Intestinal microbiota link lymphopenia to murine autoimmunity via PD-1+CXCR5−/dim B-helper T cell induction

Eri, Toshiki; Kawahata, K.; Kanzaki, Takeyuki; Imamura, Mitsuru; Michishita, Koji; Akahira, Lisa; Bannai, Ei; Yoshikawa, Noritada; Kimura, Yoshinobu; Satoh, Takeshi; Uematsu, Satoshi; Tanaka, Hirotoshi; Yamamoto, Kazuhiko

doi:10.1038/srep46037

Cited by 22 publications

(19 citation statements)

References 77 publications

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“…S3, available at Rheumatology Advances in Practice online). Given that it has been reported that PD-1 + CXCR5 − /dim CD4 + T cells and Tph cells also have a functional property as B-cell helpers [5, 13], we performed functional analysis regarding the promotion of B-cell responses. However, we failed to observe significant levels of expression of IL4 and IL21 transcripts in Tph-like cells from healthy volunteers and from patients with IgG4-RD compared with those in Tfh cells (supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Circulating PD-1+CXCR5−CD4+ T cells underlying the immunological mechanisms of IgG4-related disease

Kamekura

Yamamoto

Takano

et al. 2018

Rheumatology Advances in Practice

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Objective The aim was to study the pathological role of lymphocytes with a peripheral T helper-cell-like phenotype (PD-1 + CXCR5 − CD4 + ) in IgG4-related disease (IgG4-RD). Methods PD-1 + CXCR5 − CD4 + T cells in the blood of patients with IgG4-RD ( n = 53), patients with SS ( n = 16) and healthy volunteers ( n = 34) as controls were analysed by flow cytometry. Correlations between results obtained by flow cytometry and clinical parameters relevant to IgG4-RD were also analysed. Results The percentage and absolute number of PD-1 + CXCR5 − cells within total CD4 + T cells in IgG4-RD patients were significantly increased compared with those in healthy volunteers. Further analysis showed that there were marked positive correlations of the percentage of PD-1 + CXCR5 − CD4 + T cells with the serum level of IgG4 and the number of organs involved. Interestingly, granzyme A (GZMA) + cells were enriched in PD-1 + CXCR5 − CD4 + T cells, and the percentage and absolute number of GZMA + PD-1 + CXCR5 − CD4 + T cells were significantly elevated in IgG4-RD patients. Although no obvious change was observed in the percentage of total CD4 + T cells, the percentage and absolute number of PD-1 + CXCR5 − CD4 + T cells decreased in accordance with a reduction of serum IgG4 level after treatment with glucocorticoids. Conclusion In IgG4-RD, circulating CD4 + T-cell populations were composed of PD-1 + CXCR5 − cells, and the ratios of these cells were correlated with clinical manifestations of IgG4-RD. Further analysis of GZMA + PD-1 + CXCR5 − CD4 + T cells might lead to a deeper understanding of the pathogenesis of ectopic lymphoid follicles and the persistent inflammation in IgG4-RD.

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Section: Resultsmentioning

confidence: 99%

Circulating PD-1+CXCR5−CD4+ T cells underlying the immunological mechanisms of IgG4-related disease

Kamekura

Yamamoto

Takano

et al. 2018

Rheumatology Advances in Practice

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“…In multiple sclerosis, a decrease in Butyricimonas content resulted in SCFAs reduction, which attenuated the anti-inflammatory effects of intestinal Treg cells [34]. The study of Eri T et al also showed that the reduction of Odoribacter and Alistipes induced by long-term use of antibodies may damage intestinal barrier function and induce intestinal sepsis [35]. Based on these previous reports and our experimental results, we found that abnormal microbiome composition mediated by Drp1 could reduce the colon SCFAs level, resulting in the destruction of tight junction in IECs and the increase of intestinal permeability after shock.…”

Section: Discussionmentioning

confidence: 99%

Activated Drp1-mediated mitochondrial ROS influence the gut microbiome and intestinal barrier after hemorrhagic shock

Duan

Kuang

Xiang

et al. 2020

Aging

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A role of the mitochondrial dynamin-related protein (Drp1) on gut microbiome composition and intestinal barrier function after hemorrhagic shock has not been identified previously and thus addressed in this study. Here, we used a combination of 16S rRNA gene sequencing and mass spectrometry-based metabolomics profiling in WT and Drp1 KO mouse models to examine the functional impact of activated Drp1 on the gut microbiome as well as mitochondrial metabolic regulation after hemorrhagic shock. Our data showed that changes in mitochondrial Drp1 activity participated in the regulation of intestinal barrier function after hemorrhagic shock. Activated Drp1 significantly perturbed gut microbiome composition in the Bacteroidetes phylum. The abundance of short-chain fatty acid (SCFA) producing microbes, such as Bacteroides, Butyricimonas and Odoribacter, was markedly decreased in mice after shock, and was inversely correlated with both the distribution of the tight junction protein ZO1 and intestinal permeability. Together, these data suggest that Drp1 activation perturbs the gut microbiome community and SCFA production in a ROS-specific manner and thereby substantially disturbs tight junctions and intestinal barrier function after hemorrhagic shock. Our findings provide novel insights for targeting Drp1-mediated mitochondrial function as well as the microbiome in the treatment of intestinal barrier dysfunction after shock.

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“…43 In turn, manipulation of intestinal microbiota in mice has been shown to directly modulate lymphopenia-induced autoimmunity. 44 Lymphopenia may be a feature of pre-diagnostic PD, and reflect early pathological changes in peripheral tissues.…”

Section: Discussionmentioning

confidence: 99%

Low lymphocyte count is a risk factor for Parkinson’s disease

Jensen

Jacobs

Dobson

et al. 2020

Preprint

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Importance: Biomarkers for the early detection of Parkinsons disease (PD) are needed; emerging evidence implicates immune dysregulation. Altered leukocyte differentials and C-reactive protein (CRP), common markers of immune function, occur in patients with PD. Whether these changes drive pathogenesis remains unclear. Objectives: We sought to identify whether peripheral immune dysregulation can be seen as a pre-diagnostic feature of PD, and whether it appears to play a causal role. Design: We examined the relationship between differential leukocyte count and other markers of acute inflammation at enrolment, and incident cases of PD, in UK Biobank, a longitudinal cohort study. We used Mendelian randomization to establish whether differences in leukocyte subsets have a causal influence on risk of PD. Setting: The UK Biobank; a population-based cohort with over 500,000 participants aged 40-69 recruited in the UK between 2006 and 2010. Participants: PD cases were defined as individuals with an ICD-10 coded diagnosis of PD. Cases were defined as incident if their age at diagnosis was greater than their age at recruitment to UKB. Controls were defined as all other individuals in the dataset after applying the above exclusions. After applying exclusion criteria for pre-existing health conditions that can influence blood counts, 507 incident PD cases and 328,280 controls were included in the analysis. Exposure: Blood cell markers (absolute and relative counts) and other markers of inflammation (CRP and albumin) were obtained from blood tests of participants taken at the initial assessment visit. Results: Lower lymphocyte count was associated with increased risk of incident PD. There was weaker evidence of association between lower eosinophil and monocyte counts, lower CRP, and higher neutrophil counts on risk of incident PD. The association between lymphopenia and incident PD remained robust to sensitivity analyses. Mendelian randomization did not reveal a clear causal effect of low lymphocyte count on PD risk, but a weak trend in that direction was seen. Conclusions and relevance: In this large, prospective setting, lower lymphocyte count was associated with higher risk of subsequent PD diagnosis. The absence of a clear causal effect indicates that lymphopenia might be a consequence of prodromal PD.

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Intestinal microbiota link lymphopenia to murine autoimmunity via PD-1+CXCR5−/dim B-helper T cell induction

Cited by 22 publications

References 77 publications

Circulating PD-1+CXCR5−CD4+ T cells underlying the immunological mechanisms of IgG4-related disease

Circulating PD-1+CXCR5−CD4+ T cells underlying the immunological mechanisms of IgG4-related disease

Activated Drp1-mediated mitochondrial ROS influence the gut microbiome and intestinal barrier after hemorrhagic shock

Low lymphocyte count is a risk factor for Parkinson’s disease

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