Retargeting T Cell-Mediated Inflammation: A New Perspective on Autoantibody Action

Abstract

To understand the pathogenesis of organ-specific autoimmune disease requires an appreciation of how the T cell-mediated inflammation is targeted, and how the organ function is compromised. In this study, autoantibody was documented to influence both of these parameters by modulating the distribution of T cell-mediated inflammation. The murine autoimmune ovarian disease is induced by immunization with the ZP3330–342 peptide of the ovarian zona pellucida 3 glycoprotein, ZP3. Passively transferred or actively induced Ab to ZP3335–342 bound to the zona pellucida in the functional and degenerative ovarian follicles, and the ovaries remained histologically normal. Transfer of ZP3330–342 peptide-specific T cells targeted the degenerative follicles and spared the functional follicles, and the resultant interstitial oophoritis was associated with unimpaired ovarian function. Unexpectedly, the coexistence of ZP3330–342 peptide-specific T cells and zona-bound autoantibody led to a dramatic translocation of the ovarian inflammation to the growing and mature ovarian follicles, with destruction of the ovarian functional unit. Ab retargeted both Th1-induced mononuclear inflammation and Th2-induced eosinophilic inflammation, and retargeting was induced by murine and rat polyclonal Abs to multiple distinct native B cell determinants of the zona pellucida. Therefore, by reacting with the native determinants in tissue Ag, Ab alters the distribution of T cell-mediated inflammation, and results in destruction of the functional units of the target organ. We propose that this is a clinically important and previously unappreciated element of Ab action in autoimmune disease.

Contraception in mice immunized with recombinant zona pellucida subunit 3 proteins correlates with Th2 responses and the levels of interleukin 4 expressed by CD4+ cells

“…Previously, it has been reported that Th1-like ZP3-specific T cells migrate to the ovaries and induce mononuclear cell infiltrations, but only when ZP3 specific antibodies are present (Lou et al 2000, Lou & Borillo 2003. However, in our study we found no evidence for inflammatory cells in the ovaries upon autopsy at around 3-4 months after the first immunization with ZP antigens.…”

Maternal Autoantibody Triggers De Novo T Cell-Mediated Neonatal Autoimmune Disease

“…In adult AOD, activation of pZP3-specific T cells alone is promptly followed by spontaneous IgG autoantibody response to distant ZP3 epitopes (24). The attendant autoantibodies produced in this T to B pathway in adult mice (including CP2 and CP3 Abs), although nonpathogenic by themselves, retarget the location of the T cell-mediated inflammation in adult AOD, leading to ovarian oocyte loss and fertility reduction (18). In the nAOD model we now document the T to B pathway in reverse; namely, the capacity of autoantibody to trigger de novo pathogenic T cell response.…”

“…This chimeric peptide 2 (CP2) elicits a strong Ab response to the native ZP3 without concomitant T cell response to ZP3; despite strong binding of the Ab to the ZP in vivo, adult mice with ZP3 Ab alone do not develop any ovarian pathology (17). The only observable effect of ZP3 Ab in adults, demonstrable in ZP3-specific T cell recipients, is the capacity to retarget the location of ZP3-specific T cell-mediated injury from the interstitial atretic ovarian follicles to the normal ovarian follicles (18).…”

Immunogenicity and contraceptive potential of three infertility-relevant zona pellucida 2 epitopes in the marsupial brushtail possum (Trichosurus vulpecula)

“…This implies that antibody binding may also result in infertility by changing the conformation of the three-dimensional structure of the zona matrix, rather than simply blocking access to epitopes on individual ZP proteins. There is also evidence that antibodies against ZP antigens alter the distribution of T cell-mediated inflammation and result in destruction of the functional components within the ovary (Lou et al 2000), possibly destroying oocytes via a cell-mediated cytotoxic immune response (Jackson et al 1998).…”

“…Failure of peptides Pep12 or Pep31 to reduce fertility and for their antibodies to reliably bind to native zona suggests that they may not be genuine immunocontraceptive epitopes. Jackson et al (1998) postulated that in mice, antibodies binding to the developing ZP of growing eggs may disrupt folliculogenesis, possibly by killing (Lou et al 2000). In mice, the incidence of oophoritis and inflammatory (T cell) responses in the ovary following ZP3 immunization varies depending on mouse major histocompatibility complex (MHC) haplotype and the presence of a pathology-inducing T cell epitope within the antigen construct (Lou et al 1996, Bagavant et al 1999.…”