Association of B cell profile and receptor repertoire with the progression of Alzheimer’s disease

Park, Jongchan; Noh, Jinsung; Jang, Sukjin; Kim, Ki‐Hyun; Choi, Hyungkil; Lee, Dongjoon; Kim, Jieun; Chung, Jaeyoung; Lee, Dong Hoon; Lee, Yonghee; Lee, Hyunho; Yoo, Duck Kyun; Lee, Amos Chungwon; Byun, Min Soo; Yi, Dahyun; Han, Sang Hoon; Kwon, Sunghoon; Mook‐Jung, Inhee

doi:10.1016/j.celrep.2022.111391

Cited by 18 publications

(13 citation statements)

References 56 publications

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“…We found increased B2 cell class switching throughout the periphery and a systemic reduction of T reg levels at the investigated times (9-12 months of age). A similar B cell phenotype has been reported in human PBMC studies, implicating a change in BCR repertoire with AD pathology [70]. While some BCRs are expected to generate Aβ auto-antibodies [103], it remains to be seen whether these BCRs are specific to gut microbial antigens, including microbial amyloids [104] in AD, accumulating in the periphery due to a leaky gut [20,31,32].…”

Section: Discussionmentioning

confidence: 70%

“…Taken together, the reduced amounts of migratory gene expressing colon ASCs, increased B2 cell class switching and inflammatory markers throughout the periphery suggest whole-body B cell dysfunction in 5XFAD , with the possibility of ASC emigration from the colon. The colon B activation observed here may be linked to a dysbiosis phenotype [32,68,69], and the peripheral B cell immunological changes may be correlated with the leaky gut [31] and changing blood BCR repertoire observed in AD [70].…”

Section: Resultsmentioning

confidence: 99%

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Single-cell transcriptomics reveals colonic immune perturbations during amyloid-β driven Alzheimer’s disease in mice

Makhijani,

Emani,

Aguirre

et al. 2024

Preprint

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The "gut-brain axis" is emerging as an important target in Alzheimer's disease (AD). However, immunological mechanisms underlying this axis remain poorly understood. Using single-cell RNA sequencing of the colon immune compartment in the 5XFAD amyloid-β (Aβ) mouse model, we uncovered AD-associated changes in ribosomal activity, oxidative stress, and BCR/plasma cell activity. Strikingly, levels of colon CXCR4+ antibody secreting cells (ASCs) were significantly reduced. This corresponded with accumulating CXCR4+ B cells and gut-specific IgA+ cells in the brain and dura mater, respectively. Consistently, a chemokine ligand for CXCR4, CXCL12, was expressed at higher levels in 5XFAD glial cells and in in silico analyzed human brain studies, supporting altered neuroimmune trafficking. An inulin prebiotic fiber diet attenuated AD markers including Aβ plaques and overall frailty. These changes corresponded to an expansion of gut IgA+ cells and rescued peripheral Tregs levels. Our study points to a key glia-gut axis and potential targets against AD.

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Section: Discussionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomics reveals colonic immune perturbations during amyloid-β driven Alzheimer’s disease in mice

Makhijani,

Emani,

Aguirre

et al. 2024

Preprint

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“…B-cell-deficient mice show alveolar bone loss without bacterial infection, while clinical evidence shows that B cells and plasma cells, along with osteoclastogenic factors, are involved in alveolar bone destruction in periodontitis ( Zouali, 2017 ). AD is associated with B cell accumulation in brain tissue which can produce IgG to induce microglial activation ( Park et al, 2022 ). Experimental evidence supports the notion of infectious disease driven microglial activation in AD ( Hao et al, 2022 ) along with peripheral leukocyte infiltration of brain tissue secondary to persistent systemic inflammation ( Lu et al, 2021 ), as seen in periodontitis, in particular NK cell infiltration ( Le Page et al, 2018 ), and our findings were largely consistent.…”

Section: Discussionmentioning

confidence: 99%

Immune-related signature of periodontitis and Alzheimer’s disease linkage

Jin,

Guang,

et al. 2023

Front. Genet.

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Background: Periodontits (PD) and Alzheimer’s disease (AD) are both associated with ageing and clinical studies increasingly evidence their association. However, specific mechanisms underlying this association remain undeciphered, and immune-related processes are purported to play a signifcant role. The accrual of publicly available transcriptomic datasets permits secondary analysis and the application of data-mining and bioinformatic tools for biological discovery.Aim: The present study aimed to leverage publicly available transcriptomic datasets and databases, and apply a series of bioinformatic analysis to identify a robust signature of immune-related signature of PD and AD linkage.Methods: We downloaded gene-expresssion data pertaining PD and AD and identified crosstalk genes. We constructed a protein-protein network analysis, applied immune cell enrichment analysis, and predicted crosstalk immune-related genes and infiltrating immune cells. Next, we applied consisent cluster analysis and performed immune cell bias analysis, followed by LASSO regression to select biomarker immune-related genes.Results: The results showed a 3 gene set comprising of DUSP14, F13A1 and SELE as a robust immune-related signature. Macrophages M2 and NKT, B-cells, CD4+ memory T-cells and CD8+ naive T-cells emerged as key immune cells linking PD with AD.Conclusion: Candidate immune-related biomarker genes and immune cells central to the assocation of PD with AD were identified, and merit investigation in experimental and clinical research.

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“…cDNA libraries were sampled and synthesized as previously described [ 26 ]. All blood samples were centrifuged, and the supernatant plasma was extracted.…”

Section: Methodsmentioning

confidence: 99%

Distinct features of B cell receptors in neuromyelitis optica spectrum disorder among CNS inflammatory demyelinating diseases

Kim,

Park,

Shin

et al. 2023

J Neuroinflammation

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Background Neuromyelitis optica spectrum disorder (NMOSD) stands out among CNS inflammatory demyelinating diseases (CIDDs) due to its unique disease characteristics, including severe clinical attacks with extensive lesions and its association with systemic autoimmune diseases. We aimed to investigate whether characteristics of B cell receptors (BCRs) differ between NMOSD and other CIDDs using high-throughput sequencing. Methods From a prospective cohort, we recruited patients with CIDDs and categorized them based on the presence and type of autoantibodies: NMOSD with anti-aquaporin-4 antibodies, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with anti-myelin oligodendrocyte glycoprotein antibodies, double-seronegative demyelinating disease (DSN), and healthy controls (HCs). The BCR features, including isotype class, clonality, somatic hypermutation (SHM), and the third complementarity-determining region (CDR3) length, were analyzed and compared among the different disease groups. Results Blood samples from 33 patients with CIDDs (13 NMOSD, 12 MOGAD, and 8 DSN) and 34 HCs were investigated for BCR sequencing. Patients with NMOSD tended to have more activated BCR features compare to the other disease groups. They showed a lower proportion of unswitched isotypes (IgM and IgD) and a higher proportion of switched isotypes (IgG), increased clonality of BCRs, higher rates of SHM, and shorter lengths of CDR3. Notably, advanced age was identified as a clinical factor associated with these activated BCR features, including increased levels of clonality and SHM rates in the NMOSD group. Conversely, no such clinical factors were found to be associated with activated BCR features in the other CIDD groups. Conclusions NMOSD patients, among those with CIDDs, displayed the most pronounced B cell activation, characterized by higher levels of isotype class switching, clonality, SHM rates, and shorter CDR3 lengths. These findings suggest that B cell-mediated humoral immune responses and characteristics in NMOSD patients are distinct from those observed in the other CIDDs, including MOGAD. Age was identified as a clinical factor associated with BCR activation specifically in NMOSD, implying the significance of persistent B cell activation attributed to anti-aquaporin-4 antibodies, even in the absence of clinical relapses throughout an individual’s lifetime.

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Association of B cell profile and receptor repertoire with the progression of Alzheimer’s disease

Cited by 18 publications

References 56 publications

Single-cell transcriptomics reveals colonic immune perturbations during amyloid-β driven Alzheimer’s disease in mice

Single-cell transcriptomics reveals colonic immune perturbations during amyloid-β driven Alzheimer’s disease in mice

Immune-related signature of periodontitis and Alzheimer’s disease linkage

Distinct features of B cell receptors in neuromyelitis optica spectrum disorder among CNS inflammatory demyelinating diseases

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