Interplay of Microbiota and Citrullination in the Immunopathogenesis of Rheumatoid Arthritis

Alghamdi, Mohammed; Redwan, Elrashdy M.

doi:10.1007/s12602-021-09802-7

Cited by 12 publications

(18 citation statements)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In search of homology between bacterial proteins and RA-related T-cell epitopes using an immunoinformatics analysis, Repac et al were able to retrieve the major RA-triggering candidates among which are Proteus mirabilis , Escherichia coli , Mycobacterium tuberculosis , Klebsiella pneumoniae , Streptococcus pyogenes, and Prevotella species [ 6 ]. A possible role of some oral and gut microbial species ( Porphyromonas gingivalis and Prevotella copri ) in RA pathogenicity has also been discussed [ 9 , 10 ]. During dysbiosis, these species can mediate the process of the citrullination of bacterial or human proteins triggering an immune response and production of anti-citrullinated antibodies that cross-react with human citrullinated peptides through molecular mimicry [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mimicry of the Rheumatoid Arthritis-Related Immunodominant T-Cell Epitope within Type II Collagen (CII260-270) by the Bacterial L-Asparaginase

Moten

Teneva

Apostolova

et al. 2022

IJMS

View full text Add to dashboard Cite

The etiology of most autoimmune diseases, including rheumatoid arthritis (RA), remains unclear. Both genetic and environmental factors are believed to be involved in pathogenesis. Molecular mimicry is considered one of the mechanisms for the occurrence of autoimmune diseases. The aim of the study was to determine whether the bacterial peptide L-ASNase67-81, which mimics the immunodominant T-cell epitope CII259-273, can induce T-cell reactivity in blood samples from RA patients and healthy subjects through molecular mimicry. Using bioinformatic molecular modeling methods, we first determined whether the L-ASNase67-81 peptide binds to the HLA-DRB1*04:01 molecule and whether the formed MHCII–peptide complex interacts with the corresponding T-cell receptor. To validate the obtained results, leukocytes isolated from early RA patients and healthy individuals were stimulated in vitro with L-ASNase67-81 and CII259-273 peptides as well as with bacterial L-asparaginase or human type II collagen (huCII). The activated T cells (CD4+CD154+) were analyzed by flow cytometry (FACS), and the levels of cytokines produced (IL-2, IL-17A/F, and IFN-γ) were measured by ELISA. Our in silico analyses showed that the bacterial peptide L-ASNase67-81 binds better to HLA-DRB1*04:01 compared to the immunodominant T-cell epitope CII259-273, mimicking its structure and localization in the binding groove of MHCII. Six contact points were involved in the molecular interaction of the peptide with the TCR. FACS data showed that after in vitro stimulation with the L-ASNase67-81 peptide, the percentage of activated T cells (CD154+CD4+) was significantly increased in both cell cultures isolated from ERA patients and those isolated from healthy individuals, as higher values were observed for the ERA group (9.92 ± 0.23 vs. 4.82 ± 0.22). Furthermore, the ELISA assays revealed that after stimulation with L-ASNase67-81, a significant increase in the production of the cytokines IL-2, IL-17A/F, and IFN-γ was detected in the group of ERA patients. Our data showed that the bacterial L-ASNase67-81 peptide can mimic the immunodominant T-cell epitope CII259-273 and activate HLA-DRB1*04:01-restricted T cells as well as induce cytokine production in cells isolated from ERA patients. These results are the first to demonstrate that a specific bacterial antigen could play a role in the pathogenesis of RA, mimicking the immunodominant T-cell epitope from type II collagen.

show abstract

Section: Introductionmentioning

confidence: 99%

Molecular Mimicry of the Rheumatoid Arthritis-Related Immunodominant T-Cell Epitope within Type II Collagen (CII260-270) by the Bacterial L-Asparaginase

Moten

Teneva

Apostolova

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Indeed, increasing evidence has revealed that dysbiosis is closely connected to many diseases, including autoimmune diseases [e.g., rheumatoid arthritis ( Gianchecchi and Fierabracci, 2019 ; Alghamdi and Redwan, 2021 ) and multiple sclerosis ( Tsunoda, 2017 ; Zeng et al., 2019 ; Wang et al., 2021 )], inflammatory diseases [e.g., ankylosing spondylitis ( Ciccia et al., 2017 ; Wen et al., 2017 ; Berlinberg et al., 2021 ), infective endocarditis ( Del Giudice et al., 2021 ), and inflammatory bowel disease ( Kassam et al., 2018 ; Gianchecchi and Fierabracci, 2019 ; Pavel et al., 2021 )], and ocular diseases [e.g., age-related macular degeneration ( Rowan et al., 2017 ; Rinninella et al., 2018 ), diabetic retinopathy ( Beli et al., 2018 ), dry eye ( Cavuoto et al., 2019 ; Trujillo-Vargas et al., 2020 ), glaucoma ( Chen et al., 2018 ; Doulberis et al., 2019 ), and uveitis ( Fu et al., 2021 )].…”

Section: Introductionmentioning

confidence: 99%

The Role of the Microbiota in Graves’ Disease and Graves’ Orbitopathy

Hou

Tang²,

Chen³

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Graves‘ disease (GD) is a clinical syndrome with an enlarged and overactive thyroid gland, an accelerated heart rate, Graves’ orbitopathy (GO), and pretibial myxedema (PTM). GO is the most common extrathyroidal complication of GD. GD/GO has a significant negative impact on the quality of life. GD is the most common systemic autoimmune disorder, mediated by autoantibodies to the thyroid-stimulating hormone receptor (TSHR). It is generally accepted that GD/GO results from complex interactions between genetic and environmental factors that lead to the loss of immune tolerance to thyroid antigens. However, the exact mechanism is still elusive. Systematic investigations into GD/GO animal models and clinical patients have provided important new insight into these disorders during the past 4 years. These studies suggested that gut microbiota may play an essential role in the pathogenesis of GD/GO. Antibiotic vancomycin can reduce disease severity, but fecal material transfer (FMT) from GD/GO patients exaggerates the disease in GD/GO mouse models. There are significant differences in microbiota composition between GD/GO patients and healthy controls. Lactobacillus, Prevotella, and Veillonella often increase in GD patients. The commonly used therapeutic agents for GD/GO can also affect the gut microbiota. Antigenic mimicry and the imbalance of T helper 17 cells (Th17)/regulatory T cells (Tregs) are the primary mechanisms proposed for dysbiosis in GD/GO. Interventions including antibiotics, probiotics, and diet modification that modulate the gut microbiota have been actively investigated in preclinical models and, to some extent, in clinical settings, such as probiotics (Bifidobacterium longum) and selenium supplements. Future studies will reveal molecular pathways linking gut and thyroid functions and how they impact orbital autoimmunity. Microbiota-targeting therapeutics will likely be an essential strategy in managing GD/GO in the coming years.

show abstract

“…were overexpanded in stool samples from low educated individuals and among them HLA-DRB1-SE represented a risk factor for RA, the study illustrated. The contribution of oral and gut microbial species to the pathogenesis of RA was previously demonstrated [ 110 ]. The potential pathogenetic role of tetraspanin32 (TSPAN32), a member of the tetraspanin family, which is actively involved in the regulation of the immune responses in RA was discussed by Fagone.…”

Section: Autoimmune and Rheumatic Diseases During Auto13: (Diseases 1–9)mentioning

confidence: 99%

The mosaic of autoimmunity – Finally discussing in person. The 13th international congress on autoimmunity 2022 (AUTO13) Athens

Mahroum

Elsalti

Alwani

et al. 2022

Autoimmunity Reviews

View full text Add to dashboard Cite

Interplay of Microbiota and Citrullination in the Immunopathogenesis of Rheumatoid Arthritis

Cited by 12 publications

References 141 publications

Molecular Mimicry of the Rheumatoid Arthritis-Related Immunodominant T-Cell Epitope within Type II Collagen (CII260-270) by the Bacterial L-Asparaginase

Molecular Mimicry of the Rheumatoid Arthritis-Related Immunodominant T-Cell Epitope within Type II Collagen (CII260-270) by the Bacterial L-Asparaginase

The Role of the Microbiota in Graves’ Disease and Graves’ Orbitopathy

The mosaic of autoimmunity – Finally discussing in person. The 13th international congress on autoimmunity 2022 (AUTO13) Athens

Contact Info

Product

Resources

About