Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro
Abstract Objectives Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease with complex pathogenic mechanisms. Complement C1q has been shown to play a major role in SLE, and autoantibodies against C1q (anti‐C1q) are strongly associated with SLE disease activity and sever...
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Clinical & Translational Immunology |
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| Online Access: | https://doi.org/10.1002/cti2.1408 |
| _version_ | 1811183253295464448 |
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| author | Pascal Alexander Rabatscher Marten Trendelenburg |
| author_facet | Pascal Alexander Rabatscher Marten Trendelenburg |
| author_sort | Pascal Alexander Rabatscher |
| collection | DOAJ |
| description | Abstract Objectives Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease with complex pathogenic mechanisms. Complement C1q has been shown to play a major role in SLE, and autoantibodies against C1q (anti‐C1q) are strongly associated with SLE disease activity and severe lupus nephritis suggesting a pathogenic role for anti‐C1q. Whereas C1q alone has anti‐inflammatory effects on human monocytes and macrophages, C1q/anti‐C1q complexes favor a pro‐inflammatory phenotype. This study aimed to elucidate the inflammatory effects of anti‐C1q on peripheral blood mononuclear cells (PBMCs). Methods Isolated monocytes, isolated T cells and bulk PBMCs of healthy donors with or without concomitant T cell activation were exposed to C1q or complexes of C1q and SLE patient‐derived anti‐C1q (C1q/anti‐C1q). Functional consequences of C1q/anti‐C1q on cells were assessed by determining cytokine secretion, monocyte surface marker expression, T cell activation and proliferation. Results Exposure of isolated T cells to C1q or C1q/anti‐C1q did not affect their activation and proliferation. However, unspecific T cell activation in PBMCs in the presence of C1q/anti‐C1q resulted in increased TNF, IFN‐γ and IL‐10 secretion compared with C1q alone. Co‐culture and inhibition experiments showed that the inflammatory effect of C1q/anti‐C1q on PBMCs was due to a direct CD40–CD154 interaction between activated T cells and C1q/anti‐C1q‐primed monocytes. The CD40‐mediated inflammatory reaction of monocytes involves TRAF6 and JAK3‐STAT5 signalling. Conclusion In conclusion, C1q/anti‐C1q have a pro‐inflammatory effect on monocytes that depends on T cell activation and CD40–CD154 signalling. This signalling pathway could serve as a therapeutic target for anti‐C1q‐mediated inflammation. |
| first_indexed | 2024-04-11T09:44:51Z |
| format | Article |
| id | doaj.art-fa92f18e37f9494f90528690370584fc |
| institution | Directory Open Access Journal |
| issn | 2050-0068 |
| language | English |
| last_indexed | 2024-04-11T09:44:51Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical & Translational Immunology |
| spelling | doaj.art-fa92f18e37f9494f90528690370584fc2022-12-22T04:31:06ZengWileyClinical & Translational Immunology2050-00682022-01-01118n/an/a10.1002/cti2.1408Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitroPascal Alexander Rabatscher0Marten Trendelenburg1Laboratory of Clinical Immunology, Department of Biomedicine University of Basel Basel SwitzerlandLaboratory of Clinical Immunology, Department of Biomedicine University of Basel Basel SwitzerlandAbstract Objectives Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease with complex pathogenic mechanisms. Complement C1q has been shown to play a major role in SLE, and autoantibodies against C1q (anti‐C1q) are strongly associated with SLE disease activity and severe lupus nephritis suggesting a pathogenic role for anti‐C1q. Whereas C1q alone has anti‐inflammatory effects on human monocytes and macrophages, C1q/anti‐C1q complexes favor a pro‐inflammatory phenotype. This study aimed to elucidate the inflammatory effects of anti‐C1q on peripheral blood mononuclear cells (PBMCs). Methods Isolated monocytes, isolated T cells and bulk PBMCs of healthy donors with or without concomitant T cell activation were exposed to C1q or complexes of C1q and SLE patient‐derived anti‐C1q (C1q/anti‐C1q). Functional consequences of C1q/anti‐C1q on cells were assessed by determining cytokine secretion, monocyte surface marker expression, T cell activation and proliferation. Results Exposure of isolated T cells to C1q or C1q/anti‐C1q did not affect their activation and proliferation. However, unspecific T cell activation in PBMCs in the presence of C1q/anti‐C1q resulted in increased TNF, IFN‐γ and IL‐10 secretion compared with C1q alone. Co‐culture and inhibition experiments showed that the inflammatory effect of C1q/anti‐C1q on PBMCs was due to a direct CD40–CD154 interaction between activated T cells and C1q/anti‐C1q‐primed monocytes. The CD40‐mediated inflammatory reaction of monocytes involves TRAF6 and JAK3‐STAT5 signalling. Conclusion In conclusion, C1q/anti‐C1q have a pro‐inflammatory effect on monocytes that depends on T cell activation and CD40–CD154 signalling. This signalling pathway could serve as a therapeutic target for anti‐C1q‐mediated inflammation.https://doi.org/10.1002/cti2.1408anti‐C1q autoantibodiesC1qCD40monocytessystemic lupus erythematosusT cells |
| spellingShingle | Pascal Alexander Rabatscher Marten Trendelenburg Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro Clinical & Translational Immunology anti‐C1q autoantibodies C1q CD40 monocytes systemic lupus erythematosus T cells |
| title | Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro |
| title_full | Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro |
| title_fullStr | Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro |
| title_full_unstemmed | Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro |
| title_short | Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro |
| title_sort | anti c1q autoantibodies from systemic lupus erythematosus patients enhance cd40 cd154 mediated inflammation in peripheral blood mononuclear cells in vitro |
| topic | anti‐C1q autoantibodies C1q CD40 monocytes systemic lupus erythematosus T cells |
| url | https://doi.org/10.1002/cti2.1408 |
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