Exploring the Pathogenesis of Autoimmune Liver Diseases from the Heterogeneity of Target Cells

The incidence of autoimmune liver diseases(ALDs)and research on their pathogenesis are increasing annually.However,except for autoimmune hepatitis,which responds well to immunosuppression,primary biliary cholangitis and primary sclerosing cholangitis are insensitive to immunosuppressive therapy.Besides the known effects of the environment,genetics,and immunity on ALDs,the heterogeneity of target cells provides new insights into their pathogenesis.This review started by exploring the heterogeneity in the development,structures,and functions of hepatocytes and epithelial cells of the small and large bile ducts.For example,cytokeratin(CK)8 and CK18 are primarily expressed in hepatocytes,while CK7 and CK19 are primarily expressed in intrahepatic cholangiocytes.Additionally,emerging technologies of single-cell RNA sequencing and spatial transcriptomic are being applied to study ALDs.This review offered a new perspective on understanding the pathogenic mechanisms and potential treatment strategies for ALDs.

STUDY ON THE HETEROGENEITY OF TSH RECEPTOR ANTIBODIES IN THE PATHOGENESIS OF AUTOIMMUNE THYROID DISEASE

Objective To investigate the heterogeneity of TSH receptor antibodies ofpatients with autoimmune thyroid disease (AITD). Methods Six patients with heterogeneous TSH receptor antibodies were selected. The EBV-transformed B cell clones producing monoclonal anti-thyrotropin receptor antibodies were established from those selected patients. Results 125I-TSHbinding inhibiting immunoglobulin (TBII) values of the 6 patients ranged from 51 % to 89%. Thyroid stimulating antibody (TSAb) existed in patients No. 1,2, 4, 5 and 6 while only patients No. 1,2 and 3 had thyroid stimulation-blocking antibody (TSBAb ). After EBV-transformation of the peripheral B lymphocytes from those patients, we isolated and characterized 5 Bcell clones prepucing the TBII from patient No. 3 and 4 B cell clones prepucing TSAb from patient No. 6. Conclusion Autoantibodies against the us receptor are polyclonal and consist of heterogeneous populations with both stimulatory and inhibitory effects.

Classification of metabolic-associated fatty liver disease subtypes based on TCM clinical phenotype

Objective:To classify the subtypes of metabolic-associated fatty liver disease(MAFLD)and provide new insights into the heterogeneity of MAFLD.Methods:Electronic medical records(EMR)of MAFLD diagnosed in accordance with the diagnostic criteria of Hubei Provincial Hospital of Traditional Chinese Medicine from 2016-2020 were included in the study.for physical annotation,and the data on each clinical phenotype was normalized according to corresponding aspirational standards.The MAFLD heterogeneous medical record network(HEMnet)was constructed using sex,age,disease diagnosis,symptoms,and Western medicine prescriptions as nodes and the co-occurrence times between phenotypes as edges.K-means clustering was used for disease classification.Relative risk(RR)was used to assess the specificity of each phenotype.Statistical methods were used to compare differences in laboratory indicators among subtypes.Results:A total of patients(12,626)with a mean age of 55.02(±14.21)years were included in the study.MAFLD can be divided into five subtypes:digestive diseases(C0),mental disorders and gynecological diseases(C1),chronic liver diseases and decompensated complications(C2),diabetes mellitus and its complications(C3),and immune joint system diseases(C4).Conclusions:Patients with MAFLD experience various symptoms and complications.The classification of MAFLD based on the HEMnet method is highly reliable.

Lower and upper motor neuron involvement and their impact on disease prognosis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive muscle wasting,breathing and swallowing difficulties resulting in patient’s death in two to five years after disease onset.In amyotrophic lateral sclerosis,both upper and lower motor neurons of the corticospinal tracts are involved in the process of neurodegeneration,accounting for great clinical heterogeneity of the disease.Clinical phenotype has great impact on the pattern and rate of amyotrophic lateral sclerosis progression and overall survival prognosis.Creating more homogenous patient groups in order to study the effects of drug agents on specific manifestations of the disease is a challenging issue in amyotrophic lateral sclerosis clinical trials.Since amyotrophic lateral sclerosis has low incidence rates,conduction of multicenter trials requires certain standardized approaches to disease diagnosis and staging.This review focuses on the current approaches in amyotrophic lateral sclerosis classification and staging system based on clinical examination and additional instrumental methods,highlighting the role of upper and lower motor neuron involvement in different phenotypes of the disease.We demonstrate that both clinical and instrumental findings can be useful in evaluating severity of upper motor neuron and lower motor neuron involvement and predicting the following course of the disease.Addressing disease heterogeneity in amyotrophic lateral sclerosis clinical trials could lead to study designs that will assess drug efficacy in specific patient groups,based on the disease pathophysiology and spatiotemporal pattern.Although clinical evaluation can be a sufficient screening method for dividing amyotrophic lateral sclerosis patients into clinical subgroups,we provide proof that instrumental studies could provide valuable insights in the disease pathology.

Integrative analysis of bulk and single-cell RNA sequencing data reveals distinct subtypes of MAFLD based on N1-methyladenosine regulator expression

Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course.Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases.However,it remains unclear whether the RNA N1-methyladenosine(m1A)modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.Materials and methods:To address this issue,we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing(scRNA-seq)data to pinpoint m1A regulators in the network.This was followed by a description of the immune landscape,pathway enrichment analysis,and molecular subtyping.Results:The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes,Cluster 1 and Cluster 2.These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics,which suggest different immune-inflammatory responses in the liver.Notably,Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD.Through intersection analysis of weighted gene co-expression network analysis(WGCNA)and m1A regulatory genes,three true hub genes(ALKBH1,YTHDC1,and YTHDF3)were identified,all of which were strongly correlated with infiltrating immune cells.The specific signaling pathways involved in the three core genes were derived from genomic variation analysis.Furthermore,scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types,with endothelial cells,macrophages,and monocytes showing the most significant differences between MAFLD and normal controls.The cell-cell communication network between immune cells and nonparenchymal cells was extremely sophisticated and changed significantly in MAFLD.Conclusions:In summary,these findings demonstrate the involvement of m1A in MAFLD heterogeneity and emphasize the crucial role of m1A modulation of immune cells in regulating inflammation in MAFLD.These results may suggest potential therapeutic strategies for MAFLD.

Novel data-driven subtypes and stages of brain atrophy in the ALS-FTD spectrum

Background TDP-43 proteinopathies represent a spectrum of neurological disorders,anchored clinically on either end by amyotrophic lateral sclerosis(ALS)and frontotemporal degeneration(FTD).The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes,highlighting its heterogeneity.This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.Methods We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD(bvFTD;with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants),103 ALS,and 47 ALS-FTD patients with likely TDP-43.A Subtype and Stage Inference(SuStaIn)model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns,and we related subtypes and stages to clinical,genetic,and neuropathological features of disease.Results SuStaIn identified three novel subtypes:two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions,and a normal-appearing group without obvious brain atrophy.The limbic-predominant subtype tended to present with more impaired cognition,higher frequencies of pathogenic variants in TBK1 and TARDBP genes,and a higher proportion of TDP-43 types B,E and C.In contrast,the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A.The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients,higher cognitive capacity,higher proportion of lower motor neuron onset,milder motor symptoms,and lower frequencies of genetic pathogenic variants.The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration,higher King’s stage,and cognitive decline.Additionally,SuStaIn stages differed across clinical phenotypes,genotypes and types of TDP-43 pathology.Conclusions Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo,each with distinct brain atrophy,clinical,genetic and pathological patterns.