Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses

Naskar, Debdut; Teng, Fei; Felix, Krysta M.; Bradley, Caroline; Wu, Ho‐Ting

doi:10.4049/jimmunol.1601776

Cited by 23 publications

(15 citation statements)

References 56 publications

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“…Inducible bronchus-associated lymphoid tissue (iBALT) is a type of ectopic lymphoid tissue found in the lungs of patients with RA and is positively correlated with the severity of the patient’s lung disease [ 28 ]. Previously we have demonstrated that SFB colonization provoked young K/BxN mice to develop iBALT-like structures closely resembling the iBALT formations in patients with RA [ 29 , 30 ]. Here, we compared iBALT lesions between young and middle-aged groups with or without SFB colonization.…”

Section: Resultsmentioning

confidence: 99%

The impact of age and gut microbiota on Th17 and Tfh cells in K/BxN autoimmune arthritis

et al. 2017

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BackgroundAge is an important risk factor for rheumatoid arthritis (RA), which often develops in middle age. However, how age-associated changes in immunity impact RA is poorly understood. Gut microbiota are known to be involved in the pathogenesis of RA, but the effects of microbiota in older subjects remain mostly unknown.MethodsWe used segmented filamentous bacteria (SFB), a gut commensal species with immunomodulatory effects, and K/BxN mice, a T cell receptor (TCR) transgenic model, to study the effect of age and microbiota on autoimmune arthritis. Comparing young and middle-aged K/BxN T cells of the same TCR specificity allows us to study T cells with an age focus eliminating a key variable: TCR repertoire alteration with age. In addition to joints, we also studied pathological changes in the lung, an important extra-articular RA manifestation. We used flow cytometry to evaluate T follicular helper (Tfh) and T helper 17 (Th17) cells, as they both contribute to autoantibody production, a key disease index in both RA and K/BxN arthritis.ResultsMiddle-aged K/BxN mice had aggravated arthritis and pathological changes in the lung compared to young mice. Middle-aged mice displayed a strong accumulation of Tfh but not Th17 cells, and had defective Th17 differentiation and low expression of interleukin-23, a critical cytokine for Th17 maintenance. Although a soaring Tfh cell population accompanied by robust germinal center B cell responses were found in middle-aged mice, there was decreased cycling of Tfh cells, and SFB only induced the non-Tfh cells to upregulate Bcl-6, the Tfh master transcription factor, in the young but not the middle-aged group. Finally, the accumulated Tfh cells in middle-aged mice had an effector phenotype (CD62LloCD44hi).ConclusionAge-dependent Tfh cell accumulation may play a crucial role in the increased autoimmune disease phenotype in middle-age. SFB, a potent stimulus for inducing Tfh differentiation, fails to promote Tfh differentiation in middle-aged K/BxN mice, suggesting that most of the middle-aged Tfh cells with an effector phenotype are Tfh effector memory cells induced at an earlier age. Our results also indicate that exposure to immunomodulatory commensals may allow the young host to develop an overactive immune system reminiscent of that found in the middle-aged host.

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Section: Resultsmentioning

confidence: 99%

The impact of age and gut microbiota on Th17 and Tfh cells in K/BxN autoimmune arthritis

et al. 2017

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“…The inducible bronchus-associated lymphoid tissues (iBALT), a type of ELT found in the lung of RA patients, has been shown to correlate with lung tissue damage (Rangel-Moreno et al, 2006). K/BxN mice develop iBALT-like structures characterized by peribronchial and perivascular lymphocytic infiltration (Naskar et al, 2017). Thus, iBALT-like structures provide a clinically relevant index for RA-related lung disease in K/BxN mice.…”

Section: Introductionmentioning

confidence: 99%

Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs

Bradley

Teng

Felix

et al. 2017

Cell Host & Microbe

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SUMMARY Lung complications are a major cause of rheumatoid arthritis-related mortality. Involvement of gut microbiota in lung diseases by the gut-lung axis has been widely observed, but the underlying mechanism remains mostly unknown. Using an autoimmune arthritis model, we show that a constituent of the gut microbiota, segmented filamentous bacteria (SFB), distantly provoke lung pathology. SFB induce autoantibodies in lung during the pre-arthritic phase, and SFB-dependent lung pathology requires the T helper 17 (Th17) responses. SFB-induced gut Th17 cells are preferentially recruited to lung over spleen due to robust expression in the lung of the Th17 chemoattractant, CCL20. Additionally, we found that in peripheral tissues, SFB selectively expand dual T cell receptor (TCR)-expressing Th17 cells recognizing both an SFB epitope and self-antigen, thus augmenting autoimmunity. This study reveals mechanisms for commensal-mediated gut-lung crosstalk and dual TCR-based autoimmunity.

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“…Lung single cell preparation was described previously (Naskar et al, 2017 ). Briefly, lungs were perfused through the right ventricle of the heart with 10 ml of PBS to flush blood, then finely minced.…”

Section: Methodsmentioning

confidence: 99%

Gut Microbiota Contributes to Resistance Against Pneumococcal Pneumonia in Immunodeficient Rag−/− Mice

Felix

Jaimez

Nguyen

et al. 2018

Front. Cell. Infect. Microbiol.

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Streptococcus pneumoniae causes infection-related mortality worldwide. Immunocompromised individuals, including young children, the elderly, and those with immunodeficiency, are especially vulnerable, yet little is known regarding S. pneumoniae-related pathogenesis and protection in immunocompromised hosts. Recently, strong interest has emerged in the gut microbiota's impact on lung diseases, or the “gut-lung axis.” However, the mechanisms of gut microbiota protection against gut-distal lung diseases like pneumonia remain unclear. We investigated the role of the gut commensal, segmented filamentous bacteria (SFB), against pneumococcal pneumonia in immunocompetent and immunocompromised mouse models. For the latter, we chose the Rag−/− model, with adaptive immune deficiency. Immunocompetent adaptive protection against S. pneumoniae infection is based on antibodies against pneumococcal capsular polysaccharides, prototypical T cell independent-II (TI-II) antigens. Although SFB colonization enhanced TI-II antibodies in C57BL/6 mice, our data suggest that SFB did not further protect these immunocompetent animals. Indeed, basal B cell activity in hosts without SFB is sufficient for essential protection against S. pneumoniae. However, in immunocompromised Rag−/− mice, we demonstrate a gut-lung axis of communication, as SFB influenced lung protection by regulating innate immunity. Neutrophil resolution is crucial to recovery, since an unchecked neutrophil response causes severe tissue damage. We found no early neutrophil recruitment differences between hosts with or without SFB; however, we observed a significant drop in lung neutrophils in the resolution phase of S. pneumoniae infection, which corresponded with lower CD47 expression, a molecule that inhibits phagocytosis of apoptotic cells, in SFB-colonized Rag−/− mice. SFB promoted a shift in lung neutrophil phenotype from inflammatory neutrophils expressing high levels of CD18 and low levels of CD62L, to pro-resolution neutrophils with low CD18 and high CD62L. Blocking CD47 in SFB(−) mice increased pro-resolution neutrophils, suggesting CD47 down-regulation may be one neutrophil-modulating mechanism SFB utilizes. The SFB-induced lung neutrophil phenotype remained similar with heat-inactivated S. pneumoniae treatment, indicating these SFB-induced changes in neutrophil phenotype during the resolution phase are not simply secondary to better bacterial clearance in SFB(+) than SFB(−) mice. Together, these data demonstrate that the gut commensal SFB may provide much-needed protection in immunocompromised hosts in part by promoting neutrophil resolution post lung infection.

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Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses

Cited by 23 publications

References 56 publications

The impact of age and gut microbiota on Th17 and Tfh cells in K/BxN autoimmune arthritis

The impact of age and gut microbiota on Th17 and Tfh cells in K/BxN autoimmune arthritis

Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs

Gut Microbiota Contributes to Resistance Against Pneumococcal Pneumonia in Immunodeficient Rag−/− Mice

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