Persistent virus-specific and clonally expanded antibody-secreting cells respond to induced self-antigen in the CNS

被引:4
|
作者
Agrafiotis, Andreas [1 ,2 ]
Dizerens, Raphael [1 ]
Vincenti, Ilena [3 ]
Wagner, Ingrid [3 ]
Kuhn, Raphael [1 ]
Shlesinger, Danielle [1 ]
Manero-Carranza, Marcos [1 ]
Cotet, Tudor-Stefan [1 ]
Hong, Kai-Lin [1 ]
Page, Nicolas [3 ]
Fonta, Nicolas [3 ]
Shammas, Ghazal [3 ]
Mariotte, Alexandre [3 ]
Piccinno, Margot [3 ]
Kreutzfeldt, Mario [3 ,12 ]
Gruntz, Benedikt [1 ]
Ehling, Roy [1 ]
Genovese, Alessandro [2 ]
Pedrioli, Alessandro [2 ]
Dounas, Andreas [4 ,5 ]
Franzenburg, Soeren [6 ,7 ]
Tumani, Hayrettin [13 ]
Kuempfel, Tania [8 ,9 ,10 ,11 ]
Kavaka, Vladyslav [8 ,9 ,10 ]
Gerdes, Lisa Ann [8 ,9 ,10 ,11 ]
Dornmair, Klaus [8 ,9 ,10 ,11 ]
Beltran, Eduardo [8 ,9 ,10 ,11 ]
Oxenius, Annette [2 ]
Reddy, Sai T. T. [1 ]
Merkler, Doron [3 ,12 ]
Yermanos, Alexander [1 ,2 ,3 ,14 ]
机构
[1] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Basel, Switzerland
[2] Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland
[3] Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland
[4] Univ Zurich, Inst Biomed Engn, Zurich, Switzerland
[5] Swiss Fed Inst Technol, Zurich, Switzerland
[6] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
[7] Univ Med Ctr Schleswig Holstein, Kiel, Germany
[8] Ludwig Maximilians Univ Munchen, Univ Hosp, Fac Med, Inst Clin Neuroimmunol, Munich, Germany
[9] Ludwig Maximilians Univ Munchen, Biomed Ctr BMC, Munich, Germany
[10] Ludwig Maximilians Univ Munchen, Fac Med, Biomed Ctr BMC, Martinsried, Germany
[11] Munich Cluster Syst Neurol SyNergy, Munich, Germany
[12] Univ Hosp Geneva, Div Clin Pathol, Geneva, Switzerland
[13] Univ Hosp Ulm, Dept Neurol, Ulm, Germany
[14] Univ Med Ctr Utrecht, Ctr Translat Immunol, Utrecht, Netherlands
基金
欧洲研究理事会;
关键词
Viral infection; Autoimmunity; CNS tolerance; Multiple sclerosis; Antibody-secreting cells; CENTRAL-NERVOUS-SYSTEM; MEMORY T-CELLS; B-CELLS; MULTIPLE-SCLEROSIS; IMMUNE CELLS; AUTOIMMUNE; EXPRESSION; DISEASE; SEGMENTS; BARRIER;
D O I
10.1007/s00401-023-02537-5
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. We identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens.
引用
收藏
页码:335 / 355
页数:21
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