[Show abstract][Hide abstract]ABSTRACT: Premature atherosclerosis and thrombotic complications are major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). However, the high incidence of these complications cannot be explained by traditional risk factors alone, suggesting direct effects of an activated immune system on hemostasis. The unexpected nucleotide sequence homology between SLE patient-derived autoantibodies against complement C1q (Fab anti-C1q) and von Willebrand factor (VWF) led us to investigate a potential interaction between the complement and hemostatic systems on the level of initiating molecules. VWF was found to bind to surface-bound C1q under static conditions. The binding could specifically be inhibited by Fab anti-C1q and C1q-derived peptides. Under shear stress the C1q-VWF interaction was enhanced, resembling the binding of VWF to collagen I. Additionally, we could show that C1q-VWF complexes induced platelet rolling and firm adhesion. Furthermore, we observed VWF binding to C1q-positive apoptotic microparticles and cholesterol crystals, as well as increased VWF deposition in C1q-positive glomeruli of SLE patients compared with control nephropathy. We show, to our knowledge for the first time, binding of VWF to C1q and thus a direct interaction between starter molecules of hemostasis and the classical pathway of complement. This direct interaction might contribute to the pathogenic mechanisms in complement-mediated, inflammatory diseases.
Full-text available · Article · Nov 2016 · The Journal of Immunology
[Show abstract][Hide abstract]ABSTRACT: Antibodies against C1q (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE). The anti-C1q antibodies strongly correlate with the occurrence of lupus nephritis and low-circulating C1q levels. Previous studies have demonstrated that myeloid cells, i.e., dendritic cells and macrophages, are a major source of C1q. However, a direct effect of anti-C1q on C1q secretion by macrophages has not yet been established. In the present study, we investigated the C1q secretion profile of in vitro human monocyte-derived macrophages (HMDMs) obtained from healthy donors and from patients with SLE. The effect of SLE patient-derived anti-C1q bound to immobilized C1q (imC1q) and imC1q alone on HMDMs was investigated by C1q secretion levels, the expression of membrane-bound and intracellular C1q using flow cytometry and ImageStream(X) technology, and testing the ability of secreted C1q to activate the classical pathway (CP) of the complement. Bound anti-C1q induced significantly greater C1q secretion levels as compared with imC1q alone or healthy donor IgG. The extent of C1q secretion by HMDMs correlated with IgG anti-C1q levels of patients with SLE but not of healthy controls. Furthermore, bound autoantibodies and imC1q induced continuous and de novo C1q synthesis as evident by the intracellular C1q content, which correlated with C1q secretion levels. Finally, secreted C1q was able to activate the CP, as reflected by C4b deposition. Interestingly, anti-C1q-dependent C1q secretion could also be observed in SLE patient-derived cells. In conclusion, our data indicate that imC1q-bound anti-C1q strongly stimulate the C1q production by HMDMs. Anti-C1q-induced C1q secretion might be an important immune-modulatory factor in SLE.
[Show abstract][Hide abstract]ABSTRACT: Introduction:
Anti-C1q antibodies (anti-C1q) have been implicated in the pathogenesis of autoimmune diseases including autoimmune thyroid disorders (AITD). The aim of this study was to evaluate the association between anti-C1q and thyroid function in pregnancy-associated AITD.
In 96 pregnant women screened positive for AITD (thyroid dysfunction and/or antibodies against thyroperoxidase - TPOAb), anti-C1q were measured during the 9(th) -11(th) gestational week and after delivery (median 16 months after delivery), and compared to the corresponding serum levels of thyroid hormones. As controls, 80 healthy pregnant women, 72 non-pregnant AITD patients and 72 blood donors were included. In the non-pregnant AITD group, two serum samples ≥ 6 months apart were analysed.
As compared to blood donors, anti-C1q levels were substantially higher in all pregnant women analysed. In pregnancy, anti-C1q levels were higher in the TPOAb-positive women than in controls (37% vs. 17.5% p<0.0001). Anti-C1q-positive pregnant women screened positive for AITD had higher thyroid-stimulating hormone (TSH) levels than anti-C1q-negative ones (2.41 mU/l vs. 1.94 mU/l, p= 0.01), and TSH correlated positively with anti-C1q (r=0.226, p=0.045) in the TPOAb-positive women. After delivery, serum levels of anti-C1q decreased in the positively screened TPOAb-negative women (8.8 vs. 5.9 U/l, p=0.002), but not in the TPOAb-positive ones; and they did not correlate with TSH anymore.
Anti-C1q antibody levels increase during pregnancy in general and even more in the context of AITD, where they correlate with TSH levels. This article is protected by copyright. All rights reserved.
Article · May 2016 · Clinical & Experimental Immunology
[Show abstract][Hide abstract]ABSTRACT: Anti-C1q autoantibodies (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE) and correlate with the occurrence of proliferative lupus nephritis. A previous study of anti-C1q in experimental lupus nephritis demonstrated an important role for FcγRs in the pathogenesis of lupus nephritis, suggesting a direct effect on phagocytes. Therefore, we developed an in vitro model to study the effect of SLE patient-derived anti-C1q bound to immobilized C1q (imC1q) on human monocyte-derived macrophages (HMDMs) obtained from healthy donors and SLE patients. HMDMs were investigated by analyzing the cell morphology, LPS-induced cytokine profile, surface marker expression, and phagocytosis rate of apoptotic Jurkat cells. Morphologically, bound anti-C1q induced cell aggregations of HMDMs compared with imC1q or IgG alone. In addition, anti-C1q reversed the effect of imC1q alone, shifting the LPS-induced cytokine release toward a proinflammatory response. FcγR-blocking experiments revealed that the secretion of proinflammatory cytokines was mediated via FcγRII. The anti-C1q-induced inflammatory cytokine profile was accompanied by a downregulation of CD163 and an upregulation of LPS-induced CD80, CD274, and MHC class II. Finally, HMDMs primed on bound anti-C1q versus imC1q alone displayed a significantly lower phagocytosis rate of early and late apoptotic cells accompanied by a reduced Mer tyrosine kinase expression. Interestingly, anti-C1q-dependent secretion of proinflammatory cytokines was similar in SLE patient-derived cells, with the exception that IL-10 was slightly increased. In conclusion, anti-C1q induced a proinflammatory phenotype in HMDMs reversing the effects of imC1q alone. This effect might exacerbate underlying pathogenic mechanisms in lupus nephritis.
[Show abstract][Hide abstract]ABSTRACT: Background:
Functional deficiency of mannose-binding lectin (MBL) may contribute to the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that specific MBL2 gene polymorphisms and circulating MBL protein levels are associated with clinically relevant outcomes in the Predicting Outcome using systemic Markers In Severe Exacerbations of COPD PROMISE-COPD cohort.
We followed 277 patients with stable COPD GOLD stage II-IV COPD over a median period of 733 days (IQR 641-767) taking survival as the primary outcome parameter. Patients were dichotomized as frequent (≥2 AECOPD/year) or infrequent exacerbators. Serum MBL levels and single nucleotide polymorphisms of the MBL2 gene were assessed at baseline.
The MBL2-HYPD haplotype was significantly more prevalent in frequent exacerbators (OR: 3.33; 95 % CI, 1.24-7.14, p = 0.01). The median serum MBL concentration was similar in frequent (607 ng/ml, [IQR; 363.0-896.0 ng/ml]) and infrequent exacerbators (615 ng/ml, [IQR; 371.0-942.0 ng/ml]). Serum MBL was not associated with lung function characteristics or bacterial colonization in sputum. However, high serum MBL at stable state was associated with better survival compared to low MBL (p = 0.046, log rank test).
In COPD, the HYPD haplotype of MBL2 gene is associated with frequent exacerbations and high serum MBL is linked to increased survival. The PROMISE-COPD study was registered at www.controlled-trials.com under the identifier ISRCTN99586989 .
Full-text available · Article · Dec 2015 · Respiratory Research
[Show abstract][Hide abstract]ABSTRACT: Background:
Autoantibodies against monomeric C-reactive protein (anti-CRP-Ab) observed in patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) were suggested to be associated with active LN and a poor response to therapy during short-term follow-up. The aim of this study was to confirm this finding and to investigate the prognostic value of anti-CRP-Ab in patients with LN during long-term follow-up.
Sera of 57 SLE patients (47 women, 10 men) with biopsy proven LN and 122 healthy individuals were analyzed for the presence of anti-CRP-Ab by in-house ELISA. Anti-CRP-Ab levels were studied in relation to routine laboratory tests, urine analysis, levels of C3, C4, other immunological markers and the overall disease activity as assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The prognostic value of anti-CRP-Ab was tested in a subgroup of 29 newly diagnosed LN patients (median follow-up 5.9 years). Response to therapy at various time points was assessed with respect to baseline anti-CRP-Ab levels. At least partial response in the first/second year of treatment was considered as a "favorable outcome", while non-response, renal flare or end stage renal disease were considered as "unfavorable outcome".
Anti-CRP-Ab were only detected in patients with active renal disease and their levels correlated with SLEDAI (rs = 0.165, p = 0.002). The time to response was shorter in patients being anti-CRP-Ab negative at baseline compared to anti-CRP-Ab positive patients, p = 0.037. In the second year of therapy, baseline anti-CRP-Ab positivity was a significant predictor of "unfavorable outcome" (OR [95 % CI] = 15.6 [1.2-771]; p = 0.021). The predictive value of "baseline anti-CRP positivity" further increased when combined with "non-response to therapy in the first year". Baseline anti-CRP-Ab positivity was not a predictor of "unfavorable outcome" at the end of follow-up, (OR [95 % CI] = 5.5 [0.6-71.1], p = 0.169).
Baseline serum levels of anti-CRP-Ab seem to be a strong risk factor for a composite outcome of non-response, renal flare or end stage renal disease after two years of standard treatment of LN. The response to therapy seems to be delayed in anti-CRP-Ab positive patients.
Full-text available · Article · Dec 2015 · Arthritis research & therapy
[Show abstract][Hide abstract]ABSTRACT: Objectives:
Human studies on the role of mannose-binding lectin (MBL) in patients with invasive candidiasis have yielded conflicting results. We investigated the influence of MBL and other lectin pathway proteins on Candida colonization and intra-abdominal candidiasis (IAC) in a cohort of high-risk patients.
Prospective observational cohort study of 89 high-risk intensive-care unit (ICU) patients. Levels of lectin pathway proteins at study entry and six MBL2 single-nucleotide polymorphisms were analysed by sandwich-type immunoassays and genotyping, respectively, and correlated with development of heavy Candida colonization (corrected colonization index (CCI) >0.4) and occurrence of IAC during a 4-week period.
Within 4 weeks after inclusion a CCI>0.4 and IAC was observed in 47% and 38% of patients respectively. Neither serum levels of MBL, ficolin-1,-2,-3, MASP-2 or collectin liver 1 nor MBL2 genotypes were associated with a CCI>0.4. Similarly, none of the analysed proteins was found to be associated with IAC with the exception of lower MBL levels (HR 0.74, p=0.02) at study entry. However, there was no association of MBL deficiency (<0.5 μg/ml), MBL2 haplo- or genotypes with IAC.
Lectin pathway protein levels and MBL2 genotype investigated in this study were not associated with heavy Candida colonization or IAC in a cohort of high-risk ICU patients.
[Show abstract][Hide abstract]ABSTRACT: Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that impacts on patients quality of life. Treatment in SLE not only aims to decrease disease activity and damage accrual but also to improve health-related quality of life (HRQOL). Only few studies have examined the influence of detailed disease-related organ involvement on HRQOL
Objectives To assess HRQOL and disease activity in a national Swiss multicentre cohort of patients with SLE (1;2).
Methods Cross-sectional study on patients included in the Swiss SLE Cohort Study between April 2007 and June 2014. Inclusion criteria were: age ≥18 years, SLE defined by the American College of Rheumatology (ACR) classification criteria, written informed consent, having completed a Medical Outcome Study Short Form 36 (SF-36) at baseline and assessed for SLE disease activity at the same time. HRQOL was assessed with the mental component scale (MCS) and Physical component scale (PCS) and the eight subscales of the SF-36. Disease activity was assessed by the SLE Disease Activity Index score with the Safety of Estrogens in SLE National Assessment (SELENA-SLEDAI) modification physican's global assessement score (PGA). Disease damage was assessed by the System Lupus Internation Collaborating Clinics/ACR Damage Index for SLE (SLICC).
Results Two hundred fifty-two patients were included in the study. The median [IQR] MCS was 46.5 [34.9 – 54.1] and the median [IQR] PCS of the SF-36 was 41.1 [33.2 – 47.3]. The median [IQR] SELENA-SLEDAI score was 3 [0.75 - 8].
Univariate analysis revealed significant correlations between PCS and PGA (r=-0.18, p<0.01), ESR (r=-0.24, p<0.001), hemoglobin (r=0.16, p<0.05), steroid intake (r=-0.25, p<0.0001), immunosuppressive treatment intake (r=-0.20, p<0.01), age (r=-0.23, p<0.001), body mass index (r=-0.17, p<0.05), and SLICC (r=-0.24, p<0.001), tobacco status (r=0.16, p<0.05). Significant correlations were found between MCS and PGA (r=-0.15, p<0.05), SELENA-SLEDAI (r=-0.22, p<0.0001), and ESR (r=-0.14, p<0.05).
SELENA-SLEDAI inversely correlated with MCS (r=-0.22; p<0.001), role physical (RP) (r=-0.26; p<0.0001), bodily pain (BP) (r=-0.23; p<0.001), vitality (VT) (r=-0.15; p<0.05), social function (SF) (r= -0.14; p<0.05), social function (SF) (r=-0.14; p<0.05), role emotional (RE) (r=-0.28; p<0.0001), and mental health (MH) (r=-0.17; p<0.05). Musculoskeletal and renal involvements were the two dimensions of the SELENA-SLEDAI that correlate the most with SF-36 scores.
SLICC inversely correlated with PCS (-0.24; p<0.001), physical functionning (PF) (r=-0.21; p<0.01), RP (r=-0.14; p<0.05), and BP (r=-0.15; p<0.05). Diabetes was the dimension of the SLICC that correlates the most with SF-36 scores.
Conclusions Health-related quality of life is low in Swiss SLE patients, particularly in those with musculoskelettal and renal involvement or diabetes.
Disclosure of Interest None declared
Article · Jun 2015 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract]ABSTRACT: In cross-sectional studies autoantibodies against complement C1q (anti-C1q) were found to be highly associated with active lupus nephritis. The aim of this retrospective study was to determine the value of anti-C1q as follow-up marker of disease activity and renal involvement in patients with systemic lupus erythematosus (SLE). Fifty-two patients with SLE and a minimum of three anti-C1q measurements during follow-up were analyzed. Anti-C1q levels correlated with global disease activity scores. In subgroup analyses, patients without renal involvement did not show a significant correlation between anti-C1q levels and disease activity. In contrast, in patients with renal involvement, anti-C1q levels correlated well with global disease activity. In addition, a positive correlation with the urine protein-to-creatinine ratio and anti-dsDNA antibody levels as well as a negative correlation with complement levels was observed. Anti-C1q antibodies were found to strongly correlate with parameters of SLE disease activity during follow-up, in particular with regard to renal involvement.
Full-text available · Article · Jan 2015 · PLoS ONE
[Show abstract][Hide abstract]ABSTRACT: Objectives:
Systemic lupus erythematosus (SLE) is associated with considerable cardiovascular morbidity that has not yet been directly compared with other diseases with known cardiovascular risk.
Two hundred and forty-one patients of the multicentre Swiss SLE cohort study (SSCS) were cross-sectionally assessed for coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral artery disease (PAD). SLE patients were compared with a cohort of 193 patients with type-1 diabetes mellitus being followed at the University Hospital Basel. A subgroup analysis of 50 age- and sex-matched patients from the University Hospital Basel was performed.
Of patients within the SSCS 13.3% had one or more vascular events: 8.3% CHD, 5% CVD and 1.2% PAD. In type-1 diabetes mellitus patients, 15% had vascular events: 9.3% CHD, 3.1% CVD and 5.6% PAD. In the matched subgroup, 26% of SLE patients had vascular events (14% CHD) compared with 12% in type-1 DM patients (2% CHD). Cardiovascular risk factors were similar in both groups. Vascular events in SLE patients were associated with age, longer disease duration, dyslipidaemia, and hypertension.
Cardiovascular morbidity in SLE is at least as frequent as in age- and sex-matched type-1 diabetes mellitus patients. Therefore, aggressive screening and management of cardiovascular risk factors should be performed.
[Show abstract][Hide abstract]ABSTRACT: The role of complement has been demonstrated in experimental models of neuromyeltis optica (NMO), however, only few studies have analysed complement components longitudinally in NMO patients. We measured serum or plasma concentrations of anti-C1q antibodies and complement split products C3a, C4a and soluble C5b-9 in patients with NMO, multiple sclerosis and healthy controls. NMO patients had higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlated with disease activity, neurological disability and aquaporin-4 IgG in NMO patients suggesting a role of the alternative pathway of complement in the pathogenesis of NMO and supporting the strategy of therapeutic complement inhibition.
Full-text available · Article · Sep 2014 · Journal of Neuroimmunology
[Show abstract][Hide abstract]ABSTRACT: OBJECTIVES: To describe disease characteristics and treatment modalities in a multidisciplinary cohort of systemic lupus erythematosus (SLE) patients in Switzerland.
METHODS: Cross-sectional analysis of 255 patients included in the Swiss SLE Cohort and coming from centres specialised in Clinical Immunology, Internal Medicine, Nephrology and Rheumatology. Clinical data were collected with a standardised form. Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), an integer physician's global assessment score (PGA) ranging from 0 (inactive) to 3 (very active disease) and the erythrocyte sedimentation rate (ESR). The relationship between SLE treatment and activity was assessed by propensity score methods using a mixed-effect logistic regression with a random effect on the contributing centre.
RESULTS: Of the 255 patients, 82% were women and 82% were of European ancestry. The mean age at enrolment was 44.8 years and the median SLE duration was 5.2 years. Patients from Rheumatology had a significantly later disease onset. Renal disease was reported in 44% of patients. PGA showed active disease in 49% of patients, median SLEDAI was 4 and median ESR was 14 millimetre/first hour. Prescription rates of anti-malarial drugs ranged from 3% by nephrologists to 76% by rheumatologists. Patients regularly using anti-malarial drugs had significantly lower SELENA-SLEDAI scores and ESR values.
CONCLUSION: In our cohort, patients in Rheumatology had a significantly later SLE onset than those in Nephrology. Anti-malarial drugs were mostly prescribed by rheumatologists and internists and less frequently by nephrologists, and appeared to be associated with less active SLE.
Full-text available · Article · Aug 2014 · Swiss medical weekly: official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology
[Show abstract][Hide abstract]ABSTRACT: Cryoglobulinemia was identified and named many years ago by clinicians who related the in vitro precipitation of globulins from serum incubated in the cold with diseases. One major point was that there was no evidence for a known disease in many patients with mixed cryoglobulins. Thus, the terminology mixed essential cryoglobulinemia became accepted. The discovery of HCV as the causative agent of mixed essential cryoglobulinemia allowed not only the introduction of a new nomenclature (largely removing the designation essential), but studies of the relationship between this viral disease and the emergence of pathological clones of B cells.