大象传媒

The center for Young women with premature menopause is a four year research project managed by professor . The center听researches premature ovarian insufficiency (POI), a condition where the ovaries stop functioning normally before a woman turns 40, affecting about 3% of women. This results in early menopause and hormonal disturbances. Besides infertility, the consequences of POI include increased risk of cardiovascular diseases, osteoporosis, dementia, and autoimmune diseases. Hormone therapy counteracts menopausal symptoms associated with POI, but there is currently no treatment to restore or improve fertility. Despite these serious health consequences, the cause of POI remains unknown in the majority of women, and the disease mechanisms are understudied.

POI is a heterogeneous disorder with many different causes, where autoimmunity accounts for 3-30% of cases. The underlying cause in these women is an immunological attack on the ovaries, causing functional damage. The gradual destruction of the ovaries provides a window of opportunity to stop the immune attack with immunotherapy. Establishing a definitive autoimmune cause for POI is therefore important but remains challenging as ovary-specific autoantibodies have not yet been identified, highlighting the need for better diagnostic tests.

Furthermore, the mechanisms by which sex hormones modulate the immune system and affect the risk of autoimmunity are still unclear, although we and others have previously shown a high prevalence of autoimmune disease in women with POI. Exploring changes in the immune system in young women in menopause can clarify estrogen's role in the development of autoimmune diseases.

Through interdisciplinary national and international collaboration, this project aims to provide unique insights into a disease with devastating consequences for young women, uncover gender-specific features of the immune system, and bring diagnostic tools and new immunomodulatory treatments to the clinic with the aim of restoring fertility.

The main goal of the project is to improve diagnostic precision and treatment of ovarian insufficiency. This will be achieved through four work packages.

(1) Identify new autoantigens and autoantibodies targeting ovarian cells in women with POI - lead PI:听

Identifying autoantibodies that are highly specific to the disease will enable us to quickly and accurately diagnose whether patients have an autoimmune cause behind ovarian failure and facilitate appropriate treatment. We will use a method called PhiP-seq, in collaboration with Mark Anderson (UCSF, USA), to identify potential autoantibody candidates in serum from women with POI. Findings will be verified in a laboratory setting. We will also compare results with serum from men with autoimmune disease to ensure that the antibodies are specific to women. If we manage to find promising autoantibodies, these will be further developed to see if they can be used for diagnosis in the clinic.

Once we have identified autoantibodies, we will examine how their targets (antigens) are expressed in cells, including in which tissues, the quantity, and in relation to local immune cells. This will provide us with an increased understanding of how the disease progresses. We will also use other organs and publicly available datasets to determine whether this is specific to ovarian cells.

(2) Identify how estrogen deficiency contributes to pathogenic pathways in autoimmune diseases听- lead PI:听

To identify estrogen's impact on the immune system and how this contributes to autoimmune diseases, we will use single-cell RNA sequencing, combined with in vitro studies of primary immune cells and flow cytometry analysis of blood cells from POI patients. The PhD student will perform the majority of the work under the supervision of the WP leader. These exploratory studies will provide insights into estrogen's role in the development of POI and generate new hypotheses on disease mechanisms. This information is crucial for developing new treatment strategies and will inform possible strategies for immune modulation to reverse POI. The broad screening of cytokines may also identify useful biomarkers for autoimmune POI.

(3) Establish the genetic contribution to POI -听lead PI:听听and Elinor Vogt

We will use exome sequencing to determine the genetic contribution to POI. Exome sequencing allows for the analysis of all coding regions of the genome. By sequencing the exome of women with autoimmune POI, researchers can identify genetic variants that may contribute to the development of the condition. This includes both known and new mutations in genes involved in ovarian function and autoimmunity. Identifying such variants can provide insights into the molecular mechanisms behind POI and potentially reveal new therapeutic targets.

After identifying genetic variants through exome sequencing, it is important to conduct functional studies to understand their biological significance. This involves examining how the identified variants affect gene and protein function. For example, researchers can use cell culture models to study the effects of mutations on cell growth, differentiation, and survival. Functional validation is crucial to confirm that the identified variants actually contribute to POI and are not just incidental findings.

(4) Immunotherapy in autoimmune oophoritis -听lead PI:听听and Elinor Vogt

In a previous smaller study in collaboration with Karolinska Institute, we showed promising results in improving fertility in women with autoimmune POI using immunomodulatory therapy (Rituximab). We will听now expand this study to听a multicenter, double-blind, placebo-controlled, randomized study听investigating听the effect of immunomodulatory therapy in 40 women with autoimmune POI in Scandinavia.

We hope that positive results from this study will lead to rituximab treatment becoming standard care for women with POI.