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- Hensvold, Aase Eline Haj
(författare)
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Studies on the role of anti-citrullinated protein antibodies in rheumatoid arthritis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA) and present in about two thirds of all patients at diagnosis. They can be detected already before disease onset and have direct pathogenic effect mediated partly through the Fc (fragment crystalizable) portion with attached Fc-glycan structure. On these grounds we aimed to further characterize ACPA’s role in the pathogenesis of RA both as a risk factor and a disease biomarker. To this end we investigated ACPA occurrence in a population-derived twin cohort and ACPA in a cohort of early-untreated RA patients in relation to disease outcomes. First we screened a large population-derived twin cohort (N= 12,590; median age 64, range 48-93 years) for occurrence of ACPA using an ACPA test used in clinical routine: the Anti-CCP2 (IgG) test. Through linking the twin cohort with the Swedish National Patient Register we identified ACPA-positive individuals without RA (N=226) and ACPA-positive patients with RA (N=124). ACPA-positive individuals without RA had lower ACPA concentration and fewer different ACPA reactivities as compared to patients with ACPA-positive RA. Heritability estimates for having ACPA with or without RA were generally lower than expected (10% (95% CI: 0-43) for ACPA without RA; 23% (95% CI: 0-45) for ACPA; and 41% (95% CI: 0-74) for ACPA-positive RA). Heavy smoking and HLA-SE associated with ACPA occurrence with and without RA. Environmental factors (including smoking) appeared to be more important than genetic in determining which individuals develop ACPA, while genetic factors (and in particular HLA-SE) had a relatively larger impact in determining which ACPA-positive individuals that will ultimately develop arthritis. We also confirmed that presence of ACPA and especially high titers of ACPA have a high diagnostic accuracy for RA in a population based setting. Following this, we then screened a cohort of early-untreated RA patients (N=183) for occurrence of ACPA using either the Anti-CCP2 test or ELISA for detection of reactivities against specific citrullinated peptides. We demonstrated that ACPA (and especially anti-citrullinated-vimentin antibodies) associated with markers of bone loss (as measured by ELISA detection of serum RANKL and/or presence of bone erosions on radiographs of hands and feet). Treatment with methotrexate (MTX) significantly lowered both ACPA and RANKL serum levels. In a subgroup of these patients (N=59) we investigated the Fc-glycosylation patterns of serum IgG in relation to disease outcome further. A general low abundance of galactosylated glycans, partially restored by MTX treatment, was observed in the serum of early-untreated RA samples. This was more evident among future non-responders as compared to responders to MTX treatment. The galactosylation status of the IgG-Fc had good predictive value for MTX response. In conclusion we showed that environmental as well as genetic factors are important for ACPA occurrence, which in turn has a high diagnostic accuracy for RA. In early-untreated RA, ACPA associate with bone loss and is modulated by methotrexate treatment. Further, Fc-glycosylation patterns of antibodies are generally altered in early-untreated RA and might serve as a predictive factor for therapeutic response.
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| 2. |
- Houtman, Miranda, et al.
(författare)
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T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus
- 2018
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Ingår i: Journal of Autoimmunity. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 0896-8411 .- 1095-9157. ; 90, s. 28-38
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Tidskriftsartikel (refereegranskat)abstract
- Non-coding SNPs in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) locus have been linked with several autoimmune diseases, including rheumatoid arthritis, type I diabetes, and inflammatory bowel disease. However, the functional consequences of these SNPs are poorly characterized. Herein, we show in blood cells that SNPs in the PTPN2 locus are highly correlated with DNA methylation levels at four CpG sites downstream of PTPN2 and expression levels of the long non-coding RNA (IncRNA) LINC01882 downstream of these CpG sites. We observed that LINC01882 is mainly expressed in T cells and that anti-CD3/CD28 activated naive CD4(+) T cells downregulate the expression of LINC01882. RNA sequencing analysis of LINC01882 knockdown in Jurkat T cells, using a combination of antisense oligo-nucleotides and RNA interference, revealed the upregulation of the transcription factor ZEB1 and kinase MAP2K4, both involved in IL-2 regulation. Overall, our data suggests the involvement of LINC01882 in T cell activation and hints towards an auxiliary role of these non-coding SNPs in autoimmunity associated with the PTPN2 locus.
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| 3. |
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| 4. |
- Ytterberg, A Jimmy, et al.
(författare)
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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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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:9, s. 1772-1777
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Tidskriftsartikel (refereegranskat)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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