Commensal microbiota influence systemic autoimmune responses

Praet, Jens Van; Donovan, Erin; Vanassche, Inge; Drennan, Michael; Windels, Fien; Dendooven, Amélie; Allais, Liesbeth; Cuvelier, Claude; Loo, Fons A. J. van de; Norris, Paula S.; Kruglov, Andrey; Nedospasov, Sergei A.; Rabot, Sylvie; Tito, Raúl Y.; Raes, Jeroen; Gaboriau-Routhiau, Valérie; Cerf‐Bensussan, Nadine; Wiele, Tom Van de; Eberl, Gérard; Ware, Carl F.; Elewaut, Dirk

doi:10.15252/embj.201489966

Cited by 98 publications

(64 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Another example of a pronounced immune-modulatory function of the microbiota is the ability of segmented filamentous bacteria (SFB) to direct the immune system of mice towards increased production of T H 17 cells, thereby protecting the animals from infectious agents 55 . Our research group also showed that SFB present during the neonatal colonization process in mice are important microbial components in the development of systemic autoimmunity in adult life 56 .…”

Section: Regulation Of Intestinal Immunitymentioning

confidence: 64%

“…2). This depletion ablates formation of isolated lymphoid follicles, along with an expansion of SFB 56 . Similarly, the secretion of lymphotoxin by intestinal innate lymphoid cells has been shown to regulate the production of IgA and microbiota composition in the gut of adult animals 147 , as does TLR5 or NLRP6 deficiency in mice 148,149 .…”

Section: Other Rheumatic Diseasesmentioning

confidence: 96%

“…Our research team identified an unexpected link between the gut microbiota and development of ANAs 56 . Surprisingly, the appearance of ANAs in adult life was linked to neonatal colonization of the gut with commensal flora.…”

Section: Modulation Of Antinuclear Antibody Formation and Systemic Aumentioning

confidence: 97%

“…Environmental factors are critical in the pathogenesis of SLE, the prototypic disease for generalized autoimmunity, with development of autoantibodies preceding onset of clinical disease 143 . A 2015 study has pinpointed a potential role for the microbiota in SLE via an effect of the microbiota in lowering the threshold for activation of autoreactive B cells 56 .…”

Section: Other Rheumatic Diseasesmentioning

confidence: 99%

“…These events would lead to changes in systemic immune responses, loss of tolerance and occurrence of systemic autoimmunity. An example to which such a model applies is the induction of ANAs, including antibodies against U1RNP, SSA/Ro and DNA topoisomerase I, following neonatal depletion of the TNF superfamily cytokine lymphotoxin 56 (FIG. 2).…”

Section: Other Rheumatic Diseasesmentioning

confidence: 99%

See 4 more Smart Citations

How the microbiota shapes rheumatic diseases

et al. 2016

Self Cite

View full text Add to dashboard Cite

The human gut harbours a tremendously diverse and abundant microbial community that correlates with, and even modulates, many health-related processes. The mucosal interfaces are particularly active sites of microorganism-host interplay. Growing insight into the characteristic composition and functionality of the mucosal microbiota has revealed that the microbiota is involved in mucosal barrier integrity and immune function. This involvement affects proinflammatory and anti-inflammatory processes not only at the epithelial level, but also at remote sites such as the joints. Here, we review the role of the gut microbiota in shaping local and systemic immune responses and how disturbances in the host-microorganism interplay can potentially affect the development and progression of rheumatic diseases. Increasing our understanding of how to promote host-microorganism homeostasis could therefore reveal novel strategies for the prevention or alleviation of rheumatic disease.

show abstract

Section: Regulation Of Intestinal Immunitymentioning

confidence: 64%

Section: Other Rheumatic Diseasesmentioning

confidence: 96%

Section: Modulation Of Antinuclear Antibody Formation and Systemic Aumentioning

confidence: 97%

Section: Other Rheumatic Diseasesmentioning

confidence: 99%

Section: Other Rheumatic Diseasesmentioning

confidence: 99%

See 3 more Smart Citations

How the microbiota shapes rheumatic diseases

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

Review: Metabolic Control of Immune System Activation in Rheumatic Diseases

Perl

2017

Arthritis & Rheumatology

View full text Add to dashboard Cite

Metabolic pathways mediate lineage specification within the immune system through the regulation of glucose utilization, a process that generates energy in the form of ATP and synthesis of amino acids, nucleotides, and lipids to enable cell growth, proliferation, and survival. CD4+ T cells, a proinflammatory cell subset, preferentially produce ATP through glycolysis, whereas cells with an antiinflammatory lineage, such as memory and regulatory T cells, favor mitochondrial ATP generation. In conditions of metabolic stress or a shortage of nutrients, cells rely on autophagy to secure amino acids and other substrates, while survival depends on the sparing of mitochondria and maintenance of a reducing environment. The pentose phosphate pathway acts as a key gatekeeper of inflammation by supplying ribose‐5‐phosphate for cell proliferation and NADPH for antioxidant defenses. Increased lysosomal catabolism, accumulation of branched amino acids, glutamine, kynurenine, and histidine, and depletion of glutathione and cysteine activate the mechanistic target of rapamycin (mTOR), an arbiter of lineage development within the innate and adaptive immune systems. Mapping the impact of susceptibility genes to metabolic pathways allows for better understanding and therapeutic targeting of disease‐specific expansion of proinflammatory cells. Therapeutic approaches aimed at glutathione depletion and mTOR pathway activation appear to be safe and effective for treating lupus, while an opposing intervention may be of benefit in rheumatoid arthritis. Environmental sources of origin for metabolites within immune cells may include microbiota and plants. Thus, a better understanding of the pathways of immunometabolism could provide new insights into the pathogenesis and treatment of the rheumatic diseases.

show abstract

Effect of Impaired T Cell Receptor Signaling on the Gut Microbiota in a Mouse Model of Systemic Autoimmunity

Shirakashi

Maruya

Hirota

et al. 2022

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective T cell receptor (TCR) signaling abnormalities and gut dysbiosis are thought to be involved in the development of systemic lupus erythematosus (SLE). However, it is not known whether these mechanisms are interrelated. This study was undertaken to explore the impact of defective TCR signaling on microbiota‐driven immune responses and the consequent triggering of systemic autoimmunity. Methods The responses of B6SKG mice harboring a mutation in ZAP‐70 leading to spontaneous development of SLE were evaluated under specific pathogen–free (SPF) and germ‐free (GF) conditions. The gut microbiome was analyzed using 16S ribosomal RNA sequencing. Secretory IgA production in the gut and follicular helper T (Tfh) cell development in the spleen and Peyer's patches were analyzed. Interleukin‐17 (IL‐17)–deficient mice and segmented filamentous bacteria (SFB)–specific TCR‐transgenic mice were used to examine the role of IL‐17 and thymic selection. Results SLE development in B6SKG mice was significantly more attenuated under GF conditions than under SPF conditions. The gut microbiota in B6SKG mice was altered, which was associated with the expansion of SFB and consequent development of SLE by driving Th17 cell differentiation, which was in turn blunted by IL‐17 deficiency. Notably, although systemic Tfh development and autoantibody IgG response were enhanced, local gut Tfh and IgA responses were impaired. Moreover, experiments in SFB‐specific TCR‐transgenic mice revealed that this differential response was caused by altered thymic selection of self‐ and microbiota‐reactive TCR because of defective TCR signaling. Conclusion Our findings indicate that defective TCR signaling alters the gut microbiota and promotes systemic autoimmunity by driving Th17 cell differentiation.

show abstract

Commensal microbiota influence systemic autoimmune responses

Cited by 98 publications

References 37 publications

How the microbiota shapes rheumatic diseases

How the microbiota shapes rheumatic diseases

Review: Metabolic Control of Immune System Activation in Rheumatic Diseases

Effect of Impaired T Cell Receptor Signaling on the Gut Microbiota in a Mouse Model of Systemic Autoimmunity

Contact Info

Product

Resources

About