Abstract
Human leukocytic antigen-B27 heavy chain (HLA-B27 HC) has the tendency to fold slowly, in turn gradually forming a homodimer, (B27-HC)2 via a disulfide linkage to activate killer cells and T-helper 17 cells and inducing endoplasmic reticulum (ER) stress to trigger the IL-23/IL-17 axis for pro-inflammatory reactions. All these consequences lead to the pathogenesis of ankylosing spondylitis (AS). Sulfasalazine (SSA) is a common medication used for treatment of patients with AS. However, the effects of SSA treatment on (B27-HC)2 formation and on suppression of IL-23/IL-17 axis of AS patients remain to be determined. In the current study, we examine the (B27-HC)2 of peripheral blood mononuclear cells (PBMC), the mean grade of sarcoiliitis and lumbar spine Bath Ankylosing Spondylitis Radiology Index (BASRI) scores of 23 AS patients. The results indicated that AS patients without (B27-HC)2 on PBMC showed the lower levels of mean grade of sarcoiliitis and the lumbar spine BASRI scores. In addition, after treatment with SSA for four months, the levels of (B27-HC)2 on PBMCs were significantly reduced. Cytokines mRNA levels, including TNFα, IL-17A, IL-17F and IFNγ, were also significantly down-regulated in PBMCs. However, SSA treatment did not affect the levels of IL-23 and IL-23R mRNAs.
Highlights
Ankylosing spondylitis (AS) is an inflammatory disease that is characterized by inflammatory back pain and asymmetric peripheral oligoarthritis [1,2,3,4]
The human leukocytic antigen-B27 (HLA-B27) heavy chain (HLA-B27 HC) has a propensity to misfold slowly in the endoplasmic reticulum (ER) before it is assembled with β2m and a peptide and forms a disulfide-linked heavy-chain homodimer, (B27-HC)2, that can be displayed on cell surfaces [7,8,9,10,11,12,13]
Our results demonstrated that SSA treatment caused down-regulation of pro-inflammatory cytokine mRNA expression and reduced the production of (B27-HC)2 on peripheral blood mononuclear cells (PBMC)
Summary
Ankylosing spondylitis (AS) is an inflammatory disease that is characterized by inflammatory back pain and asymmetric peripheral oligoarthritis [1,2,3,4]. HLA-B27 is one of the major histocompatibility complex (MHC) class I molecules It consists of a heavy chain (α chain) and β2 microglobulin (β2m) and is assembled with an antigenic peptide in the endoplasmic reticulum (ER). B27-HC misfolding can induce ER stress and increase signaling of the IL-23/IL-17 axis This finding is based on a recent study that used transgenic rats that over-expressed HLA-B27/human β2m [17]. HLA-B27 HC misfolding induces ER stress and results in activation of the unfolded protein response (UPR), which in turn stimulates NF-κB activation to increase the expression of pro-inflammatory cytokines such as TNFα, IL-1, IL-6, and IL-23 [18,19,20,21,22]. SSA treatment did not affect the expression of IL-23 and IL-23 receptor (IL-23R) mRNA
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