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Departments of Obstetrics & Gynecology and Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2515
Address all correspondence and requests for reprints to: Dr. Michael H. Melner, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2515. E-mail: Mike.Melner{at}mcmail.vanderbilt.edu
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Premature ovarian failure (POF) is the loss of ovarian function in women less than 40 yr of age (reviewed in Ref. 1). It is associated with sex steroid deficiency, amenorrhea, infertility, and elevated serum gonadotropins. While there are multiple etiologies of POF including the exposure to iatrogenic treatments (chemotherapy, radiation), viral agents, and rare genetic disorders, in most patients no etiology can be identified (idiopathic POF). Significant evidence suggests that autoimmunity is a cause of some forms of ovarian failure although specific ovarian antigens are not known and the mechanisms of autoimmune disease development are unclear.
Autoimmune POF in humans is frequently associated with other
manifestations of autoimmune disease. For example, POF can precede the
onset of Addison’s disease or adrenal autoimmunity leading to a
deficiency of adrenocortical hormones (1). Autoimmune POF is
characterized by inflammatory infiltration of developing follicles,
production of anti-ovarian antibodies, atrophy, and sparing of
primordial follicles (1, 2, 3). Autoantibodies in these diseases sometimes
react with common antigens in steroid-producing cells of the ovary and
adrenal cortex. Common antigens identified have been steroidogenic
enzymes including P450 side-chain cleavage (P450scc),
17
-hydroxylase, and 3ß-hydroxysteroid dehydrogenase (4, 5, 6). The
identification of specific antigens involved in POF is important for
multiple reasons. First, the development of appropriate reagents to
screen for the presence of antibodies to these antigens could provide
an analytical tool for diagnosing the disease, identifying patients at
risk for developing the disease, and detecting patients who may respond
to immune-modulating therapies. Second, these tools could be used in
research to further understand the mechanisms of disease development
and the mechanisms of ovarian pathology associated with the disease.
Lastly, the identification of these antigens provides new information
on novel proteins in the ovary and their potential function.
Animal models of autoimmune premature ovarian failure have yielded important insight into both potential mechanisms of autoimmune disease development and ovarian antigens that may affect disease progression. These models for autoimmune ovarian failure can be induced by multiple methods such as immunization with specific ovarian antigens or neonatal thymectomy in specific genetic strains of mice. A detailed review of the findings will not be repeated here but some major developments will be summarized. The most important development in these animal models of autoimmune ovarian failure comes from multiple studies, all suggesting that the basis of the disease is a cell-mediated autoimmune reaction caused by an alteration in T cell regulation (1, 3). This is most evident in the neonatal thymectomy animal model. The removal of the thymus in specific genetic strains of mice (e.g. BALB/c or A/J) between postnatal days 2 and 5 results in autoimmune ovarian failure. There is a progressive onset of the disease that is potentiated by puberty and the most severe inflammation occurs between 4–14 weeks after thymectomy (3). The proposed mechanism of the disease (3) is that autoreactive T cells (CD4+) are generated during normal processes such as apoptosis of follicles in the ovary. These autoreactive cells are normally controlled by CD4+ T cells with suppressor activity. However, because these cells are generated in the thymus after the first week of life, neonatal thymectomy results in a dramatic loss in T cells with suppressor function. This animal model strongly implicates T cell regulation in the disease process.
Further support for the role of T cell regulation comes from other animal models of autoimmune POF. It is now clear that ovarian failure is induced in animals treated with ovarian antigens (1) such as zona pellucida protein 3 (ZP3). However, there is significant evidence indicating that autoimmune POF can develop with antigen treatment, even if the antigen is not related to known ovarian antigens. This suggests that the process of T cell activation can sometimes result in a loss of T cell regulation and the subsequent activation of autoreactive T cells (3).
The genetic susceptibility to the development of autoimmune POF may ultimately provide some key insight into the mechanisms involved. Previous studies have demonstrated a genetic component to human POF that could be documented across multiple generations (7, 8). In the autoimmune POF induced by neonatal thymectomy in genetically susceptible strains of mice, the locus that controls this phenotype (Aod2) has been mapped to mouse chromosome 3 (9). Interestingly, the Aod2 locus colocalizes with Idd3, a gene that is involved in the susceptibility to autoimmune insulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse (9). This suggests the potential involvement of a common locus in these two autoimmune responses.
The paper by Tong and Nelson (10) describes the identification and cloning of a complementary DNA (cDNA) encoding a protein that is a major antigen in the neonatal thymectomized mouse model of autoimmune premature ovarian failure. The studies are interesting in the new information they provide and for the potential new research tools they generate. On a basic level, a new gene product (designated ooplasm-specific protein 1, OP1) has been identified that appears to be specific for the oocyte. While the sequence of OP1 was not homologous to any known cDNAs/proteins and the function of the protein is not yet known, it contains some potentially relevant amino acid sequence motifs suggesting ATP/GTP-binding and phosphorylation sites for protein kinases. Follow-up studies on the function of OP1 are apparently underway and OP1 may provide new insight into the mechanisms controlling oocyte maturation and fertilization.
The identification of OP1 also provides some potentially important research tools for examining the onset and development of autoimmune POF. For example, OP1 protein obtained from expression systems could be used to detect the presence and levels of circulating antibodies and the time-course of their appearance. Autoreactive T cells and B-cells could be characterized and changes in the subpopulations of T cells examined closely to further elucidate mechanisms of disease progression. In addition, the role of immune cells within the ovary can be better assessed with the use of reagents that recognize known target antigens.
Another question in POF is the mechanism of antigen exposure and presentation in normal control animals and how the immune tolerance is converted to an active T cell response. The fate of the majority of follicles in the ovary is atresia by apoptosis (11, 12, 13) and it is possible that one mechanism by which ovarian antigens are exposed to the immune system is during some segment of these processes. The oocyte presents a very interesting model of apoptosis since oocytes are surrounded by the cumulus layer of granulosa cells and bidirectional communication occurs via gap junctions between these 2 cell types. This raises questions as to whether there is something unique about this cell communication structure that makes it susceptible to immune exposure during apoptosis. Another mechanism of antigen exposure is during an inflammatory reaction. Such a reaction could occur at sites of ovulation when there is evidence of a local inflammatory response and the release of cumulus granulosa cell-oocyte complexes. Any inefficiency in oocyte release could see degenerating oocyte-granulosa cell complexes in the presence of inflammation-associated immune cells, some of which are antigen-presenting cells (e.g. macrophages). It is interesting to note that puberty and the presence of increased serum gonadotropins appears to enhance the autoimmune response in experimental models of autoimmune POF (3). The new reagents generated by these studies could be used to help examine the onset of autoreactive antibodies and T cells.
The exact mechanisms of pathology in autoimmune POF are not clearly defined. The neonatal thymectomized mouse model coupled with a known major antigen provides a system to begin to understand the cellular processes of ovarian failure. The time-course of the development of antibodies to OP1 during autoimmune ovarian failure is not known. For example, are OP1 antibodies amplified early in the process or are do they occur late after significant inflammatory damage. Closely related to the question of time-course, it is not known whether OP1 antibodies play a role in the etiology of ovarian failure.
The similarities/differences between the neonatal thymectomized mouse model of autoimmune POF and the autoimmune POF seen in humans are difficult to assess. There appear to be methodological problems in the immunodetection of antigens, particularly using cross-species studies. By identifying a major antigen OP1 in murine autoimmune POF, it is now possible to screen for the homologous human antigen. If this presents problems using antisera, a homologous human cDNA could be isolated and used to express protein and develop detection methods for the presence of antibodies in women with autoimmune POF. Ultimately, stringent methods can be brought to task to determine whether an homologous antigen is involved in human autoimmune POF.
Autoimmune diseases have a significantly higher incidence in young women than in men (14). Much of this differential has been attributed to the effects of androgens and estrogens on components of the immune system reviewed in (15). However, studies also implicate the high levels of progesterone during pregnancy in the suppression of immune function and transitory thymic involution. Experimental evidence suggests that androgens and estrogens exert effects on the development of immune cells through their effects on the thymus and bone marrow. In addition, there is evidence that androgens and estrogens have effects on peripheral immune cells involved in cell-mediated immunity. These effects include enhancement of T cell suppressor activity by androgens and enhancement of T cell helper activity by estrogens. Androgens and estrogens also appear to have effects on humoral immunity, and there is evidence that androgens diminish autoreactive antibodies while estrogens increase autoreactive antibodies. The effects of sex steroids on immune cell function could thus be a contributing factor to the development and progression of autoimmune POF.
It is clear that significant new information has come from animal models of autoimmune POF that have expanded our understanding of the disease and given clues to potential etiologies. In addition, these models could ultimately provide screening reagents for early stages of POF in humans. The power of the thymectomized mouse model system employed by Tong and Nelson (10) includes the ability to identify genes that are critical for the development of autoimmune POF and then perform genetic manipulations to test their importance. For example, if the autoimmune susceptibility gene in the Aod2 locus is identified, transgenic mice could be generated with targeted gene disruption in susceptible strains and introduction of the gene to resistant strains. These animals could then be tested for the development of autoimmune POF after neonatal thymectomy. The data from these animal models could therefore have important implications to our understanding of autoimmune POF and possibly provide information on potential treatment strategies.
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Received June 1, 1999.
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-hydroxylase. Lancet 339:770–773[CrossRef][Medline]
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