| 1. |
- Greicius, Gediminas, 1971-
(författare)
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Links between activation and cytoskeletal regulation of B lymphocytes
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Interplay between adhesion molecules and the cytoskeleton is involved in many aspects of B lymphocyte behaviour during an immune response. Events such as cell polarisation and locomotion, collaboration with T lymphocytes and segregation in secondary lymphoid tissues all include mechanisms that recognise microenvironment and accordingly adjust morphological features of the cell. Their role in the functions of the immune system is strengthened by devastating effects observed in the absence of adhesion molecules involved in lymphocyte extravasation or in a disease known as Wiskott-Aldrich syndrome. The latter deficiency is associated with mutations in Wiskott-Aldrich syndrome protein (WASP) that among other features manifest in a decreased villosity of leukocyte membranes, presumably due to abnormal actin polymerisation.The adhesive capacity of B cells is regulated by a variety of soluble and immobilised factors. In this thesis we concentrated our attention on the role of IL-4 and cross-linking of CD40. These stimuli partially mimic signals received during B and T lymphocyte collaboration and are critical for B cell differentiation. We found that both these stimuli increased LFA-1 dependent adhesion of B lymphocytes. Additionally, the extent of cell aggregation was correlated with an increased cell locomotion, spreading and induction of microvilli-like extensions of the plasma membrane. This indicates that IL-4 or cross-linking of CD40 induced global changes in plasticity of cortical cytoskeleton. The molecular mechanisms behind these changes are not clear in detail. However, we demonstrate that the transcription factor STAT6 is needed for IL-4 induced changes in morphology of B cells. Also, changes in cortical cytoskeleton induced by CD40 and IL-4 are partially dependent on intact Cdc42/WASP system. Our findings suggest that IL-4 or CD40 signaling operate different molecular machinery in regulation of cell surface architecture and also indicate that B cells possess WASP-independent ways to regulate cortical cytoskeleton.Homotypic adhesion of activated B lymphocytes can involve adhesion systems other than the LFA-1. Carcinoembryonic antigen related cell-cell adhesion molecule-1 (CEACAM1, CD66a) belongs to the Ig superfamily and mediates homotypic cell-cell interactions. Hypothetically, aggregation of B lymphocytes would favour homophilic adhesion systems. Surprisingly, antibodies to CEACAM1 upregulated LFA-1 mediated binding. Also, cross-linking of CEACAM1 on the surface of B lymphocytes co-stimulates B cell receptor (BCR) induced proliferation and supports the initial steps of B cell differentiation.Overall, our results indicate that B lymphocytes possess several mechanisms that control cortical cytoskeleton and the architecture of the cell surface, modulating adhesive interactions with surrounding cells. These adhesive interactions may influence signaling via BCR and the initial steps of B cell differentiation and survival.
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| 2. |
- Greicius, Gediminas, et al.
(författare)
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Microvilli structures on B lymphocytes: inducible functional domains?
- 2004
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Ingår i: Int Immunol. - : Oxford University Press (OUP). - 0953-8178 .- 1460-2377. ; 16:2, s. 353-64
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Tidskriftsartikel (refereegranskat)abstract
- Interactive contact between B lymphocytes and T cells is necessary for their expansion during an immune response. It has been shown that B lymphocytes receive signals from T cells, such as IL-4 and cross-linking of CD40, which are crucial for their differentiation. We previously found that these factors induce formation of microvilli on B cells and that this was correlated with increased homotypic adhesion of B lymphocytes. In this study we have investigated if IL-4 induce segregation of proteins to microvilli and lipid rafts. Using immuno-electron microscopy we analyzed cell-surface distribution of molecules involved in B-T cell co-activation. Recruitment to detergent-resistant membrane fractions was analyzed using sucrose gradient centrifugation. We found that microvilli were enriched in ICAM-1 and MHC class II molecules. In contrast, LFA-1 and CD40 were more abundant on the smooth cell surfaces, while B7-2 (CD86) was randomly distributed. We also discovered that depletion of cholesterol, using beta-methyl-cyclodextrin, lowered the number of microvilli, indicating that intact lipid rafts are required for their expression. Moreover, activation of B lymphocytes by lipopolysaccharide (LPS) induced increased expression of GM(1), a marker for lipid rafts. However, although both surface and total levels of GM(1) were similar in B lymphocytes stimulated with either LPS or LPS plus IL-4, GM(1) was mainly expressed on microvilli in LPS plus IL-4-stimulated cells. Taken together, our results indicate that microvilli represent distinct inducible membrane domains that can regulate direct cell-cell interactions via grouping and three-dimensional presentation of cell-surface receptors.
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| 3. |
- Savari, Sayeh, et al.
(författare)
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Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+ mouse model
- 2016
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 37:5, s. 491-499
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Tidskriftsartikel (refereegranskat)abstract
- There is emerging literature emphasizing the role of inflammatory eicosanoids, including prostaglandins and leukotrienes, in cancer development. Increased expression of both the cysteinyl leukotriene receptor 1 (CysLTR1) and the enzyme responsible for the production of leukotrienes, 5-lipoxygenase (5-LOX), is associated with poor prognosis in patients with colorectal adenocarcinomas. Apc mutation is an early event in the development of sporadic and hereditary (FAP) colorectal cancer. We utilized the Apc(Min/+) mouse model of FAP/sporadic colorectal cancer to investigate the role of CysLTR1 in intestinal tumorigenesis by crossing Apc(Min/+) mice with mice lacking the Cysltr1 gene. We could observe a reduced tumor burden in the small intestine of double-mutant female (Cysltr1(-/-) Apc(Min/+)) but not double-mutant male mice, compared to gender-matched single-mutant (Cysltr1(+/+) Apc(Min/+)) mice. This reduction was in a Cysltr1 dependent manner, female double mutant mice having significantly reduced tumor formation compared to control littermates. The female double-mutant phenotype was accompanied with decreased systemic inflammation, as evidenced by significantly reduced serum levels of PGE2 and CysLTs, as well as increased CD3(+)CD8(+) T cell tumor infiltration. Furthermore, the reduced formation of polyps in double-mutant (Cysltr1(-/-) Apc(Min/+)) female mice could in part be explained by the cytotoxic action of CD3(+)CD8(+) T cells in the polyp and reduced nuclear accumulation of β-catenin in the epithelium of small intestinal polyps. Our results stress the important role that CysLTR1 plays in colorectal cancer and its potential as a therapeutic target in cancer therapy.
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| 4. |
- Westerberg, Lisa, et al.
(författare)
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Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes.
- 2001
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Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 98:4, s. 1086-1094
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Tidskriftsartikel (refereegranskat)abstract
- Patients with the immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) have lymphocytes with aberrant microvilli, and their T cells, macrophages, and dendritic cells are impaired in cytoskeletal-dependent processes. WAS is caused by a defective or a missing WAS protein (WASP). Signal mediators interleukin-4 (IL-4) and CD40 are important for actin-dependent morphology changes in B cells. A possible function of WASP and its interacting partners, Cdc42 and Rac1, was investigated for these changes. It was found that active Cdc42 and Rac1 induced filopodia and lamellipodia, respectively, in activated B cells. Evidence is given that IL-4 has a specific role in the regulated cycling of Cdc42 because IL-4 partially and transiently depleted active Cdc42 from detergent extract of activated B cells. WASP-deficient B lymphocytes were impaired in IL-4-- and CD40-dependent induction of polarized and spread cells. Microvilli were expressed on WASP-deficient B cells, but they appeared shorter and less dense in cell contacts than in wild-type cells. In conclusion, evidence is provided for the involvement of Cdc42, Rac1, and WASP in the cytoskeletal regulation of B lymphocytes. Aberrations in WASP-deficient B lymphocytes, described here, provide further evidence that WAS is a cytoskeletal disease of hematopoietic cells.
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