| 1. |
- Brady, K., et al.
(författare)
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CD40 employs p38 MAP kinase in IgE isotype switching
- 2001
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 289:1, s. 276-281
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Tidskriftsartikel (refereegranskat)abstract
- IgE switching requires the prior induction of CE germline transcripts which is mediated by the concerted binding of STAT-6 and NF kappaB to the CE promoter. These transcription factors are regulated by IL-4 and CD40, respectively. However the latter can effect other signaling pathways and the present study explores the role of p38 MAPK in induction of CE germline transcripts. CD40 and IL-4, both alone and in synergy, were initially shown to activate the CE promoter in a B cell lymphoma cell line. Under the same conditions CD40 caused activation of p38 MAPK, whereas IL-4 was ineffective. The p38 MAPK inhibitor, SB203580, and a dominant negative form of p38 MAPK decreased the CD40 activation of the CE promoter by reducing the ability of CD40 to increase the transactivation potential of NF kappaB. This study suggests that p38 MAPK is crucially important in mediating CD40 activation of NFKB which acts to induce CE germline transcripts, ultimately facilitating IgE switching. (C) 2001 Academic Press.
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| 2. |
- Högerkorp, Carl-Magnus, et al.
(författare)
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CD44-stimulated human B cells express transcripts specifically involved in immunomodulation and inflammation as analyzed by DNA microarrays
- 2003
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 101:6, s. 2307-2313
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Tidskriftsartikel (refereegranskat)abstract
- A number of studies have implicated a role for the cell surface glycoprotein CD44 in several biologic events, such as lymphopoiesis, homing, lymphocyte activation, and apoptosis. We have earlier reported that signaling via CD44 on naive B cells in addition to B-cell receptor (BCR) and CD40 engagement generated a germinal center-like phenotype. To further characterize the global role of CD44 in B differentiation, we examined the expression profile of human B cells cultured in vitro in the presence or absence of CD44 ligation, together with anti-immunoglobulin (anti-Ig) and anti-CD40 antibodies. The data sets derived from DNA microarrays were analyzed using a novel statistical analysis scheme created to retrieve the most likely expression pattern of CD44 ligation. Our results show that genes such as interleukin-6 (IL-6), IL-1alpha , and beta 2-adrenergic receptor (beta 2-AR) were specifically up-regulated by CD44 ligation, suggesting a novel role for CD44 in immunoregulation and inflammation.
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| 3. |
- Ingvarsson, Sigurdur
(författare)
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Signalling mechanisms in B cell differentiation: Studies on specific human immune response in vitro.
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We need to understand the major signalling events in human B cell differentiation in order to be able to regulate the generation of human antigen specific antibodies. This study has focused on the signalling mechanisms involved in generation of germinal centre reaction and secretion of specific antibodies by human B cells, using different in vitro immunisation technologies. Naive human B cells that were stimulated by crosslinking their sIg, CD40 and CD44 acquired a germinal centre phenotype. Signalling via these surface molecules caused increased proliferation and made the B cells enter an apoptotic cycle, which is characteristic for germinal centre B cells. Three different in vitro immunisation protocols were utilised to study the mechanisms behind secretion of human antigen specific antibodies. First, soluble antigen in the cultures was shown to abrogate specific Ig response by reducing the number of memory B cells secreting specific antibodies to a recall antigen. By crosslinking the antigen bound to the sIg of those B cells the antigen specific suppression could be lifted. Secondly, purified B cells together with isolated CD4+ T cells and a superantigen could be induced to secrete antibodies to primary antigens, by crosslinking the antigen bound to their sIg. The specific antibody secretion was totally dependent on CD40 and CD86 ligation of the B cells. The third protocol demonstrates specific IgE production using a system that induces isotype switching in vitro. Specific IgE production appears to be dependent on NFkB activation by IL-4, produced and secreted by Th2 cells generated during the primary response. This thesis provides possible signalling mechanisms for the initiation of germinal centre reactions. It also presents data on antibody production in vitro in terms of antigen presentation and cell-cell interaction.
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| 4. |
- Johansson-Lindbom, Bengt, et al.
(författare)
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Germinal Centers Regulate Human Th2 Development1
- 2003
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Ingår i: Journal of Immunology. - 1550-6606. ; 171:4, s. 1657-1666
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Tidskriftsartikel (refereegranskat)abstract
- In the present study we demonstrate that all CD4+ T cells in human tonsil expressing the Th2-selective receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) also 1) express high levels of CXCR5, and 2) display a transitional CD45RA/RO phenotype and consistently do not produce significant amounts of cytokines when immediately analyzed ex vivo. Hence, they represent precursors of Th2 effector cells, a conclusion confirmed by their robust production of IL-4, IL-5, and IL-13, but not IFN-{gamma}, after in vitro activation. CD4+ T cells, which express only intermediate levels of CXCR5, instead develop into IFN-{gamma}-producing cells under identical culture conditions, thus establishing a correlation between relative levels of CXCR5 expression and the acquired cytokine profile. Because CXCR5 is critically involved in follicular localization, the results suggest that these CRTH2+ Th2 cells preferentially develop their cytokine-producing phenotype within germinal centers (GCs), whereas extrafollicular differentiation instead promotes Th1 development. In support for this proposal, we show that T cells with an intermediate expression of CXCR5 can be forced to also produce IL-4 and IL-13 if cultured with allogenic GC B cells. Finally, we demonstrate that the previously described CD57+ GC T cells also express high levels of CXCR5 but instead of comprising a Th2 precursor, they represent anergized T cells. Taken together, these data suggest that GCs and B cells regulate CD4+ T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells, which apparently leave the lymphoid tissue before evolving a cytokine-producing phenotype, or by furnishing T cell unresponsiveness.
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| 5. |
- Åkesson, A, et al.
(författare)
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Characterization of specific IgE response in vitro against protein and drug allergens using atopic and normal donors
- 2002
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 57:3, s. 193-200
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Tidskriftsartikel (refereegranskat)abstract
- Background: As the incidence of allergy to different compounds increases in society, the need to understand and characterize specific IgE responses becomes F. obvious. Different cell culture systems have been evaluated for their ability to support such IgE secretion. Methods: One system employed human peripheral lymphocytes (PBL) from normal donors stimulated with anti-CD3 activated T cells with or without the presence of allergens like benzylpenicillin (BP) and Phlenum pratense (PP). Secretion of IgE was analyzed in ELISA and compared to the IgG response to the nonallergenic antigen tetanus toxoid (TT). Another system employed stimulation of T and B cells with a heterotope, consisting of a T helper cell epitope derived from TT, and a B cell allergen epitope derived from BP. The specific IgE secretion was compared, using lymphocytes from nor-Mal as well as BP-allergic donors. Results: Anti-CD3 stimulated T cells supported BP-specific IgE secretion in Six of 11 normal donors. This response was inhibited in four donors and enhanced in two donors by the addition of the BP-allergen to the culture. In contrast, addition of the protein allergen (PP) or antigen (TT) to the same culture system inhibited both IgE and IgG synthesis in all experiments. C-ells from the majority (10/16) of the BP-allergic donors failed to produce BP-specific IgE in vitro, when cultured in the presence of allergen. Conclusions: An allergen specific immune response is readily generated in vitro. The differential response against benzylpenicillin between different donor categories most probably reflects the level of pre-exposure to this allergen in vivo.
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