| 1. |
- Retamozo, S., et al.
(författare)
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Influence of the age at diagnosis in the disease expression of primary Sjogren's syndrome : Analysis of 12,753 patients from the Sjogren Big Data Consortium
- 2021
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Ingår i: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 39:6, s. S166-S174
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjogren's syndrome (pSS).Methods. By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression.Results. There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R-2 0.87) and the frequency of abnormal oral tests (adjusted R-2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase).Conclusion. The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.
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| 2. |
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| 3. |
- Wiley, MM, et al.
(författare)
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FUNCTIONAL EVALUATION OF THE SJOGREN'S SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOSUS DDX6-CXCR5 RISK INTERVAL
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 89-90
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Sjögren’s Syndrome (SS) and Systemic Lupus Erythematosus (SLE) are distinct chronic, complex autoimmune diseases with shared characteristics such as autoantibodies, heightened interferons, and polyarthritis. SS and SLE genome-wide association studies (GWAS) report strong associations with theDDX6-CXCR5risk interval. DDX6 suppresses interferon stimulated gene expression and CXCR5 regulates T cell functions implicated in autoimmunity.Objectives:To identify functional variants that impact regulation in theDDX6-CXCR5interval.Methods:Fine-mapping was done using ImmunoChip data from 3785 SLE, 1916 SS cases and 6893 population controls of European ancestry that were imputed and tested for SNP-trait association. Bayesian statistics assigned posterior probabilities to SNPs and defined a credible set of risk variants. Bioinformatic analyses further prioritized variants with predicted functionality. Electrophoretic mobility shift assays (EMSAs) and luciferase expression were used to validate predicted SNPs in EBV transformed B (EBV B) cells.Results:While some differences were observed, the overall SS and SLE association signals were similar. SNP-SS rs9736016 nearCXCR5and SNP-SLE rs76409436 nearDDX6were the most significant but did not show evidence of functionality. Bayesian statistics defined credible sets of variants in strong D’ in common between both SS and SLE. Bioinformatics analyses (Haploreg, RegulomeDB, ENCODE data, etc) further refined the credible set and identified 5 common SNPs with strong evidence of functionality in immune cell types: rs4938572, rs4936443, rs57494551, rs7117261 and rs4938573. EMSAs showed a significant increase in protein binding to the risk allele of rs57494551 (p=0.0001), rs7117261 (p=0.0001) and rs4938573 (p=0.0003), but not the others, using nuclear lysates from EBV B cells. Luciferase vectors with a minimal promoter or no promoter were used to test for enhancer or promoter activity, respectively. To this end, the rs57494551 risk allele exhibited a significant increase in enhancer activity (p=0.0001). In contrast, the rs7117261 risk allele decreased enhancer activity (p=0.018). The rs4938573 risk allele decreased enhancer (p=0.043) and promoter (p=0.024) activity. While rs7117261 or rs4938573 were not reported in eQTL databases, GTex data reported rs57494551 as an eQTL that altersDDX6expression in whole blood (p=1.8E-7). Additionally, these functional SNPs have been associated with looping events to several proximal promoters in nearby genes in immune cells.Conclusion:SS and SLE have similar genomic architecture across theDDX6-CXCR5risk interval. Multiple variants in the credible set exhibited allele specific changes in protein binding, as well as modified enhancer activity, promoter activity or both. Ongoing studies will use Cas9 in EBV B cells to determine which other loci are within the local regulatory network.Disclosure of Interests:Mandi M Wiley: None declared, Bhuwan Khatri: None declared, Kandice L Tessneer: None declared, Michelle L Joachims: None declared, Anna M Stolarczyk: None declared, Astrid Rasmussen Speakers bureau: Novartis, ThermoFischer, Simon J. Bowman Consultant of: Astrazeneca, Biogen, BMS, Celgene, Medimmune, MTPharma, Novartis, Ono, UCB, xtlbio, Glapagos, Speakers bureau: Novartis, Lida Radfar: None declared, Roald Omdal: None declared, Marie Wahren-Herlenius: None declared, Blake M Warner: None declared, Torsten Witte: None declared, Roland Jonsson: None declared, Maureen Rischmueller: None declared, Patrick M Gaffney: None declared, Judith A. James Grant/research support from: Progentec Diagnostics, Inc, Consultant of: Abbvie, Novartis, Jannsen, Lars Ronnblom Grant/research support from: AZ, Speakers bureau: AZ, R Hal Scofield Grant/research support from: Pfizer, Xavier Mariette: None declared, Wan-fai Ng: None declared, Kathy L Sivils: None declared, Gunnel Nordmark: None declared, Betty Tsao: None declared, Christopher Lessard: None declared
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| 4. |
- Isaguliants, M, et al.
(författare)
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Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells
- 2021
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Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic DNA-vaccination against drug-resistant HIV-1 may hinder emergence and spread of drug-resistant HIV-1, allowing for longer successful antiretroviral treatment (ART) up-to relief of ART. We designed DNA-vaccines against drug-resistant HIV-1 based on consensus clade A integrase (IN) resistant to raltegravir: IN_in_r1 (L74M/E92Q/V151I/N155H/G163R) or IN_in_r2 (E138K/G140S/Q148K) carrying D64V abrogating IN activity. INs, overexpressed in mammalian cells from synthetic genes, were assessed for stability, route of proteolytic degradation, and ability to induce oxidative stress. Both were found safe in immunotoxicity tests in mice, with no inherent carcinogenicity: their expression did not enhance tumorigenic or metastatic potential of adenocarcinoma 4T1 cells. DNA-immunization of mice with INs induced potent multicytokine T-cell response mainly against aa 209–239, and moderate IgG response cross-recognizing diverse IN variants. DNA-immunization with IN_in_r1 protected 60% of mice from challenge with 4Tlluc2 cells expressing non-mutated IN, while DNA-immunization with IN_in_r2 protected only 20% of mice, although tumor cells expressed IN matching the immunogen. Tumor size inversely correlated with IN-specific IFN-γ/IL-2 T-cell response. IN-expressing tumors displayed compromised metastatic activity restricted to lungs with reduced metastases size. Protective potential of IN immunogens relied on their immunogenicity for CD8+ T-cells, dependent on proteasomal processing and low level of oxidative stress.
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| 5. |
- Joachim, A, et al.
(författare)
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Frequent and Durable Anti-HIV Envelope VIV2 IgG Responses Induced by HIV-1 DNA Priming and HIV-MVA Boosting in Healthy Tanzanian Volunteers
- 2020
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Ingår i: Vaccines. - : MDPI AG. - 2076-393X. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated antibody responses to the human immunodeficiency virus (HIV) envelope variable regions 1 and 2 (V1V2) in 29 vaccinees who had received three HIV-1 DNA immunizations and two HIV-modified vaccinia virus Ankara (MVA) boosts in the phase I/II HIVIS03 vaccine trial. Twenty vaccinees received a third HIV-MVA boost after three years in the HIVIS06 trial. IgG and IgG antibody subclasses to gp70V1V2 proteins of HIV-1 A244, CN54, Consensus C, and Case A2 were analysed using an enzyme-linked immunosorbent assay (ELISA). Cyclic V2 peptides of A244, Consensus C, and MN were used in a surface plasmon resonance (SPR) assay. Four weeks after the second HIV-MVA, anti-V1V2 IgG antibodies to A244 were detected in 97% of HIVIS03 vaccinees, in 75% three years later, and in 95% after the third HIV-MVA. Anti-CN54 V1V2 IgG was detectable in 48% four weeks after the second HIV-MVA. The SPR data supported the findings. The IgG response was predominantly IgG1. Four weeks after the second HIV-MVA, 85% of vaccinees had IgG1 antibodies to V1V2 A244, which persisted in 25% for three-years. IgG3 and IgG4 antibodies to V1V2 A244 were rare. In conclusion, the HIV-DNA/MVA vaccine regimen induced durable V1V2 IgG antibody responses in a high proportion of vaccinees.
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| 7. |
- Khatri, B, et al.
(författare)
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GENOME-WIDE ASSOCIATION STUDY OF SJOGREN'S SYNDROME IDENTIFIES TEN NEW RISK LOCI
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 30-31
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Sjögren’s syndrome (SS) is a complex autoimmune disease with exocrine gland dysfunction leading to substantial morbidity. There are 10 published genetic susceptibility loci.Objectives:Our genome-wide association study (GWAS) aimed to identify additional risk loci of genome-wide significance (GWS; p<5E-08) in European-derived primary SS.Methods:A total of 3232 cases and 17481 controls genotyped on GWAS arrays and 619 cases and 6171 controls genotyped on ImmunoChip (IC) arrays were imputed after quality control. Logistic regression was calculated adjusting for ancestry using the first 4 principal components to identify SS-associated SNPs. GWAS and IC results were meta-analyzed using weighted Z-scores. Bayesian statistics were used to assign posterior probabilities and define credible SNP sets for each locus. Bioinformatic analyses were used to predict functionality.Results:Seven novel loci exceeded GWS in the GWAS analysis:NAB1,MIR146A-PTTG1,XKR6,MAPT-CRHR1,RPTOR-CHMP6-BAIAP2,TYK2andSYNGR1. Meta-analysis with IC data identified three more novel loci exceeding GWS:CD247,PRDM1-ATG5andTNFAIP3. Several additional loci with suggestive association (p<1E-05) were also identified:ADAMTSL2,CGNL1andPHRF1.Several identified loci have reported functional implications in immune regulation and autoimmune disease. In lupus, rs2431697 correlated with rs2431098, which was shown to alterMIR146Aexpression, resulting in type I interferon pathway imbalance. Similarly,TYK2risk association reportedly drives interferon, IL10 and RET signaling pathways.PRDM1encodes Blimp-1, a master regulator of immune cell differentiation.CD247encodes the zeta subunit of the T cell receptor complex.XKR6is implicated in apoptotic cell ingestion.ATG5is also involved in apoptosis, as well as autophagy and antigen presentation.Additional bioinformatics analyses (Haploreg, Regulome DB, ENCODE, etc.) revealed immune-relevant functional implications for each risk locus. The SS-associated credible set included variants downstream ofTNFAIP3in a region reported to abolish looping between an enhancer and theTNFAIP3promoter in lupus and a coding variant that has been shown to alter NF-kB activity and neutrophil extra-cellular traps. The rs2293765 in the 5’ UTR ofNAB1showed evidence of enhancer/promoter activities. The rs2069235 in theSYNGR1locus showed enhancer and transcription start site activities in B and T cells. The rs7210219 in theMAPT-CRHR1locus showed enhancer/promotor activities in various tissues.Conclusion:We have identified ten novel genetic susceptibility loci associated with SS pathology. Our finding increases the current number of GWS regions in SS patients of European origin, from 10 to 20. Future work is needed to identify and characterize the functional variants in each region.Disclosure of Interests:Bhuwan Khatri: None declared, Tove Ragna Reksten: None declared, Kandice L Tessneer: None declared, Astrid Rasmussen Speakers bureau: Novartis, ThermoFischer, R Hal Scofield Grant/research support from: Pfizer, Simon J. Bowman Consultant of: Astrazeneca, Biogen, BMS, Celgene, Medimmune, MTPharma, Novartis, Ono, UCB, xtlbio, Glapagos, Speakers bureau: Novartis, Joel Guthridge Grant/research support from: Xencor, Bristol Myers Squibb, DXterity, Judith A. James Grant/research support from: Progentec Diagnostics, Inc, Consultant of: Abbvie, Novartis, Jannsen, Lars Ronnblom Grant/research support from: AZ, Speakers bureau: AZ, Blake M Warner: None declared, Xavier Mariette: None declared, Roald Omdal: None declared, Javier Martin Ibanez: None declared, Maria Teruel: None declared, Janicke Liaaen Jensen: None declared, Lara A Aqrawi: None declared, Øyvind Palm: None declared, Marie Wahren-Herlenius: None declared, Torsten Witte: None declared, Roland Jonsson: None declared, Maureen Rischmueller: None declared, A Darise Farris Speakers bureau: Biogen, Marta Alarcon-Riquelme: None declared, Wan-fai Ng: None declared, Kathy L Sivils: None declared, Gunnel Nordmark: None declared, Christopher Lessard: None declared
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| 8. |
- Msafiri, F, et al.
(författare)
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Frequent Anti-V1V2 Responses Induced by HIV-DNA Followed by HIV-MVA with or without CN54rgp140/GLA-AF in Healthy African Volunteers
- 2020
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Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Antibody responses that correlated with reduced risk of HIV acquisition in the RV144 efficacy trial were assessed in healthy African volunteers who had been primed three times with HIV-DNA (subtype A, B, C) and then randomized into two groups; group 1 was boosted twice with HIV-MVA (CRF01_AE) and group 2 with the same HIV-MVA coadministered with subtype C envelope (Env) protein (CN54rgp140/GLA-AF). The fine specificity of plasma Env-specific antibody responses was mapped after the final vaccination using linear peptide microarray technology. Binding IgG antibodies to the V1V2 loop in CRF01_AE and subtype C Env and Env-specific IgA antibodies were determined using enzyme-linked immunosorbent assay. Functional antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody responses were measured using luciferase assay. Mapping of linear epitopes within HIV-1 Env demonstrated strong targeting of the V1V2, V3, and the immunodominant region in gp41 in both groups, with additional recognition of two epitopes located in the C2 and C4 regions in group 2. A high frequency of V1V2-specific binding IgG antibody responses was detected to CRF01_AE (77%) and subtype C antigens (65%). In conclusion, coadministration of CN54rgp140/GLA-AF with HIV-MVA did not increase the frequency, breadth, or magnitude of anti-V1V2 responses or ADCC-mediating antibodies induced by boosting with HIV-MVA alone.
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| 9. |
- Niewold, T, et al.
(författare)
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SKIN PROTEOME INVESTIGATION IN CUTANEOUS LUPUS ERYTHEMATOSUS (CLE) REVEALS NOVEL UNIQUE DISEASE PATHWAYS
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 335-335
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Cutaneous lupus erythematosus (CLE) is an autoimmune disease. It can be limited to the skin or be one of manifestations of systemic LE (SLE). The typical histopathologic pattern in CLE/SLE is interface dermatitis, which can also be observed in dermatomyositis (DM). While LE may affect any organ system, DM most commonly affect muscles and skin.Objectives:The aim of this study was to investigate the whole proteome of skin inflammatory foci in the cohort of CLE and DM patients in a comparatory, hypothesis-free manner and identify disease-unique molecular mechanisms.Methods:CLE (n=6), DM (n=5) patients and controls (n=6) were recruited at diagnosis or disease exacerbation. Skin biopsies were acquired, examined by a pathologist and selected inflammatory foci were laser micro-dissected. The total protein content was analyzed by mass-spectrometry, further analysis was performed by string-db.org platform. Certain proteomic findings were confirmed by immunohistochemistry (IHC).Results:CLE infiltrates were more protein rich in comparison to DM lesions. There ratio of 5x upregulated proteins in LE/DM was 60, while ratio for DM/LE was 13. Our results confirmed high abundance of (IFN)-regulated proteins both in CLE and DM, including: IFIT, MX and OAS families. Proteins expressed differentially in CLE covered complement proteins (C1b), including membrane attack complex (MAC) (C5, C6, C7, C8A and B) and complement regulators (CFHR1, CFHR2, CFHR5), as well as regulators of coagulation: thrombospondin 2 (THBS2), thrombin (F2), fibrinogen (F12) and annexin A3 (ANXA3). Importantly, we identified interleukin (IL) -16 as the only detectable and highly abundant cytokine in the CLE lesions and confirmed this finding by IHC.Conclusion:ConclusionsOur data confirm evidence on IFN-regulated processes in CLE/SLE. Importantly, we identified IL-16 as a novel cytokine most strongly upregulated locally in the skin lesions. Moreover, we identified activation of MAC, complement regulating proteins as well as involvement of coagulation/fibrinolysis system. The study brings information on novel pathways involved in the inflammatory foci of the skin lesions in CLE patients. Our findings are of interest in further search of new therapeutic targets.Disclosure of Interests: :Timothy Niewold: None declared, Karin Popovic-Silwerfeldt: None declared, Julia Lehman: None declared, Alexander Meves: None declared, Cristine Charlesworth: None declared, Benjamin Madden: None declared, Aliisa Hayry: None declared, Aleksandra Antovic: None declared, Ingrid E. Lundberg Grant/research support from: Bristol Meyer Squibb, Corbus Pharmaceuticals, Inc and Astra Zeneca, Marie Wahren-Herlenius: None declared, Elisabet Svenungsson: None declared, Vilija Oke: None declared
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| 10. |
- Thorlacius, Guðný Ella, et al.
(författare)
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Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome
- 2021
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 60:2, s. 837-848
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesClinical presentation of primary Sjögren’s syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints.MethodsWe performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls.ResultsWe found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10−62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS.ConclusionTwo subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.
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