When did the Irish-American Diaspora Make a Difference? Influencing US Diplomacy toward Northern Ireland

This article explains the changing relationship between Irish leaders, the Irish-American diaspora, Irish-American political elites, and American diplomacy. Specifically, we explore the transnational advocacy networks (TANSs) associated with the Irish diaspora and their impact on American diplomacy. In the early twentieth century, de Valera failed to mobilize Irish-America to convince President Wilson to recognize the Irish Republic. By the late twentieth century Irish-Americans became effective foreign policy entrepreneurs in Congress re-orienting US diplomacy toward Northern Ireland. Irish political elites utilized both the diaspora and their elite connections to transform the American policy of deference to its Cold War ally to an engaged diplomacy mediating and promoting peace

Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex

Citation: Garcia, B. L., Zhi, H., Wager, B., Hook, M., & Skare, J. T. (2016). Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex. Plos Pathogens, 12(1), 28. doi:10.1371/journal.ppat.1005404Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems

The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity.

The membrane attack complex of complement (C) in sublytic concentrations stimulates endothelial cells (EC) to express adhesion molecules and to release biologically active products. We have examined the ability of a cytolytically inactive form of this complex, which is incapable of inserting into the cell membrane, to upregulate the expression of adhesion molecules and of tissue factor (TF) procoagulant activity. The inactive terminal C complex (iTCC) was prepared by mixing C5b6, C7, C8, and C9 and was purified by fast protein liquid chromatography on a Superose 12 column. Binding of this complex to EC was found to be dose dependent and was inhibited by anti-C9 antibodies, as assessed both by ELISA using an mAb anti-C9 neoantigen and by measuring cell-bound 125I-labeled iTCC. Exposure of EC to iTCC resulted in a dose- and time-dependent expression of endothelial leukocyte adhesion molecule 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 accompanied by increased levels of the corresponding mRNA, but not in the rapid expression of P-selectin. Inactive TCC also induced increased TF activity evaluated by a chromogenic assay that measures the formation of factor Xa. These effects were inhibited by anti-C9 antibodies. The data support the conclusion that iTCC may induce proinflammatory and procoagulant activities on EC

Inhibition of trophoblast adhesion to endothelial cells by the sera of women with recurrent spontaneous abortions.

May anti-phospholipid or other autoantibodies interfere with trophoblast-endothelial cells interaction in women with unexplained pregnancy losses?The sera of 72 women with recurrent spontaneous abortions (RSA) containing antibodies to endothelial cells (28), trophoblast (14), and cardiolipin (10) or lacking antibodies (25), and 26 controls were examined in an inhibition assay of trophoblast adhesion to endothelial cells using an ELISA based on the recognition of trophoblast by antibodies to cytokeratin.Adhesion of trophoblast to endothelial cells was time- and dose-dependent. Patients and control sera inhibited trophoblast adhesion with mean values of 37\% and 7\%, respectively. Inhibition above 2SD of the mean control value was still observed in 58\% of the patients sera and 8\% of the control sera. Sera containing antibodies to endothelial cells had higher inhibitory effect (38\%) than those with antibodies to trophoblast (23\%) and cardiolipin (28\%) or lacking antibodies (26\%).Antibodies and other undefined factors in the sera of women with RSA inhibit adhesion of trophoblast to endothelial cells