Recently, we have demonstrated that human platelets carry preformed CD40 ligand (CD154) molecules, which rapidly appear on the platelet surface following stimulation by thrombin. Once on the surface, platelet CD154 induces an inflammatory reaction of CD40-bearing endothelial cells. This study shows that strong platelet agonists other than thrombin also lead to the expression of CD154 on the platelet surface. At the same time, several lines of evidence are presented that together indicate that thrombotic events in the vasculature are generally accompanied by activation of the inflammatory potential of platelet CD154. This study also reports the constitutive expression of CD40, the receptor for CD154, on platelets. The binding of CD154 to coexpressed CD40 in the platelet aggregate leads within minutes to hours to the cleavage of membrane-bound surface CD154 and the release of an 18-kd soluble form of the molecule. Soluble CD154 (sCD154), in contrast to transmembrane CD154, can no longer induce an inflammatory reaction of endothelial cells. These findings indicate that the interaction of platelet CD154 with CD40 on neighboring cells is temporally limited to prevent an uncontrolled inflammation at the site of thrombus formation. Thus, similar to the very tight regulation of the CD154-CD40 interaction in the immune system, an effective mechanism controls the inflammatory potential of platelet CD154 in the vascular system. IntroductionCD40, a 48-kd transmembrane protein homologous to the tumor necrosis factor (TNF) receptor, was first described as a constitutive cell-surface antigen on B cells. 1,2 The CD40 ligand (CD40L, TRAP, gp39, CD154) is a 33-kd transmembrane homologue of TNF-␣ and was originally identified as a surface molecule expressed on activated T cells. [3][4][5] Subsequent analysis of "immunodeficiency with hyper-IgM" demonstrated that interaction of CD40L on activated T cells with CD40 on B cells is required for the IgM to IgG isotype switch and thus revealed the pivotal role of the CD40L/CD40 pair for humoral immunity. 6 Later, CD40 was also found to be constitutively expressed on monocytes, macrophages, and dendritic cells. 7 In these cells, CD154, through interaction with CD40, initiates inflammatory responses such as synthesis of interleukin (IL)-1, IL-6, or TNF-␣ 8 and thus functionally resembles its structural homologue TNF-␣.More recently, CD40 was identified on vascular endothelium and was shown to mediate signals leading to de novo expression of adhesion molecules and release of proinflammatory cytokines and chemokines by endothelial cells. [9][10][11] In these original experiments, it was assumed that only activated T cells bearing CD154 can activate endothelial cells via CD40. [9][10][11] This paradigm changed with our recent finding that platelets carry preformed CD154 molecules and rapidly express them on the cell surface after activation by thrombin. 12 Furthermore, we could demonstrate that the interaction of CD154 on activated platelets with CD40 on endothelial cells elicits an inflamma...
Bovine tuberculosis (bTB) is a major zoonotic disease of cattle that is endemic in much of the world, limiting livestock productivity and representing a global public health threat. Because the standard tuberculin skin test precludes implementation of Bacille Calmette-Guérin (BCG) vaccine–based control programs, we here developed and evaluated a novel peptide-based defined antigen skin test (DST) to diagnose bTB and to differentiate infected from vaccinated animals (DIVA). The results, in laboratory assays and in experimentally or naturally infected animals, demonstrate that the peptide-based DST provides DIVA capability and equal or superior performance over the extant standard tuberculin surveillance test. Together with the ease of chemical synthesis, quality control, and lower burden for regulatory approval compared with recombinant antigens, the results of our studies show that the DST considerably improves a century-old standard and enables the development and implementation of critically needed surveillance and vaccination programs to accelerate bTB control.
Gene transcription studies have identified dual roles for the cytokines IL-17A and IL-22 in bovine tuberculosis, where they show potential as both predictors of vaccine success and correlates of infection. To allow for a detailed investigation of the cell populations responsible for production of these cytokines, we have utilised a novel bovine IL-22 specific recombinant antibody for flow cytometry. Bovine tuberculin (PPDB) induced greater IL-22 and IL-17A production in Mycobacterium bovis (M. bovis)-infected cattle compared to non-infected controls, while PWM-induced cytokine levels were similar between the two groups. In M. bovis-infected animals, PPDB specific IL-22 and IL-17A responses were observed in both CD4+ T cell and γδ T cell populations. Although both cytokines were detected in both cell types, IL-22/IL-17A double producers were rare and confined mainly to the γδ T cell population. These results support previous gene transcription studies and extend the observation of increased IL-22 and IL-17A responses in M. bovis-infected animals to the level of protein production. We were also able to characterise the cell populations responsible for these disease-related cytokine responses. The data generated can be used to further our understanding of the immunopathology of bovine tuberculosis and to produce more sensitive and specific immune-diagnostic reagents.
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