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1.
Eur Heart J Case Rep ; 5(4): ytab140, 2021 Apr.
Article in English | MEDLINE | ID: mdl-34268475

ABSTRACT

BACKGROUND: Coronavirus Disease-2019 (COVID-19) has been associated with increased incidence of pulmonary embolism (PE), even among patients at low risk for venous thrombo-embolic (VTE) events. CASE SUMMARY: We present the case of a 21-year-old male, with no previous medical history, who presented with cough, fevers, shortness of breath, pleuritic chest pain, and 1 day of dizziness with near syncope as well as acutely worsened dyspnoea. He was subsequently diagnosed with COVID-19 and massive PE. He underwent successful catheter-directed thrombolysis (CDT), and his clinical status improved. One day following initial CDT, he developed acute respiratory failure and hypotension and was diagnosed with recurrent massive PE. He was treated with repeat CDT and extracorporeal membrane oxygenation (ECMO) to provide time for right ventricular recovery. The patient was able to be weaned off ECMO after 9 days and was eventually extubated and discharged to an acute rehabilitation facility. DISCUSSION: Beyond COVID-19, no hypercoagulable risk factors were identified despite thorough investigation. This case highlights the thrombogenic potential and morbid sequelae of SARS-CoV-2 infection, even in young patients. It also highlights the use of CDT and ECMO among patients with massive PE and COVID-19. To date, this is the youngest reported patient to develop massive PE in the setting of COVID-19.

2.
Cell Host Microbe ; 22(5): 697-704.e4, 2017 11 08.
Article in English | MEDLINE | ID: mdl-29120746

ABSTRACT

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.


Subject(s)
Autoimmune Diseases/immunology , Autoimmune Diseases/microbiology , Autoimmunity , Bacteria/immunology , Gastrointestinal Microbiome/immunology , Lung/immunology , Th17 Cells/immunology , Animals , Apoptosis/immunology , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/microbiology , Autoantibodies , Bacteria/pathogenicity , Cell Differentiation/immunology , Cell Proliferation , Chemokine CCL20/metabolism , Disease Models, Animal , Feces/microbiology , Lung/microbiology , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Transgenic , Spleen , Symbiosis , Th17 Cells/metabolism
3.
Arthritis Res Ther ; 19(1): 188, 2017 08 15.
Article in English | MEDLINE | ID: mdl-28810929

ABSTRACT

BACKGROUND: Age 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. METHODS: We 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. RESULTS: Middle-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). CONCLUSION: Age-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.


Subject(s)
Arthritis, Rheumatoid/immunology , Autoimmune Diseases/immunology , Gastrointestinal Microbiome/immunology , T-Lymphocytes, Helper-Inducer/immunology , Th17 Cells/immunology , Age Factors , Animals , Arthritis, Rheumatoid/genetics , Autoimmune Diseases/genetics , Cell Differentiation/genetics , Cell Differentiation/immunology , Cell Proliferation/genetics , Lung/immunology , Lung/metabolism , Lung/pathology , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Transgenic , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Th17 Cells/metabolism
4.
J Immunol ; 198(5): 1855-1864, 2017 03 01.
Article in English | MEDLINE | ID: mdl-28130500

ABSTRACT

Rheumatoid arthritis is an autoimmune disorder that affects the joints and other organs. Pulmonary complications contribute significantly to rheumatoid arthritis mortality. Retinoic acid and its synthetic compound AM80 play roles in immunoregulation but their effect on mucosal autoimmunity remains largely unknown. T follicular helper (Tfh) and Th17 cells are known to promote inflammation and autoantibody production. Using the K/BxN autoimmune arthritis model, we elucidate a novel mechanism whereby oral AM80 administration suppressed lung mucosa-associated Tfh and autoantibody responses by increasing the gut-homing α4ß7 integrin expression on Tfh cells. This diverted Tfh cells from systemic (non-gut) inflamed sites such as the lung into the gut-associated lymphoid tissues, Peyer's patches, and thus reduced the systemic autoantibodies. AM80 also inhibited the lung Th17 response. AM80's effect in the lungs was readily applied to the joints as AM80 also inhibited Tfh and Th17 responses in the spleen, the major autoantibody producing site known to correlate with K/BxN arthritis severity. Finally, we used anti-ß7 treatment as an alternative approach, demonstrating that manipulating T cell migration between the gut and systemic sites alters the systemic disease outcome. The ß7 blockade prevented both Tfh and Th17 cells from entering the non-immunopathogenic site, the gut, and retained these T effector cells in the systemic sites, leading to augmented arthritis. These data suggest a dual beneficial effect of AM80, targeting both Tfh and Th17 cells, and warrant strict safety monitoring of gut-homing perturbing agents used in treating intestinal inflammation.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Autoimmunity/drug effects , Benzoates/therapeutic use , Lung/immunology , Tetrahydronaphthalenes/therapeutic use , Th17 Cells/immunology , Animals , Arthritis, Rheumatoid/immunology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/prevention & control , Autoimmunity/immunology , Benzoates/administration & dosage , Benzoates/adverse effects , Cell Differentiation/immunology , Disease Models, Animal , Integrins/deficiency , Integrins/genetics , Integrins/immunology , Intestines/immunology , Lung/cytology , Lymph Nodes/cytology , Lymph Nodes/immunology , Mice , Peyer's Patches/immunology , T-Lymphocytes, Helper-Inducer/immunology , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effects
5.
Immunity ; 44(4): 875-88, 2016 Apr 19.
Article in English | MEDLINE | ID: mdl-27096318

ABSTRACT

Gut microbiota profoundly affect gut and systemic diseases, but the mechanism whereby microbiota affect systemic diseases is unclear. It is not known whether specific microbiota regulate T follicular helper (Tfh) cells, whose excessive responses can inflict antibody-mediated autoimmunity. Using the K/BxN autoimmune arthritis model, we demonstrated that Peyer's patch (PP) Tfh cells were essential for gut commensal segmented filamentous bacteria (SFB)-induced systemic arthritis despite the production of auto-antibodies predominantly occurring in systemic lymphoid tissues, not PPs. We determined that SFB, by driving differentiation and egress of PP Tfh cells into systemic sites, boosted systemic Tfh cell and auto-antibody responses that exacerbated arthritis. SFB induced PP Tfh cell differentiation by limiting the access of interleukin 2 to CD4(+) T cells, thereby enhancing Tfh cell master regulator Bcl-6 in a dendritic cell-dependent manner. These findings showed that gut microbiota remotely regulated a systemic disease by driving the induction and egress of gut Tfh cells.


Subject(s)
Arthritis/immunology , Cell Differentiation/immunology , Cell Movement/immunology , Gastrointestinal Microbiome/immunology , Peyer's Patches/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Autoantibodies/immunology , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/immunology , Dendritic Cells/immunology , Interleukin-2/immunology , Interleukin-2 Receptor alpha Subunit/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Peyer's Patches/cytology , Proto-Oncogene Proteins c-bcl-6 , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes, Helper-Inducer/cytology
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