![]() This results in a quantitative profile of B cell clonal selection that can further be validated via recombinant expression of antibodies of interest. Current iterations of this technology provide both single-cell antibody repertoires (full-length, paired heavy and light chain antibody sequences) and single-cell transcriptomes. Recent advancements in sequencing and microfluidic techniques have enabled comprehensive profiling of B cells and their corresponding antibody repertoires. In addition, despite recent advances in the field regarding transcriptional characteristics of disease-relevant B cells subsets found in the inflamed CNS, whether these cells can undergo clonal selection and be locally reactivated to CNS-restricted autoantigens remains unknown. While autoreactive antibodies to various protein targets such as MOG, DPPX, and aquaporin-4 have been profiled and are even used in diagnostics of certain neurological disorders, the cellular counterparts and origins within or outside the CNS of these antibodies remain unclear. Furthermore, the success of B cell-depleting therapies in patients with multiple sclerosis and other chronic autoimmune conditions with presence of neuronal auto-antibodies provides compelling evidence that B cells are crucially involved in the pathophysiology of these diseases. ![]() Yet, B cells are involved in the pathogenesis of neuroinflammatory diseases by a variety of mechanisms including antigen presentation to T cells, transport of antigens to secondary lymphoid organs, secretion of pro-inflammatory or anti-inflammatory cytokines, and pathogenic antibodies. This is particularly true in the case of the CNS, where the formation and existence of resident B cells is still under debate. Such Trm are poised to respond to secondary exposures or can participate in compartmentalized inflammation in the CNS, In contrast, much less is known about the phenotype and function of tissue-resident B cells and their interference with circulating counterparts. Thereby, T cells have previously been shown to be able to locally reside in a variety of non-lymphoid tissues, including the CNS, and to adopt a tissue-resident memory phenotype (Trm). Upon infiltration, T and B cells can adopt a wide range of phenotypes and effector functions that can either protect against pathogenic threat or, conversely, contribute to disease. However, in CNS inflammatory conditions, the number of immune cells entering the CNS parenchyma through the blood–brain barrier or blood–cerebrospinal fluid barrier increases dramatically. The access of circulating immune cells into the CNS is restricted in healthy individuals under steady-state conditions with only very low numbers of lymphocytes residing in the brain. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. ![]() 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. 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. 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. ![]() 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. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). We identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. ![]()
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