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The classical and lectin pathways of complement activation neutralise pathogens and stimulate key immunological processes. Both pathways are initiated by collagen-containing, soluble pattern-recognition molecules associated with specific serine proteases. In the classical pathway, C1q binds to antibody-antigen complexes or bacterial surfaces to activate C1r and C1s. In the lectin pathway, mannan-binding lectin (MBL) and ficolins bind to carbohydrates on pathogens to activate MASP-2. To characterise the interactions leading to classical pathway activation, we have analysed binding between human C1q, C1r and C1s, which associate to form C1, using full-length and truncated protease components. We show that C1r and C1s bind to C1q independently. The CUB1-EGF fragments contribute most towards binding, but CUB2 of C1r, but not of C1s, is also important. Each C1rs tetramer presents a total of six binding sites, one for each of the collagenous domains of C1q. We also demonstrate that subcomponents of the lectin and classical pathways cross-interact. Thus, although the stoichiometries of complexes differ, interactions are analogous, with equivalent contacts between recognition and protease subcomponents. Importantly, these new data are contrary to existing models of C1, and enable us to propose a new model, using MBL-MASP interactions as a template.

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INTRODUCTION: Abdominal pain, frequent in patients with chronic pancreatitis (CP), has a negative impact on quality of life (QOL). Psychiatric comorbidities including anxiety and depression are associated with pain, but their prevalence and effects on QOL in CP have not been quantified. We studied the prevalence of anxiety and depression in patients with CP and their associated patient and disease characteristics and impact on QOL. METHODS: This was a cross-sectional, multicenter prospective study. Patients were screened with the Hospital Anxiety and Depression Scale questionnaire. A Hospital Anxiety and Depression Scale score >7 on the respective anxiety or depression subscales indicated the presence of anxiety or depression and was used as a surrogate for the diagnosis of psychiatric comorbidities. Patient demographics, disease characteristics, QOL (EORTC-QLQ-C30), and pain symptoms (Brief Pain Inventory Short Form) were compared between patients with and without psychiatric comorbidities. RESULTS: One hundred seventy-one patients with CP (mean age 53.8 ± 13.7 years, 60% men) were included. Anxiety and depression were present in 80 (46.8%) and 66 (38.6%) patients, with overlap in 50 (29%). Patients with anxiety or depression reported higher pain prevalence, pain severity, and pain interference scores (all P < 0.001). Psychiatric comorbidities also associated with reduced global health scores and functional subscales (all P < 0.001) and higher symptom burden (P ≤ 0.03). An independent association was noted between global health status and depression (P < 0.001). DISCUSSION: Psychiatric comorbidities are prevalent in patients with CP and associated with pain and QOL. Where the effect of anxiety on QOL may be mediated via pain, depression is independently related to QOL. These findings warrant consideration in the management of patients with CP.

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