АнтиCD40L предотвращает аутоиммунный энцефаломиелит, абстрагированные клетки B и смягчает его аутоиммунный энцефаломиелит.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Tyystjärvi Sofia, Ruiz Navarro Diego E, Kulisch Leni-Mihaela, Hartmann Annika H, Sie Christopher, Schmidt Monika, Chen Hsin-Hsiang, Muschaweckh Andreas, Heink Sylvia, Richter Lisa C, Seeholzer Lea, Steiger Katja, Kalluri Sudhakar Reddy, Ryan Sean K, Wirak Gregory S, Ofengeim Dimitry, Afzali Ali Maisam, Korn Thomas
Аннотация
Оригинал публикации
Anti-CD40L prevents meningeal B cell aggregates and mitigates progressive autoimmune encephalomyelitis.
Compartmentalized inflammation within the CNS is considered to drive progressive immunopathology in multiple sclerosis (MS) independently of relapses. Meningeal tertiary lymphoid structures (TLS) represent an immune niche associated with histological signs of immunopathology, including demyelination in the adjacent CNS parenchyma. Here, we show that the opticospinal encephalomyelitis (OSE) mouse model, in which meningeal TLS develop spontaneously based on the interaction of myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic T cells with MOG B cell receptor (BCR) transgenic B cells, recapitulates the dynamics and the histological features of meningeal TLS observed in human MS. Based on scRNAseq datasets of meningeal TLS from OSE mice, the CD40L-CD40 pathway is highly active in the T cell-B cell interaction in this niche. Accordingly, a monoclonal antibody to CD40L, applied systemically, abrogates the T-B interaction in the systemic compartment and even more so in the meningeal compartment. This leads to near-complete clearance of meningeal TLS, concomitant with clinical improvement of the progressive disease phase of OSE mice. In contrast, systemic B cell depletion with a monoclonal antibody to CD20 does not improve signs of progressive disease in the OSE model. Treatment with anti-CD40L is more effective in disrupting T-B interaction, the more the T-B interaction relies on the CD40L-CD40 pathway, and thus leads to a "semi-selective" targeting of meningeal TLS. In addition, not only B cells but the entire antigen-presenting compartment in the CNS is remodeled in the absence of CD40 engagement. Since these effects persist even after withdrawal of anti-CD40L treatment, no rebound episodes or resumption of progression are observed. In conclusion, anti-CD40L treatment may be an effective intervention to mitigate progressive immunopathology associated with meningeal TLS. Beyond B cells, anti-CD40L treatment also modulates and likely silences other CD40-dependent antigen-presenting cells in the CNS, including myeloid cells and astrocyte subsets.