In order to improve the treatment regimen of patients with autoimmunity it is critical to better define the pathogenic T cell population involved. To accomplish this we will take advantage of a novel application that for the first time will allow a highly focused dissection of the pathogenic T cell repertoire. This analysis will bridge the gap that hitherto existed in understanding the effector mechanisms of an autoreactive immune response, using alopecia areata as a prototypic example. Since severe cases of alopecia areata are rarely managed with systemic agents, this organ-specific autoimmune disease represents a unique opportunity to longitudinally characterize the evolution of an autoreactive immune response in vivo in the absence of confounding immunosuppressive medications. No study to date has followed in detail an autoreactive repertoire longitudinally from a patient's initial presentation to the establishment of chronic autoimmunity. The specific hypothesis being tested is that pathogenic self-directed T cells can be identified, characterized and followed longitudinally in patients with alopecia areata by combining CDR-3 length repertoire analysis with magnetic sorting and flow cytometry. The goal will be to determine: how this pathogenic T cell response evolves over time, the surface phenotype of the pathogenic T cells, and the in vivo or directly ex vivo cytokine secretion profile of the individual pathogenic T cells.
The specific aims are as follows.
Specific Aim 1 : Identify activated clonotypic T cells in patients with alopecia areata.
Specific Aim 2 : Determine if the same clonotypic T cell expansions are present longitudinally as a patient's disease evolves.
Specific Aim 3 : Determine the pathogenic T cell's surface expression of activation markers, chemokine receptors, and integrin adhesion molecules as well as the pathogenic T cell's cytokine secretion profile.
Under normal circumstances the immune system protects against foreign invading pathogens such as bacteria and viruses. The T cells are a type of cell of the immune system. These cells have the ability to distinguish viral and bacterial proteins from enogenous """"""""self"""""""" proteins and cells that make up your body. Alopecia areata is an autoimmune disease. In autoimmunity the usually protective T cells mistakingly recognize enogenous """"""""self"""""""" proteins as foreign, which leads to tissue and organ damage. We propose to study these T cells to determine how the autoimmune disease response evolves over time. We will also characterize the surface of the autoreactive T cells and the molecules they secrete.
| Maverakis, Emanual; Miyamura, Yoshinori; Bowen, Michael P et al. (2010) Light, including ultraviolet. J Autoimmun 34:J247-57 |
