| 1. |
- Da Costa, Mariana Gaya, et al.
(författare)
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Age and sex-associated changes of complement activity and complement levels in a healthy caucasian population
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9:NOV
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The complement system is essential for an adequate immune response. Much attention has been given to the role of complement in disease. However, to better understand complement in pathology, it is crucial to first analyze this system under different physiological conditions. The aim of the present study was therefore to investigate the inter-individual variation in complement activity and the influences of age and sex. Methods: Complement levels and functional activity were determined in 120 healthy volunteers, 60 women, 60 men, age range 20-69 year. Serum functional activity of the classical pathway (CP), lectin pathway activated by mannan (MBL-LP) and alternative pathway (AP) was measured in sera, using deposition of C5b-9 as readout. In addition, levels of C1q, MBL, MASP-1, MASP-2, ficolin-2, ficolin-3, C2, C4, C3, C5, C6, C7, C8, C9, factor B, factor D, properdin, C1-inhibitor and C4b-binding protein, were determined. Age- and sex-related differences were evaluated. Results: Significantly lower AP activity was found in females compared to males. Further analysis of the AP revealed lower C3 and properdin levels in females, while factor D concentrations were higher. MBL-LP activity was not influenced by sex, but MBL and ficolin-3 levels were significantly lower in females compared to males. There were no significant differences in CP activity or CP components between females and males, nevertheless females had significantly lower levels of the terminal components. The CP and AP activity was significantly higher in the elderly, in contrast to MBL-LP activity. Moreover, C1-inhibitor, C5, C8, and C9 increased with age in contrast to a decrease of factor D and C3 levels. In-depth analysis of the functional activity assays revealed that MBL-LP activity was predominantly dependent on MBL and MASP-2 concentration, whereas CP activity relied on C2, C1-inhibitor and C5 levels. AP activity was strongly and directly associated with levels of C3, factor B and C5. Conclusion: This study demonstrated significant sex and age-related differences in complement levels and functionality in the healthy population. Therefore, age and sex analysis should be taken into consideration when discussing complement-related pathologies and subsequent complement-targeted therapies.
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| 2. |
- van Delft, Myrthe A. M., et al.
(författare)
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The anti-carbamylated protein antibody response is of overall low avidity despite extensive isotype switching
- 2018
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 57:9, s. 1583-1591
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To better understand the contribution of autoantibodies in RA and the biology of their responses, we evaluated the avidity of the anti-carbamylated protein (anti-CarP) antibody response.Methods: The avidity of anti-CarP antibody, ACPA and anti-tetanus toxoid IgG were determined using elution assays. Anti-CarP IgG avidity was measured in sera of 107 RA patients, 15 paired SF and serum samples and 8 serially sampled sera before and after disease onset.Results: The avidity of anti-CarP IgG is low compared with the avidity of anti-tetanus toxoid IgG present in the same sera. Likewise, although less pronounced, anti-CarP also displayed a lower avidity as compared with the avidity of ACPA IgG. No difference in anti-CarP IgG avidity is observed between ACPA positive or ACPA negative patients. Anti-CarP IgG avidity is higher in anti-CarP IgM-negative compared with IgM-positive individuals. Furthermore, the anti-CarP avidity in serum is higher than in SF. Using samples of individuals that over time developed RA we observed no anti-CarP avidity maturation in the years before disease onset. In contrast to ACPA avidity, the anti-CarP avidity is not associated with severity of joint destruction.Conclusion: The anti-CarP response is of overall low avidity, even lower than the ACPA IgG avidity, and does not show apparent avidity maturation before or around disease onset. Overall, isotype switch and avidity maturation seem to be uncoupled as isotype switch occurs without avidity maturation, pointing towards a commonality in the regulation of both autoantibody responses as opposed to the pathways governing recall responses.
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| 3. |
- van Schaarenburg, Rosanne A., et al.
(författare)
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Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency
- 2015
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 62, s. 39-44
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease.Methods: We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published.Results: Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages.Conclusion: Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach.
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| 4. |
- Verheul, Marije K., et al.
(författare)
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Triple positivity for anti–citrullinated protein autoantibodies, rheumatoid factor, and anti–carbamylated protein antibodies conferring high specificity for rheumatoid arthritis : implications for very early identification of at‐risk individuals
- 2018
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Ingår i: Arthritis & Rheumatology. - Hoboken : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 70:11, s. 1721-1731
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In rheumatoid arthritis(RA), the autoantibodies anti-citrullinated protein antibodies(ACPA) and rheumatoid factor(RF) are commonly used to aid RA diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPA and RF alone. Also, anti-carbamylated protein(anti-CarP) antibodies have diagnostic and prognostic value as the presence of anti-CarP antibodies associates with joint damage in RA patients and with future RA development in arthralgia patients. Therefore, we aimed to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA.METHODS: A literature search resulted in twelve studies, consisting of RA patients, pre-RA individuals, disease controls, healthy first-degree relatives of RA patients or healthy controls, in which data on RF, ACPA and anti-CarP antibody-status was available. Random effects meta-analyses were carried out for several antibody combinations.RESULTS: The individual antibodies are highly prevalent in RA(34%-80%) compared to the control groups, but are also present in non-RA controls(0%-23%). To classify most people correctly as RA or non-RA, the combination of ACPA and/or RF often performs well(specificity:65-100, sensitivity:59-88). However, triple positivity for ACPA, RF and anti-CarP antibodies results in a higher specificity(98-100) (accompanied by a lower sensitivity(11-39)).CONCLUSIONS: As the rheumatology field is moving towards very early identification of RA and possible screening for individuals at maximum risk in populations with a low pre-test probability, triple positivity provides interesting information on individuals at risk to develop RA.
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| 5. |
- Ziegelasch, Michael, et al.
(författare)
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Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus : results from two well-defined European cohorts.
- 2016
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Ingår i: Arthritis Research & Therapy. - : BioMed Central. - 1478-6354 .- 1478-6362. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data.METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available.RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients.CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.
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| 6. |
- Boeters, Debbie M., et al.
(författare)
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The prevalence of ACPA is lower in rheumatoid arthritis patients with an older age of onset but the composition of the ACPA response appears identical
- 2017
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 19:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody-positive and one autoantibody-negative. Existing data on the relation between age of onset and prevalence of autoantibodies were conflicting. Therefore this multicohort study assessed the age of onset in relation to the presence of autoantibodies. The association with characteristics of the anti-citrullinated protein antibodies (ACPA) response was also explored. Methods: The 1987 criteria-positive RA patients included in the Leiden EAC, BARFOT, ESPOIR, Umeå and Lund cohorts (n = 3321) were studied at presentation for age of onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies. Logistic regression analyses were performed; effect sizes were summarized in inverse-weighted meta-analyses. Within ACPA-positive RA, ACPA level was studied in all cohorts; ACPA isotypes, ACPA fine specificity and ACPA avidity index and clinical characteristics were studied in the Leiden EAC. Results: From the age of 50 onward, the proportion of ACPA-negative RA patients increased with age in the five cohorts. Similar observations were made for RF and anti-CarP. The composition of the ACPA response did not change with increasing age of onset with respect to titer, isotype distribution, fine specificity and avidity index. With increasing age of onset, RA patients smoked less often, had higher acute phase reactants and more often had a sub(acute) symptom onset. Conclusions: Data of five cohorts revealed that with older age of onset ACPA-negative RA is more frequent than ACPA-positive RA, while characteristics of ACPA-positive RA as judged by the composition of the ACPA response appeared not age dependent. Further biologic studies are needed to characterize the pathogenesis of ACPA-negative polyarthritis at older age and to promote personalized treatment decisions in ACPA-negative patients in daily practice.
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| 7. |
- Brink, Mikael, et al.
(författare)
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Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage
- 2015
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. Methods: A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). Results: The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P < 0.001) and also increased significantly after disease onset (P < 0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P < 0.05, all). Conclusions: The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.
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| 8. |
- 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. - 1478-6354 .- 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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| 9. |
- Foltyn Zadura, Anna, et al.
(författare)
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Factor H autoantibodies and deletion of Complement Factor H-Related protein-1 in rheumatic diseases in comparison to atypical hemolytic uremic syndrome.
- 2012
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Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: INTRODUCTION: Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS). Autoantibodies to complement inhibitor factor H (FH), particularly in association with deletions of the gene coding for FH-related protein 1 (CFHR1), are associated with aHUS. METHODS: Autoantibodies against FH, factor I (FI) and C4b-binding protein (C4BP) were measured by ELISA, while CFHR1 homozygous deletion was determined with Western blotting of sera. Epitopes for FH autoantibodies were mapped using recombinant fragments of FH. RESULTS: FH autoantibodies were detected in SLE (6.7%, n = 60, RA patients (16.5%, n = 97 in the Swedish cohort and 9.2%, n = 217 in the Dutch cohort) and thrombosis patients positive for the lupus anticoagulants (LA+) test (9.4%, n = 64) compared with aHUS patients (11.7%, n = 103). In the control groups (n = 354), an average of 4% of individuals were positive for FH autoantibodies. The frequencies observed in both RA cohorts and LA+ patients were statistically significantly higher than in controls. We also found that an average of 15.2% of the FH-autoantibody positive individuals in all studied disease groups had homozygous deficiency of CFHR1 compared with 3.8% of the FH autoantibody negative patients. The levels of FH autoantibodies varied in individual patients over time. FH autoantibodies found in LA+, SLE and RA were directed against several epitopes across FH in contrast to those found in aHUS, which bound mainly to the C-terminus. Autoantibodies against FI and C4BP were detected in some patients and controls but they were not associated with any of the diseases analyzed in this study. CONCLUSIONS: Autoantibodies against FH are not specific for aHUS but are present at a significant frequency in rheumatic diseases where they could be involved in pathophysiological mechanisms.
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| 10. |
- Nilsson, Sara C., et al.
(författare)
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A mutation in factor I that is strongly associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation
- 2007
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Ingår i: Molecular Immunology. - 0161-5890 .- 1872-9142. ; 44:1-3, s. 221-221
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Factor I (FI) is the major complement inhibitor that degrades C3b and C4b in the presence of cofactors C4b binding protein (C4BP), factor H (FH), membrane cofactor protein (MCP) or complement receptor 1 (CR1). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study we report three unrelated patients with an identical heterozygous mutation, G261D, in FI heavy chain who developed severe aHUS at different time points in their lives. Two patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and control serum samples we did not observe major differences in complement hemolytic activity, FI plasma levels or the capability to degrade C4b or C3b. A recombinant protein was produced in order to analyze the functional consequences of the mutation. Mutant FI had a slightly different migration pattern during electrophoresis under reducing conditions. An alteration due to alternative splicing or glycosylation was ruled out, thus the altered migration may be due to proximity of the mutation to a cysteine residue. The recombinant mutant FI degraded C3b and C4b in a manner comparable to wild type protein. In conclusion, despite the strong association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation.
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