Context-dependent induction of autoimmunity by TNF signaling deficiency
TNF inhibitors are widely used to treat inflammatory diseases; however, 30%–50% of treated patients develop new autoantibodies, and 0.5%–1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high-affinity autoantibodies are...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.149094 |
| _version_ | 1818549688753717248 |
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| author | Tam D. Quach Weiqing Huang Ranjit Sahu Catherine M.M. Diadhiou Chirag Raparia Roshawn Johnson Tung Ming Leung Susan Malkiel Peta Gay Ricketts Stefania Gallucci Çagla Tükel Chaim O. Jacob Martin L. Lesser Yong-Rui Zou Anne Davidson |
| author_facet | Tam D. Quach Weiqing Huang Ranjit Sahu Catherine M.M. Diadhiou Chirag Raparia Roshawn Johnson Tung Ming Leung Susan Malkiel Peta Gay Ricketts Stefania Gallucci Çagla Tükel Chaim O. Jacob Martin L. Lesser Yong-Rui Zou Anne Davidson |
| author_sort | Tam D. Quach |
| collection | DOAJ |
| description | TNF inhibitors are widely used to treat inflammatory diseases; however, 30%–50% of treated patients develop new autoantibodies, and 0.5%–1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high-affinity autoantibodies are often made. We found that TNF deficiency in Sle1 mice induced TH17 T cells and enhanced the production of germline encoded, T-dependent IgG anti-cardiolipin antibodies but did not induce GC formation or precipitate clinical disease. We then asked whether a second hit could restore GC formation or induce pathogenic autoimmunity in TNF-deficient mice. By using a range of immune stimuli, we found that somatically mutated autoantibodies and clinical disease can arise in the setting of TNF deficiency via extrafollicular pathways or via atypical GC-like pathways. This breach of tolerance may be due to defects in regulatory signals that modulate the negative selection of pathogenic autoreactive B cells. |
| first_indexed | 2024-12-12T08:36:37Z |
| format | Article |
| id | doaj.art-0bc079a9637640159ce2bb095af989d7 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T08:36:37Z |
| publishDate | 2022-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-0bc079a9637640159ce2bb095af989d72022-12-22T00:30:55ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-03-0175Context-dependent induction of autoimmunity by TNF signaling deficiencyTam D. QuachWeiqing HuangRanjit SahuCatherine M.M. DiadhiouChirag RapariaRoshawn JohnsonTung Ming LeungSusan MalkielPeta Gay RickettsStefania GallucciÇagla TükelChaim O. JacobMartin L. LesserYong-Rui ZouAnne DavidsonTNF inhibitors are widely used to treat inflammatory diseases; however, 30%–50% of treated patients develop new autoantibodies, and 0.5%–1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high-affinity autoantibodies are often made. We found that TNF deficiency in Sle1 mice induced TH17 T cells and enhanced the production of germline encoded, T-dependent IgG anti-cardiolipin antibodies but did not induce GC formation or precipitate clinical disease. We then asked whether a second hit could restore GC formation or induce pathogenic autoimmunity in TNF-deficient mice. By using a range of immune stimuli, we found that somatically mutated autoantibodies and clinical disease can arise in the setting of TNF deficiency via extrafollicular pathways or via atypical GC-like pathways. This breach of tolerance may be due to defects in regulatory signals that modulate the negative selection of pathogenic autoreactive B cells.https://doi.org/10.1172/jci.insight.149094Immunology |
| spellingShingle | Tam D. Quach Weiqing Huang Ranjit Sahu Catherine M.M. Diadhiou Chirag Raparia Roshawn Johnson Tung Ming Leung Susan Malkiel Peta Gay Ricketts Stefania Gallucci Çagla Tükel Chaim O. Jacob Martin L. Lesser Yong-Rui Zou Anne Davidson Context-dependent induction of autoimmunity by TNF signaling deficiency JCI Insight Immunology |
| title | Context-dependent induction of autoimmunity by TNF signaling deficiency |
| title_full | Context-dependent induction of autoimmunity by TNF signaling deficiency |
| title_fullStr | Context-dependent induction of autoimmunity by TNF signaling deficiency |
| title_full_unstemmed | Context-dependent induction of autoimmunity by TNF signaling deficiency |
| title_short | Context-dependent induction of autoimmunity by TNF signaling deficiency |
| title_sort | context dependent induction of autoimmunity by tnf signaling deficiency |
| topic | Immunology |
| url | https://doi.org/10.1172/jci.insight.149094 |
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