Immune system involvement in the regulation of ovarian function and augmentation of cancer

Abstract

Increasing evidence indicates a role for the immune system and mesenchymal-epithelial interactions in the regulation of ovarian function. Cytokines produced by mesenchymal cells can stimulate development and regression of ovarian structures. We report here that mesenchymal cells releasing surface molecules among epithelial cells--namely vascular pericytes and monocyte-derived cells (MDC)--and intraepithelial T lymphocytes are associated with oogenesis and formation of new primary follicles in both fetal and adult human ovaries. These activated mesenchymal cells interact with the ovarian surface epithelium, which appears to be a source of secondary germ cells and granulosa cells. Activated pericytes and MDC are also associated with stimulation of thecal development during selection of growing secondary follicles from the cohort of primary follicles. However, survival of the dominant follicle during mid-follicular phase selection is associated with a lack of activity of mesenchymal cells and retardation of thecal development, since immature granulosa cells lacking aromatase are unable to resist high levels of thecal androgens. Once the selected follicle matures (late follicular phase), it shows enhanced activity of thecal mesenchymal cells and advanced thecal development. Corpus luteum (CL) development is accompanied by a high activity of vascular pericytes and MDC. In mature CL and CL of pregnancy, luteal MDC and pericytes show a stable (inactive) state. Regression of the CL is associated with regression of pericytes, transformation of MDC into dendritic cells, infiltration by T lymphocytes, and binding of immunoglobulin G to the luteal cells. The immunoglobulin M (IgM) binds to young but not mature luteal cells. In the CL of pregnancy, IgM binds to luteal vessels, but not to luteal cells. Regressing CL shows IgM binding to both luteal cells and vessels. In ovarian cancers, highly activated MDC and sometimes activated pericytes (poorly differentiated carcinomas) are present. IgM binding is similar to that seen in the CL of pregnancy. These data indicate that vascular pericytes, MDC, T cells, and immunoglobulins may play an important role in the regulation of ovarian physiology and contribute to the augmentation of ovarian cancer growth.

Ovarian Stem Cell Niche and Follicular Renewal in Mammals

“…2H) in fetal and adult human ovaries are accompanied by activated Thy-1 pericytes (arrowhead, insert; adult ovary, compare with resting follicles-rf) and activated (HLA-DR þ ) MDC (arrows, Fig. 2H; fetal ovary); compare with a resting follicle (Bukovsky et al, 2005a;Bukovsky, 2006a). The DR þ MDC penetrate the follicular basement membrane (dashed line, Fig.…”

“…The Thy-1 expression appears to be associated with initiation of primordial follicle growth, since resting primordial follicles usually lie in Thy-1 depleted areas showing an ''ovary-in-ovary'' pattern (Bukovsky et al, 2004;Bukovsky, 2006a). Panel C shows that resting primordial follicles (red asterisks) lie in an area with less pronounced Thy-1 expression (left) as compared to the growing (yellow asterisks) and degenerating follicles (black asterisks).…”

“…2A). This activity of MDC is associated with cellular division (Bukovsky et al, 2001;Bukovsky, 2006a). This is accompanied by an emergence of germ cells, which are depleted of the major histocompatibility complex Class I (MHC-I) expression (red asterisks, Fig.…”

“…Subsequent SD of germ cells (asterisks, panel F) is accompanied by CD14 primitive MDC only (arrowhead). Beside the germ cells, the OSC are also a source of primitive granulosa cells (pgc, panel G), differentiating in fetal ovaries between mesenchymal cell cords (mcc; Bukovsky et al, 2005a;Bukovsky, 2006a).…”

“…Furthermore, activated resident vascular pericytes and bone marrow derived monocytes accompany initiation of follicular growth, selection, and preovulatory maturation of autologous oocytes (Bukovsky et al, 1995;Bukovsky, 2006a).…”