We recently identified a common environmental agent with the potential capacity to terminate self tolerance and to strongly enhance autoimmune response and disease. The purpose of our proposal is to establish a causal link for this environmental effect. Neonatal female mice in a colony infested with rodent pinworm (Syphacia obvelata) were no longer tolerant or unresponsive to the ovarian peptide pZP3, or to the lupus-related peptide pRo60. When injected with pZP3 at birth (given in water, without adjuvant), the mice developed a strong Th2 response to pZP3 with production of IL4 and IL5 (and not IFNgamma), IgGI-dominant autoantibodies, and eosinophilic oophoritis. The Th2 response was recalled upon challenge as adults with pZP3 in CFA, indicating a long lasting Th2 memory for pZP3. Neonatal injection of the lupus-related pRo60 peptide in water also led to diversified antibody response to distant Ro60 epitopes, and memory for pRo60. When pinworm infection was eradicated by fenbendazole, the Th2 neonatal response to pZP3 instantly disappeared. These findings support an association between pinworm infection and autoimmunity, and have prompted a novel hypothesis of autoimmunity pathogenesis. In presence of an environmental modifier (pinworm infestation), stimulation by self or crossreactive foreign antigen (pZP3 in water) early in life, terminates or prevents self-tolerance to the antigen; instead, it provokes T cell response and memory. This may result in early- onset autoimmune disease, or it may confer adult-onset acute or chronic autoimmune disease on subsequent antigen challenge. The data further support a pathogenic Th2-mediated autoimmune response.
In Aim 1, we will establish the causal role of pinworm infection on the neonatal Th2 response to pZP3 by studying clean mice deliberately infected with pinworm. We will determine if the (phenomenon is triggered by another rodent nematode Heligmosomoides polygvrus, whether pinworm affects the response to other self antigens, and whether pinworm infection triggers autoimmune ovarian disease by non-ovarian peptides that crossreact with pZP3.
Aim 2 will focus on one potential mechanism of the pinworm effect. We hypothesize that pinworm infestation leads to activation of the immature neonatal antigen presenting cells (APC). The modified APC then present the pZP3 to naive T cells, to elicit a Th2-biased autoimmune response. We will examine whether pinworm-infested mice have activated APC. If they do, we will inhibit the neonatal response by blocking APC activation. In summary, with this hypothesis-driven proposal, we will explore a common and natural infectious agent and its capacity to terminate self tolerance and provoke autoimmune disease in neonatal mice.
| Agersborg, S S; Garza, K M; Tung, K S (2001) Intestinal parasitism terminates self tolerance and enhances neonatal induction of autoimmune disease and memory. Eur J Immunol 31:851-9 |
