Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.

Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation play a role in pathogenesis. Mechanisms underlying the associated inflammation are not fully understood, and while CD1a-expressing Langerhans cells are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. Here we observed that house dust mite (HDM) generates neolipid antigens for presentation by CD1a to T cells in the blood and skin lesions of affected individuals. HDM-responsive CD1a-reactive T cells increased in frequency after birth and showed rapid effector function, consistent with antigen-driven maturation. To define the underlying mechanisms, we analyzed HDM-challenged human skin and observed allergen-derived phospholipase (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2 and such cells infiltrated the skin after allergen challenge. Filaggrin insufficiency is associated with atopic dermatitis, and we observed that filaggrin inhibits PLA2 activity and inhibits CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity, such as Gell and Coombs are predicated on the idea that non-peptide stimulants of T cells act as haptens that modify peptides or proteins. However our results point to a broader model that does not posit haptenation, but instead shows that HDM proteins generate neolipid antigens which directly activate T cells. Specifically, the data identify a pathway of atopic skin inflammation, in which house dust mite-derived phospholipase A2 generates antigenic neolipids for presentation to CD1a-reactive T cells, and define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach

Paths to peace: conflict management trajectories in militarized interstate disputes

When multiple third-parties (states, coalitions, and international organizations) intervene in the same conflict, do their efforts inform one another? Anecdotal evidence suggests such a possibility, but research to date has not attempted to model this interdependence directly. The current project breaks with that tradition. In particular, it proposes three competing explanations of how previous intervention efforts affect current intervention decisions: a cost model (and a variant on it, a limited commitments model), a learning model, and a random model. After using a series of Markov transition (regime-switching) models to evaluate conflict management behavior within militarized interstate disputes in the 1946-2001 period, this study concludes that third-party intervention efforts inform one another. More specifically, third-parties examine previous efforts and balance their desire to manage conflict with their need to minimize intervention costs (the cost and limited commitments models). As a result, third-parties intervene regularly using verbal pleas and mediation, but rely significantly less frequently on legal, administrative, or peace operations strategies. This empirical threshold to the intervention costs that third-parties are willing to bear has strong theoretical foundations and holds across different time periods and third-party actors. Furthermore, the analysis indicates that the first third-party to intervene in a conflict is most likely to use a strategy designed to help the disputants work toward a resolution of their dispute. After this initial intervention, the level of third-party involvement declines and often devolves into a series of verbal pleas for peace. Such findings cumulatively suggest that disputants hold the key to effective conflict management. If the disputants adopt and maintain an extreme bargaining position or fail to encourage third-parties to accept greater intervention costs, their dispute will receive little more than verbal pleas for negotiations and peace

Replication data for: Democratization and International Border Agreements

Does the removal of salient external threats foster democratization? Recent research proposes an affirmative answer but either fails to examine democratization at the monadic level, to consider small-scale democratization, or to account for factors known to influence the democratization process. The current study addresses this deficit by (re)examining democratization during the period 1919–2006. The findings suggest a strong relationship between border settlement and democratization. A state that settles all of its interstate borders democratizes; any outstanding unsettled borders, however, prevent significant democratization. Furthermore, although border settlement contributes to democratization, it does not significantly affect democratic regime change. This empirical evidence cumulatively specifies a more precise relationship between external threat and democratization than previous work and thereby contributes directly to the recent debate between the territorial and democratic peace theories. It also suggests that democratization may proceed more readily if states address unsettled borders first

Replication Data for "Foundations for Integrating the Democratic and Territorial Peace Arguments"

The democratic and territorial peace arguments explain interstate peace via distinct mechanisms. Yet they can be integrated. I theoretically derive both the unique domains in which each argument might operate and the ways in which the two arguments might reinforce one another. An analysis of the period 1816-2001 demonstrates support for a more integrative approach. Within contiguous dyads, border settlement significantly reduces conflict, even for non-democratic dyads. Democratic dyads, however, experience no such effect in the absence of border settlement. Nonetheless, the democratic peace functions strongly in non-contiguous dyads, and even the most peaceful, contiguous dyads require both democracy and border settlement. Such findings offer a foundation for further theoretical development that integrates the two arguments

Replication data for: Signing Up for Peace: International Boundary Agreements, Democracy, and Militarized Interstate Conflict

Can states usher in more peaceful relations with their neighbors by signing agreements that delineate their territorial boundaries? Theory suggests such a possibility, but the empirical evidence to date remains limited by research design and variable measurement decisions. After assembling a new data set on international boundary agreements, the current study conducts the first thorough test of this question during the period 1816–2001. The findings indicate that once neighboring states settle their borders, they are less likely to go to war or experience militarized interstate disputes with one another. These pacific effects persist across numerous time periods even after controlling for joint democracy, a characteristic that both theory and this analysis show to be positively related to settled borders. Through these findings, the study suggests that signing international boundary agreements can bring neighbors a more peaceful relationship with one another, regardless of the characteristics of their respective governmental regimes

Signing Up for Peace: International Boundary Agreements, Democracy, and Militarized Interstate Conflict

Can states usher in more peaceful relations with their neighbors by signing agreements that delineate their territorial boundaries? Theory suggests such a possibility, but the empirical evidence to date remains limited by research design and variable measurement decisions. After assembling a new data set on international boundary agreements, the current study conducts the first thorough test of this question during the period 1816–2001. The findings indicate that once neighboring states settle their borders, they are less likely to go to war or experience militarized interstate disputes with one another. These pacific effects persist across numerous time periods even after controlling for joint democracy, a characteristic that both theory and this analysis show to be positively related to settled borders. Through these findings, the study suggests that signing international boundary agreements can bring neighbors a more peaceful relationship with one another, regardless of the characteristics of their respective governmental regimes

Replication Data for: Conflict Management Efforts of Allies in Interstate Disputes

Motivations for conflict management are rarely discussed in terms of commitments that potential third-parties have toward one or both disputants. The current study addresses this lacuna by examining how the design of alliances affects conflict management behavior. In particular, we argue that third-party states’ willingness to manage interstate conflicts depends on both the existence of an alliance relationship and the depth of that relationship. We test this argument using data on conflict management within militarized interstate disputes during the period 1946-2000. We find that allies are more likely than non-allies to manage their partner’s disputes. Underneath this aggregate relationship, however, we also find that the depth of alliance commitments strongly influences this behavior. Deeper commitments – both across and within alliance types – increase the likelihood of conflict management significantly

Replication data for: The Conflict Management Efforts of Allies in Interstate Disputes

Motivations for conflict management are rarely discussed in terms of commitments that potential third-parties have toward one or both disputants. The current study addresses this lacuna by examining how alliance designs affect conflict management behavior. Specifically, we argue that third-party states'™ willingness to manage interstate conflicts depends on both the existence and depth of an alliance relationship. We test this argument using data on conflict management within militarized interstate disputes during the period 1946-2000. We find that allies are more likely than non-allies to manage their partner'™s disputes. Underneath this aggregate relationship, however, we also find that the depth of alliance commitments strongly influences this behavior. Deeper commitments -- both across and within alliance types --“ increase the likelihood of conflict management significantly

Replication data for: Clearing the Hurdle: Border Settlement and Rivalry Processes

Why do interstate rivalries end? In pursuit of this question, we advance a territorial theory of rivalry to account for termination, which bridges the limited theoretical work on rivalry termination, the logic of commitment problems, and recent research associated with the territorial peace. We argue that unsettled borders are caused by an underlying commitment problem that contributes to the formation and perpetuation of rivalry. Ending the rivalry (by settling the borders) requires overcoming this fundamental commitment problem. We suggest that the signing of an international border agreement therefore represents a tangible indicator that states have overcome this commitment problem. After such agreements, we therefore expect rivalry termination to hasten and the rivalries that persist to experience fewer, shorter, and less severe conflict episodes. Empirical analysis of rivalries during the period 1816-2001 confirm these expectations. Such findings offer support to our unified (territorial) theory of rivalry and suggest that those seeking to manage rivalries might first focus upon unsettled borders as they attempt to create more peaceful interstate relations