Anti-HMGB1 auto-Abs influence fatigue in patients with Crohn's disease

Abstract

Fatigue is common in all chronic inflammatory and autoimmune diseases. A conceptual model for understanding the biological basis of fatigue describes it as being a part of the sickness behaviour response generated by pro-inflammatory cytokines and other mediators. We hypothesised that the pro-inflammatory high mobility group box 1 (HMGB1) protein is a fatigue-inducing molecule and that auto-Abs against HMGB1 reduce fatigue. We measured Abs against disulphide (ds) HMGB1 and fully reduced (fr) HMGB1 in plasma from 57 patients with Crohn's disease. Fatigue was rated using the fatigue visual analogue scale (fVAS) and disease activity with faecal calprotectin, C-reactive protein and the Simple Endoscopic Score for Crohn's disease. Multivariable regression models identified anti-dsHMGB1 and anti-frHMGB1 Abs as the strongest contributing factors for fVAS scores (B = -29.10 (P = 0.01), R² = 0.17, and B = -17.77 (P = 0.01), R² = 0.17, respectively). Results indicate that anti-HMGB1 auto-Abs alleviate fatigue possibly by down-regulating HMGB1-induced sickness behaviour.

Keywords: Anti-HMGB1 antibodies; Crohn’s disease; HMGB1; fatigue; sickness behaviour.

Figure 1.

Association between fatigue and levels of anti-HMGB1 Ab variants. Univariable linear regression analysis in 56 patients with Crohn’s disease and 28 healthy control subjects, using the fatigue visual analogue scale (fVAS) as the dependent variable and anti-dsHMGB1 Abs (a) or anti-frHMGB1 Abs (b) as the independent variable. For each group, a fitted regression line is shown, continuous for patients and dotted for healthy control subjects.

Figure 2.

A model for HMGB1-induced fatigue and sickness behaviour. Inflamed and damaged cells in the intestine release HMGB1 protein. HMGB1 activate macrophages by binding TLR4 and receptor for advanced glycation end-products (RAGE). This leads to release of pro-inflammatory cytokines, including IL-1β. In the central nervous system, IL-1β binds to a complex of IL-1 type I (IL-1RI) receptors and accessory protein (AcPb) on neuronal cells and induces sickness behaviour and fatigue. Anti-HMGB1 Abs bind HMGB1 and thus down-regulate HMGB1-induced fatigue. Created with BioRender.com.