TLR7 and IgM: Dangerous Partners in Autoimmunity

Amendt, Timm; Yu, Philipp

doi:10.3390/antib12010004

Cited by 7 publications

(4 citation statements)

References 87 publications

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“…It has also been demonstrated that gut microbiota induces a homeostatic humoral response, not only restricted to IgG, but also IgA and IgM. Therefore, we determined all three classes ( 53 ) against the most abundant bacteria in the gut of TLR7Tg mice. Although we found an increased adaptive IgG2c and IgA response in TLR7Tg mice against B. acidifaciens , the IgM response was unexpectedly higher.…”

Section: Discussionmentioning

confidence: 99%

Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals

et al. 2023

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IntroductionSystemic lupus erythematosus is an autoimmune disease with multisystemic involvement including intestinal inflammation. Lupus-associated intestinal inflammation may alter the mucosal barrier where millions of commensals have a dynamic and selective interaction with the host immune system. Here, we investigated the consequences of the intestinal inflammation in a TLR7-mediated lupus model.MethodsIgA humoral and cellular response in the gut was measured. The barrier function of the gut epithelial layer was characterised. Also, microbiota composition in the fecal matter was analysed as well as the systemic humoral response to differential commensals.ResultsThe lupus-associated intestinal inflammation modifies the IgA+ B cell response in the gut-associated lymphoid tissue in association with dysbiosis. Intestinal inflammation alters the tight junction protein distribution in the epithelial barrier, which correlated with increased permeability of the intestinal barrier and changes in the microbiota composition. This permeability resulted in a differential humoral response against intestinal commensals.DiscussionLupus development can cause alterations in microbiota composition, allowing specific species to colonize only the lupus gut. Eventually, these alterations and the changes in gut permeability induced by intestinal inflammation could lead to bacterial translocation.

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Section: Discussionmentioning

confidence: 99%

Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals

et al. 2023

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“…Importantly, given heat inactivation, washing, and use of healthy control serum in the assay, this also demonstrated that IgM alone was sufficient to stimulate pathologic complement activity in some cases of CM-HUS. Together these results suggest a role for both "natural, polyreactive" and "autoreactive" IgM in the disease 51 .…”

Section: Pre-sensitization Of Piga or Dko Cells With Cm-hus Sera And ...mentioning

confidence: 72%

Complement Biosensors Identify a Classical Pathway Stimulus in Complement-Mediated Hemolytic Uremic Syndrome

Cole,

Ranjan,

Gerber

et al. 2024

Preprint

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Complement-mediated hemolytic uremic syndrome (CM-HUS) is a thrombotic microangiopathy characterized by germline variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement “biosensors’’ by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-HUS and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies IgM-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ~50% of CM-HUS patients who lack an alternative pathway “driving” variant and suggests at least a subset of CM-HUS is characterized by a breakdown of IgM immunologic tolerance.Key PointsCM-HUS has a CP stimulus driven by polyreactive IgM, addressing the mystery of why 40% of CM-HUS lack complement specific variantsComplement biosensors and the bioluminescent mHam can be used to aid in diagnosis of CM-HUS and monitor complement inhibitor therapy

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“…Our bi-variate Mendelian randomization analysis intimates that Type 1 Diabetes, Multiple Sclerosis, and Rheumatoid Arthritis exert deleterious effects on anemia, with multivariable MR substantiating the detrimental interrelation among Type 1 Diabetes, Multiple Sclerosis, and anemia. These adverse associations may be mediated through mechanisms pertinent to immune responses 49 , chronic in ammation, and drug interactions. In Type 1 Diabetes, the autoimmune apparatus erroneously targets pancreatic β-cells, a dysregulation similarly manifested in certain anemic conditions 50 .…”

Section: Discussionmentioning

confidence: 99%

Genetic Associations Between Autoimmune Diseases and Anemia: A Mendelian Randomization Analysis to Inform Clinical Practice.

shi,

zhuang,

chen

et al. 2024

Preprint

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Background: Autoimmune diseases and anemia are clinically distinct yet recent studies suggest a potential association. The causal link is unclear, prompting this study's utilization of univariate and multivariate Mendelian randomization analyses to probe a possible causal connection. Method: A thorough literature review and analysis of summary statistics from genome-wide association studies (GWAS) data, sourced from public databases, were conducted. Ten autoimmune diseases and anemia were selected for scrutiny. Single Nucleotide Polymorphisms (SNPs) significantly associated with these diseases were identified, serving as instrumental variables with anemia as the outcome variable. Both univariable and multivariable Mendelian randomization analyses were performed to assess the causal link. Results: Ten autoimmune diseases were analyzed concerning their relationship with anemia. Univariate analysis revealed that Type 1 Diabetes, Multiple Sclerosis, and Rheumatoid Arthritis genetically contribute to anemia risk. Multivariate analysis sustained a significant association between the genetic predisposition toward Type 1 Diabetes, Multiple Sclerosis and anemia risk. Conclusion: This study supports the notion that autoimmune diseases negatively influence anemia risk, suggesting that targeting autoimmune diseases may be key to mitigating anemia risk. The relationship between autoimmune diseases and anemia warrants further investigation for potential preventive and treatment strategies.

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TLR7 and IgM: Dangerous Partners in Autoimmunity

Cited by 7 publications

References 87 publications

Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals

Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals

Complement Biosensors Identify a Classical Pathway Stimulus in Complement-Mediated Hemolytic Uremic Syndrome

Genetic Associations Between Autoimmune Diseases and Anemia: A Mendelian Randomization Analysis to Inform Clinical Practice.

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