| 1. |
- Amarzguioui, Mohammed, et al.
(författare)
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Extensive Intimal Apolipoprotein A1-Derived Amyloid Deposits in a Patient with an Apolipoprotein A1 Mutation
- 1998
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 242:3, s. 534-539
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Tidskriftsartikel (refereegranskat)abstract
- In the aortic intima amyloid deposits are often associated with atherosclerotic plaques. In a recent study of one patient with aortic intimal amyloid the major fibril protein was an N-terminal fragment of apolipoprotein A1 (apoA1) consisting of 69 amino acid residues. In the present study, we have screened the apoA1 gene for mutations in autopsy cases with aortic intimal amyloid immunohistochemically positive for apoA1, using single stranded conformational polymorphism (SSCP) analysis and DNA sequencing. All cases except one had a normal apoA1 gene sequence. One case of exceptionally severe atherosclerosis combined with extensive intimal amyloid deposits showed an apoA1 deletion corresponding to Lys 107. Thus, wild type apoA1 is amyloidogenic but our findings suggest that the expression of a mutant apoA1-form may be associated with enhanced amyloidogenicity.
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| 2. |
- Danielsson, Olof, et al.
(författare)
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Apoptosis in idiopathic inflammatory myopathies with partial invasion; a role for CD8(+)cytotoxic T cells?
- 2020
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Ingår i: PLOS ONE. - San Francisco, CA, United States : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- Polymyositis and inclusion body myositis are idiopathic inflammatory myopathies, with a pathology characterized by partial invasion of non-necrotic muscle fibres by CD8(+)cytotoxic T-cells, leading to fibre degeneration. Although the main effector pathway of CD8(+)T-cells is to induce apoptosis of target cells, it has remained unclear if apoptosis occurs in these diseases, and if so, if it is mediated by CD8(+)T-cells. In consecutive biopsy sections from 10 patients with partial invasion, muscle fibres and inflammatory cells were assessed by immunohistochemistry and apoptotic nuclei by the TUNEL assay. Analysis of muscle fibre morphology, staining pattern and quantification were performed on digital images, and they were compared with biopsies from 10 dermatomyositis patients and 10 controls without muscle disease. Apoptotic myonuclei were found in muscle with partial invasion, but not in the invaded fibres. Fibres with TUNEL positive nuclei were surrounded by CD8(+)T-cells, granzyme B(+)cells and macrophages, but lacked FAS receptor expression. In contrast, apoptotic myonuclei were rare in dermatomyositis and absent in controls. The findings confirm that apoptosis occurs in idiopathic inflammatory myopathies and support that it is mediated by CD8(+)cytotoxic T- cells, acting in parallel to the process of partial invasion.
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| 3. |
- Danielsson, Olof, et al.
(författare)
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Skeletal muscle immunohistochemistry of acquired and hereditary myopathies
- 2021
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Ingår i: Current Opinion in Rheumatology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1040-8711 .- 1531-6963. ; 33:6, s. 529-536
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review The continued development in the field of immunohistochemistry (IHC) has improved the ability to diagnose muscle diseases. Many hereditary diseases are diagnosed by the absence or abnormal localization of proteins. Detection of secondary pathological protein expression is also used in diagnostics, and to study disease processes. We relate and discuss recent reports, where IHC has been an important tool in the investigation of muscle diseases. Recent findings In idiopathic inflammatory myopathies, IHC has extended its role to diagnose subgroups. This is most evident concerning immune-mediated necrotizing myopathy and antisynthetase syndrome. The availability of new antibodies has increased the sensitivity of a muscle biopsy to diagnose several hereditary myopathies. The introduction of protein restoration therapies in muscular dystrophies also comes with the need to detect and measure protein levels. For the study of disease processes at the protein level, in both acquired and hereditary myopathies IHC, often combined with gene studies, PCR-based methods, western blotting and electron microscopy, continues to bring forth interesting results. IHC is an integrated tool in muscle pathology, where recent studies contribute to improved diagnostic skills and increased insights into disease processes.
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| 4. |
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| 5. |
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| 6. |
- Havarinasab, Said, et al.
(författare)
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Immunosuppressive and autoimmune effects of thimerosal in mice
- 2005
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Ingår i: TOXICOLOGY AND APPLIED PHARMACOLOGY. - : Elsevier BV. - 0041-008X. ; 204:2, s. 109-21
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Tidskriftsartikel (refereegranskat)abstract
- The possible health effects of the organic mercury compound thimerosal (ethylmercurithiosalicylate), which is rapidly metabolized to ethylmercury (EtHg), have recently been much debated and the effect of this compound on the immune system is largely unknown. We therefore studied the effect of thimerosal by treating A.SW (H-2(s)) mice, susceptible to induction of autoimmunity by heavy metals, with 10 mg thimerosal/L drinking water (internal dose ca 590 mu g Hg/kg body weight/day) for up to 30 days. The lymph node expression of IL-2 and IL-15 mRNA was increased after 2 days, and of IL-4 and IFN-gamma rnRNA after 6 and 14 days. During the first 14 days treatment, the number of splenocytes, including T and B cells as well as Ig-secreting cells decreased. A strong immunostimulation superseded after 30 days treatment xvith increase in splenic weight, number of splenocytes including T and B cells and Ig-secreting cells, and Th2- as well as Th-l-dependent serum immunoglobulins. Antinucleolar antibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin, and systemic immune-complex deposits developed. The H-2(s) strains SJL and B10.S also responded to thimerosal treatment with ANoA. The A.TL and B10.TL strain, sharing background genes with the A.SW and B10.S strain, respectively, but with a different H-2 haplotype (tl), did not develop ANoA, linking the susceptibility to H-2. Thimerosal-treated H-2(s) mice homozygous for the nu mutation (SJL-nu/nu), or lacking the T-cell costimulatory molecule CD28 (B10.S-CD28(-/-)), did not develop ANoA, which showed that the autoimmune response is T-cell dependent. Using H-2(s) strains with targeted mutations, we found that IFN-gamma and IL-6, but not IL-4, is important for induction of ANoA by thimerosal. The maximum added renal concentration of thimerosal (EtHg) and inorganic mercury occurred after 14 days treatment and was 8 1 mu g Hg/g. EtHg made tip 59% and inorganic mercury 41% of the renal mercury. In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury.
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| 7. |
- Häggqvist, Bo, 1962-, et al.
(författare)
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Effects of deviating the Th2-response in murine mercury-induced autoimmunity towards a Th1-response
- 2003
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 134:2, s. 202-209
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Tidskriftsartikel (refereegranskat)abstract
- T-helper cells type 1 (Th1) and type 2 (Th2) play an important role in the pathogenesis of autoimmune diseases. In many Th1-dependent autoimmune models, treatment with recombinant interleukin-12 (rIL-12) accelerates the autoimmune response. Mercury-induced autoimmunity (HgIA) in mice is an H-2 regulated condition with antinucleolar antibodies targeting fibrillarin (ANoA), systemic immune-complex (IC) deposits and transient polyclonal B-cell activation (PBA). HgIA has many characteristics of a Th2 type of reaction, including a strong increase of IgE, but disease induction is critically dependent on the Th1 cytokine IFN-γ. The aim of this study was to investigate if a strong deviation of the immune response in HgIA towards Th1 would aggravate HgIA. Injections of both rIL-12 and anti-IL-4 monoclonal antibody (α-IL-4) reduced the HgCl2-(Hg-)induced concentration of the Th2-dependent serum IgE and IgG1, but increased the Th1-dependent serum IgG2a. The IgG-ANoA developed earlier and attained a higher titre after combined treatment, and the ANoA titre of the IgG1 isotype decreased while the ANoA titre of the Th1-associated IgG2a, IgG2b and IgG3-ANoA isotypes increased. Treatment with rIL-12 alone increased the Hg-induced IgG2a and IgG3 ANoA titres, the PBA, and the IC deposits in renal and splenic vessel walls, while treatment with α-IL-4 + Hg inhibited renal but not splenic vessel wall IC deposits. We conclude that manipulating the cytokine status, by altering the Th1/Th2 balance, will influence autoimmune disease manifestations. This might be an important way of modulating human autoimmune diseases.
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| 8. |
- Häggqvist, Bo, et al.
(författare)
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IL-10 is not a major determinant for resistance to murine mercury-induced systemic autoimmunity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Systemic autoimmune diseases have a complicated and largely unknown etiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive fimctions in the immune system have lately received much interest. One of the cytokines in focus in this respect is IL-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation for the IL-10 gene in a strain resistant to heavy-metal induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A. SW strain during the induction of autoimmunity by metals.The wild-type C57BL/6J (B6-WT) strain did not react with lymphoproliferation, polyclonal B-cell activation, increases in antinuclear autoantibodies (ANA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, in agreement with previous obsetvations there was a modest increase in serum IgG1, IgE and IgG2a. Treatment with Ag caused only a weak increase in IgE and IgG1. The B6.129P2-µ10tm1Cgn /J strain (IL-10 deficient B6 mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but compared with Hg-treated B6-WT mice there was a significant increase in homogeneous ANA and a higher serum IgE concentration. The IL-10 deficient B6 controls showed a spontaneous increase in splenic weight as well as serum IgM and IgG1 compared with the B6-WT control mice. These signs of immune activation were also present in the IL-10 deficient B6 mice treated with Hg, while treatment with Ag reduced these features making the response similar to that in the B6-WT controls.The susceptible A.SW mice treated with rIL-10 and Hg showed during ongoing intense rIL-10 treatment reduced induction of ANoA, reduction in antichromatin antibodies (ACA), and a reduced increase in serum IgE compared with mice which received Hg but not rIL-10. In conclusion, the reduced ANoA induction during riL-10 treatment indicates suppressive effect of IL-10 on autoimmune development. Lack of IL-10 may promote development of ANA, ACA, and serum IgE, but is not likely to be crucial for resistance to heavy-metal induced autoimmunity.
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| 9. |
- Häggqvist, Bo, 1962-, et al.
(författare)
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Interleukin-10 in murine metal-induced systemic autoimmunity
- 2005
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 141:3, s. 422-431
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Tidskriftsartikel (refereegranskat)abstract
- Systemic autoimmune diseases have a complicated and largely unknown aetiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive functions in the immune system have lately received much interest. One of the cytokines in focus in this respect is interleukin (IL)-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on the induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation of the IL-10 gene in a strain resistant to heavy metal-induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A.SW strain during the induction of autoimmunity by metals. The wild-type C57BL/6 J (B6-WT) strain did not react with lymphoproliferation, polyclonal B cell activation, anti-nucleoar autoantibodies (ANoA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, serum IgG1 and IgE showed a modest increase during Hg treatment, while Ag caused a weak increase in IgE and IgG2a. The B6-129P2-Il10tm1Cgn/J strain (IL-10-deficient mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but showed a higher median titre of homogeneous ANA compared with Hg-treated B6-WT mice. Both control and Hg-treated (but not Ag-treated) IL-10-deficient mice showed an increase in splenic weight and serum IgG1 compared with B6-WT control and Hg-treated mice. An early, significant increase in serum IgE was seen in Hg-treated IL-10-deficient and WT mice compared with the controls, the increase was 42- and sixfold, respectively. During ongoing intense treatment with rIL-10 in combination with Hg the susceptible A.SW mice showed a reduced development of ANoA and antichromatin antibodies, as well as serum IgE, compared with mice receiving Hg but not rIL-10. In conclusion, IL-10 suppresses several aspects of HgIA, but is not crucial for resistance to heavy metal-induced autoimmunity. Peroral silver treatment suppresses the spontaneous immune activation seen in IL-10-deficient mice. © 2005 British Society for Immunology.
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| 10. |
- Häggqvist, Bo, et al.
(författare)
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Interleukin-10 in murine mercury-induced systemic autoimmunity
- 2005
-
Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 141:3, s. 422-431
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic autoimmune diseases have a complicated and largely unknown etiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive fimctions in the immune system have lately received much interest. One of the cytokines in focus in this respect is IL-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation for the IL-10 gene in a strain resistant to heavy-metal induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A. SW strain during the induction of autoimmunity by metals.The wild-type C57BL/6J (B6-WT) strain did not react with lymphoproliferation, polyclonal B-cell activation, increases in antinuclear autoantibodies (ANA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, in agreement with previous obsetvations there was a modest increase in serum IgG1, IgE and IgG2a. Treatment with Ag caused only a weak increase in IgE and IgG1. The B6.129P2-µ10tm1Cgn /J strain (IL-10 deficient B6 mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but compared with Hg-treated B6-WT mice there was a significant increase in homogeneous ANA and a higher serum IgE concentration. The IL-10 deficient B6 controls showed a spontaneous increase in splenic weight as well as serum IgM and IgG1 compared with the B6-WT control mice. These signs of immune activation were also present in the IL-10 deficient B6 mice treated with Hg, while treatment with Ag reduced these features making the response similar to that in the B6-WT controls.The susceptible A.SW mice treated with rIL-10 and Hg showed during ongoing intense rIL-10 treatment reduced induction of ANoA, reduction in antichromatin antibodies (ACA), and a reduced increase in serum IgE compared with mice which received Hg but not rIL-10. In conclusion, the reduced ANoA induction during riL-10 treatment indicates suppressive effect of IL-10 on autoimmune development. Lack of IL-10 may promote development of ANA, ACA, and serum IgE, but is not likely to be crucial for resistance to heavy-metal induced autoimmunity.
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