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C3a and adverse pregnancy outcomes
Abstracts / Molecular Immunology 47 (2010) 2198–2294
did not bind directly to glycans but rather to C3 convertases. In conclusion, our findings demonstrate that AP activation by b1,3 glucan containing particles can occur in the absence of P, but b1,6 glucan (only) containing particles require P to activate AP. This may lead to a better understanding of how P facilitates AP activation by fungi. doi:10.1016/j.molimm.2010.05.015 100 Procarboxypeptidase R deficiency causes increased lethality in concanavalin A-induced hepatitis in female mice Suzuka Asai, Masaki Imai, Noriaki Kimbara, Toyohiro William Campbell, Hidechika Okada, Noriko Okada
Tada,
Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Japan Carboxypeptidase R (CPR) is an enzyme generated by proteolytic cleavage of its zymogen (proCPR). The enzyme is also known as thrombin-activatable fibrinolysis inhibitor (TAFI). CPR cleaves arginine, the C-terminal basic amino acid, from inflammatory peptides such as complement components C3a and C5a, bradykinin, enkephalin, and the thrombin-cleaved N-terminal fragment osteopontin (cleaved N-OPN). In the mouse model of concanavalin A (Con A)-induced immune-mediated fulminating hepatitis, cleaved N-OPN is one of the important peptides that induce the production of chemokines or cytokines. Some studies using rodent hepatitis models showed that higher amounts of OPN and cleaved N-OPN accumulated in female livers compared with those in the males’. In the current study using proCPR deficient female mice, we showed that a lack of CPR activity increases the levels of blood ALP, AST and ALT significantly within 2 hours after injection of Con A. Furthermore, injection of 500 g of Con A into the mouse tail vein can induce 100% lethality in proCPR-deficient female but not in male mice. These in vivo findings suggest that CPR helps to protect against Con A-induced hepatitis. doi:10.1016/j.molimm.2010.05.016 101 C3a and adverse pregnancy outcomes Anne Lynch a , James Murphy b , Ronald Gibbs a , Patricia Giclas c , Jane Salmon d , V. Michael Holers e a
Department of Obstetrics and Gynecology, University of Colorado, Denver, United States b Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado, United States c Pediatrics Department, National Jewish Health, Denver, Colorado, United States d Hospital for Special Surgery, Weill Medical College, Cornell University, New York, United States e Departments of Medicine and Immunology, University of Colorado Denver, United States We have previously demonstrated that elevated levels of the complement activation fragment Bb in early pregnancy are associated with subsequent development of preeclampsia. The objective of this study was to examine whether early elevations of complement are present in other adverse pregnancy outcomes by examining the levels of the chemotactic peptide C3a. We conducted a prospective study of 1004 women in Denver, Colorado. A plasma sample was obtained before 20 weeks’ gestation. The cohort was followed for the development of pregnancy outcomes defined as hypertensive disease of pregnancy, preterm (<37 weeks’ gesta-
2199
tion) birth (PTB), premature rupture of the membranes (PROM), intrauterine fetal loss and growth restriction. Analysis included univariable and multivariable logistic regression. An adverse pregnancy outcome occurred in 213 (21%) of the cohort. The mean levels (ng/L) of C3a in early pregnancy were significantly (P < 0.0001) higher among women with an adverse outcome (858 ± 434) compared with women with an uncomplicated pregnancy (741 ± 407). Adjusted for parity and pre-pregnancy BMI, women with levels of C3a in the upper quartile in early pregnancy were 3 times more likely to have an adverse outcome later in pregnancy compared with women in the lower quartile (adjusted odds ratio (AOR) = 3.0, 95% confidence interval (CI) 1.8–5, P < 0.0001). The relationship remained significant when restricted to the 461 women who had their blood drawn in the first trimester (AOR = 2.5, 95% CI = 1.2–5.5, P = 0.02). The link between early elevated C3a levels and adverse pregnancy outcomes was driven by a significant (P < 0.05) association of C3a with gestational hypertension, PTB, and PROM. A higher concentration of C3a as early as the first trimester of pregnancy is an independent risk factor for adverse pregnancy outcomes, suggesting that complement-related inflammatory events early in pregnancy contribute to poor pregnancy outcomes. doi:10.1016/j.molimm.2010.05.017 102 The complement system in obesity Anne Lynch a , Robert H. Eckel b , James Murphy c , Patricia Giclas d , V. Michael Holers e a
Department of Obstetrics and Gynecology, University of Colorado, Denver, United States b Department of Medicine, University of Colorado, Denver, United States c Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado, United States d Pediatrics Department, National Jewish Health, Denver, Colorado, United States e Departments of Medicine and Immunology, University of Colorado Denver, United States Components of the complement system are found in adipose tissue. However, there has been little recognition of the significance of the complement system in this cellular environment. The objective of this study in a cohort of 930 normotensive pregnant women was to determine if the maternal pre-pregnant BMI was predictive of levels of the complement activation fragments Bb and C3a measured in the first 20 weeks of pregnancy. Levels of BMI and the complement activation fragments were examined as continuous and categorical variables using univariable and linear regression analysis (P < 0.05). A pre-pregnant BMI of over 30 was found in 96 (10%) of the women, 213 (23%) were overweight (BMI 25–30) and 621 (67%) had a BMI less than 25. There was a significant relationship between maternal pre-pregnancy BMI and early pregnancy levels of Bb and C3a (P < 0.0001 and 0.0006, respectively). The mean BMI ± standard deviation (SD) in the four quartiles of Bb from lowest to highest were: 23 ± 3.8 (quartile 1), 23.4 ± 4.0 (quartile 2), 24.5 ± 5.0 (quartile 3) and 25.1 ± 5.5 (quartile 4), P < 0.0001. A similar significant difference was seen across quartiles of C3a. The proportion of women with a pre-pregnant BMI over 30 (obese) quadrupled from 10% among women with an early pregnancy Bb level in the lower quartile to 43% in women with Bb level in the upper quartile. Twenty-percent of the obese women had C3a levels in the lower quartile compared with 38% in upper quartile. The relationship between the maternal pre-prepregnant BMI with elevated levels of Bb and C3a in the first half of pregnancy remained
did not bind directly to glycans but rather to C3 convertases. In conclusion, our findings demonstrate that AP activation by b1,3 glucan containing particles can occur in the absence of P, but b1,6 glucan (only) containing particles require P to activate AP. This may lead to a better understanding of how P facilitates AP activation by fungi. doi:10.1016/j.molimm.2010.05.015 100 Procarboxypeptidase R deficiency causes increased lethality in concanavalin A-induced hepatitis in female mice Suzuka Asai, Masaki Imai, Noriaki Kimbara, Toyohiro William Campbell, Hidechika Okada, Noriko Okada
Tada,
Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Japan Carboxypeptidase R (CPR) is an enzyme generated by proteolytic cleavage of its zymogen (proCPR). The enzyme is also known as thrombin-activatable fibrinolysis inhibitor (TAFI). CPR cleaves arginine, the C-terminal basic amino acid, from inflammatory peptides such as complement components C3a and C5a, bradykinin, enkephalin, and the thrombin-cleaved N-terminal fragment osteopontin (cleaved N-OPN). In the mouse model of concanavalin A (Con A)-induced immune-mediated fulminating hepatitis, cleaved N-OPN is one of the important peptides that induce the production of chemokines or cytokines. Some studies using rodent hepatitis models showed that higher amounts of OPN and cleaved N-OPN accumulated in female livers compared with those in the males’. In the current study using proCPR deficient female mice, we showed that a lack of CPR activity increases the levels of blood ALP, AST and ALT significantly within 2 hours after injection of Con A. Furthermore, injection of 500 g of Con A into the mouse tail vein can induce 100% lethality in proCPR-deficient female but not in male mice. These in vivo findings suggest that CPR helps to protect against Con A-induced hepatitis. doi:10.1016/j.molimm.2010.05.016 101 C3a and adverse pregnancy outcomes Anne Lynch a , James Murphy b , Ronald Gibbs a , Patricia Giclas c , Jane Salmon d , V. Michael Holers e a
Department of Obstetrics and Gynecology, University of Colorado, Denver, United States b Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado, United States c Pediatrics Department, National Jewish Health, Denver, Colorado, United States d Hospital for Special Surgery, Weill Medical College, Cornell University, New York, United States e Departments of Medicine and Immunology, University of Colorado Denver, United States We have previously demonstrated that elevated levels of the complement activation fragment Bb in early pregnancy are associated with subsequent development of preeclampsia. The objective of this study was to examine whether early elevations of complement are present in other adverse pregnancy outcomes by examining the levels of the chemotactic peptide C3a. We conducted a prospective study of 1004 women in Denver, Colorado. A plasma sample was obtained before 20 weeks’ gestation. The cohort was followed for the development of pregnancy outcomes defined as hypertensive disease of pregnancy, preterm (<37 weeks’ gesta-
2199
tion) birth (PTB), premature rupture of the membranes (PROM), intrauterine fetal loss and growth restriction. Analysis included univariable and multivariable logistic regression. An adverse pregnancy outcome occurred in 213 (21%) of the cohort. The mean levels (ng/L) of C3a in early pregnancy were significantly (P < 0.0001) higher among women with an adverse outcome (858 ± 434) compared with women with an uncomplicated pregnancy (741 ± 407). Adjusted for parity and pre-pregnancy BMI, women with levels of C3a in the upper quartile in early pregnancy were 3 times more likely to have an adverse outcome later in pregnancy compared with women in the lower quartile (adjusted odds ratio (AOR) = 3.0, 95% confidence interval (CI) 1.8–5, P < 0.0001). The relationship remained significant when restricted to the 461 women who had their blood drawn in the first trimester (AOR = 2.5, 95% CI = 1.2–5.5, P = 0.02). The link between early elevated C3a levels and adverse pregnancy outcomes was driven by a significant (P < 0.05) association of C3a with gestational hypertension, PTB, and PROM. A higher concentration of C3a as early as the first trimester of pregnancy is an independent risk factor for adverse pregnancy outcomes, suggesting that complement-related inflammatory events early in pregnancy contribute to poor pregnancy outcomes. doi:10.1016/j.molimm.2010.05.017 102 The complement system in obesity Anne Lynch a , Robert H. Eckel b , James Murphy c , Patricia Giclas d , V. Michael Holers e a
Department of Obstetrics and Gynecology, University of Colorado, Denver, United States b Department of Medicine, University of Colorado, Denver, United States c Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado, United States d Pediatrics Department, National Jewish Health, Denver, Colorado, United States e Departments of Medicine and Immunology, University of Colorado Denver, United States Components of the complement system are found in adipose tissue. However, there has been little recognition of the significance of the complement system in this cellular environment. The objective of this study in a cohort of 930 normotensive pregnant women was to determine if the maternal pre-pregnant BMI was predictive of levels of the complement activation fragments Bb and C3a measured in the first 20 weeks of pregnancy. Levels of BMI and the complement activation fragments were examined as continuous and categorical variables using univariable and linear regression analysis (P < 0.05). A pre-pregnant BMI of over 30 was found in 96 (10%) of the women, 213 (23%) were overweight (BMI 25–30) and 621 (67%) had a BMI less than 25. There was a significant relationship between maternal pre-pregnancy BMI and early pregnancy levels of Bb and C3a (P < 0.0001 and 0.0006, respectively). The mean BMI ± standard deviation (SD) in the four quartiles of Bb from lowest to highest were: 23 ± 3.8 (quartile 1), 23.4 ± 4.0 (quartile 2), 24.5 ± 5.0 (quartile 3) and 25.1 ± 5.5 (quartile 4), P < 0.0001. A similar significant difference was seen across quartiles of C3a. The proportion of women with a pre-pregnant BMI over 30 (obese) quadrupled from 10% among women with an early pregnancy Bb level in the lower quartile to 43% in women with Bb level in the upper quartile. Twenty-percent of the obese women had C3a levels in the lower quartile compared with 38% in upper quartile. The relationship between the maternal pre-prepregnant BMI with elevated levels of Bb and C3a in the first half of pregnancy remained