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  • 1.
    Alfirevic, Ana
    et al.
    University of Liverpool, UK.
    Gonzalez-Galarza, Faviel
    University of Liverpool, UK.
    Bell, Catherine
    University of Liverpool, UK.
    Martinsson, Klara
    University of Liverpool, UK.
    Platt, Vivien
    University of Liverpool, UK.
    Bretland, Giovanna
    University of Liverpool, UK.
    Evely, Jane
    University of Liverpool, UK.
    Lichtenfels, Maike
    University of Liverpool, UK.
    Cederbrant, Karin
    Safety Assessment, AstraZeneca, Gartuna, Södertälje, Sweden.
    French, Neil
    University of Liverpool, UK.
    Naisbitt, Dean
    University of Liverpool, UK.
    Park, B Kevin
    University of Liverpool, UK.
    Jones, Andrew R
    University of Liverpool, UK.
    Pirmohamed, Munir
    University of Liverpool, UK.
    In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers2012Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 4, nr 6, artikel-id 51Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood.

    METHODS: To study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView.

    RESULTS: We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity.

    CONCLUSIONS: Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI.

  • 2.
    Bell, Catherine C.
    et al.
    University of Liverpool, England.
    Faulkner, Lee
    University of Liverpool, England.
    Martinsson, Klara
    University of Liverpool, England.
    Farrell, John
    University of Liverpool, England.
    Alfirevic, Ana
    University of Liverpool, England.
    Tugwood, Jonathan
    University of Manchester, England.
    Pirmohamed, Munir
    University of Liverpool, England.
    Naisbitt, Dean J.
    University of Liverpool, England.
    Park, B. Kevin
    University of Liverpool, England.
    T-cells from HLA-B*57: 01+ human subjects are activated with abacavir through two independent pathways and induce cell death by multiple mechanisms2013Ingår i: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 26, nr 5, s. 759-766Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Susceptibility to abacavir hypersensitivity has been attributed to possession of the specific human leukocyte antigen allele HLA-B*57:01. HLA-B*57:01-restricted activation of CD8+ T-cells provides a link between the genetic association and the iatrogenic disease. The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between abacavir accumulation in antigen presenting cells and the T-cell response. Seventy-four CD8+ clones expressing different Vβ receptors were shown to proliferate and kill target cells via different mechanisms when exposed to abacavir. Certain clones were activated with abacavir in the absence of antigen presenting cells. Analysis of the remaining clones revealed two pathways of drug-dependent T-cell activation. Overnight incubation of antigen presenting cells with abacavir, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation. In contrast, a 1 h antigen presenting cell pulse did not activate any of the clones. Accumulation of abacavir in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h. However, intracellular abacavir was not detectable by mass spectrometry after pulsing. These data suggest that T-cells can be activated by abacavir through a direct interaction with surface and intracellular major histocompatibility complex (MHC) molecules. With the former, abacavir seemingly participates in the MHC T-cell receptor binding interaction. In contrast, the latter pathway likely involves MHC binding peptides displayed as a consequence of abacavir exposure, but not abacavir itself.

  • 3.
    Martinsson, Klara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fcγ-receptors in systemic autoimmune conditions: lessons from murine mercury-induced autoimmunity2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In this thesis we investigated the role of activating (FcγRI, FcγRIII) and inhibitory (FcγRIIB) Fcγ-receptors on systemic autoimmunity using two mouse strains, DBA/1 (H-2q) and BALB/c mice (H-2d), susceptible to induction of autoimmunity by mercury (Hg).

    Fc-receptors for IgG (FcγR) link cellular and humoral immune responses, control the balance between activating and inhibitory immune responses and are important in the development of several autoimmune diseases. Mercury induces a T cell-dependent autoimmune condition, Hg-induced autoimmunity (HgIA) in genetically (H-2s,q,f,t2) susceptible mice characterized in its fullblown type by lymphoproliferation, hypergammaglobulinemia, systemic immune-complex (IC) deposits and antinucleolar antibodies (ANoA). All manifestations in HgIA are dependent on the presence of IFN-γ.

    Hg-treated BALB/c mice lacking activating FcγRs (FcγRI, FcγIII and FcεRI) showed significantly higher levels of both IgG1- and IgG2a-CIC whereas renal mesangial and vessel wall IC deposits were severely delayed and reduced/abolished, compared to mice without mutations (wild type, wt). Wt mice developed modest levels of IgG1- and IgG2a-CIC followed by a distinct formation of IC deposits in the renal glomerular mesangium, as well in renal and splenic vessel walls. Compared to wt mice, the mice lacking the inhibitory FcγRIIB showed similar titres of IC deposits in the renal mesangium, whereas vessel wall IC deposits were reduced.

    DBA/1 mice deficient for the FcRγ-chain (lack of the activating receptors FcγRI, FcγIII and FcεRI) or FcγRIII and treated with Hg showed a delayed and attenuated IgG1, IgG2a and IgG2b ANoA response compared to wt mice.

    Increasing the Hg dose or prolonging the treatment time could not override the attenuated ANoA response seen in FcγRIII mice. Female Hg-treated FcγRIIB mice showed a significant increase of IgG2b ANoA development compared to wt mice.

    The total serum IgG1 response due to treatment with Hg was attenuated in both BALB/c mice lacking the Fcγ-chain, and in DBA/1 mice lacking either the Fcγ- chain or specifically the FcγRIII compared to wt mice. This indicates that FcγRIII is the receptor important for the in HgIA characteristic serum IgG1 response. On the other hand, Hg-treated FcγRIIB deficient BALB/c and DBA/1 mice showed an increase of both serum IgG1 and IgE compared to wt mice.

    The cytokine profile in DBA/1 wt mice treated with Hg revealed a more marked Th1 profile compared to FcγRIII deficient mice. In contrast, the total Th2 and Th17 profile increased in both wt and FcγRIII deficient mice. However, during Hg treatment IL-21 mRNA expression was significantly reduced in FcγRIII deficient mice compared with wt mice. The increased Th1 profile in the wt mice could not be attributed to an increase of IFN-γ secretion from the major IFN-γ cell source, NK cells.

    We conclude that FcγRIII are important for the formation of IC deposits as shown by the delayed and reduced formation of IC deposits and the high levels of CIC in mice lacking FcγRIII. The expression of FcγRIII is also of importance for the rapidity and final strength of the ANoA response probably due to a reduced expression of Th1 cytokines and inflammatory factors. The ANoA response is modestly counter-regulated by FcγRIIB. The increase of serum IgG1 in HgIA is dependent on FcγRIII which is likely to be mediated by the low expression of IL- 21 in mice deficient for FcγRIII. In contrast, lack of FcγRIIB increases both the serum IgG1 and IgE response.

    Delarbeten
    1. The role of Fc-receptors in murine mercury-induced systemic autoimmunity
    Öppna denna publikation i ny flik eller fönster >>The role of Fc-receptors in murine mercury-induced systemic autoimmunity
    2006 (Engelska)Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 144, nr 2, s. 309-318Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Inorganic mercury (Hg) in genetically susceptible mouse strains induces a T cell-dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, anti-nuclear antibodies (ANA) and systemic immune-complex (IC) deposits. The exact phenotypic expression of HgIA in different strains depends on H-2 and non-H-2 genes. Fc receptors (FcRs) are important in the development of many autoimmune diseases. In this study, the effect of targeted mutations for activating and inhibiting FcRs in the BALB/c model of HgIA was examined. Hg-treated BALB/c mice without mutation (wild-type, wt) showed heavy IC deposits in the renal glomerular mesangium, as well as in renal and splenic vessel walls. The renal mesangial IC deposits were severely reduced in Hg-treated BALB/c mice without the gamma-chain (lack of the activating receptors FcgammaRI, FcgammaRIII and FcinRI), but unchanged in mice lacking the inhibitory FcgammaRIIB. The Hg-induced vessel wall IC deposits present in wt mice were abolished and reduced in the FcRgamma and FcgammaRIIB strains, respectively. Hg-treated BALB/c wt mice and mice without the gamma-chain showed an increase in serum IgE, while the increase in IgG1 was attenuated in the latter strain. In contrast, absence of the inhibiting FcgammaRIIB augmented the Hg-induced increase of both serum IgG1 and IgE. In conclusion, FcRs are important mainly for the induction of systmeic IC deposits in the HgIA model, but also affects serum IgG1 and IgE levels.

    Nyckelord
    Autoimmunity, Fc ! R, Fc ! RIIB, mercury, mice
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-19156 (URN)10.1111/j.1365-2249.2006.03057.x (DOI)16634805 (PubMedID)
    Tillgänglig från: 2009-06-12 Skapad: 2009-06-12 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity
    Öppna denna publikation i ny flik eller fönster >>The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity
    2008 (Engelska)Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 31, nr 1, s. 22-29Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Fc-receptors for IgG (FcgammaR) link cellular and humoral immune responses, controlling the balance between activating and inhibitory immune responses, and are involved in autoimmune diseases. Mercury (Hg) induces an autoimmune condition in genetically (H-2(s,q,f)) susceptible mice characterized by lymphoproliferation, hypergammaglobulinemia and IgG antinucleolar antibodies (ANoA). Here we investigate the role of activating (FcgammaRI, FcgammaRIII) and inhibitory (FcgammaRIIb) Fc-receptors on mercury-induced autoimmunity (HgIA) using DBA/1 mice (H-2(q)) with targeted FcgammaR mutations and wild type (wt) mice. Mice deficient for the FcRgamma-chain or FcgammaRIII and treated with 15 mg/L HgCl(2) showed a delayed and attenuated IgG1, IgG2a and IgG2b ANoA response compared to wt mice. Female Hg-treated FcgammaRIIB(-/-) mice showed a significant increased of IgG2b ANoA development compared to wt mice. The total serum IgG1 response due to Hg was attenuated in FcRgamma(-/-) and FcgammaRIII(-/-) mice compared to wt mice. Hg-treated FcgammaRIIB(-/-) mice showed an increase of both serum IgG1 and IgE compared to wt mice. We conclude that FcgammaRIII is of importance for the rapidity and final strength of the ANoA response and the increase in serum IgG1 in HgIA, while lack of FcgammaRIIb increases the IgG2b ANoA response and the serum IgG1 and IgE response.

    Nyckelord
    Mercury, FcgR, Autoimmunity, Mice, ANoA
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-19157 (URN)10.1016/j.jaut.2008.01.002 (DOI)18314309 (PubMedID)
    Tillgänglig från: 2009-06-12 Skapad: 2009-06-12 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. Lack of Fcγ-receptors increases circulating immune complexes but delays development of tissue immune complex deposits
    Öppna denna publikation i ny flik eller fönster >>Lack of Fcγ-receptors increases circulating immune complexes but delays development of tissue immune complex deposits
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Inorganic mercury (Hg) induces in susceptible mouse strains a T-cell dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, antinuclear antibodies, and immune-complex (IC) deposits in glomeruli and vessel walls. Activating Fcγ-receptors (FcγRs) are important for induction of HgIA. We have examined if activating FcγRs affect circulating immune complexes (CIC), the initial development of tissue IC deposits and their composition in HgIA. BALB/c mice with a targeted mutation for activating FcγRs and BALB/c mice without any mutation (wild type - wt - mice) were treated up to 35 days with Hg. Wild type mice showed a significant but modest increase of CIC from day 12 until day 18 and day 35 for IgG2a- and IgG1-containing CIC, respectively. Mercury-treated FcγR−/− mice showed significantly higher CIC levels than Hg-treated wt mice during the entire treatment time for IgG1-CIC, and after 26 and 35 days for IgG2a-CIC. Tissue IC deposits developed later in the FcγR−/− mice especially in the renal mesangium. After 35 days of Hg treatment the fraction of mice with and/or the amount of IgG1 and C3c deposits were significantly reduced in vessel walls and for IgG1 also in the renal mesangium compared with wt mice. We conclude that susceptible mice lacking activating FcγRs respond to an autoimmune stimulus with increased levels and altered quality of CIC compared with wt mice. It is likely that lack of FcγRs reduced elimination of CIC as indicated by delayed and significantly reduced IC deposits in the tissues of mice without activating receptors.

    Nyckelord
    Mercury, FcγR, CIC, autoimmunity, mice
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-19158 (URN)
    Tillgänglig från: 2009-06-12 Skapad: 2009-06-12 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
    4. Cytokines in induction of ANoA and hypergammaglobulinemia in mercury-induced autoimmunity: a lesson from Fc!RIII deficient mice
    Öppna denna publikation i ny flik eller fönster >>Cytokines in induction of ANoA and hypergammaglobulinemia in mercury-induced autoimmunity: a lesson from Fc!RIII deficient mice
    (Engelska)Manuskript (Övrigt vetenskapligt)
    Abstract [en]

    Xenobiotic agents such as metals, drugs, toxic oils and pristane can induce autoimmune diseases. Heavy metal induction of autoimmunity has been observed for mercury (Hg), silver and gold in mice. Mercury-induced autoimmunity (HgIA) in mice is characterised by lymphoproliferation, hypergammaglobulinemia, antinucleolar autoantibodies (ANoA) and immune complex deposits in the renal glomerular mesangium and systemically in vessel walls. HgIA is T-cell dependent, IFNγ is necessary for all manifestations of HgIA, and the activating Fc!RIII enhance development of ANoA. This study focused firstly on exploring the cytokine profile in the genetically susceptible DBA/1 (H-2q) wild type (wt) and DBA/1 FcγRIII-/- mice treated with 15 mg/l Hg, and secondly on the hypothesis that IFN-! producing NK cells are vital for induction of ANoA in the HgIA model. DBA/1 wt mice showed a significantly more marked Th1 profile compared to DBA/1 FcγRIII-/- mice following Hg treatment, whereas the total Th2 and Th17 profile increased in both DBA/1 wt and DBA/1 FcγRIII-/- mice. However, during Hg treatment IL-21 mRNA expression was significantly reduced in DBA/1 FcγRIII-/- mice compared with DBA/1 wt mice. However, we were unable to show that the increased Th1 profile in the DBA/1 wt mice was due to IFN-γsecretion from NK cells. Our findings suggest that the delayed ANoA induction in DBA/1 FcγRIII-/- mice is due to the attenuated Th1 profile. In addition the reduced expression of IL-21 in DBA/1 FcγRIII-/- mice might be responsible for the lack of serum IgG1 response in these mice.

    Nyckelord
    Fc!RIII, NK-cells, autoimmunity, cytokines, mercury
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-19159 (URN)
    Tillgänglig från: 2009-06-12 Skapad: 2009-06-12 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
  • 4.
    Martinsson, Klara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Cederbrant, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet.
    Cytokines in induction of ANoA and hypergammaglobulinemia in mercury-induced autoimmunity: a lesson from Fc!RIII deficient miceManuskript (Övrigt vetenskapligt)
    Abstract [en]

    Xenobiotic agents such as metals, drugs, toxic oils and pristane can induce autoimmune diseases. Heavy metal induction of autoimmunity has been observed for mercury (Hg), silver and gold in mice. Mercury-induced autoimmunity (HgIA) in mice is characterised by lymphoproliferation, hypergammaglobulinemia, antinucleolar autoantibodies (ANoA) and immune complex deposits in the renal glomerular mesangium and systemically in vessel walls. HgIA is T-cell dependent, IFNγ is necessary for all manifestations of HgIA, and the activating Fc!RIII enhance development of ANoA. This study focused firstly on exploring the cytokine profile in the genetically susceptible DBA/1 (H-2q) wild type (wt) and DBA/1 FcγRIII-/- mice treated with 15 mg/l Hg, and secondly on the hypothesis that IFN-! producing NK cells are vital for induction of ANoA in the HgIA model. DBA/1 wt mice showed a significantly more marked Th1 profile compared to DBA/1 FcγRIII-/- mice following Hg treatment, whereas the total Th2 and Th17 profile increased in both DBA/1 wt and DBA/1 FcγRIII-/- mice. However, during Hg treatment IL-21 mRNA expression was significantly reduced in DBA/1 FcγRIII-/- mice compared with DBA/1 wt mice. However, we were unable to show that the increased Th1 profile in the DBA/1 wt mice was due to IFN-γsecretion from NK cells. Our findings suggest that the delayed ANoA induction in DBA/1 FcγRIII-/- mice is due to the attenuated Th1 profile. In addition the reduced expression of IL-21 in DBA/1 FcγRIII-/- mice might be responsible for the lack of serum IgG1 response in these mice.

  • 5.
    Martinsson, Klara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Lack of Fcγ-receptors increases circulating immune complexes but delays development of tissue immune complex depositsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Inorganic mercury (Hg) induces in susceptible mouse strains a T-cell dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, antinuclear antibodies, and immune-complex (IC) deposits in glomeruli and vessel walls. Activating Fcγ-receptors (FcγRs) are important for induction of HgIA. We have examined if activating FcγRs affect circulating immune complexes (CIC), the initial development of tissue IC deposits and their composition in HgIA. BALB/c mice with a targeted mutation for activating FcγRs and BALB/c mice without any mutation (wild type - wt - mice) were treated up to 35 days with Hg. Wild type mice showed a significant but modest increase of CIC from day 12 until day 18 and day 35 for IgG2a- and IgG1-containing CIC, respectively. Mercury-treated FcγR−/− mice showed significantly higher CIC levels than Hg-treated wt mice during the entire treatment time for IgG1-CIC, and after 26 and 35 days for IgG2a-CIC. Tissue IC deposits developed later in the FcγR−/− mice especially in the renal mesangium. After 35 days of Hg treatment the fraction of mice with and/or the amount of IgG1 and C3c deposits were significantly reduced in vessel walls and for IgG1 also in the renal mesangium compared with wt mice. We conclude that susceptible mice lacking activating FcγRs respond to an autoimmune stimulus with increased levels and altered quality of CIC compared with wt mice. It is likely that lack of FcγRs reduced elimination of CIC as indicated by delayed and significantly reduced IC deposits in the tissues of mice without activating receptors.

  • 6.
    Martinsson, Klara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    The role of Fc-receptors in murine mercury-induced systemic autoimmunity2006Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 144, nr 2, s. 309-318Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inorganic mercury (Hg) in genetically susceptible mouse strains induces a T cell-dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, anti-nuclear antibodies (ANA) and systemic immune-complex (IC) deposits. The exact phenotypic expression of HgIA in different strains depends on H-2 and non-H-2 genes. Fc receptors (FcRs) are important in the development of many autoimmune diseases. In this study, the effect of targeted mutations for activating and inhibiting FcRs in the BALB/c model of HgIA was examined. Hg-treated BALB/c mice without mutation (wild-type, wt) showed heavy IC deposits in the renal glomerular mesangium, as well as in renal and splenic vessel walls. The renal mesangial IC deposits were severely reduced in Hg-treated BALB/c mice without the gamma-chain (lack of the activating receptors FcgammaRI, FcgammaRIII and FcinRI), but unchanged in mice lacking the inhibitory FcgammaRIIB. The Hg-induced vessel wall IC deposits present in wt mice were abolished and reduced in the FcRgamma and FcgammaRIIB strains, respectively. Hg-treated BALB/c wt mice and mice without the gamma-chain showed an increase in serum IgE, while the increase in IgG1 was attenuated in the latter strain. In contrast, absence of the inhibiting FcgammaRIIB augmented the Hg-induced increase of both serum IgG1 and IgE. In conclusion, FcRs are important mainly for the induction of systmeic IC deposits in the HgIA model, but also affects serum IgG1 and IgE levels.

  • 7.
    Martinsson, Klara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Louise
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet.
    Kleinau, Sandra
    Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity2008Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 31, nr 1, s. 22-29Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fc-receptors for IgG (FcgammaR) link cellular and humoral immune responses, controlling the balance between activating and inhibitory immune responses, and are involved in autoimmune diseases. Mercury (Hg) induces an autoimmune condition in genetically (H-2(s,q,f)) susceptible mice characterized by lymphoproliferation, hypergammaglobulinemia and IgG antinucleolar antibodies (ANoA). Here we investigate the role of activating (FcgammaRI, FcgammaRIII) and inhibitory (FcgammaRIIb) Fc-receptors on mercury-induced autoimmunity (HgIA) using DBA/1 mice (H-2(q)) with targeted FcgammaR mutations and wild type (wt) mice. Mice deficient for the FcRgamma-chain or FcgammaRIII and treated with 15 mg/L HgCl(2) showed a delayed and attenuated IgG1, IgG2a and IgG2b ANoA response compared to wt mice. Female Hg-treated FcgammaRIIB(-/-) mice showed a significant increased of IgG2b ANoA development compared to wt mice. The total serum IgG1 response due to Hg was attenuated in FcRgamma(-/-) and FcgammaRIII(-/-) mice compared to wt mice. Hg-treated FcgammaRIIB(-/-) mice showed an increase of both serum IgG1 and IgE compared to wt mice. We conclude that FcgammaRIII is of importance for the rapidity and final strength of the ANoA response and the increase in serum IgG1 in HgIA, while lack of FcgammaRIIb increases the IgG2b ANoA response and the serum IgG1 and IgE response.

  • 8.
    Martinsson, Klara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Mousavi, Seyed Ali
    Rikshospital University Hospital, Oslo.
    Berg, Trond
    University of Oslo.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Deficiency of Activating Fc gamma-Receptors Reduces Hepatic Clearance and Deposition of IC and Increases CIC Levels in Mercury-Induced Autoimmunity2010Ingår i: PLOS ONE, ISSN 1932-6203, Vol. 5, nr 10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Inorganic mercury (Hg) induces a T-cell dependent, systemic autoimmune condition (HgIA) where activating Fc gamma-receptors (Fc gamma Rs) are important for the induction. In this study we examined the influence of activating Fc gamma Rs on circulating levels and organ localization of immune complexes (IC) in HgIA. Methods and Principal Findings: Mercury treated BALB/c wt mice showed a significant but modest increase of circulating IC (CIC) from day 12 until day 18 and day 35 for IgG2a- and IgG1- CIC, respectively. Mercury-treated mice lacking the transmembrane gamma-chain of activating Fc gamma Rs (FcR gamma(-/-)) had significantly higher CIC levels of both IgG1-CIC and IgG2a-CIC than wt mice during the treatment course. The hepatic uptake of preformed CIC was significantly more efficient in wt mice compared to Fc gamma R-/- mice, but also development of extrahepatic tissue IC deposits was delayed in FcR gamma(-/-) mice. After 35 days of Hg treatment the proportion of immune deposits, as well as the amounts was significantly reduced in vessel FcR gamma(-/-) mice compared to wt mice. Conclusions: We conclude that mice lacking functional activating Fc gamma Rs respond to Hg with increased levels and altered quality of CIC compared with wt mice. Lack of functional activating Fc gamma Rs delayed the elimination of CIC, but also significantly reduced extrahepatic tissue localization of CIC.

  • 9.
    Roos, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Martinsson, Klara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Ziegelasch, Michael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sommarin, Yngve
    Euro Diagnost AB, Sweden.
    Svärd, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Falun Central Hospital, Sweden.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten.
    Circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking2016Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, nr 119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: A possible association between mucosal immunization and inflammation, as well as the initiation and propagation of rheumatoid arthritis (RA), is attracting renewed interest. The aim of this study was to evaluate the possible occurrence and clinical correlations of circulating secretory immunoglobulin A (SIgA) antibodies against the second-generation cyclic citrullinated peptides (CCP) among patients with recent-onset RA followed prospectively over 3 years. Methods: Baseline serum samples from 636 patients with recent-onset RA were analyzed for SIgA anti-CCP antibodies by using an enzyme-linked immunosorbent assay with a secondary antibody directed against secretory component. SIgA anti-CCP status at baseline was analyzed in relation to smoking, HLA-DRB1/shared epitope (SE), and the disease course over 3 years. Significant findings were evaluated in regression analysis that included age, sex, smoking, and SE. Results: Seventeen percent of the patients tested positive for circulating SIgA anti-CCP, and the occurrence was confirmed by detection of secretory component in an affinity-purified IgA anti-CCP fraction. SIgA anti-CCP positivity at baseline was associated with slightly higher baseline erythrocyte sedimentation rate (ESR) (mean 38 vs. 31 mm/first hour, p = 0.004) and C-reactive protein (CRP) (mean 30 vs. 23 mg/L, p = 0.047). During follow-up, SIgA anti-CCP-positive patients had a higher mean AUC regarding ESR (adjusted p = 0.003), although there were no significant differences regarding CRP, tender and swollen joint counts, or radiological joint damage (median Larsen progression 1.0 vs. 1.0, p = 0.22). SIgA anti-CCP was associated significantly with smoking (79 % ever smokers among SIgA anti-CCP-positive patients vs. 59 % in SIgA anti-CCP-negative patients, adjusted OR 2.19, 95 % CI 1.01-4.37, p = 0.027) but not with carriage of the SE (80 % vs. 73 %, p = 0.62). Conclusions: Circulating SIgA anti-CCP, which is present in a subgroup of patients with early RA, is not related to SE, but it is environmentally linked to cigarette smoking. This finding strengthens the hypothesis that immunization against citrullinated peptides and/or proteins may occur at mucosal surfaces of the airways. Analysis of SIgA antibodies in serum may be a convenient and more versatile means to investigate the "mucosal connection" in RA compared with analyses in mucosal fluid samples.

  • 10.
    Sjöwall, Christopher
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Martinsson, Klara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Cardell, Kristina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Ekstedt, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in nonalcoholic fatty liver disease2015Ingår i: Translational research : the journal of laboratory and clinical medicine, ISSN 1878-1810, Vol. 165, nr 6, s. 658-666Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The identification of individuals with severe liver fibrosis among patients with chronic liver disease is of major importance when evaluating prognosis, potential risk for complications, and when deciding treatment strategies. Although percutaneous liver biopsy is still considered a "gold standard" for staging of liver fibrosis, attempts to find reliable noninvasive markers of liver fibrosis are frequent. Inflammation is essential for the progression of fibrosis. The urokinase plasminogen activator and its receptor have been associated with hepatic inflammation and fibrosis in mice. High serum concentrations of soluble urokinase plasminogen activator receptor (suPAR) are suggested to be involved in inflammation, tissue remodeling, and cancer metastasis. Here, we evaluated serum suPAR as a noninvasive test to detect liver fibrosis in 82 well-characterized patients with nonalcoholic fatty liver disease (NAFLD), and in 38 untreated patients with chronic hepatitis C virus (HCV) infection at the time of their first liver biopsy. suPAR levels were increased in chronic liver disease compared with blood donors (P < 0.001). Patients with HCV had higher suPAR concentrations than patients with NAFLD (P < 0.002). suPAR levels were associated with the severity of fibrosis, particularly in NAFLD, but did not correlate with inflammation. Regarding the performance in predicting severity of fibrosis, suPAR was essentially as good as other commonly used noninvasive fibrosis scoring systems. The results in HCV confirm previous observations. However, this is the first study to investigate suPAR as a biomarker in NAFLD, and the results indicate that suPAR may constitute a severity marker related to fibrosis and prognosis rather than reflecting inflammation.

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