In Utero Exposure to Autoantigens: Reappraisal of Tolerance Induction and Underlying Mechanisms

Immunological tolerance refers to a state of immune nonreactivity specific to particular antigens as the holy grail in the field of transplantation and in the management of autoimmune diseases. The concept of tolerance originated from Owen’s observation of blood cell sharing in twin calves. It paved the way to Medawar’s discovery of “actively acquired tolerance”, indicating that tolerance is essentially a learning experience for T-cells, thereby committing the antigens present in pre-immune fetuses to memory of their patterns as “self”. Having worked on fetal exposure to foreign antigens over the years, we failed to universally induce tolerance as envisaged by Medawar, but found that the immunological outcome varied according to the type or nature of antigens introduced. Soluble peptides such as ovalbumin and human papilloma virus E7 peptides caused a sensitization event, whereas alloantigens from exosomes, B-cells and marrow cells might lessen or abrogate T-cell alloreactivity. Long-lasting skin tolerance only ensued while marrow inocula could confer a state of significant hematopoietic chimerism in postnatal life. The inconsistent or even opposite outcomes have clouded the picture of Medawar’s concept that developing immune system “learns” to discriminate between self and nonself. It then prompts us to examine whether in utero exposure to autoantigens can confer self-tolerance to preclude postnatal induction of autoimmune diseases in murine models. Soluble thyroglobulin for experimental autoimmune thyroiditis or insoluble type II collagen for collagen induced arthritis will be used as autoantigen inocula to evaluate for a dose-response relationship in fetal recipients. The outcome, either tolerogenic or immunogenic, will be of great significance for the mechanisms underlying self-tolerance development or the pathogenesis of autoimmunity. This research project will also involve a thorough investigations into the interactions between fetal immune system and antigens, mainly focusing on innate fetal macrophages that emerge early during gestation as the first immune cells capable of surveying their surroundings, and take up a variety of antigens in fetal life. We demonstrated that fetal macrophages were responsible for endocytosing ovalbumin and differentiated toward dendritic cells to subsequently initiate T-cell immunity. It highlighted the role of fetal macrophages in regulating the immunological outcome of fetal antigen exposure regardless of T-cell maturity. They could attenuate proteolysis within lysosomes to effectively retain the memory of internalized antigens for delayed presentation. Therefore, lysosomal pathway of antigen processing in fetal macrophages is critical to the regulation of adaptive immune recognition and downstream T-cell responses. Investigations of lysosomes will include the maturity of its enzyme system and its luminal pH levels in association with coupling status of V-ATPase V0 and V1 domains. Demystifying lysosomal pathway of antigen processing in fetal macrophage may add valuable information for the molecular machinery of antigen degradation, thereby advancing our knowledge about the influence of antigen degradation on tolerance or immunity induction.

Project ID:PC10907-1228
External Project ID:MOST109-2314-B182-041-MY3