Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy - PubMed (original) (raw)
Observational Study
Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
Angela C Baird et al. World J Gastroenterol. 2016.
Abstract
Aim: To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy.
Methods: Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders" (n = 12) and "non-responders" (n = 12) and compared to healthy controls (n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.
Results: Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders (P < 0.05). Following TLR stimulation, non-responders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls (P < 0.01) and diminished TNF (P < 0.001) and IL-1β (P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) (P < 0.01) but increased number of CD4+ regulatory T cells (Tregs) (P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2, -4 and -7 activation (P < 0.001).
Conclusion: Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.
Keywords: Anti-tumor necrosis factor therapy; IRAK4; Inflammatory bowel disease; Innate immunity; Toll-like receptor; Ulcerative colitis.
Conflict of interest statement
Conflict-of-interest statement: To the best of our knowledge, there is no conflict of interest to declare.
Figures
Figure 1
Toll-like receptor signalling pathway. TLR: Toll-like receptor.
Figure 2
Basal cytokine production in responders and non-responders compared to healthy controls. The basal expression of pro-inflammatory (TNF, IL-1β, IL-6), regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-5, -9, -13, 17A) cytokines were assessed and compared in peripheral blood mononuclear cells isolated from healthy controls (C) (n = 12) and UC patients who are in remission following anti-TNF therapy, responders (R) (n = 12) and those who failed to respond, non-responders (NR) (n = 12). Results were expressed as mean with 95%CI. The P values represent statistical significance of < 0.05 between the groups denoted. TNF: Tumor necrosis factor; IL: Interleukin.
Figure 3
Toll-like receptor-induced tumour necrosis factor, interleukin-1β, -6 and -10 in responders and non-responders compared to healthy controls. The differences in basal and stimulated (A) TNF, (B) IL-1β, (C) IL-6 and (D) IL-10 production in PBMCs post TLR stimulation. Results were calculated and expressed as fold-change from baseline (± SD). The P values represent statistical significance of < 0.05 between the groups as denoted. PBMC: Peripheral blood mononuclear cells; TLR: Toll-like receptor; TNF: Tumor necrosis factor; IL: Interleukin.
Figure 4
Peripheral blood mononuclear cells phenotype and toll-like receptor /CD14 protein levels in responders and non-responders compared to healthy controls. A: Percentage of monocytes, pDC and CD4+ regulatory T cells were determined from total population of PBMCs isolated from responders (R, n = 12), non-responders (NR, n = 12) and healthy controls (C, n = 12) by FACS analysis. Data are expressed as mean percentage (± SD) of total cell population; B: Basal (black columns) and stimulated (white columns) TLR2, TLR4, TLR7, TLR9 and CD14 protein levels in PBMCs isolated from C (n =12), R (n =12) and NR (n = 12) were assessed by surface and intracellular staining followed by FACS analysis. Data are expressed as mean fluorescence intensity (MFI ± SD). The P values represent statistical significance of < 0.05 between the groups as denoted. PBMC: Peripheral blood mononuclear cells; TLR: Toll-like receptor; pDC: Plasmacytoid dendritic cells.
Figure 5
Basal and stimulated toll-like receptor signalling pathways in responders and non-responders compared to healthy controls. PBMCs isolated from responders (R, n = 12), non-responders (NR, n = 12) and healthy controls (C, n = 12) were stimulated with TLR2, TLR4, TLR7 or TLR9 agonists for 24-48 h prior to intracellular staining for total IRAK4 (top), total Iκβα (middle) and phosphorylated (activated) NFκB (pNFκβ) (bottom) followed by FACS analysis. Data are expressed as MFI ± SD. a_P_ < 0.05 vs stimulated healthy control C (white open bars); c_P_ < 0.05 compared to stimulated responders (white open bars); e_P_ < 0.05 compared to basal (black solid bars). Grey open boxes represent differences in total IRAK4 expression compared to responders and controls. PBMC: Peripheral blood mononuclear cells; TLR: Toll-like receptor; NFκB: Nuclear factor kappa B; Iκβα: Inhibitor of NFκB.
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