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  • 1.
    Andersson, Mattias K.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Pemberton, Alan D.
    Miller, Hugh R. P.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Extended cleavage specificity of mMCP-1, the major mucosal mast cell protease in mouse - High specificity indicates high substrate selectivity2008In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 45, no 9, p. 2548-2558Article in journal (Refereed)
    Abstract [en]

    Mucosal mast cells are in the mouse predominantly found in the epithelium of the gastrointestinal tract. They express the beta-chymases mMCP-1 and mMCP-2. During nematode infections these intraepithelial mast cells increase in numbers and high amounts of mMCP-1 appear in the jejunal lumen and in the circulation. A targeted deletion of this enzyme leads to decreased ability to expel the intraepithelial nematode Trichinella spiralis. A suggested role for mMCP-1 is alteration of epithelial permeability by direct or indirect degradation of epithelial and endothelial targets, however, no such substrates have yet been identified. To enable a screening for natural substrates we performed a detailed analysis of the extended cleavage specificity of mMCP-1, using substrate phage display technology. In positions P1 and P1' distinct preferences for Phe and Ser, respectively, were observed. In position P2 a high selectivity for large hydrophobic amino acids Phe, Trp and Leu was detected, and in position P2' aliphatic amino acids Leu, Val and Ala was preferred. In positions P3 and P4, N-terminal of the cleaved bond, mMCP-1 showed specificity for aliphatic amino acids. The high selectivity in the P2, P1, P1' and P2' positions indicate that mMCP-1 has a relatively narrow set of in vivo substrates. The consensus sequence was used to screen the mouse protein database for potential substrates. A number of mouse extracellular or membrane proteins were identified and cell adhesion and connective tissue components were a dominating subfamily. This information, including the exact position of potential cleavage sites, can now be used in a more focused screening to identify which of these target molecules is/are responsible for the increased intestinal permeability observed in parasite infected mice.

  • 2. Belov, Katherine
    et al.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Immunoglobulin genetics of Ornithorhynchus anatinus (platypus) and Tachyglossus aculeatus (short-beaked echidna).2003In: Comp Biochem Physiol A Mol Integr Physiol, ISSN 1095-6433, Vol. 136, no 4, p. 811-9Article in journal (Refereed)
  • 3.
    Belov, Katherine
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. MOLECULAR IMMUNOLOGY, LARS HELLMAN.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Platypus IgM and the divergence of the two extant monotreme lineages.2003In: Australian Mammology, Vol. 25, p. 87-94Article in journal (Refereed)
  • 4. Belov, Katherine
    et al.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Cooper, D.W.
    Characterization of IgG from a monotreme, Tachyglossus aculeatus2002In: Immunogenetics, Vol. 53, p. 1065-1071Article in journal (Refereed)
  • 5. Belov, Katherine
    et al.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Cooper, D.W.
    Characterization of of echidna IgM provides insight into the time of divergence of extant mammals.2002In: Developmental and Comparative Immunology, Vol. 26, p. 831-839Article in journal (Refereed)
  • 6. Belov, Katherine
    et al.
    Lam, Mary K P
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Colgan, Donald J
    Evolution of the major histocompatibility complex: Isolation of class II beta cDNAs from two monotremes, the platypus and the short-beaked echidna.2003In: Immunogenetics, ISSN 0093-7711, Vol. 55, no 6, p. 402-11Article in journal (Other scientific)
  • 7. Belov, Katherine
    et al.
    Lam, MKP
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Colgan, DJ.
    Evolution of the major histocompatibility complex: Isolation of class II _ cDNAs from two monotremes, the platypus and the short-beaked echidna.2003In: Immunogenetics, Vol. 55, p. 402-411Article in journal (Refereed)
  • 8. Belov, Katherine
    et al.
    Miller, Robert D
    Ilijeski, Aron
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Harrison, Gavan A
    Isolation of monotreme T-cell receptor alpha and beta chains.2004In: Immunogenetics, ISSN 0093-7711, Vol. 56, no 3, p. 164-9Article in journal (Refereed)
  • 9. Belov, Katherine
    et al.
    Zenger, K.R.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Cooper, D.W.
    Echidna IgA supports mammalian unity and traditional Therian relationship2002In: Mammalian Genome, Vol. 13, p. 656-663Article in journal (Refereed)
  • 10. Feyerabend, Thorsten B
    et al.
    Hausser, Heinz
    Tietz, Annette
    Blum, Carmen
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Straus, Anita H
    Takahashi, Hélio K
    Morgan, Ellen S
    Dvorak, Ann M
    Fehling, Hans Jörg
    Rodewald, Hans-Reimer
    Loss of histochemical identity in mast cells lacking carboxypeptidase A.2005In: Mol Cell Biol, ISSN 0270-7306, Vol. 25, no 14, p. 6199-210Article in journal (Refereed)
  • 11.
    Gallwitz, Maike
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Enoksson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Expression profile of novel members of the rat mast cell protease (rMCP)-2 and (rMCP)-8 families, and functional analyses of mouse mast cell protease (mMCP)-82007In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 59, no 5, p. 391-405Article in journal (Refereed)
    Abstract [en]

    Four hematopoietic serine proteases are common to the mast cell chymase locus of all analyzed mammals: α-chymase, cathepsin G, granzyme B, and granzyme C/H. Apart from these common genes, the mouse and rat loci hold additional granzyme-, β-chymase-, and Mcpt8-like genes. To better understand the functional consequences of these additional enzymes and to be able to compare human and rodent immune functions, we have analyzed the expression of novel β-chymase- and Mcpt8-like genes in the rat. Four novel genes, i.e., Mcpt2-rs2a, Mcpt2-rs2c, Mcpt8-rs1, and Mcpt8-rs4 were transcribed in tissues holding mucosal mast cells (MMC), where also the classical MMC protease Mcpt2 was expressed. We also found transcripts of rat vascular chymase (rVch) in some of these tissues. RVch is a β-chymase that converts angiotensin I, like the human chymase. Rat MMC may therefore have similar angiotensin-converting properties as chymase-positive human mast cells, although these are mostly regarded the counterpart of rat connective tissue mast cells. The human mast cells that are considered the counterpart of rat MMC express, however, only tryptase, whereas rat MMC express various proteases, but no tryptase. We further studied the proteolytic activity of mMCP-8 as a first representative for the Mcpt8-subfamily. Based on sequence comparison and molecular modeling, mMCP-8 may prefer aspartic acid in substrate P1 position. However, we could not detect hydrolysis of chromogenic substrates or phage-displayed random nonapeptides despite numerous trials. On the other hand, we have obtained evidence that the function of the Mcpt8-like proteases depends on proteolytic activity. Namely, the expression of the only Mcpt8-family member with a mutation in the catalytic triad, Mcpt8-rs3, was strongly reduced. Thus, the substrate specificity of mMCP-8 may be too narrow to be detected with the employed methods, or the enzyme may require a substrate conformation that is not provided by the analyzed peptides.

  • 12.
    Gallwitz, Maike
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Rapid species-specific diversification of the mast cell chymase locus during mammalian evolution.2006In: Immunogenetics, Vol. 58, p. 641-654Article in journal (Refereed)
  • 13.
    Gallwitz, Maike
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Reimer, Jenny
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Expansion of the mast cell chymase locus over the past 200 million years of mammalian evolution2006In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 58, no 8, p. 655-669Article in journal (Refereed)
    Abstract [en]

    The acidic granules of natural killer (NK) cells, T cells, mast cells, and neutrophils store large amounts of serine proteases. Functionally, these proteases are involved, e.g., in the induction of apoptosis, the recruitment of inflammatory cells, and the remodeling of extra-cellular matrix. Among the granule proteases are the phylogenetically related mast cell chymases, neutrophil cathepsin G, and T-cell granzymes (Gzm B to H and Gzm N), which share the characteristic absence of a Cys191–Cys220 bridge. The genes of these proteases are clustered in one locus, the mast cell chymase locus, in all previously investigated mammals. In this paper, we present a detailed analysis of the chymase locus in cattle (Bos taurus) and opossum (Monodelphis domestica). The gained information delineates the evolution of the chymase locus over more than 200 million years. Surprisingly, the cattle chymase locus contains two α-chymase and two cathepsin G genes where all other studied chymase loci have single genes. Moreover, the cattle locus holds at least four genes for duodenases, which are not found in other chymase loci. Interestingly, duodenases seem to have digestive rather than immune functions. In opossum, on the other hand, only two chymase locus-related genes have been identified. These two genes are not arranged in one locus, but appear to have been separated by a marsupial-specific chromosomal rearrangement. Phylogenetic analyses place one of the opossum genes firmly with mast cell α-chymases, which indicates that the α-chymase had already evolved as a separate, clearly identifiable gene before the separation of marsupials and placental mammals. In contrast, the second gene in opossum is positioned phylogenetically between granzymes, cathepsin G, and the duodenases. These genes, therefore, probably evolved as separate subfamilies after the separation of placental mammals from marsupials. In platypus, only one chymase locus-like sequence could be identified. This previously published “granzyme” does not cluster clearly with any of the chymase locus gene families, but shares the absence of the Cys191–Cys220 bridge with the other chymase locus proteases. These findings indicate that all chymase locus genes are derived from a single ancestor that was present more than 200 million years ago.

  • 14.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Therapeutic vaccines against IgE-mediated allergies.2008In: Expert Rev Vaccines, ISSN 1744-8395, Vol. 7, no 2, p. 193-208Article in journal (Refereed)
  • 15.
    Henningsson, Frida
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Ledin, Johan
    Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Lunderius, Carolina
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Wilén, M
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Pejler, Gunnar
    Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Altered storage of proteases in mast cells from mice lacking heparin: a possible role for heparin in carboxypeptidase A processing.2002In: Biological Chemistry, Vol. 383, p. 793-801Article in journal (Refereed)
  • 16.
    Johansson, Jeannette
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Aveskogh, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Munday, Barry
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Heavy chain V region diversity in the duck-billed platypus (Ornithorhynchus anatinus): Long and highly variable complementarity-determining region 3 compensates for limited germ line diversity.2002In: J. Immunol., Vol. 168, p. 5155-5162Article in journal (Refereed)
  • 17.
    Johansson, Jeannette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Ledin, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Hellman.
    Vernersson, Molly
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Lövgren-Bengtsson, Karin
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Identification of Adjuvants that Enhance the Therapeutic Antibody Response to Host IgE2004In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 22, no 21-22, p. 2873-2880Article in journal (Refereed)
    Abstract [en]

    In the development of a novel vaccine against atopic allergies, we have screened for adjuvants that enhance the therapeutic antibody response against self immunoglobulin E (IgE). The response against self IgE is induced by administration of a vaccine antigen, which contains both self and non-self IgE regions, together with an adjuvant. We evaluated five commonly used adjuvants; Freund's, aluminium hydroxide, ISCOMs, Montanide ISA 51 and Montanide ISA 720, and found that the mineral oil-based adjuvants; Montanide ISA 51 and Freund's induced at least 5-10-fold higher anti-self IgE titers than any of the other candidates. However, with one exception, Alum, the immune responses against the carrier, i.e. the non-self regions, were similar for all adjuvants, indicating that the ability to induce responses against self and non-self antigens differ among adjuvants. The responses against non-self IgE were more than 50-fold higher than antibody responses against self IgE in both the Freund's and Montanide 51-administered animals, indicating that the response against self molecules is markedly inhibited by tolerance-inducing mechanisms. Co-administration of Montanide ISA 51 with immuno-stimulatory substances from bacteria; muramyldipeptide (MDP), monophosphoryl-lipid A (MPL) or a formyl-methionine-containing tripeptide (fMLP), did not elevate the anti-self IgE response. Hence, adjuvants based on pure mineral oil without additional immuno-stimulatory substances appear to be the best adjuvant candidates in therapeutic vaccines aimed at regulating the in vivo levels of self-proteins.

  • 18.
    Johansson, Jeannette
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Salazar, Janice N
    Aveskogh, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Munday, Barry
    Miller, Robert D
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    High variability in complementarity-determining regions compensates for a low number of V gene families in the lambda light chain locus of the platypus.2005In: Eur J Immunol, ISSN 0014-2980, Vol. 35, no 10, p. 3008-19Article in journal (Other scientific)
  • 19.
    Karlson, Ulrika
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Pejler, Gunnar
    Fröman, Gunnar
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Rat mast cell protease 4, a beta chymase with a unusually stringent substrate specificity.2002In: J. Biol. Chem., Vol. 277, p. 18579-18585Article in journal (Refereed)
  • 20.
    Ledin, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Arnemo, Jon M.
    Liberg, Olof
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    High plasma IgE levels within the Scandinavian wolf population, and its implications for mammalian IgE homeostasis2008In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 45, no 7, p. 1976-1980Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin E (IgE) serves as an important link between innate and adaptive immunity through its ability to bind high affinity receptors on mast cells and basophils. Large differences in IgE levels may here affect this important link, and IgE levels in natural non-domestic animal populations may therefore be very informative concerning the levels of IgE that this system have been balanced against during recent mammalian evolution. However, very few such studies have been performed. Here, we present an analysis of total IgE levels in 65 Scandinavian wolves: 57 free living (wild), and 8 wolves in captivity (Zoo). The 57 wild wolves correspond to approximately 30% of the entire wolf population in Sweden and Norway and thus represent a large fraction of the entire population, making this a unique sample from a wild canine population. The median IgE level in these wolves was 67 μg/ml, which is approximately twice the level seen in domestic dogs and more than 100 times the levels in non-atopic humans. The collected information from domestic and wild populations now indicate that the very low IgE levels observed in man and laboratory rodents are most likely an effect of a life in a relatively parasite free environment, and that total IgE levels under maximally stimulatory (normal) conditions may reach 100-200 μg/ml.

  • 21.
    Ledin, Anna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Bergvall, Kerstin
    Hillbertz, Nicolette Salmon
    Hansson, Helene
    Andersson, Göran
    Hedhammar, Ake
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Generation of therapeutic antibody responses against IgE in dogs, an animal species with exceptionally high plasma IgE levels.2006In: Vaccine, ISSN 0264-410X, Vol. 24, no 1, p. 66-74Article in journal (Refereed)
  • 22.
    Looman, Camilla
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Mark, Charlotta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Abrink, Magnus
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    MZF6D, a novel KRAB zinc-finger gene expressed exclusively in meiotic male germ cells.2003In: DNA and Cell Biology, ISSN 1044-5498, Vol. 22, no 8, p. 489-96Article in journal (Refereed)
  • 23.
    Looman, Camilla
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Åbrink, Magnus
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Mark, Charlotta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    KRAB zinc finger proteins; an analysis of the molecular mechanisms governing their increase in numbers and complexity during evolution.2002In: Molecular Biology and Evolution, Vol. 12, p. 2118-2130.Article in journal (Refereed)
  • 24.
    Looman, Camilla
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Åbrink, Magnus
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Mark, Charlotta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    MZF6D, a novel KRAB zinc finger gene expressed exclusively in meiotic male germ cells.2003In: DNA and Cell Biology, Vol. 22, p. 489-496Article in journal (Refereed)
  • 25.
    Magnusson, Sofia E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Engström, Marianne
    Jacob, Uwe
    Ulfgren, Ann-Kristin
    Kleinau, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    High synovial expression of the inhibitory Fc gamma RIIb in rheumatoid arthritis2007In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 9, no 3, p. R51-Article in journal (Refereed)
    Abstract [en]

    Activating Fc gamma receptors (FcγRs) have been identified as having important roles in the inflammatory joint reaction in rheumatoid arthritis (RA) and murine models of arthritis. However, the role of the inhibitory FcγRIIb in the regulation of the synovial inflammation in RA is less known. Here we have investigated synovial tissue from RA patients using a novel monoclonal antibody (GB3) specific for the FcγRIIb isoform. FcγRIIb was abundantly expressed in synovia of RA patients, in sharp contrast to the absence or weak staining of FcγRIIb in synovial biopsies from healthy volunteers. In addition, the expression of FcγRI, FcγRII and FcγRIII was analyzed in synovia obtained from early and late stages of RA. Compared with healthy synovia, which expressed FcγRII, FcγRIII but not FcγRI, all activating FcγRs were expressed and significantly up-regulated in RA, regardless of disease duration. Macrophages were one of the major cell types in the RA synovium expressing FcγRIIb and the activating FcγRs. Anti-inflammatory treatment with glucocorticoids reduced FcγR expression in arthritic joints, particularly that of FcγRI. This study demonstrates for the first time that RA patients do not fail to up-regulate FcγRIIb upon synovial inflammation, but suggests that the balance between expression of the inhibitory FcγRIIb and activating FcγRs may be in favour of the latter throughout the disease course. Anti-inflammatory drugs that target activating FcγRs may represent valuable therapeutics in this disease.

  • 26.
    Magnusson, Sofia E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Pejler, Gunnar
    Kleinau, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Åbrink, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mast cell chymase contributes to the antibody response and the severity of autoimmune arthritis2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 3, p. 875-882Article in journal (Refereed)
    Abstract [en]

    Mast cells are implicated in rheumatoid arthritis, but the mechanism by which they contribute to disease progression is not clarified. Here we investigated whether mouse mast cell protease-4 (mMCP-4), a chymase present in the mast cell secretory granule, contributes to experimental arthritis. Two models of arthritis were investigated in mMCP-4(+/+) and mMCP-4(-/-) DBA/1 mice: collagen-induced arthritis (CIA) was induced by immunization with collagen II (CII) in Freund's complete adjuvant, and a passive model of arthritis was induced by administration of anti-CII antibodies. The clinical scores were significantly reduced in the mMCP-4(-/-) animals as compared to mMCP-4(+/+) controls in both arthritis models. In CIA, the number of affected paws was lower in the CII-immunized mMCP-4(-/-) mice, with less cartilage destruction, pannus formation, and mononuclear cell and mast cell influx in the mMCP-4(-/-) joints. Interestingly, the lower clinical scores in the CII-immunized mMCP-4(-/-) mice coincided with lower serum levels of immunoglobulin G anti-CII antibodies. Our findings identify a pathogenic role of mMCP-4 in autoimmune arthritis.

  • 27.
    Magnusson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Wennerberg, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Matt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindqvist, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kleinau, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Reduced IgG1-immune complex binding and low TNF production characterize monocytes in rheumatoid arthritis and correlates with disease statusManuscript (Other academic)
  • 28.
    Mathsson, Linda
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Klinisk immunologi.
    Tejde, Andreas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Klinisk immunologi.
    Carlson, Kristina
    Department of Medical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Höglund, Martin
    Department of Medical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Nilsson, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Nilsson-Ekdahl, Kristina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Rönnelid, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Klinisk immunologi.
    Cryoglobulin-induced cytokine production via FcgammaRIIa: inverse effects of complement blockade on the production of TNF-alpha and IL-10. Implications for the growth of malignant B-cell clones.2005In: British Journal of Haematology, Vol. 129, no 6, p. 830-838Article in journal (Refereed)
    Abstract [en]

    Monoclonal antibodies produced by patients with lymphoproliferative diseases sometimes appear as cryoglobulins (CG), immunoglobulins (Ig) that reversibly agglutinate and form immune complexes (IC) when cooled below normal body temperature or through variation in pH and ionic strength. In accordance with our findings of IC-induced cytokine production from peripheral blood mononuclear cells (PBMC) in systemic lupus erythematosus, we investigated whether CG can also induce cytokine production. One IgG and one IgM type I CG from two patients with multiple myeloma and Waldenstrom's macroglobulinaemia were individually purified and added to PBMC cultures. In separate experiments temperature and ionic strength were varied, or FcgammaRIIa, FcgammaRIII and complement activation were blocked; supernatant cytokine levels were then determined by enzyme-linked immunosorbent assay. CG-induced cytokine production from monocytes varied with precipitation induced by changes in temperature and ionic strength and was mediated via FcRIIa- and complement-dependent mechanisms. Complement blockade resulted in increased IgG CG-induced interleukin (IL)-10 production that was inversely correlated with decreased production of tumour necrosis factor-alpha. CG-induced IL-10 might be a growth factor for malignant B-lymphocytes in CG-associated lymphoproliferative diseases with constant complement consumption. Knowledge of mechanisms underlying CG-induced cytokine production can be useful for designing treatments for type I CG-associated pathology in lymphoproliferative diseases.

  • 29. Miska, K.B
    et al.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Miller, Robert D.
    Characterization of b2-microglobulin coding sequence from three non-placental mammals; the duck billed platypus, the short beaked echidna, and the grey short-tailed opossum.2003In: Developmental and Comparative Immunology, Vol. 3, p. 247-256.Article in journal (Refereed)
  • 30. Miska, K.B
    et al.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Miller, Robert D.
    The major histocompatibility complex in monotremes; an analysis of the evolution of the MHC Class I genes across all three mammalian subclasses.2002In: Immunogenetics, Vol. 54, p. 381-393.Article in journal (Refereed)
  • 31. Nowak, Melissa A
    et al.
    Parra, Zuly E
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Miller, Robert D
    The complexity of expressed kappa light chains in egg-laying mammals.2004In: Immunogenetics, ISSN 0093-7711, Vol. 56, no 8, p. 555-63Article in journal (Other scientific)
  • 32. Parra, Zuly E.
    et al.
    Arnold, Tamara
    Nowak, Melissa A.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Miller, Robert D
    TCR gamma chain diversity in the spleen of the duckbill platypus (Ornithorhynchus anatinus).2006In: Developmental and Comparative Immunology, ISSN 0145-305X, Vol. 30, p. 699-710Article in journal (Refereed)
  • 33.
    Prokopec, Kajsa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    B cells in Autoimmunity: Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    B cells are normally regulated to prevent activation against self-proteins through tolerance mechanisms.  However, occasionally there is a break in tolerance and B cells can become self-reactive, which might lead to the development of autoimmune disease. The activation of self-reactive B cells is regulated by receptors on the B cell surface, such as Fc gamma receptor IIb (FcγRIIb), complement receptor type 1 (CR1), and CR type 2 (CR2).

    In this thesis I have studied the role of FcγRIIb, CR1 and CR2 on B cells in autoimmune arthritis. By using a model for rheumatoid arthritis, I discovered that the initial self-reactive B cell response in arthritis was associated with the splenic marginal zone B cell population. Marginal zone B cells express high levels of CR1/CR2 and FcγRIIb, suggesting that they normally require high regulation. Further, female mice deficient in CR1/CR2 displayed increased susceptibility to arthritis compared to CR1/CR2-sufficient female mice. When investigating whether sex hormones affected arthritis susceptibility, we found that ovariectomy, of the otherwise fairly resistant CR1/CR2-sufficient mice, reduced the expression of CR1 on B cells and rendered the mice more susceptible to arthritis.

    In humans, a significantly reduced CR1 and FcγRIIb expression was found on B cells in aging women, but not in men. This may contribute to the increased risk for women to develop autoimmune disease as reduced receptor expression may lead to the activation of self-reactive B cells. In agreement, lower CR1, CR2 and FcγRIIb expression was seen in patients with rheumatoid arthritis.

     

    Finally, a soluble form of FcγRIIb was used to investigate FcγRIIb’s ability to bind self-reactive IgG in an attempt to treat autoimmune arthritis. Treatment of mice with established arthritis was associated with less self-reactive IgG antibodies and consequently less disease, suggesting that soluble FcγRIIb may be used as a novel treatment in arthritis.

    List of papers
    1. Marginal zone B cells are naturally reactive to collagen type II and are involved in the initiation of the immune response in collagen-induced arthritis
    Open this publication in new window or tab >>Marginal zone B cells are naturally reactive to collagen type II and are involved in the initiation of the immune response in collagen-induced arthritis
    Show others...
    2011 (English)In: Cellular & Molecular Immunology, ISSN 1672-7681, Vol. 8, no 4, p. 296-304Article in journal (Refereed) Published
    Abstract [en]

    Antibodies against type II collagen (CII) are essential for development of collagen-induced arthritis (CIA), but how and where the B-cell response to CII is initiated is not fully known. We show here that naive DBA/1 mice display naturally reactive IgM and IgG anti-CII producing B cells prior to immunization. The CII-reactive B cells were observed in the spleen and recognized as marginal zone (MZ) B cells. After CII immunization, CII-specific B cells expanded rapidly in the spleen, in contrast to the lymph nodes, with the initial response derived from MZ B cells and later by follicular (FO) B cells. This was evident despite that the MZ B cells were subject to stringent tolerance mechanisms by having a greater Fc gamma receptor IIb expression than the FO B cells. Further, the MZ B cells migrated to the FO areas upon immunization, possibly providing antigen and activating FO T cells and subsequently FO B cells. Thus, around CIA onset increased numbers of IgG anti-CII producing FO B cells was seen in the spleen, which was dominated by IgG2a- and IgG2b-positive cells. These data demonstrate that CII-reactive MZ B cells are present before and expand after CII immunization, suggesting an initiating role of MZ B cells in the development of CIA.

    Keywords
    arthritis, B cells, collagen type II, ELISpot, marginal zone, mice
    National Category
    Medical and Health Sciences
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-109185 (URN)10.1038/cmi.2011.2 (DOI)000292320800004 ()
    Note
    Manuscript original title: Marginal zone B cells are naturally reactive to collagen type II and initiate the immune response in collagen-induced arthritisAvailable from: 2009-10-15 Created: 2009-10-10 Last updated: 2012-07-11Bibliographically approved
    2. Enhanced susceptibility to low-dose collagen-induced arthritis in CR1/2-deficient female mice: possible role of estrogen on CR1 expression
    Open this publication in new window or tab >>Enhanced susceptibility to low-dose collagen-induced arthritis in CR1/2-deficient female mice: possible role of estrogen on CR1 expression
    2009 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 8, p. 2450-2458Article in journal (Refereed) Published
    Abstract [en]

    The influence of complement receptor 1 and 2 (CR1/2) was investigated on the susceptibility to low-dose collagen-induced arthritis (CIA) in wild-type (WT) and CR1/2-deficient DBA/1 mice. Significantly enhanced CIA was observed in female CR1/2-deficient mice compared with WT female mice, while male mutant and WT mice showed similar arthritis development. The enhanced CIA was accompanied with higher complement levels and a prolonged IgM anti-collagen type II response. When investigating whether estrogen contributed to the different arthritis susceptibility, we found that ovariectomy rendered WT females more sensitive to low-dose CIA and to the same extent as CR1/2-deficient females, while CR1/2-deficient mice were unaffected by ovariectomy. Notably, the ovariectomized WT mice displayed reduced CR1(+) B220(+) B-cell numbers and CR1 expression compared with sham-operated WT mice, suggesting a stimulatory effect of estrogen on CR1. In accordance, a significant correlation was observed between reduced CR1 expression in B cells and increased age in healthy female blood donors but not in male donors. Our findings demonstrate an important role of CR1/2 in suppressing CIA in female mice under low-antigen conditions. The data suggest that estrogen promote CR1 expression in B cells. These findings provide insight to the increased frequency of rheumatoid arthritis in postmenopausal women.

    Keywords
    complement receptor, B cells, knockout mice, autoimmunity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-107312 (URN)10.1096/fj.08-125849 (DOI)000268836700013 ()19351702 (PubMedID)
    Available from: 2009-08-05 Created: 2009-08-05 Last updated: 2017-12-13Bibliographically approved
    3. Down regulation of Fc and complement receptors on B cells in rheumatoid arthritis
    Open this publication in new window or tab >>Down regulation of Fc and complement receptors on B cells in rheumatoid arthritis
    Show others...
    2010 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 137, no 3, p. 322-329Article in journal (Refereed) Published
    Abstract [en]

    B cell tolerance is regulated by receptors that modulate B cell receptor signaling, such as Fc gamma receptor IIb (FcγRIIb; CD32b) and complement receptors (CR) 1 and 2. Deficiency in these receptors may contribute to autoimmunity. To address this we have investigated the receptor expression in healthy individuals in comparison with rheumatoid arthritis (RA) patients. In healthy subjects we found that women had overall lower Fcgamma;RIIb expression on B cells than men that significantly decreased with age. RA patients had fewer FcγRIIb, CR1 and CR2 positive B cells and decreased receptor expressions compared to healthy subjects. Further, the RA B cells displayed a significantly increased proliferative response when cultured with interleukin-2 in vitro. In summary, the dysregulated B cells in RA are associated with lower FcγRIIb, CR1 and CR2 levels. The reduced FcγRIIb expression on B cells in women may influence the increased frequency of autoimmunity in women.

    Keywords
    B cells, Fc receptor, Complement receptor, Autoimmunity, Rheumatoid arthritis
    National Category
    Rheumatology and Autoimmunity
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-108924 (URN)10.1016/j.clim.2010.08.006 (DOI)000284300600003 ()
    Available from: 2009-10-15 Created: 2009-10-05 Last updated: 2017-12-12Bibliographically approved
    4. Amelioration of collagen-induced arthritis by human recombinant soluble FcγRIIb
    Open this publication in new window or tab >>Amelioration of collagen-induced arthritis by human recombinant soluble FcγRIIb
    Show others...
    2008 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 127, no 2, p. 225-233Article in journal (Refereed) Published
    Abstract [en]

    Immune complex (IC) binding to Fc gamma receptors (FcγRs) is central for inflammatory reactions seen in autoimmune diseases. Consequently, a therapeutic agent with a possibility to interfere with binding of pathogenic IC to FcγRs would be valuable in autoimmune disorders such as rheumatoid arthritis (RA). Here we have explored the therapeutic effect of a recombinant solublehuman FcγRIIb (sFcγRIIb) protein in collagen-induced arthritis (CIA). In vitro studies of the sFcγRIIb demonstrated binding to mouse IgG, suggesting that sFcγRIIb can absorb pathogenic IgG anticollagen type II (CII) IC in vivo. Hence, administration of sFcγRIIb significantly reduced CIA severity compared to control treated mice. The sFcγRIIb treated mice had significantly less IgG anti-CII antibodies in serum and lowermRNA levels of inflammatory cytokines compared to controlmice. In conclusion, sFcγRIIb treatment ameliorates CIA by reducing IC-stimulated inflammation and joint swelling. This suggests that recombinant sFcγRIIb may be useful as therapeutic agent in RA.

    Keywords
    Fc gamma receptors, Collagen-induced arthritis, Mice, Autoimmunity, Therapy, Antibody, Rheumatology, Cytokines
    National Category
    Medical and Health Sciences
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-98880 (URN)10.1016/j.clim.2008.02.002 (DOI)000255231100015 ()18346938 (PubMedID)
    Available from: 2009-03-04 Created: 2009-03-04 Last updated: 2017-12-13Bibliographically approved
  • 34.
    Prokopec, Kajsa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Rhodiner, Mia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Matt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindqvist, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kleinau, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Down regulation of Fc and complement receptors on B cells in rheumatoid arthritis2010In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 137, no 3, p. 322-329Article in journal (Refereed)
    Abstract [en]

    B cell tolerance is regulated by receptors that modulate B cell receptor signaling, such as Fc gamma receptor IIb (FcγRIIb; CD32b) and complement receptors (CR) 1 and 2. Deficiency in these receptors may contribute to autoimmunity. To address this we have investigated the receptor expression in healthy individuals in comparison with rheumatoid arthritis (RA) patients. In healthy subjects we found that women had overall lower Fcgamma;RIIb expression on B cells than men that significantly decreased with age. RA patients had fewer FcγRIIb, CR1 and CR2 positive B cells and decreased receptor expressions compared to healthy subjects. Further, the RA B cells displayed a significantly increased proliferative response when cultured with interleukin-2 in vitro. In summary, the dysregulated B cells in RA are associated with lower FcγRIIb, CR1 and CR2 levels. The reduced FcγRIIb expression on B cells in women may influence the increased frequency of autoimmunity in women.

  • 35.
    Reimer, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Enoksson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Samollow, Paul
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Extended substrate specificity of opossum chymase: Implications for the origin of mast cell chymases2008In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 45, no 7, p. 2116-2125Article in journal (Refereed)
    Abstract [en]

    Serine proteases are major granule constituents of mast cells, neutrophils, T cells and NK cells. The genes encoding these proteases are arranged in different loci. The mast cell chymase locus e.g. comprises at least one alpha-chymase, one cathepsin G, and two granzyme genes in almost all mammalian species investigated. However, in the gray, short-tailed opossum (Monodelphis domestica) this locus contains only two genes. Phylogenetic analyses place one of them clearly with the alpha-chymases, whereas the other gene is equally related to cathepsin G and the granzymes. To study the function of opossum chymase, and to explore the evolutionary origin of mast cell chymases, we have analyzed the cleavage specificity of this enzyme. The protease was expressed in mammalian cells and the extended substrate specificity was determined using a randomized phage-displayed nonapeptide library. A strong preference for the aromatic amino acids Trp over Phe and Tyr in the P1 position was observed. This is in contrast to human chymase and mouse mast cell protease-4, which prefer Phe over Tyr and Trp in this position. However, in most other positions this enzyme shows amino acid preferences very similar to human chymase and mouse mast cell protease-4, i.e. aliphatic amino acids in positions P4, P3, P2 and P1', and acidic amino acids (Glu and Asp) in the P2' position. The overall specificity of MC chymase thereby seems to have been conserved over almost 200 million years of mammalian evolution, indicating a strong selective pressure in maintaining this specificity and an important role for these enzymes in mast cell biology.

  • 36.
    Reimer, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Magnusson, Sofia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Juremalm, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Wernersson, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Isolation of transcriptionally active umbilical cord blood-derived basophils expressing FcεRI, HLA-DR and CD203c2006In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 61, no 9, p. 1063-1070Article in journal (Refereed)
    Abstract [en]

    Backgrounds: Basophils are inflammatory cells associated with allergy and parasite infections. Investigation of their true biological function has long been hampered by the difficulty in obtaining sufficient amounts of pure basophils and by the lack of phenotypic markers. Moreover, it has been very difficult to clone and identify basophil-specific granule proteins, partially because of an almost complete lack of mRNA in mature circulating basophils.

    Methods: To obtain transcriptionally active immature basophils, umbilical cord blood cells were cultured in the presence of interleukin (IL)-3. The cells were analysed by flow cytometry and by histological staining.

    Results: The continuous presence of IL-3 in cord blood cultures resulted in the expansion of basophil precursors co-expressing Fc epsilon RI and the recently described mast cell/basophil marker, 97A6 (CD203c). Several nonbasophil markers (i.e. CD3, CD14, CD15, CD16, CD19 and CD21) were absent on the cultured basophils. However, we show that in early cultures, almost 60% of the CD203c(+) cells co-express human leukocyte antigen (HLA)-DR, a marker that is absent on mature circulating basophils. The presence of HLA-DR on basophil precursors may explain the low recovery (24 +/- 5.2%) obtained after isolation of cultured basophils, when using a conventional basophil isolation kit that removes HLA-DR+ cells. A novel purification method was developed, including a two-step cocktail of antibodies against selected markers, which resulted in both high purity (95 +/- 0.5%) and recovery (59 +/- 1.5%) of cultured basophils.

    Conclusions: We here establish cord blood cultures as a source from which transcriptionally active basophil precursors can be isolated in reasonable quantities for thorough biochemical characterization.

  • 37.
    Vernersson, Molly
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Aveskogh, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Munday, Barry
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Evidence for an early appearance of modern post switch immunoglobulin isotypes in mammalian evolution (II), cloning of IgE, IgG1 and IgG2 from a monotreme, the duck billed platypus Ornithorhynchus anatinus.2002In: European Journal of Immunology, Vol. 32, p. 2145-2155.Article in journal (Refereed)
  • 38.
    Vernersson, Molly
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Ledin, Anna
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Johansson, Jeannette
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Generation of therapeutic antibody responses against IgE through vaccination2002In: The FASEB J:, Vol. 16, p. 875-877 + On LineArticle in journal (Refereed)
  • 39.
    Wernersson, Sara
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Reimer, Jenny
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Poorafshar, Maryam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Karlson, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Wermenstam, Niklas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Bengtén, Eva
    Wilson, Melanie
    Pilström, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
    Granzyme-like sequences in bony fish shed light on the emergence of hematopoietic serine proteases during vertebrate evolution2006In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 30, no 10, p. 901-918Article in journal (Refereed)
    Abstract [en]

    Hematopoietic serine proteases (SPs) are stored in the granules of different leukocytes and these enzymes are important effector molecules in the immune system of mammals. However, very little is known about the presence of these proteins in lower vertebrates. Herein, the primary structures of five novel fish SPs, from the Atlantic cod (Gadus morhua) and the channel catfish (Ictalurus punctatus), are presented. One of the cod SPs is a homologue to human GzmA and K. The other fish SPs identified are termed 'Gzm-like' and are distantly related to a large heterogeneous group of hematopoietic SPs, including most of the T-cell Gzms (B-H), the mast cell chymases, the mast cell/basophil proteases of the mouse mast cell protease-8 subfamily (W-family) and the neutrophil cathepsin G. Extensive BLAST-searches in genome and expressed sequence tag (EST) databases identified 40 additional teleost SPs related to the mammalian hematopoietic SP family. Subsequent phylogenetical analyses clearly demonstrate that the diversification into different subgroups within the GzmB/chymase/cathepsin G-related family has occurred independently in bony fishes and in mammals. In contrast, our findings suggest that the three subgroups, including (1) GzmK and the potent apoptosis-inducing GzmA, (2) the neutrophil proteases (proteinase 3, N-elastase and azurocidin), and (3) adipsin, have all evolved as distinct groups before the separation of tetrapods from the ray-finned fish approximately 420 million years ago.

1 - 39 of 39
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