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.

Less, but not gone—gluten-free diet effects on fatigue in celiac disease: a prospective controlled study

“…Those findings suggests that subclinical disease activity might be involved in generating fatigue by stimulating fatigue signaling pathways. Another possible factor could be that the mechanisms that downregulate inflammation and immunity might contribute to fatigue, as suggested in studies on other inflammatory diseases ( 40 – 43 ). In our study, a fraction of patients had shown evidence of disease activity (e.g., elevated anti-tTG-IgA and signs of villous atrophy) after the GFD.…”

High mobility group box 1 and a network of other biomolecules influence fatigue in patients with Crohn’s disease

“…EDTA-blood was centrifuged at 2800 g for 15 min at 4 °C and plasma samples stored immediately at − 80 °C in aliquots until further analysis. Based on previous experiences and findings in our laboratory regarding potential biomarkers for fatigue (Bårdsen et al 2019 , 2016 ; Kvivik et al 2021 ; Grimstad et al 2020 ; Larssen et al 2019 ; Harboe et al 2009 ) we selected a panel of relevant candidate proteins. Plasma concentrations of IL-1RA were measured by a sandwich immunoassay with electrochemiluminescence detection on a Meso ® QuickPlex SQ 120 Imager (Meso Scale Discovery, Rockville, MD).…”

“…A mechanism for regulating HMGB1 is production of autoantibodies against HMGB1. We have previously shown that high levels of anti-HMGB1 antibodies (abs) in plasma from patients with Crohn’s disease are negatively associated with high fatigue (Kvivik et al 2021 ), suggesting a protective/down-regulating role for these specific abs.…”

HMGB1 in depression: An overview of microglial HMBG1 in the pathogenesis of depression

“…Depending on the redox state, there are three forms of HMGB1, namely, disulfide HMGB1 (ds-HMGB1), fully reduced HMGB1 (fr-HMGB1) and fully oxidized HMGB1 (ox-HMGB1) ( Frank et al, 2015 ; Kang et al, 2014 ). Ds-HMGB1 promotes inflammation and ultimately results in systemic inflammation ( Frank et al, 2016 ; Kvivik et al, 2021 ; Xiong et al, 2022 ) via binding to Toll like receptors (TLRs, e.g., TLR2 and TLR4) when cysteines at positions 23 and 45 become oxidized, while cysteine at position C106 remains in a reduced thiol state ( Yamasoba et al, 2016 ). Several studies indicate that ds-HMGB1 exacerbates neuroinflammation, resulting in anxiety, aversion and fatigue in mice or patients ( Du et al, 2022 ; Kvivik et al, 2021 ).…”

“…Ds-HMGB1 promotes inflammation and ultimately results in systemic inflammation ( Frank et al, 2016 ; Kvivik et al, 2021 ; Xiong et al, 2022 ) via binding to Toll like receptors (TLRs, e.g., TLR2 and TLR4) when cysteines at positions 23 and 45 become oxidized, while cysteine at position C106 remains in a reduced thiol state ( Yamasoba et al, 2016 ). Several studies indicate that ds-HMGB1 exacerbates neuroinflammation, resulting in anxiety, aversion and fatigue in mice or patients ( Du et al, 2022 ; Kvivik et al, 2021 ). Xiong et al demonstrated that ds-HMGB1 bound to myeloid differentiation protein-2 to activate NLRP3, thereby releasing inflammatory factors (e. g., TNF-α, IL-1β, and IL-10) and impairing cognitive behaviors in mice with sepsis-associated encephalopathy ( Xiong et al, 2022 ).…”