B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4 Journal Article
| Authors: | Afzali, A. M.; Nirschl, L.; Sie, C.; Pfaller, M.; Ulianov, O.; Hassler, T.; Federle, C.; Petrozziello, E.; Kalluri, S. R.; Chen, H. H.; Tyystjärvi, S.; Muschaweckh, A.; Lammens, K.; Delbridge, C.; Büttner, A.; Steiger, K.; Seyhan, G.; Ottersen, O. P.; Öllinger, R.; Rad, R.; Jarosch, S.; Straub, A.; Mühlbauer, A.; Grassmann, S.; Hemmer, B.; Böttcher, J. P.; Wagner, I.; Kreutzfeldt, M.; Merkler, D.; Pardàs, I. B.; Schmidt Supprian, M.; Buchholz, V. R.; Heink, S.; Busch, D. H.; Klein, L.; Korn, T. |
| Article Title: | B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4 |
| Abstract: | Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4. © The Author(s) 2024. |
| Keywords: | immunohistochemistry; human cell; genetics; nonhuman; flow cytometry; t lymphocyte; animal cell; mouse; animal; metabolism; animals; mice; apoptosis; gene expression; spleen; dendritic cell; interleukin 21; protein; immunofluorescence; immunoreactivity; histology; central nervous system; b lymphocyte; t lymphocyte receptor; mycobacterium tuberculosis; antigen; thymus; receptors, antigen, t-cell; cd4+ t lymphocyte; sialidase; epithelium cell; autoantigen; autoantigens; autoimmunity; real time polymerase chain reaction; upregulation; rodent; rag1 protein; autoantibody; major histocompatibility complex; autoantibodies; thymocyte; immunopathology; lymphocyte antigen receptor; tetramer; paralysis; gas chromatography; nervous system; cell; pertussis toxin; ablation; active immunization; cd40 antigen; aquaporin 4; myelin oligodendrocyte glycoprotein; myelooptic neuropathy; autoimmune encephalomyelitis; lymphocyte function associated antigen 1; experimental autoimmune encephalomyelitis; isolation; enrofloxacin; quadriplegia; cd19 antibody; humans; human; article; cell antigen; single cell rna seq; medullary thymic epithelial cell; neuromyelitis optica; aquaporin 4 antibody; autoimmune disease of the central nervous system |
| Journal Title: | Nature |
| Volume: | 627 |
| Issue: | 8003 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-03-14 |
| Start Page: | 407 |
| End Page: | 415 |
| Language: | English |
| DOI: | 10.1038/s41586-024-07079-8 |
| PUBMED: | 38383779 |
| PROVIDER: | scopus |
| PMCID: | PMC10937377 |
| DOI/URL: | |
| Notes: | Source: Scopus |
