Are Major League Baseball Starting Pitchers Compensated for Stadium Risk?

This paper examines the significance of stadium effects on the determination of starting pitcher salaries. It models stadium effect first under the assumption of perfect certainty, and then includes risk through uncertainty. Using starting pitchers’ statistics between 1990 and 2008, this paper determines that the stadium effect is not significant in the model with perfect certainty, but becomes significant when uncertainty (risk) is introduced. An unexpected result of the test shows, however, that there is a fundamental difference between the American League, where the stadium effect is significant, and the National League, where it is insignificant in both models

T follicular helper cells differentiate from Th2 cells in response to helminth antigens

The relationship of T follicular helper (TFH) cells to other T helper (Th) subsets is controversial. We find that after helminth infection, or immunization with helminth antigens, reactive lymphoid organs of 4get IL-4/GFP reporter mice contain populations of IL-4/GFP-expressing CD4+ T cells that display the TFH markers CXCR5, PD-1, and ICOS. These TFH cells express the canonical TFH markers BCL6 and IL-21, but also GATA3, the master regulator of Th2 cell differentiation. Consistent with a relationship between Th2 and TFH cells, IL-4 protein production, reported by expression of huCD2 in IL-4 dual reporter (4get/KN2) mice, was a robust marker of TFH cells in LNs responding to helminth antigens. Moreover, the majority of huCD2/IL-4–producing Th cells were found within B cell follicles, consistent with their definition as TFH cells. TFH cell development after immunization failed to occur in mice lacking B cells or CD154. The relationship of TFH cells to the Th2 lineage was confirmed when TFH cells were found to develop from CXCR5− PD-1− IL-4/GFP+ CD4+ T cells after their transfer into naive mice and antigen challenge in vivo

Migratory CD103+ dendritic cells suppress helminth-driven type 2 immunity through constitutive expression of IL-12

CD8alpha(+) and CD103(+) dendritic cells (DCs) play a central role in the development of type 1 immune responses. However, their role in type 2 immunity remains unclear. We examined this issue using Batf3(-/-) mice, in which both of these DC subsets are missing. We found that Th2 cell responses, and related events such as eosinophilia, alternative macrophage activation, and immunoglobulin class switching to IgG1, were enhanced in Batf3(-/-) mice responding to helminth parasites. This had beneficial or detrimental consequences depending on the context. For example, Batf3 deficiency converted a normally chronic intestinal infection with Heligmosomoides polygyrus into an infection that was rapidly controlled. However, liver fibrosis, an IL-13-mediated pathological consequence of wound healing in chronic schistosomiasis, was exacerbated in Batf3(-/-) mice infected with Schistosoma mansoni. Mechanistically, steady-state production of IL-12 by migratory CD103(+) DCs, independent of signals from commensals or TLR-initiated events, was necessary and sufficient to exert the suppressive effects on Th2 response development. These findings identify a previously unrecognized role for migratory CD103(+) DCs in antagonizing type 2 immune responses

TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand.

T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells. TSLP-induced T cells expressed CXCR5, CXCL13, ICOS, PD1, BCL6, BTLA, and SAP, among other Tfh markers. Functionally, TSLP-DC-polarized T cells induced IgE secretion by memory B cells, and this depended on IL-4Rα. TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13. Mechanistically, TSLP-induced Tfh differentiation depended on OX40-ligand, but not on ICOS-ligand. Our results delineate a pathway of human Tfh differentiation in Th2 environments

The development and maintenance of B cell responses to microbial challenge

Humoral responses are a critical component of the immune system and antibodies play an important role in the response to many pathogens. The work presented in this thesis examines the development, maintenance, and regulation of antibody production. T follicular helper (TFH) cells have been shown to provide B cell help in germinal centers (GCs). However, infection with T. gondii results in a loss of splenic organization, including the GCs. Thus, studies were performed to evaluate this splenic disorganization and the effects of this process on antibody responses. Furthermore, experiments to better understand the development of TFH cells revealed that TFH cells can arise from CD4+ T cells that have committed to the Th2 lineage in response to SEA immunization. However, aberrant B cell response can lead to antibody-mediated autoimmune disease, thus studies were conducted to further elucidate regulatory mechanisms to control GC responses. These revealed that IL-27 can inhibit GC responses through effects on TFH cells and directly through B cells. Finally, antibody responses are maintained long term through long-lived plasma cells in the bone marrow. Analysis of the Treg population in the bone marrow demonstrates a role for these cells in maintaining plasma cells, a relationship that can be transiently disrupted as both populations are lost during infection. Collectively, these studies highlight developmental processes and regulatory mechanisms that support B cell responses

The development and maintenance of B cell responses to microbial challenge

Humoral responses are a critical component of the immune system and antibodies play an important role in the response to many pathogens. The work presented in this thesis examines the development, maintenance, and regulation of antibody production. T follicular helper (TFH) cells have been shown to provide B cell help in germinal centers (GCs). However, infection with T. gondii results in a loss of splenic organization, including the GCs. Thus, studies were performed to evaluate this splenic disorganization and the effects of this process on antibody responses. Furthermore, experiments to better understand the development of TFH cells revealed that TFH cells can arise from CD4+ T cells that have committed to the Th2 lineage in response to SEA immunization. However, aberrant B cell response can lead to antibody-mediated autoimmune disease, thus studies were conducted to further elucidate regulatory mechanisms to control GC responses. These revealed that IL-27 can inhibit GC responses through effects on TFH cells and directly through B cells. Finally, antibody responses are maintained long term through long-lived plasma cells in the bone marrow. Analysis of the Treg population in the bone marrow demonstrates a role for these cells in maintaining plasma cells, a relationship that can be transiently disrupted as both populations are lost during infection. Collectively, these studies highlight developmental processes and regulatory mechanisms that support B cell responses