PROJECT SUMMARY
Ultraviolet B light (UVB; 280-315nm) is a common environmental trigger that can induce skin
inflammation and flares in several autoimmune diseases. UVB light is an established trigger for skin flares in
SLE patients, and regional spikes in atmospheric UVB intensity correlate with flare frequency among SLE
patients within that geographic region. In mice, IgE antibodies are elevated after UVB exposure, and previous
work shows that skin-reactive IgE also plays a key role in removing damaged keratinocytes after carcinogen
exposure. However, the role of self-reactive IgE has not been studied in photosensitivity reactions in
autoimmunity.
Regulatory T (Treg) cells play a central role in maintaining immune system homeostasis and modulating
immune responses. Foxp3 is a master regulator of Treg development and function. FOXP3 mutations in patients
with IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), which result in a
deficiency in Tregs, result in lethal autoimmunity, similar to the disease observed in Foxp3 deficient mice. While
highly conserved in both amino acid sequence and gene structure, one difference between humans and mice is
that the human FOXP3 gene encodes two major alternatively spliced isoforms: a full-length version that uses
all 10 exons (FOXP3FL, the only isoform in mice) and a shorter isoform lacking exon 2 (FOXP3¿E2). Recent
studies have shown that Tregs from patients with some autoimmune diseases express increased levels of the
¿E2 isoform compared to those from healthy donors. Consistent with this finding, we have found that Tregs from
SLE patients have increased expression of the FOXP3¿E2 isoform.
To study the role of the ¿E2 isoform in Treg function we generated a new mouse strain with Foxp3 exon
2 deletion. Interestingly, we found that Foxp3¿E2 mice develop hallmark features of SLE, including anti-DNA
and anti-nuclear autoantibodies, increased number and size of spontaneous germinal centers and kidney
deposition of antibody complexes, by 4-5 weeks of age. Importantly, these mice display a marked increase in
circulating IgE and develop IgE-specific autoantibodies against skin antigens, including Keratins 2 and 14. In
addition, these mice have IgE deposits in the skin, which increase dramatically following UVB irradiation. Our
central hypothesis is Foxp3DE2-expressing Tregs fail to regulate germinal center responses and
promote IgE autoantibodies. To test this hypothesis, we will first determine the role of Foxp3¿Ex2-expressing
Tregs in germinal center function, focusing on the relationship between Tfh and Tfr cells. Next, we will assess
the role of autoreactive IgE in UVB-mediated skin inflammation in these mice. These studies will provide
insights into the role of Foxp3¿E2 Treg function and the development and progression of inflammatory skin
disease.