disease rheumatoid arthritis, it is the MBCs that have the highest levels of LFA-1 and VLA-4; moreover, compared with healthy donors, naïve B and MBCs of patients receiving anti-TNF medication have enhanced levels of the active form of LFA-1. Commensurate levels of the active αL subunit can be induced on B cells from healthy donors by exposure to the integrin ligands. Thus, our findings establish the selective use of the integrins LFA-1 and VLA-4 in the localization and adhesion of MBCs in both mice and humans.
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| 3. |
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| 4. |
- Chen, Dongfeng, et al.
(författare)
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CD99 expression is strongly associated with clinical outcome in children with B-cell precursor acute lymphoblastic leukaemia
- 2019
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 184:3, s. 418-423
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Tidskriftsartikel (refereegranskat)abstract
- Our study aimed to determine the expression pattern and clinical relevance of CD99 in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Our findings demonstrate that high expression levels of CD99 are mainly found in high-risk BCP-ALL, e.g. BCR-ABL1 and CRLF2 Re/Hi, and that high CD99 mRNA levels are strongly associated with a high frequency of relapse, high proportion of positive for minimal residual disease at day 29 and poor overall survival in paediatric cohorts, which indicate that CD99 is a potential biomarker for BCP-ALL.
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| 5. |
- Chen, Dongfeng, et al.
(författare)
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The Expression Pattern of the Pre-B Cell Receptor Components Correlates with Cellular Stage and Clinical Outcome in Acute Lymphoblastic Leukemia.
- 2016
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (IGHM, IGLL1 and VPREB1) is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that TCF3-PBX1 ALL express high levels of IGHM, IGLL1 and VPREB1, and are arrested at the pre-B stage. By contrast, ETV6-RUNX1 ALL express low levels of IGHM or VPREB1, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of IGHM, IGLL1 and VPREB1 are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients.
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| 6. |
- Engström, Marianne, et al.
(författare)
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Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis
- 2018
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A relationship between rheumatoid arthritis (RA) and periodontitis has been suggested from findings that individuals with RA are prone to have advanced periodontitis and vice versa. In search of possible common pathogenetic features of these two diseases, we investigated the presence of citrullinated proteins and expression of endogenous peptidylarginine deiminases (PAD2 and PAD4), in periodontal tissue of individuals with periodontitis and healthy controls, in relation to the periodontal pathogens Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), producing leukotoxin as virulence factor. These two oral bacteria have been suggested to be linked to anti-citrullinated protein antibodies in patients with RA.METHODS: Gingival tissue biopsies were obtained from 15 patients with periodontitis and 15 individuals without periodontal disease. Presence of CD3-positive lymphocytes, citrullinated proteins, PAD2, PAD4, P. gingivalis as well as A. actinomycetemcomitans and Mannheimia haemolytica produced leukotoxins were analysed by immunohistochemistry, followed by triple-blind semi-quantitative analysis. Mann-Whitney and Fisher's exact tests were used to analyse differences between groups. PADI2 and PADI4 mRNA levels were assessed by RT-qPCR and analysed using Wilcoxon signed rank test.RESULTS: Increased staining of citrullinated proteins was observed in gingival connective tissue from subjects with periodontitis (80%, 12/15) compared to healthy gingival tissue (27%, 4/15), whereas no differences were observed in gingival epithelium. There was also an increased staining of the citrullinating enzymes PAD2 and PAD4 in gingival connective tissue of patients with periodontitis whereas similar levels of PAD2 and PAD4 were observed in the gingival epithelium of the two groups. Similarly, the mRNA levels of PADI2 and PADI4 were also increased in the gingival tissue of patients with periodontitis compared to healthy controls. Furthermore, presence of P. gingivalis and leukotoxins was comparable in both epithelium and connective tissue, from the different investigated individuals with and without periodontitis, and there were no correlations between the presence of periodontal pathogens and the expression of citrullinated proteins or PAD enzymes.CONCLUSION: Chronic gingival inflammation is associated with increased local citrullination and PAD2 and PAD4 expression in periodontitis. The increased citrullination and PAD2 and PAD4 expression in periodontitis were, however, independent of the presence of periodontal pathogen P. gingivalis and A. actinomycetemcomitans leukotoxin.
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| 7. |
- Gerasimcik, Natalija, et al.
(författare)
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Deletion of Dock10 in B cells results in normal Development but a Mild Deficiency upon In Vivo and In Vitro stimulations
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- We sought to identify genes necessary to induce cytoskeletal change in B cells. Using gene expression microarray, we compared B cells stimulated with interleukin-4 (IL-4) and anti-CD40 antibodies that induce B cell spreading, cell motility, tight aggregates, and extensive microvilli with B cells stimulated with lipopolysaccharide that lack these cytoskeletal changes. We identified 84 genes with 10-fold or greater expression in anti-CD40 + IL-4 stimulated B cells, one of these encoded the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 10 (Dock10). IL-4 selectively induced Dock10 expression in B cells. Using lacZ expression to monitor Dock10 promoter activity, we found that Dock10 was expressed at all stages during B cell development. However, specific deletion of Dock10 in B cells was associated with a mild phenotype with normal B cell development and normal B cell spreading, polarization, motility, chemotaxis, aggregation, and Ig class switching. Dock10-deficient B cells showed lower proliferation in response to anti-CD40 and IL-4 stimulation. Moreover, the IgG response to soluble antigen in vivo was lower when Dock10 was specifically deleted in B cells. Together, we found that most B cell responses were intact in the absence of Dock10. However, specific deletion of Dock10 in B cells was associated with a mild reduction in B cell activation in vitro and in vivo.
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| 8. |
- Gerasimcik, Natalija, et al.
(författare)
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The Rho GTPase Cdc42 Is Essential for the Activation and Function of Mature B Cells
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 194:10, s. 4750-4758
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Tidskriftsartikel (refereegranskat)abstract
- The Rho GTPase Cdc42 coordinates regulation of the actin and the microtubule cytoskeleton by binding and activating the Wiskott-Aldrich syndrome protein. We sought to define the role of intrinsic expression of Cdc42 by mature B cells in their activation and function. Mice with inducible deletion of Cdc42 in mature B cells formed smaller germinal centers and had a reduced Ab response, mostly of low affinity to T cell-dependent Ag, compared with wild-type (WT) controls. Spreading formation of long protrusions that contain F-actin, microtubules, and Cdc42-interacting protein 4, and assumption of a dendritic cell morphology in response to anti-CD40 plus IL-4 were impaired in Cdc42-deficient B cells compared with WT B cells. Cdc42-deficient B cells had an intact migratory response to chemokine in vitro, but their homing to the B cell follicles in the spleen in vivo was significantly impaired. Cdc42-deficient B cells induced a skewed cytokine response in CD4(+) T cells, compared with WT B cells. Our results demonstrate a critical role for Cdc42 in the motility of mature B cells, their cognate interaction with T cells, and their differentiation into Ab-producing cells.
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| 9. |
- Gerasimcik, Natalija, et al.
(författare)
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The small rho GTPases Rac1 and Rac2 are important for T-cell independent antigen responses and for suppressing switching to IgG2b in Mice
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The Rho GTPases Cdc42, Rac1, and Rac2 coordinate receptor signaling to cell adhesion, migration, and proliferation. Deletion of Rac1 and Rac2 early during B cell development leads to failure in B cell entry into the splenic white pulp. Here, we sought to understand the role of Rac1 and Rac2 in B cell functionality and during the humoral antibody response. To circumvent the migratory deficiency of B cells lacking both Rac1 and Rac2, we took the approach to inducibly delete Rac1 in Rac2(-/-) B cells in the spleen (Rac1(B)Rac2(-/-) B cells). Rac1(B)Rac2(-/-) mice had normal differentiation of splenic B cell populations, except for a reduction in marginal zone B cells. Rac1(B)Rac2(-/-) B cells showed normal spreading response on antibody-coated layers, while both Rac2(-/-) and Rac1(B)Rac2(-/-) B cells had reduced homotypic adhesion and decreased proliferative response when compared to wild-type B cells. Upon challenge with the T-cell-independent antigen TNP-conjugated lipopolysaccharide, Rac1(B)Rac2(-/-) mice showed reduced antibody response. In contrast, in response to the T-cell-dependent antigen sheep red blood cells, Rac1(B)Rac2(-/-) mice had increased serum titers of IgG1 and IgG2b. During in vitro Ig class switching, Rac1(B)Rac2(-/-) B cells had elevated germline gamma 2b transcripts leading to increased Ig class switching to IgG2b. Our data suggest that Rac1 and Rac2 serve an important role in regulation of the B cell humoral immune response and in suppressing Ig class switching to IgG2b.
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