Studying the Regulatory Effects of Betaretrovirus infection in the NOD.c3c4 mouse model of Primary Biliary Cholangitis

• Author / Creator

  Messeha, Kerolous Samy

• A human betaretrovirus (HBRV) has been previously characterized in patients with primary biliary cholangitis (PBC). HBRV shares between 91% to 99% nucleotide similarity with the mouse mammary tumor virus (MMTV). Retroviruses are known to suppress host immune responses by the presence of immunosuppressive domains (ISD) located in the Envelope (Env) portion. These ISDs have been shown to inhibit lymphocyte proliferation and promote secretion of IL-10, an immunoregulatory cytokine. For example, HBRV Env has been found to harbor two ISDs in the Env protein that inhibit lymphocyte proliferation and trigger IL-10 secretion in vitro (M. Rahbari, CDDW, 2015). In vivo, we investigated whether MMTV Env protein harbors an ISD with similar immunoregulatory characteristics. Then, we addressed the hypothesis that B cells in the PBC mouse model (NOD.c3c4) are promoted to secret more IL-10 in response to the presence of MMTV infection. To test the characteristics of ISD, splenocytes from healthy BALB/c were stimulated by 85 individual peptides composed from the HBRV Env. Then, ELISA was used to detect the levels of IL-10 secretion. In addition to, T cell proliferation assays were performed to assess the ability of each ISD to inhibit lymphocyte division. To assess the role of B cells in response to MMTV infection, splenocytes from infected NOD.c3c4 and healthy C57Bl/6 were immunostained for the viral proteins, B cell markers and IL-10. These studies showed that the ISD significantly promoted higher secretion of IL-10 compared to the other Env peptides. In the proliferation assays, there was reduction in proliferation by 20% (p < 0.01) and 44% (p < 0.001) in BALB/c and C57Bl/6 splenocytes respectively. Furthermore, the NOD.c3c4 mice had a significant expansion of B cells secreting IL-10 compared to C57Bl/6 (p < 0.001). MMTV ISD modulate the immune response via inhibiting lymphocyte proliferation and promoting IL-10 secretion, which we hypothesize prevents antiviral immune responses and enables disease progression. Moreover, MMTV-infected B cells may play an appreciable role in the development of the PBC-like phenotype in NOD.c3c4 mice. More B cells secreting IL-10 were found in NOD.c3c4 compared to healthy mouse strains. This study reveals the immune modulation of MMTV and potentially enables a better understanding of PBC pathophysiology. Further work may reveal a different role for IL-10 in disease progression.

• Subjects / Keywords

  • Mouse Mammary Tumor virus
  • B cells
  • Primary Biliary Cholangitis

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-e5k4-qm45

• License

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