Over 100 years ago, it was noted that more women than men were affected by autoimmune diseases including Sjögren's syndrome (SS), systemic lupus erythematosus and rheumatoid arthritis. SS is a predominantly female, incurable, autoimmune exocrinopathy whose pathogenesis remains unknown. It is one of the most common autoimmune disease with 2 million patients in USA. SS is best characterized by lymphocytic infiltration into and destruction of the salivary gland but it is, associated interstitial cystitis and lymphoma. Thus a significant percent of SS patients develop lymphoid malignancies. We have investigated one model of estrogen deficiency, the aromatase knockout (Ar-/-) mouse and report here that estrogen deficiency results in an immune disorder, distinct from autoimmune nephritis, found in ERa -/- mice (Shim et al. PNAS 2004) and myeloid leukemia found in ERb -/- mice (Shim et al. PNAS 2003, reviewed Nature Cancer Review 2003 ). Life time loss of estrogen causes spontaneous development of SS without pre-conditioning. Like in the human disease, we found severe destruction of salivary glands, and lymphocytic infiltration into the kidney, hepato-biliary system, lung and pancreas. Also we found estrogen treatment could rescue one indication of SS in Ar-/- mice thus the disease seems to be reversible. Moreover wild type mice fed phytoestrogen-free diet for a year showed clearly higher incidence of SS, than their littermates on a normal diet. Our finding indicates that phytoestrogens in the diet can reduce the incidence of SS and that one early event in SS can be inhibited by treatment with estrogen.

It is a very important key to our understanding of the role of estrogen in the immune system that three different genetic models of estrogen deficiency result in three different diseases of the immune system. Although it has been known for 100 years that estrogen is responsible for the high incidence of autoimmunity in females, exact role of estradiol has never been understood. This is because estrogen has contradictory effects on the immune system. We can now state that the different effects of estradiol are mediated by its interaction with the two estrogen receptors, ERa and ERb. The net effect of estradiol is determined by a balance between ERa and ERb within different cells of the immune system. In the total absence of estradiol, the immune system is different from both the ERa and the ERb deficient system. Since daily consumption of phytoestrogen in food seems to largely reduce SS symptoms, this may be one simple way to reduce the social coast of treatment of SS patients. Since the phytoestrogen in soy are much better ligands for ERb than ERa, ERb-selective agonists might have clinical value to prevent SS.

Scientific Impacts considering sexual dimorphism of autoimmune diseases

Sexual dimorphism of autoimmunity has been a qestion over a century, female sexhormone, estrogen thought to be a key regulator on autoimmunity. However so far, loss of estrogen ( ovariectomy, knock-out mice for estrogen receptor) and higher estrogen in vivo could not answer the question since estrogen clearly shows contradictory effect on various autoimmunities. Here we show as the first evidence that loss of an enzyme, called aromatase which is a key enzyme of estrogen biogenesis directly associated exocrinopathy in mice. Estrogen is synthesizing through complicate metabolic pathways from cholestrol. And autoimmune diseases are multigenic disorders therefore, here we suggest that many enzymes that involved in steroid hormone metabolism have to be reviewed as genetic risk factors to understand geneder different of autoimmune disease which has not been considered yet. Those new investigations will help to understand this very old mysteries on the sexual dimorphism of autoimmune diseases.

Social Impacts

1. SS is common and currently incurable disease
2. Defective estrogen synthesis is normal process of ageing in women
3. Our results indicates that loss of estrogen directly causes SS
4. HRT has been widely applied in western countries and our reports indicated that HRT may be benefit for SS patients
5. Dietary phyto-estrogen will help prevent SS and reduce the cost of public health
6. SS is associated with a high risk for lymphoma and other fatal diseases, early prevention of SS could prevent further more serious diseases.

We believe that our report addresses issues which have both scientific and social impact.

Related publications

Gil-Jin Shim, Ling Wang, Sandra Andersson, Noemi Nagy, Lorand Levente Kis, Qinghong Zhang, Sari Makela, Margaret Warner and Jan-Ake Gustafsson. Disruption of the Estrogen Receptor Beta Gene in Mice Causes Myeloproliferative Disease Resembling Chronic Myeloid Leukemia with Lymphoid Blast Crisis. Proc. Natl. Acad. Sci. U S A. 2003 May 27;100(11):6694-9.

Gil-Jin Shim, Kis LL, Warner M, Gustafsson JA. Autoimmune glomerulonephritis with spontaneous formation of splenic germinal centers in mice lacking the estrogen receptor alpha gene. Proc. Natl. Acad. Sci. U S A. 2004 Feb 10;101(6):1720-4.