B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupus
IntroductionMHC class II molecules are essential for appropriate immune responses against pathogens but are also implicated in pathological responses in autoimmune diseases and transplant rejection. Previous studies have shed light on the systemic contributions of MHC haplotypes to the development a...
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1258046/full |
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| author | Camilla Wibrand Thomas R. Wittenborn Lasse Frank Voss Lasse Frank Voss Gudrun Winther Lisbeth Jensen Alexey Ferapontov Alexey Ferapontov Alexey Ferapontov Sofie V. Fonager Cecilia Fahlquist-Hagert Søren E. Degn Søren E. Degn |
| author_facet | Camilla Wibrand Thomas R. Wittenborn Lasse Frank Voss Lasse Frank Voss Gudrun Winther Lisbeth Jensen Alexey Ferapontov Alexey Ferapontov Alexey Ferapontov Sofie V. Fonager Cecilia Fahlquist-Hagert Søren E. Degn Søren E. Degn |
| author_sort | Camilla Wibrand |
| collection | DOAJ |
| description | IntroductionMHC class II molecules are essential for appropriate immune responses against pathogens but are also implicated in pathological responses in autoimmune diseases and transplant rejection. Previous studies have shed light on the systemic contributions of MHC haplotypes to the development and severity of autoimmune diseases. In this study, we addressed the B cell intrinsic MHC haplotype impact on follicular inclusion, germinal center (GC) participation and plasma cell (PC) differentiation in the context of systemic lupus erythematosus (SLE).MethodsWe leveraged the 564Igi mouse model which harbors a B cell receptor knock-in from an autoreactive B cell clone recognizing ribonuclear components, including double-stranded DNA (dsDNA). This model recapitulates the central hallmarks of the early stages of SLE. We compared 564Igi heterozygous offspring on either H2b/b, H2b/d, or H2d/d background.ResultsThis revealed significantly higher germinal center (GC) B cell levels in the spleens of H2b/b and H2b/d as compared to H2d/d (p<0.0001) mice. In agreement with this, anti-dsDNA-antibody levels were higher in H2b/b and H2b/d than in H2d/d (p<0.0001), with H2b/b also being higher compared to H2b/d (p<0.01). Specifically, these differences held true both for autoantibodies derived from the knock-in clone and from wild-type (WT) derived clones. In mixed chimeras where 564Igi H2b/b, H2b/d and H2d/d cells competed head-to-head in the same environment, we observed a significantly higher inclusion of H2b/b cells in GC and PC compartments relative to their representation in the B cell repertoire, compared to H2b/d and H2d/d cells. Furthermore, in mixed chimeras in which WT H2b/b and WT H2d/d cells competed for inclusion in GCs associated with an epitope spreading process, H2b/b cells participated to a greater extent and contributed more robustly to the PC compartment. Finally, immature WT H2b/b cells had a higher baseline of BCRs with an autoreactive idiotype and were subject to more stringent negative selection at the transitional stage.DiscussionTaken together, our findings demonstrate that B cell intrinsic MHC haplotype governs their capacity for participation in the autoreactive response at multiple levels: follicular inclusion, GC participation, and PC output. These findings pinpoint B cells as central contributors to precipitation of autoimmunity. |
| first_indexed | 2024-03-09T14:20:54Z |
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| id | doaj.art-b133c1b93d4d46dd8350a1c4ec2d9740 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-09T14:20:54Z |
| publishDate | 2023-11-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-b133c1b93d4d46dd8350a1c4ec2d97402023-11-28T14:14:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12580461258046B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupusCamilla Wibrand0Thomas R. Wittenborn1Lasse Frank Voss2Lasse Frank Voss3Gudrun Winther4Lisbeth Jensen5Alexey Ferapontov6Alexey Ferapontov7Alexey Ferapontov8Sofie V. Fonager9Cecilia Fahlquist-Hagert10Søren E. Degn11Søren E. Degn12Laboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Health Technology, Technical University of Denmark, Kongens Lyngby, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkCenter for Cellular Signal Patterns (CellPAT), Aarhus University, Aarhus, DenmarkInterdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkLaboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, DenmarkCenter for Cellular Signal Patterns (CellPAT), Aarhus University, Aarhus, DenmarkIntroductionMHC class II molecules are essential for appropriate immune responses against pathogens but are also implicated in pathological responses in autoimmune diseases and transplant rejection. Previous studies have shed light on the systemic contributions of MHC haplotypes to the development and severity of autoimmune diseases. In this study, we addressed the B cell intrinsic MHC haplotype impact on follicular inclusion, germinal center (GC) participation and plasma cell (PC) differentiation in the context of systemic lupus erythematosus (SLE).MethodsWe leveraged the 564Igi mouse model which harbors a B cell receptor knock-in from an autoreactive B cell clone recognizing ribonuclear components, including double-stranded DNA (dsDNA). This model recapitulates the central hallmarks of the early stages of SLE. We compared 564Igi heterozygous offspring on either H2b/b, H2b/d, or H2d/d background.ResultsThis revealed significantly higher germinal center (GC) B cell levels in the spleens of H2b/b and H2b/d as compared to H2d/d (p<0.0001) mice. In agreement with this, anti-dsDNA-antibody levels were higher in H2b/b and H2b/d than in H2d/d (p<0.0001), with H2b/b also being higher compared to H2b/d (p<0.01). Specifically, these differences held true both for autoantibodies derived from the knock-in clone and from wild-type (WT) derived clones. In mixed chimeras where 564Igi H2b/b, H2b/d and H2d/d cells competed head-to-head in the same environment, we observed a significantly higher inclusion of H2b/b cells in GC and PC compartments relative to their representation in the B cell repertoire, compared to H2b/d and H2d/d cells. Furthermore, in mixed chimeras in which WT H2b/b and WT H2d/d cells competed for inclusion in GCs associated with an epitope spreading process, H2b/b cells participated to a greater extent and contributed more robustly to the PC compartment. Finally, immature WT H2b/b cells had a higher baseline of BCRs with an autoreactive idiotype and were subject to more stringent negative selection at the transitional stage.DiscussionTaken together, our findings demonstrate that B cell intrinsic MHC haplotype governs their capacity for participation in the autoreactive response at multiple levels: follicular inclusion, GC participation, and PC output. These findings pinpoint B cells as central contributors to precipitation of autoimmunity.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1258046/fullB cellsMHCautoimmunityautoantibodiesgerminal centerscomplement |
| spellingShingle | Camilla Wibrand Thomas R. Wittenborn Lasse Frank Voss Lasse Frank Voss Gudrun Winther Lisbeth Jensen Alexey Ferapontov Alexey Ferapontov Alexey Ferapontov Sofie V. Fonager Cecilia Fahlquist-Hagert Søren E. Degn Søren E. Degn B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupus Frontiers in Immunology B cells MHC autoimmunity autoantibodies germinal centers complement |
| title | B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupus |
| title_full | B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupus |
| title_fullStr | B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupus |
| title_full_unstemmed | B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupus |
| title_short | B cell MHC haplotype affects follicular inclusion, germinal center participation and plasma cell differentiation in a mouse model of lupus |
| title_sort | b cell mhc haplotype affects follicular inclusion germinal center participation and plasma cell differentiation in a mouse model of lupus |
| topic | B cells MHC autoimmunity autoantibodies germinal centers complement |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1258046/full |
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