| 1. |
- Boman, Antonia, et al.
(författare)
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Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis : a prospective longitudinal inception cohort study
- 2019
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort.Methods: The ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment.Results: Frequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were significantly associated with number of ACPA reactivities. The ACPA reactivities modified differently the development of DAS28 over 24 months (identified using trajectories). Anti-Filaggrin307-324, anti-hnRNP (Peptide)-Z1 and anti-F4-CIT-R antibodies anticipated lower DAS28 values (p<0.01–0.05), while positivity for anti-Fibrinogen(Fib)β62-78(74), and anti-Fibα563-583 predicted higher DAS28 (p<0.01 both). Interaction between anti-Fibß36-52, anti-Pept-5 and anti-Bla-26 antibodies, respectively, and DAS28 during 24 months decreased significantly the DAS28 values (p<0.01–0.05). Corticosteroids and biologicals were related to DAS28-area under the curve and Larsen score 24 months. Anti-vimentin2-17 antibodies remained significantly associated with Larsen score at baseline and 24 months, respectively, and radiological progression, besides biologicals at 24 months adjusted for sex and age.Conclusions: Several ACPA reactivities modified significantly the DAS28 development during the first 24 months and were significantly associated with Larsen score at baseline, 24 months and radiological progression.
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| 2. |
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| 3. |
- Brink, Mikael, et al.
(författare)
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Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious. Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays. Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected >= 15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [a-enolase (CEP-1/Eno(5-21))], fibrinogen (Fib)beta(36-52), Fiba(580-600), filaggrin (CCP-1/Fil(307-324)) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development. Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.
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| 5. |
- Circiumaru, Alexandra, et al.
(författare)
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Anti-Citrullinated Protein Antibody Reactivity towards Neutrophil-Derived Antigens : Clonal Diversity and Inter-Individual Variation
- 2023
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Why the adaptive immune system turns against citrullinated antigens in rheumatoid arthritis (RA) and whether anti-citrullinated protein antibodies (ACPAs) contribute to pathogenesis are questions that have triggered intense research, but still are not fully answered. Neutrophils may be crucial in this context, both as sources of citrullinated antigens and also as targets of ACPAs. To better understand how ACPAs and neutrophils contribute to RA, we studied the reactivity of a broad spectrum of RA patient-derived ACPA clones to activated or resting neutrophils, and we also compared neutrophil binding using polyclonal ACPAs from different patients.Methods: Neutrophils were activated by Ca2+ ionophore, PMA, nigericin, zymosan or IL-8, and ACPA binding was studied using flow cytometry and confocal microscopy. The roles of PAD2 and PAD4 were studied using PAD-deficient mice or the PAD4 inhibitor BMS-P5.Results: ACPAs broadly targeted NET-like structures, but did not bind to intact cells or influence NETosis. We observed high clonal diversity in ACPA binding to neutrophil-derived antigens. PAD2 was dispensable, but most ACPA clones required PAD4 for neutrophil binding. Using ACPA preparations from different patients, we observed high patient-to-patient variability in targeting neutrophil-derived antigens and similarly in another cellular effect of ACPAs, the stimulation of osteoclast differentiation.Conclusions: Neutrophils can be important sources of citrullinated antigens under conditions that lead to PAD4 activation, NETosis and the extrusion of intracellular material. A substantial clonal diversity in targeting neutrophils and a high variability among individuals in neutrophil binding and osteoclast stimulation suggest that ACPAs may influence RA-related symptoms with high patient-to-patient variability.
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| 6. |
- Eloranta, Maija-Leena, et al.
(författare)
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Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:8, s. 2418-2427
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Interferon-alpha (IFNalpha) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFNalpha production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated. METHODS: Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFNalpha production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E2 (PGE2), reactive oxygen species (ROS), or the cytokines IFNalpha2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor alpha (TNFalpha) were explored. RESULTS: Monocytes inhibited IFNalpha production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFNalpha production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFNalpha2b/GM-CSF increased their IFNalpha production. RNA-containing ICs caused production of ROS, PGE2, and TNFalpha, especially in monocytes. These mediators and IL-10 suppressed IFNalpha production in PBMC cultures, with ROS and PGE2 also inhibiting IFNalpha production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFNalpha2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase. CONCLUSION: IFNalpha production induced by RNA-containing ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro- and antiinflammatory molecules. This should be considered when designing and applying new therapies.
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| 7. |
- Grönwall, Caroline, et al.
(författare)
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A Comprehensive Evaluation of the Relationship Between Different IgG and IgA Anti-Modified Protein Autoantibodies in Rheumatoid Arthritis
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), -acetylated (KAc), and malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. In this comprehensive study, we analyze 30 different IgG and IgA AMPA reactivities to Cit, Carb, KAc, and MAA antigens detected by ELISA and autoantigen arrays in N=1985 newly diagnosed RA patients. Association with patient characteristics such as smoking and disease activity were explored. Carb and KAc reactivities by different assays were primarily seen in patients also positive for anti-citrulline reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG reactivity to acetylation was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking status. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles. Our serology results were complemented by screening of monoclonal antibodies derived from single B cells from RA patients for the same antigens as the RA cohort. Certain CCP2+ clones had Carb or Carb+KAc+ multireactivity, while such reactivities were not found in CCP2- clones. We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Carb and KAc could be considered reactivities within the "Cit-umbrella" similar to ACPA fine-specificities, while MAA reactivity is distinctly different.
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| 8. |
- Hensvold, Aase, et al.
(författare)
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The human bone marrow plasma cell compartment in rheumatoid arthritis-Clonal relationships and anti-citrulline autoantibody producing cells
- 2023
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 136
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Tidskriftsartikel (refereegranskat)abstract
- A majority of circulating IgG is produced by plasma cells residing in the bone marrow (BM). Long-lived BM plasma cells constitute our humoral immune memory and are essential for infection-specific immunity. They may also provide a reservoir of potentially pathogenic autoantibodies, including rheumatoid arthritis (RA)-associated anti-citrullinated protein autoantibodies (ACPA). Here we investigated paired human BM plasma cell and peripheral blood (PB) B-cell repertoires in seropositive RA, four ACPA+ RA patients and one ACPA- using two different single-cell approaches, flow cytometry sorting, and transcriptomics, followed by recombinant antibody generation. Immunoglobulin (Ig) analysis of >900 paired heavy-light chains from BM plasma cells identified by either surface CD138 expression or transcriptome profiles (including gene expression of MZB1, JCHAIN and XBP1) demonstrated differences in IgG/A repertoires and N-linked glycosylation between patients. For three patients, we identified clonotypes shared between BM plasma cells and PB memory B cells. Notably, four individuals displayed plasma cells with identical heavy chains but different light chains, which may indicate receptor revision or clonal convergence. ACPA-producing BM plasma cells were identified in two ACPA+ patients. Three of 44 recombinantly expressed monoclonal antibodies from ACPA+ RA BM plasma cells were CCP2+, specifically binding to citrullinated peptides. Out of these, two clones reacted with citrullinated histone-4 and activated neutrophils. In conclusion, single-cell investigation of B-cell repertoires in RA bone marrow provided new understanding of human plasma cells clonal relationships and demonstrated pathogenically relevant disease-associated autoantibody expression in long-lived plasma cells.
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| 9. |
- Kokkonen, Heidi, et al.
(författare)
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Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis
- 2015
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Ingår i: Arthritis Research & Therapy. - : BioMed Central. - 1478-6362 .- 1478-6354. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: It has previously been shown that an increased number of antibodies against citrullinated peptides/proteins (ACPA) predate the onset of rheumatoid arthritis (RA). Over time antibody positivity expands, involving more specific responses when approaching the onset of symptoms. We investigated the impact of human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking on the development of ACPA, as well as in combination with ACPA during the state of quiescent autoimmunity (before the onset of symptoms), on the development of RA. Methods: Blood samples donated to the Medical Biobank of Northern Sweden from individuals prior to the onset of symptoms of RA (n = 370) and after onset (n = 203) and from population-based controls (n = 585) were used. Antibodies against 10 citrullinated peptides, fibrinogen (Fib alpha 561-583, alpha 580-600, beta 62-81a, beta 62-81b, beta 36-52), vimentin (Vim2-17, 60-75), filaggrin (CCP-1/Fil307-324),alpha-enolase (CEP-1/Eno5-21), collagen type II (citC1359-369), and anti-cyclic citrullinated peptide (CCP) 2 antibodies were analysed. Results: HLA-SE-positive individuals were more frequently positive for ACPA compared with HLA-SE-negative individuals prior to the onset of symptoms of RA, particularly for antibodies against CEP-1 and Fib beta 62-81a (72). Smoking was associated with antibodies against Vim2-17 and citC1359-369. HLA-SE and smoking showed increasing association to the presence of the antibodies closer to disease onset. The highest odds ratio (OR) for development of RA was for the combination of HLA-SE alleles and ACPA positivity, especially for antibodies against Fib beta 62-81b, CCP-1/Fil307-324, and Fib beta 36-52. A gene-environment additive interaction between smoking and HLA-SE alleles for the risk of disease development was found, with the highest OR for individuals positive for antibodies against Fib beta 36-52, CEP-1, and Fib alpha 580-600. Conclusions: The relationships between antibodies against the different ACPA specificities, HLA-SE, and smoking showed a variable pattern in individuals prior to the onset of RA. The combination of smoking and HLA-SE alleles was significantly associated with the development of some of the antibody specificities closer to onset of symptoms, and these associations remained significant at diagnosis. An additive gene-environment interaction was found for several of the antibodies for the development of RA.
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