News and Publications

Human Autoantibodies as Biological Markers of Disease

R.L. Ochs, F. Alcantara, C.L. Parsons,* Y. Muro,** D. Iglehart,*** E.K.L. Chan, E.M. Tan

* University of California, San Diego, CA
** Nagoya University, Nagoya, Japan
*** Duke University Medical Center, Durham, NC

We use human autoantibodies as tools for investigating the basic cell and molecular biology of human diseases.

AUTOANTIBODIES IN INTERSTITIAL CYSTITIS AND ATOPIC DERMATITIS

Interstitial cystitis is a chronic inflammatory disease of the bladder characterized by bladder pain and urinary frequency and urgency. Although the cause of interstitial cystitis is currently unknown, previously mentioned etiologic agents or causes include bacteria, viruses, toxic substances in the urine, direct physical trauma to the bladder wall, and bladder-specific autoimmune disease. We have focused on an autoimmune etiology to explain some of the signs and symptoms of interstitial cystitis.

Initially, we found that 36% of patients with interstitial cystitis had autoantibodies that react with nuclear antigens. In immunofluorescence assays, more than half of the sera containing antinuclear antibodies had a nuclear dense fine-speckled (DFS) staining pattern. During studies on autoantibodies in other chronic inflammatory conditions, we found that sera from 41% of 64 patients with atopic dermatitis also had antinuclear autoantibodies and that many of the sera had a nuclear DFS staining pattern. Sera from 28% of the 64 patients both showed the nuclear DFS staining pattern and reacted with a cloned DFS recombinant protein. In contrast, sera from 10% of patients with interstitial cystitis or asthma reacted with the recombinant DFS protein and had the DFS staining pattern. These data indicate that the cloned DFS protein is a shared autoantigen targeted by IgG autoantibodies in subpopulations of patients with atopic dermatitis, interstitial cystitis, and asthma.

Atopic dermatitis is a chronic, relapsing, pruritic skin disorder that generally first appears in childhood and often progresses to asthma or allergic rhinitis in adulthood. No objective laboratory marker for atopic dermatitis is available, but patients with this disorder often have elevated serum levels of IgE; allergic reactivity to foods and other common allergens such as pollens, molds, and insects; and the presence of antinuclear antibodies. The prevalence of atopic dermatitis appears to be increasing; 10--15% of the population is affected at some time during childhood.

On the basis of our studies, we conclude that the major autoantibody-autoantigen system in patients with interstitial cystitis is the same as the major system in patients with atopic dermatitis. We are investigating the common traits of these seemingly disparate diseases that might account for this discovery.

AUTOANTIBODIES IN BREAST CANCER

We are examining the sera of women with breast cancer for the presence of autoantibodies. Thus far, we found that approximately 50% of women with breast cancer have detectable levels of self-reactive antibodies. This immunologic response may reflect the presence of molecules altered by mutation or overexpression that may play an important role in the development or maintenance of malignant neoplasms. Altered molecular pathways in cancer might make some molecules immunogenic and lead to the production of antibodies that might be useful in detecting novel proteins involved in the malignant process. Characterization of novel breast cancer proteins that are the target of autoantibodies may lead to a better understanding of the basic cellular and molecular biology of malignant breast tumors and may provide novel targets for therapy.

PUBLICATIONS

Casiano, C.A., Ochs, R.L., Tan, E.M. Distinct cleavage products of nuclear proteins in apoptosis and necrosis revealed by autoantibody probes. Cell Death Differ. 5:183, 1998.

Derenzini, M., Trere, D., Pession, A., Montanaro, L., Sirri, V., Ochs, R.L. Nucleolar function and size in cancer cells. Am. J. Pathol. 152:1291, 1998.

Hashimoto, S., Ochs, R.L., Rosen, F., Quach, J., McCabe, G., Solan, J., Seegmiller, J.E., Terkeltaub, R., Lotz, M. Chondrocyte-derived apoptotic bodies and calcification of articular cartilage. Proc. Natl. Acad. Sci. U.S.A. 95:3094, 1998.

LaMorte, V.J., Dyck, J.A., Ochs, R.L., Evans, R.M. Localization of nascent RNA and CREB binding protein with the PML-containing nuclear body. Proc. Natl. Acad. Sci. U.S.A. 95:4991, 1998.

Ochs, R.L. Methods used to study structure and function of the nucleolus. Methods Cell Biol. 53:303, 1998.

Scully, R., Chen, J., Ochs, R.L., Keegan, K., Hoekstra, M., Feunteun, J., Livingston, D.M. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90:425, 1997.