Under normal conditions, self-reactive lymphocytes
are killed, inactivated or suppressed by regulatory T cells, resulting in
unresponsiveness to self-antigens. Disruption of these control mechanisms
results in the survival and pathogenic activation of self-reactive lymphocytes.
It is unclear how self-reactive lymphocytes are spontaneously activated in the
absence of overt infection or other stimuli, leading to autoimmune disease.
If the initiators of activation and subsequent disease can be delineated, and
the antigen targets of pathogenic antibodies identified, means of controlling
these autoimmune reactions may be uncovered.
Antigen identification in autoimmune hemolytic anemia
(AIHA)
In this study, we use a mouse model of spontaneous, acute systemic autoimmunity
that principally manifests as AIHA to identify the target antigens in this disease.
Pinpointing the targets of autoimmune activity remains a central challenge to
defining the mechanisms of autoreactive lymphocyte activation. Because
IL-2-deficient mice develop autoantibodies that that are highly specific to RBC
proteins, they can be used as a tool to identify autoantigens. By identifying
the targets of autoaggressive T cells during AIHA we can better understand the
functional activities of these cells. These tools will enable the distinction of
autoreactive T cells from the expanded and activated bystander cells. This work is
supported by a grant from the National Institutes of Health: 5R00HL090706
Tolerance mechanisms to a systemic, endogenous
antigen
The goals of this project are to define the cellular and molecular mechanisms by
which T cells maintain tolerance to systemically produced cell surface proteins and
identify the mechanisms that go awry during the development of systemic autoimmunity.
An intact immune system utilizes several tolerance mechanisms to prevent responses
of self-reactive T cells. To understand how tolerance to systemic antigen is
maintained we have generated TCR retrogenic (Rg) mice reactive against red blood
cell proteins. The results from these studies should provide important insights
into the multi-step loss of tolerance that occurs leading to autoimmune pathogenesis.
Role of CD8 T cells in autoimmune hemolytic anemia
(AIHA)
IFNγ-producing CD4 and CD8 T cells accumulate during systemic autoimmune disease
in IL-2-deficient mice. It is clear that CD4 T cells are necessary for disease
progression, and we have previously shown that IL-2-KO CD4 T cells from sick mice
can transfer autoimmunity and lymphadenopathy to recipient mice. However, the
importance of CD8 T cells to the initiation and propagation of autoimmunity is
unknown. Several groups have demonstrated a protective role for CD8 T cells in
inflammation and autoimmunity, while others have suggested a pathogenic role.
The goal of this project is to define the function of CD8 T cells during spontaneous
autoimmune disease. We are currently addressing the importance of these autoreactive
CD8 T cells relative to that of the self-reactive CD4 T cells, and evaluating the
mechanisms by which CD8 T cells influence the autoimmune disease process.
