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- Brauner, Susanna, et al.
(author)
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H1N1 vaccination in Sjogren's syndrome triggers polyclonal B cell activation and promotes autoantibody production
- 2017
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76:10, s. 1755-1763
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Journal article (peer-reviewed)abstract
- ObjectivesVaccination of patients with rheumatic disease has been reported to result in lower antibody titres than in healthy individuals. However, studies primarily include patients on immunosuppressive therapy. Here, we investigated the immune response of treatment-naive patients diagnosed with primary Sjogren's syndrome (pSS) to an H1N1 influenza vaccine.Methods Patients with Sjogren's syndrome without immunomodulatory treatment and age-matched and gender-matched healthy controls were immunised with an H1N1 influenza vaccine and monitored for serological and cellular immune responses. Clinical symptoms were monitored with a standardised form. IgG class switch and plasma cell differentiation were induced in vitro in purified naive B cells of untreated and hydroxychloroquine-treated patients and healthy controls. Gene expression was assessed by NanoString technology.ResultsSurprisingly, treatment-naive patients with Sjogren's syndrome developed higher H1N1 IgG titres of greater avidity than healthy controls on vaccination. Notably, off-target B cells were also triggered resulting in increased anti-EBV and autoantibody titres. Endosomal toll-like receptor activation of naive B cells in vitro revealed a greater propensity of patient-derived cells to differentiate into plasmablasts and higher production of class switched IgG. The amplified plasma cell differentiation and class switch could be induced in cells from healthy donors by preincubation with type 1 interferon, but was abolished in hydroxychloroquine-treated patients and after in vitro exposure of naive B cells to chloroquine.ConclusionsThis comprehensive analysis of the immune response in autoimmune patients to exogenous stimulation identifies a mechanistic basis for the B cell hyperactivity in Sjogren's syndrome, and suggests that caution is warranted when considering vaccination in non-treated autoimmune patients.
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| 2. |
- Meisgen, Sabrina
(author)
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Risk factors for autoimmune-mediated congenital heart block
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Placental transfer of maternal Ro/SSA and La/SSB autoantibodies during pregnancy is associated with conduction disturbances and inflammation in the developing fetal heart, termed autoimmune-mediated congenital heart block (CHB). Maternal Ro/SSA and La/SSB autoantibodies are the main risk factors associated with the fetal cardiac manifestations to date, however, the low recurrence rate despite persisting autoantibodies in subsequent pregnancies indicates that additional factors determine fetal susceptibility. The complex interactions between fetal genetic variants and factors that influence the intrauterine environment are thought to trigger or prevent the onset of CHB in Ro/SSA and/or La/SSB exposed pregnancies. The identification of such variants and factors was the main aim of this thesis. Genome-wide SNP association studies in families with at least one child affected by CHB and an anti-Ro52/SSA positive mother identified distinct cellular pathways associated with CHB. Exploration of potential candidate genes in the CHB-associated regions identified auxilin as a novel fetal susceptibility gene affecting cardiac excitation-contraction coupling. Discovery of additional CHB-associated variants affecting genes involved in vesicular or transmembrane transport and cardiac function further supported the idea that genetic variants in pathways connected to cardiac conduction and contractility may influence fetal susceptibility to disease. Furthermore, CHB-associated variants affecting genes with function assigned to immune responses emerged from our association studies and are likely to contribute to the inflammatory and tissue destructive processes connected with CHB. Ro/SSA autoantibodies are associated with interferon activation, and we found that cardiomyocyte expression of CHB-associated genes is affected by interferon-alpha stimulation. PBMCs from neonates with CHB and exposed to Ro/SSA autoantibodies in utero also displayed differential expression of several CHB-associated genes. Interestingly, expression of auxilin was altered in cardiomyocytes and PBMCs, validating the relevance of this particular gene and its pathway in CHB pathogenesis. We further identified and confirmed distinct class I and II HLA allele associations with CHB implementing potential impact for disease. Among the factors that may influence the intrauterine environment, we found that seasonal timing of pregnancy, infections, outdoor activity and psychological stress associated with the risk for CHB in Ro/SSA positive pregnancies. Finally, we also investigated potential cross-targets for the maternal anti-Ro52/p200 antibodies, and fetal intrauterine exposure to these maternal autoantibody specificities may further influence clinical outcomes of CHB. In summary, our data expands the current understanding of CHB pathogenesis, and suggests that the overall fetal susceptibility to CHB and degree of disease severity depends on a combination of genetic risk variants, their overall functional consequences, and their interactions with intrauterine factors in addition to the effect of fetal exposure to maternal Ro/SSA autoantibodies.
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| 3. |
- Meisgen, Sabrina, et al.
(author)
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The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence
- 2014
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:6, s. 640-651
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block.SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases, and 95 unaffected siblings).RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n=1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of p<2.59×10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (p<0.03 and p<0.05, respectively), while HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (p<0.04 and p<0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (p<0.02).CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, while DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.
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