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- Areschoug, Thomas, et al.
(författare)
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Evasion of macrophage scavenger receptor A-mediated recognition by pathogenic streptococci
- 2008
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 38:11, s. 3068-3079
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Tidskriftsartikel (refereegranskat)abstract
- PRR recognize conserved structures on pathogenic microbes and are important for the defense against invading microorganisms. However, accumulating evidence indicates that many pathogens have evolved mechanisms to avoid recognition by PRR. One type of PRR is the macrophage scavenger receptor A (SR-A), which has been shown to play an important role in recognition and non-opsonic phagocytosis of pathogenic bacteria. The bacterial ligands for SR-A have been suggested to be LPS or lipoteichoic acid. Here, we use murine bone marrow-derived macrophages to analyze the role of SR-A in non-opsonic phagocytosis of two major Gram-positive pathogens, streptococcus agalactiae (group B streptococcus; GBS) and Streptococcus pyogenes. We show that the polysaccharide capsule of GBS and the surface M protein of S. pyogenes, two important virulence factors, prevent SR-A-mediated non-opsonic phagocytosis of streptococci. The sialic acid moiety of the GBS capsule was crucial for its ability to prevent recognition by SR-A. Moreover, we show that a ligand on GBS recognized by SR-A in the absence of capsule is the surface lipoprotein BIr. These findings represent the first example of a microbial strategy to prevent recognition by SR-A and suggest that bacterial surface proteins may be of importance as ligands for SR-A.
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- Berntman, Emma, et al.
(författare)
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The role of CD1d-restricted NK T lymphocytes in the immune response to oral infection with Salmonella typhimurium.
- 2005
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 35:7, s. 2100-2109
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Tidskriftsartikel (refereegranskat)abstract
- CD1d-restricted natural killer T (NKT) cells belong to the innate-like lymphocytes which respond rapidly to stress and infectious challenge. We have studied murine CD1d-restricted NKT cells in the early immune response to virulent Salmonella enterica serovar Typhimurium after oral infection. In the liver and spleen, neutrophil and macrophage numbers had increased several-fold by day 5 post-infection, while the frequency of B and T lymphocytes decreased. These cellular changes occurred independently of CD1d-restricted NKT cells, and further, CD1d-restricted T cells did not influence the bacterial load. However, in CD1d+ mice NK1.1+ T cells and invariant CD1d-restricted T cells were activated by the infection, as demonstrated by an increase in size, up-regulation of CD69 and production of IFN-. The NK1.1 antigen was down-modulated on these cells during the course of infection, while TCR levels were unaffected. While dendritic cells (DC) up-regulated CD1d-levels upon 24 h of in vitro exposure to the bacteria, increased CD1d expression was not evident on DC in vivo during infection. Furthermore, in vitro re-stimulation of CD1d-restricted T cells isolated from infected mice demonstrated a significant skewing of the cytokine profile, with suppressed IL-4 and increased IFN- production.
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- Bjursten, Malin, 1976, et al.
(författare)
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Long-term treatment with anti-alpha 4 integrin antibodies aggravates colitis in G alpha i2-deficient mice.
- 2005
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:8, s. 2274-83
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Tidskriftsartikel (refereegranskat)abstract
- Targeted deletion of the heterotrimeric G protein, Galphai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha4 integrins. In previous studies, short-term administration of anti-alpha4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha4 integrin antibodies on colitis in Galphai2(-/- )mice. Long-term blockade of alpha4 integrin significantly increased the severity of colitis in Galphai2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1beta, TNF-alpha and IFN-gamma. Blockade of alpha4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with alpha4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.
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- Blomqvist, Maria K., 1975, et al.
(författare)
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Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells.
- 2009
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Ingår i: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 39:7, s. 1726-35
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Tidskriftsartikel (refereegranskat)abstract
- The glycosphingolipid sulfatide (SO(3)-3Galbeta1Cer) is a demonstrated ligand for a subset of CD1d-restricted NKT cells, which could regulate experimental autoimmune encephalomyelitis, a murine model for multiple sclerosis, as well as tumor immunity and experimental hepatitis. Native sulfatide is a mixture of sulfatide isoforms, i.e. sulfatide molecules with different long-chain bases and fatty acid chain lengths and saturation. Here, we demonstrate that sulfatide-specific CD1d-restricted murine NKT hybridomas recognized several different sulfatide isoforms. These included the physiologically relevant isoforms C24:1 and C24:0, major constituents of the myelin sheet of the nervous system, and C16:0, prominent in the pancreatic islet beta-cells. The most potent sulfatide isoform was lysosulfatide (lacking a fatty acid). Shortened fatty acid chain length (C24:1 versus C18:1), or saturation of the long fatty acid (C24:0), resulted in reduced stimulatory capacity, and fatty acid hydroxylation abolished the response. Moreover, sulfatide was not responsible for the natural autoreactivity toward splenocytes by XV19 T hybridoma cells. Our results reveal a promiscuity in the recognition of sulfatide isoforms by a CD1d-restricted NKT-cell clone, and suggest that sulfatide, a major component of the myelin sheet and pancreatic beta-cells, is one of several natural ligands for type II CD1d-restricted NKT cells.
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- Bockermann, Robert, et al.
(författare)
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Type II collagen without adjuvant induces eosinophilic arthritis.
- 2007
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 37:2, s. 540-548
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophilia is a characteristic feature of many inflammatory diseases including inflammatory bowel disease and asthma. It also occurs in a subtype of rheumatoid arthritis but the role of eosinophils has been unclear and animal models have been lacking. Here, we introduce a new mouse model to study the role of eosinophilia in arthritis. Intraperitoneal injection of type II collagen alone, without any adjuvant, was sufficient to induce chronic arthritis in a mouse with transgenic T cells specific for type II collagen. The arthritis was accompanied by infiltration of eosinophils into the synovial tissue and the disease could be blocked with neutralizing anti-IL-5 antibodies. To our knowledge, this is the first description of an eosinophilic disease form of destructive arthritis.
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- Boeiers, Ulrika, et al.
(författare)
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Collagen type II is recognized by a pathogenic antibody through germline encoded structures
- 2008
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 38:10, s. 2784-2795
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Tidskriftsartikel (refereegranskat)abstract
- Collagen type II (CII) is a cartilage-specific target of pathologic humoral autoimmune responses in rheumatoid arthritis as well as in the collagen-induced arthritis model. The aim of the present study is to investigate the critical amino acid residues conferring CII epitope specificity of the prototypic arthritogenic murine mAb CIIC1. A homology model of the CIIC1 single-chain antibody fragment (CIIC1scFv) in complex with its triple helical epitope was established. in silico predictions based on extensive molecular dynamics simulations were experimentally tested by the recombinant expression and functional analysis of CIIC1scFv containing alanine replacements allowing the identification of crucial CII-binding sites in the CDR2 and CDR3 regions of both heavy and light chains. Since the conversion of the CIIC1scFv sequence into the respective germline at all 13 somatically mutated positions did not affect its CII binding, our data indicate that potentially harmful cartilage-specific humoral autoimmunity could be germline encoded. The molecular modeling further demonstrates that the rigid collagen triple helix restricts the likelihood of molecular interactions with the CDR regions of the antibody considerably compared with globular antigens. These sterical constraints provide an explanation as to why somatic mutations in the arthritogenic autoantibody have no obvious impact on CII recognition.
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- Bokarewa, Maria, 1963, et al.
(författare)
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Arthritogenic dsRNA is present in synovial fluid from rheumatoid arthritis patients with an erosive disease course.
- 2008
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 38:11, s. 3237-44
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Tidskriftsartikel (refereegranskat)abstract
- Viruses may be part of the pathogenesis of rheumatoid arthritis (RA). Double stranded RNA (dsRNA) is a prototypic viral conformation of nucleic acid that is highly arthritogenic in mice. Therefore, we developed an ELISA to detect dsRNA in sera and synovial fluids (SF) in RA patients and in osteoarthritic controls. The developed ELISA recognizes picogram levels of viral or synthetic dsRNA but shows no reactivity against DNA, synthetic ssRNA, or total RNA prepared from mammalian cells. Before analysis by ELISA, each sample was subjected to RNA precipitation. The RA patients had significantly higher levels of dsRNA than the osteoarthritis patients in SF and in sera. In 7 of 17 RA patients, EBV was present in SF and in all but one of these this was accompanied by the presence of dsRNA. No parvovirus, cytomegalovirus, or polyomavirus was detected. The anti-viral cytokine IFN-alpha was detected in SF in 10 of 21 RA patients, but in none of the osteoarthritis patients. Notably, RA patients with erosive disease course had significantly higher levels of dsRNA in SF than non-erosive patients, but no correlation between dsRNA levels and the presence of RF or levels of C-reactive protein, IL-6, or IFN-alpha was observed.
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