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- Reynisdóttir, Guðrún Björk
(author)
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Molecular and epidemiological investigations of lung involvement in very early rheumatoid arthritis
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Rheumatoid arthritis (RA) is a systemic inflammatory joint disease with at least two distinct clinical phenotypes defined by the presence or absence of antibodies, i.e. rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs). These two phenotypes differ both with respect to risk factors and disease outcome, with seropositive disease being more likely associated with extra-articular manifestations, such as lung manifestations, and tobacco exposure. Both ACPA and RF can be detected in the blood years prior to the onset of joint inflammation suggesting that these antibodies are initially generated outside the joints. The current thesis investigates the pathogenic link between lungs and joints with a focus on the potential role of the lung as an initiating site for the RA-associated autoimmunity. We investigated a cohort of patients with early, untreated RA, who underwent high resolution computed tomography and conducted lung function tests. A subgroup of these patients was subjected to bronchoscopy with retrieval of bronchoalveolar lavage (BAL) and bronchial biopsies. All investigations were repeated after six months of anti-rheumatic treatment. We found more prevalent lung abnormalities, both parenchymal (54%) and airway (66%) in RA patients as compared to controls. The parenchymal abnormalities were significantly more frequent in the subgroup of ACPA-positive RA patients compared to ACPA-negative patients. The same was true after compensating for smoking. Signs of inflammation and immune activation with more lymphocytic infiltration and expression of citrullinated proteins were found in the lungs of ACPA-positive as compared to ACPA-negative patients. ACPAs were enriched in the BAL as compared to the blood compartment of ACPA-positive patients. Using mass spectrometry we were able to identify two novel citrullinated vimentin peptides that were present in a majority of bronchial (n=6) and RA synovial biopsies (n=7) tested. Immune reactivity against these targets was specifically detected in the blood of RA patients. At 6 months follow-up one third of patients with lung fibrosis (11%) at baseline had progressed and additionally 3 patients had developed new radiological changes suggestive of early interstitial lung disease. Moreover, there was an increase in airway obstruction, with a decline in forced expiratory volume in one second in all patients, more prominent in smokers. In conclusion, lung changes in early RA are prevalent and may be progressive despite anti-rheumatic treatment. Taken together our results support the hypothesis that the lung may be an early important player in the pathogenesis of RA in a subset of patients. These findings encourage new therapeutic strategies to target the local inflammation in the lungs, with the aim to prevent the progress of autoimmunity in ACPA-positive healthy individuals.
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- Reynisdottir, Inga, et al.
(author)
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High expression of ZNF703 independent of amplification indicates worse prognosis in patients with luminal B breast cancer
- 2013
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In: Cancer Medicine. - : Wiley. - 2045-7634. ; 2:4, s. 437-446
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Journal article (peer-reviewed)abstract
- Amplification of 8p12-p11 is relatively common in breast cancer and several genes within the region have been suggested to affect breast tumor progression. The aim of the study was to map the amplified 8p12-p11 region in a large set of breast tumors in an effort to identify the genetic driver and to explore its impact on tumor progression and prognosis. Copy number alterations (CNAs) were mapped in 359 tumors, and gene expression data from 577 tumors (359 tumors included) were correlated with CNA, clinical–pathological factors, and protein expression (39 tumors). 8p12-p11 was amplified in 11.4% of tumors. The smallest region of amplification harbored one full-length gene, ZNF703. ZNF703 mRNA expression was significantly higher in estrogen receptor (ER)-positive than ER-negative tumors (P = 2 × 10−16), a reflection of high expression in luminal tumors. Forty-eight percent of tumors with ZNF703 amplification were luminal B tumors in which the best correlation between DNA copy number and mRNA was seen (P = 1.2 × 10−7) as well as correlation between mRNA and protein expression (P = 0.02). High ZNF703 mRNA correlated with poor survival in patients with ER-positive luminal B tumors (log rank P = 0.04). Furthermore, high ZNF703 mRNA expression correlated with poor outcome in patients with ZNF703 copy number neutral, ER-positive, luminal B tumors (log rank P = 0.004). The results support ZNF703 as the driver gene of the 8p12 amplification and suggest that independent of amplification, high expression of the gene affects prognosis in luminal B tumors.
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- Ytterberg, A Jimmy, et al.
(author)
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Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis : identification and validation
- 2015
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:9, s. 1772-1777
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Immunological events in the lungs might trigger production of anti-citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA.PATIENTS AND METHODS: Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA.RESULTS: Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA.CONCLUSIONS: Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.
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