Oratie uitgesproken door Prof.Dr. Leendert A. Trouw bij de aanvaarding van het ambt van hoogleraar Immunologie aan de Universiteit Leiden op vrijdag 2 februari 2024
Beukel, M.D. van den; Wesemael, T.J. van; Hoogslag, A.T.W.; Borggreven, N.; Huizinga, T.W.J.; Helm-van Mil, A.H.M. van der; ... ; Trouw, L.A. 2023
Objective In rheumatoid arthritis (RA) around two-thirds of patients are autoantibody positive for rheumatoid factor, anti-citrullinated protein antibodies and/or anti-carbamylated protein... Show moreObjective In rheumatoid arthritis (RA) around two-thirds of patients are autoantibody positive for rheumatoid factor, anti-citrullinated protein antibodies and/or anti-carbamylated protein antibodies. The remaining seronegative subgroup of patients is clinically heterogeneous and thus far, biomarkers predicting the disease course are lacking. Therefore, we analysed the value of other autoantibodies in RA directed against malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE).Methods In sera of 648 patients with RA and 538 patients without RA from the Leiden Early Arthritis Clinic, anti-MAA and anti-AGE IgG antibody levels were measured using ELISA. Associations between genetic risk factors, acute phase reactants, radiological joint damage, remission and anti-PTM positivity were investigated using regression, correlation and survival analyses.Results Anti-AGE and anti-MAA were most prevalent in RA (44.6% and 46.1% respectively) but were also present in non-RA arthritis patients (32.9% and 30.3% respectively). Anti-AGE and anti-MAA antibodies were associated with HLA-DRB1*03 within seronegative RA (OR=1.98, p=0.003, and OR=2.37, p<0.001, respectively) and, for anti-AGE also in non-RA arthritis patients (OR=2.34, p<0.001). Presence of anti-MAA antibodies was associated significantly with markers of inflammation, erythrocyte sedimentation rate and C reactive protein, in all groups independent of anti-AGE. Interestingly, the presence of anti-AGE and anti-MAA antibodies was associated with radiological progression in patients with seronegative RA, but not evidently with sustained drug-free remission.Conclusions Anti-AGE and anti-MAA were present in around 45% of RA patients and 30% of non-RA arthritis patients, and although not specific for RA, their presence associated with HLA, inflammation and, for RA, with clinical outcomes especially in patients with seronegative RA. Show less
IgG3 antibodies have potent effector functions, but are not used as therapeutics and structural data are missing. Here, the authors combine cryoEM and MS to study IgG3-mediated complement... Show moreIgG3 antibodies have potent effector functions, but are not used as therapeutics and structural data are missing. Here, the authors combine cryoEM and MS to study IgG3-mediated complement activation to provide the first structural insights into IgG3.IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralisation and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural information. Here, we use cryoEM to solve structures of antigen-bound IgG3 alone and in complex with complement components. These structures reveal a propensity for IgG3-Fab clustering, which is possible due to the IgG3-specific flexible upper hinge region and may maximise pathogen neutralisation by forming high-density antibody arrays. IgG3 forms elevated hexameric Fc platforms that extend above the protein corona to maximise binding to receptors and the complement C1 complex, which here adopts a unique protease conformation that may precede C1 activation. Mass spectrometry reveals that C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains. Structural analysis shows this to be caused by the height of the C1-IgG3 complex. Together, these data provide structural insights into the role of the unique IgG3 extended hinge, which will aid the development and design of upcoming immunotherapeutics based on IgG3. Show less
Essen, M.F. van; Peereboom, E.T.M.; Schlagwein, N.; Gijlswijk-Janssen, D.J. van; Nelemans, T.; Joeloemsingh, J.V.; ... ; Kooten, C. van 2023
Factor H is a pivotal complement regulatory protein that is preferentially produced by the liver and circulates in high concentrations in serum. There has been an increasing interest in the... Show moreFactor H is a pivotal complement regulatory protein that is preferentially produced by the liver and circulates in high concentrations in serum. There has been an increasing interest in the extrahepatic production of comple-ment factors, including by cells of the immune system, since this contributes to non-canonical functions of local complement activation and regulation. Here we investigated the production and regulation of factor H and its splice variant factor H-like protein 1 (FHL-1) by human myeloid cells. As validation, we confirmed the pre -dominant presence of intact factor H in serum, despite a strong but comparable mRNA expression of CFH and FHL1 in liver. Comparable levels of CFH and FHL1 were also observed in renal tissue, although a dominant staining for FHL-1 was shown within the proximal tubules. Human in vitro generated pro-and anti-inflammatory macrophages both expressed and produced factor H/FHL-1, but this was strongest in pro-inflammatory macro-phages. Production was not affected by LPS activation, but was increased upon stimulation with IFN-gamma or CD40L. Importantly, in both macrophage subsets mRNA expression of FHL1 was significantly higher than CFH. More -over, production of FHL-1 protein could be confirmed using precipitation and immunoblotting of culture su-pernatants. These data identify macrophages as producers of factor H and FHL-1, thereby potentially contributing to local complement regulation at sites of inflammation. Show less
Moel, E.C. de; Derksen, V.F.A.M.; Trouw, L.A.; Bang, H.; Goekoop-Ruiterman, Y.P.M.; Steup-Beekman, G.M.; ... ; Woude, D. van der 2018
Background Anti-citrullinated protein antibodies (ACPA) are thought to be highly specific for RA. ACPA are associated with risk factors for RA and with joint destruction, and are therefore presumed... Show moreBackground Anti-citrullinated protein antibodies (ACPA) are thought to be highly specific for RA. ACPA are associated with risk factors for RA and with joint destruction, and are therefore presumed to be involved in RA pathogenesis. ACPA-positive RA patients also have increased cardiovascular mortality (1). In cardiovascular disease, inflammatory changes occur in vessel walls, raising the question whether ACPA (presumed to be pro-inflammatory) may contribute to this process.Objectives To investigate the prevalence and prognostic implications of ACPA in patients with cardiovascular disease without RA.Methods ACPA were determined by anti-CCP3 commercial assay in baseline sera from 290 patients with ST-elevation myocardial infarction participating in the MISSION intervention study (2). Patients with RA were excluded. The association between ACPA and long-term mortality was investigated.Results 30/290 (10.3%) of the non-RA patients with cardiovascular disease were ACPA-positive. ACPA-positive non-RA patients had a significantly increased long-term cardiac mortality compared to ACPA-negative non-RA patients (Figure). Corrected for age, ACPA positivity was independently associated with long-term mortality [HR 2.4 (CI 1.1–5.4) p-Value=0.026].Conclusions ACPA can be detected in a considerable proportion of non-RA patients with cardiovascular disease. This challenges the presumed specificity of ACPA for RA. In both RA and cardiovascular disease, ACPA are associated with a worse disease outcome possibly by an ACPA-specific enhancement of inflammation. Future studies into ACPA in patients with cardiovascular disease offer the opportunity to dissect which risk factors are associated with ACPA in RA versus non-RA patients. This may supply crucial insights into the development of this autoimmune reaction. Show less
