Aberrant expression of interleukin-23-regulated miRNAs in T cells from patients with ankylosing spondylitis

IL-17–producing Th17 cells are implicated in the pathogenesis of rheumatoid arthritis (RA) and TNF-α, a proinflammatory cytokine in the rheumatoid joint, facilitates Th17 differentiation. Anti-TNF therapy ameliorates disease in many patients with rheumatoid arthritis (RA). However, a significant proportion of patients do not respond to this therapy. The impact of anti-TNF therapy on Th17 responses in RA is not well understood. We conducted high-throughput gene expression analysis of Th17-enriched CCR6+CXCR3−CD45RA−CD4+T (CCR6+T) cells isolated from anti-TNF–treated RA patients classified as responders or nonresponders to therapy. CCR6+T cells from responders and nonresponders had distinct gene expression profiles. Proinflammatory signaling was elevated in the CCR6+T cells of nonresponders, and pathogenic Th17 signature genes were up-regulated in these cells. Gene set enrichment analysis on these signature genes identified transcription factor USF2 as their upstream regulator, which was also increased in nonresponders. Importantly, short hairpin RNA targetingUSF2in pathogenic Th17 cells led to reduced expression of proinflammatory cytokines IL-17A, IFN-γ, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as transcription factor T-bet. Together, our results revealed inadequate suppression of Th17 responses by anti-TNF in nonresponders, and direct targeting of the USF2-signaling pathway may be a potential therapeutic approach in the anti-TNF refractory RA.

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Arthritis and Foodborne Bacteria

Journal of Food Protection ◽

10.4315/0362-028x-57.10.935 ◽

1994 ◽

Vol 57 (10) ◽

pp. 935-941 ◽

Cited By ~ 11

Author(s):

JAMES L. SMITH

Keyword(s):

T Cells ◽

Ankylosing Spondylitis ◽

Reactive Arthritis ◽

Molecular Mimicry ◽

Food Poisoning ◽

Cell Subset ◽

Bacterial Cells ◽

Hla B27 ◽

Reiter's Syndrome ◽

Reiter’S Syndrome

Diarrheic episodes caused by the foodborne pathogens Campylobacter, Salmonella, Shigella or Yersinia may lead to a sterile arthritis such as reactive arthritis, Reiter's syndrome or ankylosing spondylitis. Reiter's syndrome and reactive arthritis have been shown to be sequelae in a few well-studied bacterial food poisoning outbreaks. Reactive arthritis, Reiter's syndrome and ankylosing spondylitis show strong familial association related to the gene for HLA-B27 (HLA = human leucocyte antigen) antigen. Why HLA-B27-positive individuals are more susceptible to arthritis is not known, but molecular mimicry between the HLA-B27 antigen and antigens of triggering bacteria has been demonstrated and this mimicry has been proposed as a mechanism involved in etiology of the arthritides. Antigens from bacteria that triggered the arthritis are present in arthritic joints but bacterial cells are not found. Antibodies and T-cells specific for the triggering bacteria have been demonstrated in arthritic patients. T-cells present in synovial joints respond specifically to the particular arthritic triggering pathogen. The cells that respond to bacterial antigens belong to the T-cell subset TH1 that secrete a limited number of cytokines but it is not known if cytokines are involved in arthritis. A few studies have demonstrated that T-cells from the joints of arthritic patients respond to both bacterial and human heat shock proteins indicating that autoimmunity may be involved in causation of arthritis. While only about 2% of a population exposed to a triggering infection will acquire arthritis, these individuals undergo pain and suffering as well as economic hardships as a result of their disease.

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