Pregnancy enables expansion of autoreactive regulatory T cells in an animal model of multiple sclerosis
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ABSTRACT:
PROVIDER: PRJNA506836 | ENA |
REPOSITORIES: ENA
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Project description:Disease activity of autoimmune disorders such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) is temporarily suppressed by pregnancy. However, whether disease amelioration is due to non-specific immunomodulation or mediated by antigen-specific regulation of disease-causing conventional T cells (Tcon) and immuno- suppressive regulatory T cells (Treg), remains elusive. In the present study, we systematically analyzed changes of the T cell receptor (TCR) β repertoire driven by EAE and pregnancy using TCR sequencing. We demonstrate that EAE, but not pregnancy, robustly increased TCR repertoire clonality in both peripheral Tcon and Treg. Notably, pregnancy was required for the expansion of Treg harboring the dominant EAE-associated TRBV chain 13.2 and increased the frequency of EAE-associated clonotypes within the Treg compartment. Our findings indicate that pregnancy supports the expansion of Treg clonotypes that are equipped to recognize EAE- associated antigens. These Treg are thereby particularly suited to control corresponding encephalitogenic Tcon responses and likely contribute to pregnancy-associated protection in autoimmunity.
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Project description:Autoimmune diseases are often associated with HLA molecules. Multiple sclerosis (MS) is a prototypical example with the HLA-DR15 haplotype as strongest genetic factor. How it contributes to MS is not clear, but key to understand this and other autoimmune diseases. Autoreactive CD4+ T cells and proinflammatory B cells are central pathogenetic factors, and since HLA-DR molecules present peptides to CD4+ T cells, we characterized the peptidomes of the two HLA-DR15 allomorphs DR2a and DR2b on B cells. Self-peptides from HLA-DR α- and β-chains themselves are abundantly presented on B cells. We identified autoreactive CD4+ T cell clones, which recognize HLA-DR-derived self-peptides and peptides from the MS-related infectious agents EBV and Akkermansia and the autoantigen RAS guanyl-releasing protein 2. Our data demonstrate how the two MS-associated HLA-DR15 allomorphs function as antigen-presenting structures and source of peptides during peripheral maintenance of autoreactive T cells and activation by MS-associated pathogens.
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Project description:Transcriptional profiling of mouse bone marrow B220+CD23–CD43–IgD– autoreactive immature B cells from 3-83Igi,Rag1-/-,H-2b mice relative to non-autoreactive immature B cells from 3-83Igi,H-2d mice. Goal was to determine genes that potentially mediate negative and positive selection of immature B cells.
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Project description:Background: pregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood. This data series contains the subset of data used to generate a MS signature comparing female MS specimens before pregnancy with respect to female MS specimens at ninth month pregnancy. Subjects were followed in the outpatients clinic and blood was collected before pregnancy and at the following time points during pregnancy: first trimester (gestational age at sampling 12 weeks), second trimester (24 weeks), and third trimester (36 weeks). Before-pregnancy samples were obtained in a treatment-free period and after anticonceptional drug withdrawal. Peripheral blood mononuclear cells (PBMCs) obtained from 17 women (8 MS patients before pregnancy and 9 MS patients at 9th month pregnancy) were analyzed by oligonucleotide microarray technology.
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Project description:Background: pregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood. This data series contains the subset of data used to generate a MS signature comparing female MS specimens before pregnancy with respect to female MS specimens at ninth month pregnancy.
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Project description:Bovine pregnancy-associated glycoproteins (boPAGs) are extensively glycosylated secretory proteins of trophoblast cells. Roughly 20 different boPAG members are known but their distribution patterns and degree of glycosylation during pregnancy are not well characterized. The objective of the present study was the development of a parallel reaction monitoring-based assay for the profiling of different boPAGs during pregnancy and after gestation. Furthermore, we investigated the effects of N-glycosylation on our analytical results. BoPAGs were purified from cotyledons of four different pregnancy stages. The assay detects 25 proteotypic peptides from 18 boPAGs in a single run. The highest abundances were found for boPAG 1 in both, glycosylated and deglycosylated samples. Strongest effects of glycosylation were detected during mid and late pregnancy as well as in afterbirth samples. Furthermore, we identified different boPAG-clusters based on the observed relative protein abundances between glycosylated and deglycosylated samples. A linkage between the impact of glycosylation and potential N-glycosylation sites or phylogenetic relation was not detected. In conclusion, the newly developed parallel reaction monitoring-based assay enables for the first time a comprehensive semi-quantitative profiling of 18 different boPAGs during pregnancy and post-partum on protein level, thereby investigating the influence of glycosylation. The results of this study provide new and important starting points to address further research on boPAGs to better understand their physiological role during pregnancy and for the development of new pregnancy detection tests.
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