| 1. |
- Laki, Judit, et al.
(författare)
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Very high levels of anti-citrullinated protein antibodies are associated with HLA-DRB1*15 non-shared epitope allele in patients with rheumatoid arthritis
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:7, s. 2078-2084
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Tidskriftsartikel (refereegranskat)abstract
- Objective Production of anticitrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLADRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA. Methods HLADRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients. Results No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLADRB1*15 allele was associated with high ACPA levels (P = 0.0002). A similar trend was detected in HLADRB1*15positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLADRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P < 0.0001 by Mantel-Haenszel test with a fixed-effects model). Conclusion Our data indicate that HLADRB1*15 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLADRB1*15 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending.
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| 2. |
- Landsverk, Ole J. B., et al.
(författare)
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Antibody-secreting plasma cells persist for decades in human intestine
- 2017
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Ingår i: Journal of Experimental Medicine. - NewYork, USA : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 214:2, s. 309-317
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19(+) PC subset was dynamically exchanged, whereas of two CD19(-) PC subsets, CD45(+) PCs exhibited little and CD45(-) PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45(-) PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19(-) PC subsets support selection and maintenance of protective PCs for life in human intestine.
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| 3. |
- Lindh, Ingrid, et al.
(författare)
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Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice
- 2014
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Ingår i: Arthritis Research & Therapy. - London : BioMed Central (BMC). - 1478-6354 .- 1478-6362. ; 16:4
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Antibodies towards type II collagen (CII) are detected in patients with rheumatoid arthritis (RA) and in non-human primates and rodents with collagen induced arthritis (CIA). We have previously shown that antibodies specific for several CII-epitopes are pathogenic using monoclonal antibodies from arthritic mice, although the role of different anti-CII epitopes has not been investigated in detail in other species. We therefore performed an inter-species comparative study of the autoantibody response to CII in patients with RA versus monkeys and mice with CIA. METHODS: Analysis of the full epitope repertoire along the disease course of CIA was performed using a library of CII triple-helical peptides. The antibody responses to the major CII epitopes were analyzed in sera and synovial fluid from RA patients, and in sera from rhesus monkeys (Macaca mulatta), common marmosets (Callithrix jacchus) and mice. RESULTS: Many CII epitopes including the major C1, U1, and J1 were associated with established CIA and arginine residues played an important role in the anti-CII antibody interactions. The major epitopes were also recognized in RA patients, both in sera and even more pronounced in synovial fluid: 77% of the patients had antibodies to the U1 epitope. The anti-CII immune response was not restricted to the anti-citrulline protein antibodies (ACPA) positive RA group. CONCLUSION: CII conformational dependent antibody responses are common in RA and are likely to originate from rheumatoid joints but did not show a correlation with ACPA response. Importantly, the fine specificity of the anti-CII response is similar with CIA in monkeys and rodents where the recognized epitopes are conserved and have a major pathogenic role. Thus, anti-CII antibodies may both contribute to, as well as be the consequence of, local joint inflammation. © 2014 Lindh et al.; licensee BioMed Central Ltd.
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| 4. |
- Snir, Omri, et al.
(författare)
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Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients
- 2010
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:1, s. 44-52
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Tidskriftsartikel (refereegranskat)abstract
- MCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti-CCP+/anti-MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA-predisposing genes.
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| 5. |
- Snir, Omri, et al.
(författare)
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Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumatoid arthritis
- 2012
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Ingår i: Arthritis and Rheumatism. - : John Wiley & Sons. - 0004-3591 .- 1529-0131. ; 64:8, s. 2482-2488
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Tidskriftsartikel (refereegranskat)abstract
- Objective Type II collagen (CII) is a cartilage-specific protein to which a loss of immune tolerance may trigger autoimmune reactions and cause arthritis. The major T cell epitope on CII, amino acids 259273, can be presented by several HLADRB1*04 alleles in its native or posttranslational glycosylated form. The present study was undertaken to functionally explore and compare CII-autoreactive T cells from blood and synovial fluid of patients with rheumatoid arthritis (RA).Methods Peripheral blood was obtained from HLADRB1*04positive RA patients (n = 10) and control subjects (n = 10) and stimulated in vitro with several variants of the CII259273 epitope, i.e., unmodified, glycosylated on Lys-264, glycosylated on Lys-270, or glycosylated on both Lys-264 and Lys-270. Up-regulation of CD154 was used to identify responding T cells. These cells were further characterized by intracellular staining for interleukin-17 (IL-17), interferon-? (IFN?), and IL-2 by flow cytometry. Synovial T cells from RA patients were investigated in parallel.Results Multifunctional T cell responses toward all examined variants of the CII259273 peptide could be detected in RA patients and, to a lesser extent, also in healthy HLA-matched controls (P < 0.001). In RA patients, a comparison between blood- and joint-derived T cell function revealed a significant increase in levels of the proinflammatory cytokine IFN? in synovial T cells (P = 0.027). Studies of longitudinally obtained samples showed that T cell responses were sustained over the course of disease, and even included epitope spreading.Conclusion The identification of inflammatory T cell responses to both glycosylated and nonglycosylated variants of the major CII epitope in RA patients suggests that CII autoreactivity in RA may be more common than previously recognized.
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| 6. |
- Snir, Omri
(författare)
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Specific autoimmunity in rheumatoid arthritis : T cells, antibodies and genetic regulation
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Complex interactions between genes and environmental factors may result in destruction of the body’s own cells and tissues by the immune system, i.e. autoimmunity. Rheumatoid arthritis (RA) is a chronic joint inflammation mediated by all arms of the immune system that can lead to tissue destruction and functional disabilities. Many genetic variants and environmental factors that affect the immune system in RA have been revealed in recent years, however it is still not known precisely how they regulate and control autoimmunity. In this work I studied the function and specificity of adaptive immunity in RA, and also addressed influences from known genetic variants that predispose for disease. First, autoantibody responses to several RA-associated citrullinated autoantigens were studied in a cohort of patients with established RA. Antibody responses and their interrelationships were examined, both in the whole study cohort and following stratification to HLA-DRB1 types, since HLA-DRB1 alleles are the strongest genetic risk factors known for RA. The autoantibodies were found to be highly specific for RA and displayed only limited cross reactivity. HLA-DRB1*04 alleles strongly associated with the presence of these autoantibodies both in sera and synovial fluid. T cells are believed to be central mediators of RA pathogenesis, however studying T cell specificity has been proven difficult. The stinking HLA-DRB1*04 association with different anti-citrulline antibody responses encouraged us to revisit T cell recognition and responses to citrullinated proteins. We identified an epitope from vimentin that binds HLA-DRB1*0401 in its citrullinated but not in its native form and T cell recognition and function were investigated. CD4 T cells from both HLADRB1* 0401 RA patients and healthy donors recognized citrullinated vimentin. However, T cells derived from RA patients secreted higher levels of cytokines, suggesting previous activation and/or cytokine dysregulation in RA. This study required a development of an assay sensitive enough to allow detection of rare antigen-specific CD4 T cells. Having such a tool, we further applied the same method to functionally examine type-II collagen (CII)-reactive CD4 T cells from peripheral blood and synovial fluid from HLA-DR*04 RA patients. T cells indeed recognized different variants of the immunodominant T cell epitope of CII and displayed epitope spreading throughout the disease. Synovial fluid derived T cells produced higher levels of inflammatory cytokines as compared to blood suggesting local reactivation. Many more RA predisposing genetic variants have been identified outside the HLA-DRB1 locus in recent years. We therefore continued to study the association with autoantibody specificities in two independent cohorts of RA patients. Several genetic variants were found to control autoantibodies formation; some associated with several autoantibodies whereas others exclusively linked with a single fine specificity. In summary, our data suggest that both B and T cells selectively respond to autoantigens in RA and are controlled by HLA and additional RA-predisposing genes. This work emphasizes the importance of multidisciplinary investigation for the understanding of interaction between genes and immunity in order to functionally explain epidemiological findings. We further hope that our findings regarding T and B cell specificities will encourage others to continue in this direction, which may pave the road towards specific therapy in patients following precise gene-immune investigation.
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| 7. |
- Wahlund, Casper J.E., et al.
(författare)
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Sustained and intermittent hypoxia differentially modulate primary monocyte immunothrombotic responses to IL-1β stimulation
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Venous thromboembolism (VTE) is a leading cause of preventable deaths in hospitals, and its incidence is not decreasing despite extensive efforts in clinical and laboratory research. Venous thrombi are primarily formed in the valve pockets of deep veins, where activated monocytes play a crucial role in bridging innate immune activation and hemostatic pathways through the production of inflammatory cytokines, chemokines, and tissue factor (TF) – a principal initiator of coagulation. In the valve pocket inflammation and hypoxia (sustained/intermittent) coexist, however their combined effects on immunothrombotic processes are poorly understood. Inflammation is strongly associated with VTE, while the additional contribution of hypoxia remains largely unexplored. To investigate this, we modelled the intricate conditions of the venous valve pocket using a state-of-the-art hypoxia chamber with software-controlled oxygen cycling. We comprehensively studied the effects of sustained and intermittent hypoxia alone, and in combination with VTE-associated inflammatory stimuli on primary monocytes. TF expression and activity was measured in monocytes subjected to sustained and intermittent hypoxia alone, or in combination with IL-1β. Monocyte responses were further analyzed in detailed by RNA sequencing and validated by ELISA. Stimulation with IL-1β alone promoted both transcription and activity of TF. Interestingly, the stimulatory effect of IL-1β on TF was attenuated by sustained hypoxia, but not by intermittent hypoxia. Our transcriptome analysis further confirmed that sustained hypoxia limited the pro-inflammatory response induced by IL-1β, and triggered a metabolic shift in monocytes. Intermittent hypoxia alone had a modest effect on monocyte transcript. However, in combination with IL-1β intermittent hypoxia significantly altered the expression of 2207 genes and enhanced the IL-1β-stimulatory effects on several chemokine and interleukin genes (e.g., IL-19, IL-24, IL-32, MIF), as well as genes involved in coagulation (thrombomodulin) and fibrinolysis (VEGFA, MMP9, MMP14 and PAI-1). Increased production of CCL2, IL-6 and TNF following stimulation with intermittent hypoxia and IL-1β was confirmed by ELISA. Our findings provide valuable insights into how the different hypoxic profiles shape the immunothrombotic response of monocytes and shed new light on the early events in the pathogenesis of venous thrombosis.
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