Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis

Mark Asquith, Patrick Stauffer, Sean Davin, Claire Mitchell, Phoebe Lin, James (Jim) Rosenbaum

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Objective: The HLA–B27/β2-microglobulin (β2m)–transgenic (Tg) rat is a leading model of B27-associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. Previous studies have shown that adult HLA–B27/β2m–Tg rats have an altered intestinal microbiota. This study sought to better define the age-dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA. Methods: Intestinal contents were collected from wild-type and HLA–B27/β2m–Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ≥16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription–polymerase chain reaction (qRT-PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR. Results: An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA–B27/β2m–Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA–B27/β2m–Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA-coated fecal bacteria were significantly associated with expression of HLA–B27 and arthritis development. Conclusion: HLA–B27/β2m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA–B27/β2m–Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.

Original languageEnglish (US)
Pages (from-to)2151-2162
Number of pages12
JournalArthritis and Rheumatology
Volume68
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

Dysbiosis
Mucosal Immunity
Th17 Cells
Bacteria
Immunoglobulin A
16S Ribosomal RNA
Cytokines
Transgenic Rats
RNA Sequence Analysis
Peptides
Th1 Cells
Gastrointestinal Contents
Regulatory T-Lymphocytes
Pathologic Processes
Age of Onset
Innate Immunity
Arthritis
Flow Cytometry
Mucous Membrane
Inflammation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology

Cite this

Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis. / Asquith, Mark; Stauffer, Patrick; Davin, Sean; Mitchell, Claire; Lin, Phoebe; Rosenbaum, James (Jim).

In: Arthritis and Rheumatology, Vol. 68, No. 9, 01.09.2016, p. 2151-2162.

Research output: Contribution to journalArticle

@article{9514e8e0ed1e49998a85f96c6e3cf346,
title = "Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis",
abstract = "Objective: The HLA–B27/β2-microglobulin (β2m)–transgenic (Tg) rat is a leading model of B27-associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. Previous studies have shown that adult HLA–B27/β2m–Tg rats have an altered intestinal microbiota. This study sought to better define the age-dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA. Methods: Intestinal contents were collected from wild-type and HLA–B27/β2m–Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ≥16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription–polymerase chain reaction (qRT-PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR. Results: An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA–B27/β2m–Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA–B27/β2m–Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA-coated fecal bacteria were significantly associated with expression of HLA–B27 and arthritis development. Conclusion: HLA–B27/β2m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA–B27/β2m–Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.",
author = "Mark Asquith and Patrick Stauffer and Sean Davin and Claire Mitchell and Phoebe Lin and Rosenbaum, {James (Jim)}",
year = "2016",
month = "9",
day = "1",
doi = "10.1002/art.39681",
language = "English (US)",
volume = "68",
pages = "2151--2162",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "9",

}

TY - JOUR

T1 - Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis

AU - Asquith, Mark

AU - Stauffer, Patrick

AU - Davin, Sean

AU - Mitchell, Claire

AU - Lin, Phoebe

AU - Rosenbaum, James (Jim)

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Objective: The HLA–B27/β2-microglobulin (β2m)–transgenic (Tg) rat is a leading model of B27-associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. Previous studies have shown that adult HLA–B27/β2m–Tg rats have an altered intestinal microbiota. This study sought to better define the age-dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA. Methods: Intestinal contents were collected from wild-type and HLA–B27/β2m–Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ≥16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription–polymerase chain reaction (qRT-PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR. Results: An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA–B27/β2m–Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA–B27/β2m–Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA-coated fecal bacteria were significantly associated with expression of HLA–B27 and arthritis development. Conclusion: HLA–B27/β2m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA–B27/β2m–Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.

AB - Objective: The HLA–B27/β2-microglobulin (β2m)–transgenic (Tg) rat is a leading model of B27-associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. Previous studies have shown that adult HLA–B27/β2m–Tg rats have an altered intestinal microbiota. This study sought to better define the age-dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA. Methods: Intestinal contents were collected from wild-type and HLA–B27/β2m–Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ≥16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription–polymerase chain reaction (qRT-PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR. Results: An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA–B27/β2m–Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA–B27/β2m–Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA-coated fecal bacteria were significantly associated with expression of HLA–B27 and arthritis development. Conclusion: HLA–B27/β2m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA–B27/β2m–Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.

UR - http://www.scopus.com/inward/record.url?scp=84971518457&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84971518457&partnerID=8YFLogxK

U2 - 10.1002/art.39681

DO - 10.1002/art.39681

M3 - Article

C2 - 26992013

AN - SCOPUS:84971518457

VL - 68

SP - 2151

EP - 2162

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 9

ER -