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1.
Acta Neuropathol ; 145(3): 335-355, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36695896

RESUMO

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.


Assuntos
Células Produtoras de Anticorpos , Autoantígenos , Camundongos , Animais , Linfócitos B , Vírus da Coriomeningite Linfocítica , Encéfalo
2.
Genes Immun ; 23(6): 183-195, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36028771

RESUMO

Adaptive immune repertoires are composed by the ensemble of B and T-cell receptors within an individual, reflecting both past and current immune responses. Recent advances in single-cell sequencing enable recovery of the complete adaptive immune receptor sequences in addition to transcriptional information. Here, we recovered transcriptome and immune repertoire information for polyclonal T follicular helper cells following lymphocytic choriomeningitis virus (LCMV) infection, CD8+ T cells with binding specificity restricted to two distinct LCMV peptides, and B and T cells isolated from the nervous system in the context of experimental autoimmune encephalomyelitis. We could relate clonal expansion, germline gene usage, and clonal convergence to cell phenotypes spanning activation, memory, naive, antibody secretion, T-cell inflation, and regulation. Together, this dataset provides a resource for immunologists that can be integrated with future single-cell immune repertoire and transcriptome sequencing datasets.


Assuntos
Autoimunidade , Coriomeningite Linfocítica , Animais , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Coriomeningite Linfocítica/genética , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos , Receptores de Antígenos de Linfócitos T/genética
3.
Sci Transl Med ; 14(640): eabl6058, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35417190

RESUMO

In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8+ TRM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8+ TRM. Subsequently, CD8+ TRM expanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8+ T cells. However, in the absence of CD4+ T cells, TCF-1+ CD8+ TRM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8+ T cells expressing TCF-1 that predominantly exhibited a TRM-like phenotype. Together, our study provides evidence for CD8+ TRM-driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Autoantígenos , Linfócitos T CD4-Positivos , Sistema Nervoso Central , Humanos , Inflamação , Vírus da Coriomeningite Linfocítica
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