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Thymus and fertility: New insights of thymic-gonadal-relaxin axis
The 3rd Word Congress on Reproduction, Oxidative Stress and Antioxidants (2014)
  • , Emory University
A nexus between the immune and reproductive systems involves, among others, bidirectional effects between gonads and thymus. The human thymus is continuously viewed as the main site of tolerance to auto-antigens that are specifically expressed by T-cells - along with the macrophages and cytotoxicity, whereas tolerance to tissue-restricted auto-antigens is ascribed to extrathymic (peripheral) mechanisms. The phenomenon of promiscuous expression of tissue-restricted self-antigens by medullary thymic epithelial cells has led to a reassessment of the role of central T-cell tolerance in preventing organ-specific autoimmunity (including the idiopathic infecundity). Both genetic and epigenetic mechanisms account for this unorthodox mode of gene expression.
More empirical studies are required to tackle the immune-reproductive pathways. The following barriers contribute to the unfortunate scarcity of thymic theme in reproductive health scholarship:
(1) being a temporary organ thymus shrinks with puberty, and therefore is erroneously viewed as gradually losing its relations to the HPA axis;
(2) ethical constraints and technical obstacles in conducting empirical studies on thymus of reproductive age men and women.
Nonetheless, reproductive autoimmune failure can be associated with overall activation of immune system or with immune responses (both innate and adaptive) directed against ovarian antigens. Majority of the antiovarian auto-antibodies target the β-subunit of follicle stimulating hormone (anti-FSH). In female infertility, the expansion of cells responding to low-affinity ligands (allo-antigen) or anomalies in the deletion of high-affinity autoreactive T-cells leading to autoimmune reactions is a possibility to explore.
Infertility and recurrent spontaneous abortion (RSA) are frequently attributed to the immunological disturbance. A deeper insight into apparently unexplained infertility and RSA supports the theory of both alloimmune and autoimmune involvements, in which natural killer (NK) cells and auto-antibodies are the role players.
Successful pregnancy is considered a Th1–Th2 cooperation phenomenon, with a predominantly Th2-type lymphocyte response, together with the emerging role of interleukin (IL)-12, IL-15, and IL-18 and of other unidentified soluble factors dependent on NK cells.
The uterine NK cells comprise the largest population at implantation site, and their activity, characteristics, and abundance suggest that they participate at the decidualization process that induces NK activation and recruitment in each menstrual cycle and vice versa. However, NK cell alteration may be associated with impaired pregnancy, and the modulation in the number of circulating NK cells is most likely to be a primary event rather than an the outcome of active inflammation or autoimmune process in the pathogenesis of immunological infertility. [1]
Studies on animal models suggest on the reduced fecundity of parasites due to the thymus-dependent immunological responses in mice.[2]Removal of thymus retards the growth of the testes in young guinea pigs.[3]Another study defines the thymus factor (TF) to inhibit the binding activity of 125I-hCG to its testicular receptor. The inhibitory effect of TF on hCG binding is dose related, suggesting a modulation function of TF at the testis receptor level.[4]
Reproductive autoimmune failure syndrome was originally described by Gleicher et al. in 1987, in women with endometriosis, infertility and increased auto-antibodies.[5]Autoimmune mechanisms as well as an increased production of multiple autoantibodies are involved in such infertility disorders as premature ovarian failure (POF), endometriosis, polycystic ovary syndrome (PCOS), unexplained infertility, and repeatedly unsuccessful in vitro fertilization (IVF) attempts and may be responsible for the pathophysiology of preeclampsia or spontaneous abortions. [7]
The autoimmune infertility might be a polyclonal event featured by immunological defects at the T-cell level which - similarly to classical autoimmune diseases - may manifest itself in abnormal antibody production. [8, 9]However, like state above, most clinical studies are restricted to detecting serum antibodies in determining autoimmune activation in the infertile couple - due to the technical difficulties.
Yet, thymus performs many roles in immune-related fertility issues. Autoimmune regulator genes (AIREG) influence thymic production of ovarian antigens and prevents autoimmune-mediated premature reproductive senescence. For example, immunemediated ovarian follicular depletion is a mechanism of infertility in mice.[10] Such animal models are important informers as to the mechanism of the ovarian autoimmune disease in women. Thymic expression of the ovarian genes controlled by the AIREG deem crucial in preventing ovarian autoimmune disease.
It is also established that treatment of patients with chronic prostatitis is complicated by infertility by microwave (460 MHz) action on the area of the thyroid and thymus glands.[11]T-lymphocyte inhibition by human seminal plasma is due to multiple factors, and reduced amounts of these factors may contribute to development and persistence of sperm autoimmunity in the infertile men.[12]
When debating over the immune stress in infertility, no concept is integrate without mentioning the role of relaxin. A peptide of the insulin superfamily, relaxin consists of seven peptides of high structural but low sequence similarity; relaxin-1 (RLN1), 2 (RLN2) and 3 (RLN3), and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. In females, it is produced by the corpus luteum of the ovary, the breast and during pregnancy, through the placenta, chorion, and decidua. In males, it is produced in the prostate and is found in the semen.
Discovered more than 75 years prior to the identification of the receptors that mediate actions of relaxin, there has been however a slow move toward understanding the role of relaxin – except of the notion of it being a hormone of pregnancy. Yet, relaxin is equipped for many other physiological roles, including vasomotor regulations, or the ability to induce matrix metalloproteinases.
The recent de-orphanisation of four receptors LGR7, LGR8, GPCR135 (SALPR) and GPCR142 (GPR100) that respond to and bind at least one of the three forms of relaxin , allows dissection of this system to determine the precise role of each receptor and enable the identification of new targets for treatment of numerous disease states.
Some studies suggest, that the reduced incidence and severity of rheumatoid arthritis in pregnancy is attributed to the estradiol-17β and relaxin. [13]
Relaxin-3, the newly established member of relaxin peptide family, is produced by GABA-ergic projection neurons in the nucleus incertus (NI), in the pontine periventricular gray matter of the brain. Relaxin-3 is a modulator of stress responses, metabolism, arousal and behavioral activation. It is shown, that relaxin-3 (or INSL7) is the endogenous ligand for an orphan G-protein-coupled receptor, GPCR135 (aka somatostatin, an angiotensin-like peptide receptor), but it also activates GPCR142. [14]Yet, a definitive role remains elusive due to discrepancies between models and a propensity to investigate pharmacological effects over endogenous function.
Relaxin antagonists may act as contraceptives or prevent the development of breast cancer metastases. Recent research has added considerable knowledge to the signaling pathways activated by relaxin, which will aid our understanding of how relaxin acts in infertility.
During phylogeny and ontogeny, thymus appears as a nodal point between the two major systems of cell-to-cell signaling, between the neuroendocrine and immune systems. The neuroendocrine polypeptide precursors play a dual role in T-cell selection played by the thymic repertoire.
Thymic neuroendocrine-related polypeptides are source of auto-antigens which are presented by the major histocompatible system of thymic epithelium. The intrathymic T-cell education to neuroendocrine self-antigens cannot be strictly counted out in terms of the antigen presentation by dedicated presenting cells. [15]
Little is known about the role of relaxin in modulating cell-mediated immunity, and acute or chronic thymic atrophy. For the first time in reproductive health scholarship, a putative thymus-gonadal-relaxin axis is speculated through the pathway presented in Figure 1 :
  • thymus,
  • relaxin,
  • fecundity,
  • fertility,
  • immunomodulation,
  • natural killer cells,
  • antiovarian autoantibodies,
  • 125I-hCG,
  • receptor de-orphanisation
Publication Date
Spring May, 2014
Citation Information
"Thymus and fertility: New insights of thymic-gonadal-relaxin axis" The 3rd Word Congress on Reproduction, Oxidative Stress and Antioxidants (2014)
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