Oral administration of Domain-I of beta-2glycoprotein-I induces immunological tolerance in experimental murine antiphospholipid syndrome. (May 2019)

• Record Type: Journal Article
• Authors: Shemer, Asaf; Willis, Rohan; Gonzalez, Emilio B.; Romay-Penabad, Zurina; Shovman, Ora; Shoenfeld, Yehuda; Blank, Miri; Amital, Howard
• Is Part Of: Journal of autoimmunity. Volume 99(2019)
• Page Start: 98
• Page End: 103
• Publication Date: 2019-05
• Subjects: Antiphospholipid syndrome -- Beta2glycoprotein-I -- Autoimmunity -- Antiphospholipid syndrome -- Oral tolerance; APS antiphospholipid syndrome -- β2GPI beta 2 glycoprotein-I -- DI domain-I -- DV domain-V -- miRNA microRNA -- Treg T regulatory cell; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2019.02.002
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: It is well established that the humoral immunity in antiphospholipid syndrome (APS) is presented by circulating pathogenic anti -β2GPI autoantibodies targeting mainly domain I of the β2GPI protein, playing a major role in the disease pathogenesis. Previously, we have demonstrated that treatment of experimental APS mice with tolerogenic dendritic cells loaded with domain-I was more efficient in tolerance induction than with the whole molecule or domain-V. In the current study we had orally administered a domain-I derivative of the β2GPI molecule, as a new therapeutic approach to induce oral tolerance in this mouse model of APS. BALB/c mice immunized with β2GPI, were fed with either domain-I, domain-V derivative or the complete β2GPI protein. β2GPI immunized mice developed experimental APS which were fed with domain-I significantly had decreased fetal loss (p < 0.004), a lower size of thrombi (p < 0.001) and lower circulating anti -β2GPI Abs in comparison to mice fed with domain-V or PBS (p < 0.002). Likewise, Domain-I fed mice had a lowered inflammatory response, exhibited by decreased expression of inflammatory cytokines (IFNγ, IL-6, IL-17) and elevated production of IL-10 anti-inflammatory cytokine by splenocytes. Moreover, the anti-inflammatory response in the domain-I fed APS mice was associated with increased circulating miRNA variations (155, 146, 182, 98) by RT-PCR, which are associated with immunomodulation of the immune network. We propose that oral tolerance with domain-I can be a novel therapy for patients with APS. Highlights: Immunization of naïve mice with DI-β2GPI induces experimental APS equal to immunization with β2GPI. Oral administration of DI-β2GPI to APS mice induces tolerance and ameliorate experimental APS. DI-b2GPI induced oral tolerance was manifested by inhibition of inflammatory cytokines, enhanced IL-10 and Treg cells. The tolerance induction by DI-β2GPI was associated with miRNA expression related to immunomodulation.