DataSheet_1_C1q as a target molecule to treat human disease: What do mouse studies teach us?.docx

The complement system is a field of growing interest for pharmacological intervention. Complement protein C1q, the pattern recognition molecule at the start of the classical pathway of the complement cascade, is a versatile molecule with additional non-canonical actions affecting numerous cellular processes. Based on observations made in patients with hereditary C1q deficiency, C1q is protective against systemic autoimmunity and bacterial infections. Accordingly, C1q deficient mice reproduce this phenotype with susceptibility to autoimmunity and infections. At the same time, beneficial effects of C1q deficiency on disease entities such as neurodegenerative diseases have also been described in murine disease models. This systematic review provides an overview of all currently available literature on the C1q knockout mouse in disease models to identify potential target diseases for treatment strategies focusing on C1q, and discusses potential side-effects when depleting and/or inhibiting C1q.</p

Exemplary courses of anti-C1q levels in relation to disease activity during follow up.

<p>(green: SLEDAI score, blue: ECLAM score, black: anti-C1q-level, x-axis: time points of measurement). Patients 1–8 showed an initial flare with high anti-C1q titers. After initiation of therapy disease activity as well as anti-C1q levels dropped reaching stable remission. Patients 9–16 showed flares during follow-up with either persistingly elevated levels of anti-C1q and/or a simultaneous increase of anti-C1q titers. Pat. 17 and 18 showed a stable low disease activity with concurrent low anti-C1q titers. Patients 19–24 showed a lack of correlation between disease activity and anti-C1q levels. Such a lack of correlation could be observed in patients with and without renal lupus.</p

Correlation between anti-C1q and disease activity indices for (A) patients without renal involvement and (B) patients with renal involvement.

<p>Patients without renal involvement did not show a significant correlation between anti-C1q and activity indices (SLEDAI R = 0.05, p = 0.6; ECLAM R = 0.16, p = 0.07) whereas patients with renal involvement in the history showed a significant correlation between anti-C1q levels and activity indices (SLEDAI R = 0.47, p<0.0001; ECLAM R = 0.28, p<0.0001).</p

Correlation between Anti-C1q and disease activity indices for all patients and data points.

<p>SLEDAI: R = 0.43, p<0.0001 and ECLAM: R = 0.24, p<0.0001</p

Patient characteristics.

<p>On average, the patients fulfilled 5 (median, range 4–9) ACR criteria for the classification of SLE. Forty-eight patients (92%) were positive for ANA and thirty-seven (71%) for anti-dsDNA antibodies. In these patients, a total of 460 anti-C1q measurements were identified and used for further analyses corresponding to a median of 6 data points per patients (range 3 to 29). The median age of the patients was 42 (range 14–68 years); ten patients (19%) were male and 42 female (81%). Twenty-six patients (50%) had a history of renal involvement as confirmed by renal biopsy, in another 5 patients renal involvement was descripted in the absence of available biopsy data.</p><p>Patient characteristics.</p

Correlation between anti-C1q and urine protein-to-creatinine ratio, anti-dsDNA antibodies and complement C3, C4, and CH50 for all patients, patients without renal involvement and patients with renal involvement.

<p>1) = all patients, 2) = only patients without renal involvement, 3) = only patients with renal involvement (A) Correlation between anti-C1q and urine protein-to-creatinine ratio: (A1): R = 0.41, p<0.0001; (A2): R = 0.32, p = 0.01; p<0.0001 (A3): R = 0.28, p<0.0001; (B) Correlation between anti-C1q and anti-dsDNA measured with Farr assay: (B1): R = 0.59, p<0.0001; (B2): R = 0.4, p = 0.01; (B3): R = 0.6, p<0.0001; (C) Correlation between anti-C1q and anti-dsDNA measured with FEIA: (C1): R = 0.42, p<0.0001; (C2): R = 0.37, p = 0.002; (C3): R = 0.47, p<0.0001; (D) Correlation between anti-C1q and complement C3: (D1): R = -0.36, p<0.0001; (D2): R = -0.33, p = 0.0003; (D3): R = -0.3, p<0.0001; (E) Correlation between anti-C1q and C4: (E1): R = -0.24, p<0.0001; (E2): R = -0.35, p = 0.0001; (E3): R = 0.16; p = 0.006; (F) Correlation between anti-C1q and CH50: (F1): R = -0.26, p<0.0001; (F2): R = -0.42, p = 0.002; (F3): R = -0.3, p<0.0001.</p

Clinical characteristics of the study group.

<p> AITD: autoimmune thyroid disorders. TPOAb: antibodies against thyroperoxidase. The data were obtained from questionnaires filled by the participating women.</p

Prevalence of atopy, asthma and allergy with regard to MBL status.

<p>–1000 ng/ml; high: >1000 ng/ml. MBL2 genotypes represent the allelic variations associated with low, intermediate or high MBL levels. Statistical analysis was performed using the Chi-square test. Serum MBL levels are regarded as low if they are <100 ng/ml; intermediate: 100</p

Serum MBL levels in pregnant women screened for AITD.

<p>–1000 ng/ml and high: >1000 ng/ml. Low serum MBL levels: <100 ng/ml; intermediate: 100</p

Serum levels of MBL and thyroid parameters in pregnant women screened for autoimmune thyroid disorders in the 9-12^th gestational wks.

<p>^*(p<0.05), ^**(p<0.01), ^***(p<0.001) (Mann Whitney test). Positivity in screening: TSH<0.06 or >3.67 mIU/l and/or TPOAb>143 kU/l. TSH: thyroid stimulating hormone; FT4: free thyroxine; TPOAb: antibodies against thyroperoxidase. All 212 women included provided a blood sample for MBL analysis after delivery. In 103women, MBL could also be measured in a sample frozen at screening in pregnancy, which summed up to 96 pairs (pregnancy vs. follow-up). Statistical significances of comparison between values in positively vs. negatively screened women are marked by </p