| 1. |
- Lönnqvist, Anna, 1980, et al.
(författare)
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Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy.
- 2009
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Ingår i: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 39:2, s. 447-56
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Tidskriftsartikel (refereegranskat)abstract
- The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.
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| 2. |
- Admyre, C, et al.
(författare)
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Exosomes - nanovesicles with possible roles in allergic inflammation.
- 2008
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 63:4, s. 404-8
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Forskningsöversikt (refereegranskat)abstract
- Exosomes are nano-sized membrane vesicles which are released extracellularly after fusion of multivesicular endosomes with the cell membrane. Despite their characteristic composition of proteins compared to the cell membrane, no exosome-specific molecule has so far been characterized. Exosomes are found in bronchoalveolar lavage (BAL), urine, serum and breast milk, and are released from several cells implicated in allergy including mast cells, dendritic cells (DC), T cells and epithelial cells. Antigen-loaded exosomes have been shown to be highly immunogenic and we propose that exosomes could be a modulating factor in allergic responses. Allergen-presenting exosomes could transport allergen and stimulate allergen-specific T cells, and possibly also biasing T cell responses depending on the molecules present on the exosome surface. Furthermore, exosomes from mast cells, highly active in allergic reactions, have been found to induce DC maturation and also to be able to transport functional RNA to recipient cells, suggesting a new pathway for cell communication. Reversely, tolerizing exosomes e.g. tolerosomes, from gut or breast milk, could block an allergic response or prevent allergy development. A better understanding of the role of exosomes in allergies could make us understand how allergy can be prevented or lead to the development of more efficient treatments.
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| 3. |
- Almqvist, Nina, 1974, et al.
(författare)
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Autoantibodies: Focus on anti-DNA antibodies
- 2011
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Ingår i: Self/Nonself. - : Informa UK Limited. - 1938-2030 .- 1938-2049. ; 2:1, s. 11-18
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Forskningsöversikt (refereegranskat)abstract
- Ever since the days of Ehrlich and the birth of humoral immunity, self-reactivity or ‘horror autotoxicus’ as referred to by Paul Ehrlich, has been of great concern. For instance, in patients with the autoimmune disease systemic lupus erythematosus (SLE), anti-nuclear and anti-DNA antibodies have been recognized for many years. Despite this, the exact mechanism as to how the immune system fails to protect the individual and allows these autoantibodies to develop in this and other systemic autoimmune diseases remains uncertain. So how can we explain their presence? Evidence suggests that B cells expressing autoreactive antibodies do not normally arise but rather undergo negative selection as they develop. In light of this, it might seem contradictory that not all autoreactive B cell clones are eliminated, although this may not even be the intention since autoantibodies are also found in healthy individuals and may even protect from autoimmunity. Here, we will discuss autoantibodies, in particular those recognizing DNA, with regard to their reactivity and their potentially pathogenic or protective properties.
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| 4. |
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| 5. |
- Almqvist, Nina, 1974
(författare)
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The role of exosomes and microflora in establishing mucosal tolerance and the protection against allergic disease
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The role of exosomes and microflora in establishing mucosal tolerance and the protection against allergic disease Nina Almqvist, Departement of Rheumatology and Inflammation Research, The Sahlgrenska Academy University of Gothenburg, Guldhedsgatan 10A, 413 46 Göteborg, Sweden The breakdown of immune regulation to innocuous environmental antigens at mucosal sites can result in a number of different diseases such as, allergies and inflammatory bowel disease (IBD). Allergy is one of the most common diseases with a prevalence of up to 40% in children from developed countries. The healthy immune system prevents allergic sensitization by establishing immunological tolerance to innoccus antigens present at mucosal sites. Oral administration of soluble protein antigens is a very effective way to establish antigen-specific tolerance to the ingested protein, a process known as oral or mucosal tolerance. This is an active process, which is maintained by the specific recognition of antigens by CD4+ T-cells with a down regulatory function, and it is the default response to harmless antigens entering at mucosal sites. The process of oral tolerance starts with sampling of luminal antigens by the intestinal epithelial cells (IEC), processing and assembly with MHC II and subsequently a release of tolerogenic exosomes, small (40-90 nm) membrane bound vesicles of endocytic origin, produced by intestinal epithelial cells (IEC) and can be isolated from serum shortly after an antigen feed. We have previously shown that these exosomes potently transfer antigen-specific tolerance to naive recipients. Moreover, exosome-mediated tolerance is MHC class II dependent, which in turn requires an intact immune system in the fed donor. The hygiene hypothesis states that microbial exposure is required to properly educate the immune system. A full microbial flora in the gut generally provides the required stimuli for the maturation of the intestinal immune system and the intestinal epithelial cells to enable tolerogenic processing of orally administrated antigens. It is not known which individual bacterial species or what bacterial products that delivers the necessary signals. The focus of this thesis was to further study the role of exosomes in oral tolerance and their capacity to protect against an allergic sensitization and whether microbial stimuli would effect the outcome of such response. We also wanted to examine the role of dendritic cells in exosome-induced tolerance, focusing on plasmacytoid dendritic cells (pDC). We found that exosomes both isolated from serum and when isolated from intestinal epithelial cells in culture protect against an allergic sensitization in an antigen-specific manner. We could also show that the tolerant animals had higher levels of activated regulatory T cells in the draining lymph nodes indicating that exosome-induced tolerance is most likley mediated by regulatory T cells. Furthermore, we could also show that the tolerogenic effect of exosomes from serum could be enhanced when the gut epithelium was exposed to enterotoxin from S. aureus (SEA). When investingating the uptake of IEC derived exosomes by dendritic cells we could show that both conventional dendritic cells (cDC) and pDCs phagocytose exosomes. The capacity of pDCs to phagocytose have been questioned but our results indicate that they most readily ingest both exosomes and latex beads the size of exosomes. We also compared the capacity of the DCs to process and present the antigens carried by exosomes and found that pDCs induce higher antigen-specific T cell proliferation as compared to cDCs which suggest that pDCs in fact are better at both phagocytosis of IEC derived exosomes as well as presenting the antigen they carry. In conclusion, exosomes have the capacity to induce antigen-specific tolerance and protect against allergy. This exosome-induced tolerance could possibly be mediated by pDCs. Furthermore, in agreement with the hygiene hypothesis we could conclude that certain microbial stimuli, here SEA, does effect the tolerogenic processing, due to a more activated immune system in the gut.
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| 6. |
- Lin, Xiao Ping, et al.
(författare)
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Human small intestinal epithelial cells constitutively express the key elements for antigen processing and the production of exosomes.
- 2005
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Ingår i: Blood cells, molecules & diseases. - : Elsevier BV. - 1079-9796. ; 35:2, s. 122-8
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Tidskriftsartikel (refereegranskat)abstract
- In humans, the small intestinal epithelial cells (IEC) have a high constitutive expression of MHC class II (MHC II), and contains lysosomes. The IEC also contains MHC II rich multivesicular compartments and has been shown to produce exosomes. This suggests a role for the IEC in antigen processing and presentation either directly or indirectly by the production of exosomes. However, the presence and localisation in the IEC of other key molecules involved in this process has not been studied previously. In the present work, we have investigated small intestinal biopsies from healthy adults and the HT29 IEC cell line with monoclonal antibodies against molecules involved in the antigen processing/presenting systems and molecules typically found on exosomes derived from professional APCs and IECs. Immunohistology was performed to study the expression and localisation of MHC II (HLA-DR), HLA-DM, MHC I (HLA-ABC), CD1d, Invariant chain, Lamp-1, CD68, CD63, B7.1, B7.2, ICAM-1, Cathepsin D/S/L and the IEC specific marker A33 in the IECs. We found that the IECs from the biopsies constitutively express MHC II, HLA-DM, MHC I, Invariant chain, Lamp-1, CD 68, CD63 and A33, and these markers were also found in the IFN-g treated HT-29 cells. All these molecules were found apically in the IECs of the biopsies, localised mainly in vesicular structures. Interestingly, in the baso-latereral area of the IEC, only MHC II, MHC I, Lamp 1, CD68, CD63 and A33 were found and also here with vesicular staining pattern which matches the molecules previously found on exosomes derived professional APCs and human IEC lines. CD1d, B7, ICAM-1, CD9 and cathepsin D and L were absent in the IEC compartment, but cathepsin S showed a relatively weak staining in the apical part of the IEC. The staining pattern and the morphological localisation of these markers suggest a prominent antigen processing/loading and trafficking compartment, and a possible baso-lateral release of exosomes in the normal human IEC.
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| 7. |
- Mårtensson, Inga-Lill, 1957, et al.
(författare)
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The pre-B cell receptor checkpoint.
- 2010
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Ingår i: FEBS letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 584:12, s. 2572-9
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Forskningsöversikt (refereegranskat)abstract
- B lymphocytes are essential antibody-producing cells of the immune system. During the development of progenitor B cells to mature B cells that express a membrane-bound antibody, the B cell receptor (BCR), the cells undergo selection at several checkpoints, which ensures that a diverse antibody repertoire is generated and that the BCRs recognise foreign-, but not self-, antigens. In this review, we consider the pre-BCR checkpoint. Mutations or alterations that affect this checkpoint underpin the development of pre-B cell leukemias, primary immunodeficiency, and possibly, systemic autoimmunity.
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| 8. |
- Mårtensson, Inga-Lill, 1957, et al.
(författare)
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The Pre-B Cell Receptor; Selecting for or against Autoreactivity
- 2012
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 76:3, s. 256-262
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Forskningsöversikt (refereegranskat)abstract
- Antibodies represent a crucial component of humoral immunity as protection against invading pathogens, to which they bind and thereby trigger mechanisms that lead to the disposal of the pathogen. Antibodies are assembled from Ig heavy chains (HCs) and light chains (LCs) and are found in both a secreted and a membrane-bound form, termed B cell receptors (BCRs), where the latter allows the ‘right’ B cell to respond upon recognition of its cognate antigen. The antibody repertoire is almost unlimited because of a process in which germ line V(D)J gene segments, encoding the variable (antigen-binding) region of the antibody HCs and LCs, are recombined. As this process is random, it is apparent that it results in a vast variety of antibodies, those that recognize foreign but also those that recognize self- (auto-) antigens. Control mechanisms are, therefore, in place to ensure that as few autoreactive B cells as possible are allowed to proceed in development. This counter-selection takes place through various mechanisms and at several stages as the cells develop from pre-B cells to antibody-secreting plasma cells. At the first major checkpoint, at the pre-BI to pre-BII cell transition, antibody HCs assemble with the invariant surrogate LC (SLC) forming a pre-BCR. Herein, we will discuss the role of the pre-BCR in the selection at this stage, how a dysfunctional pre- BCR affects selection and its effects on later stages, and whether the pre-BCR selects for or against autoreactivity.
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| 9. |
- Svensson, Alexandra, 1978, et al.
(författare)
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Exposure to Human Herpes Virus type 6 protects against allergic asthma in mice
- 2010
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Ingår i: Journal of Allergy & Therapy. - : OMICS Publishing Group. - 2155-6121. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that infection with Human Herpes Virus (HHV)-6 during the first 18 months in life protects against IgE sensitization and Th2 driven immunity. The aim of this study was to investigate if exposure to HHV-6 affects the allergic response and the adaptive immunity in vivo. For this purpose, a well known mouse model of ovalbumin (OVA)-induced allergic asthma was used. BALB/c mice were OVA sensitized, and exposed to HHV-6 intra-peritoneal on two occasions, followed by intranasal challenge with OVA on five consecutive days one week after the second sensitization. 24 hours after the final OVA exposure, serum, bronchoalveolar lavage (BAL) and lung-tissue were collected. We show that mice exposed to HHV-6 have significantly lower frequency of OVA-specific IgE compared to control mice. This was associated with significantly reduced numbers of inflammatory cells and eosinophils in the BAL fluid of HHV-6 exposed mice. HHV-6 exposure also significantly inhibited the production of IL-4, IL-5 and IL-13 in the BAL fluid and in the lung tissue of the virus exposed mice. In conclusion, we suggest that exposure to HHV-6 protect against allergic asthma in mice, by limiting the Th2-driven inflammation.
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