Inflammation and Spermatogenesis.

THEAS MARÍA SUSANA; JACOBO PATRICIA VERÓNICA; PÉREZ CECILIA; GUAZZONE VANESA ANABELLA; LUSTIG LIVIA

Spermatogenesis: Biology and Clinical Implications

, ed.Taylor and Francis Group, CRC Press

Año: 2018; p. 1 - 267

The testis is an immunologically privileged site with a unique immunosuppressor microenvironment able to tolerate haploid germ cell antigens that appear at puberty and to easily accept tissue grafts. The existence of the blood-testis barrier, the secretion of immunosuppressor mediators by somatic cells, mainly Sertoli cells, and the immunomodulatory function of regulatory T (Treg) cells, contribute to immunoprivilege. However, this immunosuppressed microenvironment does not prevent the testis from developing inflammatory and immune reactions in response to different stressors such as pathogens or tissue damage. Infection and inflammation are widely accepted as important etiological factors of subfertility or infertility. Prevalence rates up to 15% have been reported in patients examined in infertility clinics (1). The most frequent orchitis or epididymo-orchitis induced by specific pathogens occur by retrograde ascent of different urethral bacterial pathogens (Escherichia coli, Chlamydia trachomatis, and Neisseria gonorrhea, among others) or systemic viral infections. The best-known orchitogenic viruses in humans are mumps virus and HIV. Mumps virus induces innate immune responses in mice through retinoic acid-inducible gene signaling and TLR2 expressed by Sertoli and Leydig cells which results in the production of pro-inflammatory cytokines and chemokines (2). Both viruses are able to replicate in Leydig cells in vitro, inhibiting testosterone (3-4). AIDS patients often suffer from oligozoospermia or azoospermia and hypogonadism (5). Immunosuppression is also a potential mechanism for HIV persistence in the testis (6).Orchitis is characterized by impairment of seminiferous tubules (ST) presenting germ cell sloughing and degeneration associated with interstitial and peritubular immune infiltrates of T cells and macrophages that may eventually invade ST. Granulomas may also occur in severe orchitis. Increase of Th1 and Th17 pro-inflammatory cytokines have been demonstrated in human orchitis associated with oligozoospermia and fibrosis contributing to transient or permanent subfertility or infertility (1, 7, 8). Mast cells and peritubular cells are involved in testicular fibrosis mainly through increased production of pro-fibrotic cytokines (9). Lymphomonocyte infiltration is also frequent in pathologies other than infection in which the testicular parenchyma is damaged, such as neoplasia, trauma, toxic agents, and cryptorchidia (10-13). Continuous release of spermatic antigens from impaired ST induces disruption of tolerance and induction of an autoimmune inflammatory response (14). Orchitis may also have a genetic basis, as a manifestation of polyglandular autoimmune syndrome. In particular, this rare autosomal recessive disease is caused by mutation of the AIRE gene or is related to a defect in Treg cell function (15-16).