Date of Award:
Doctor of Philosophy (PhD)
Gregory J. Podgorski
Three major questions were addressed in this dissertation: 1)Do immune abnormalities associated with autism primarily alter CD4+ T cell-mediated or humoral immune responses? 2) Are specific T cell clones expanded in autism? 3) Which, if any, infectious agents play a role in autism?
CD4+ T cell-mediated (Th1) or humoral (Th2) immune responses can be distinguished on the basis of the cytokines expressed. CD4+ T-cells secrete interleukin type 2 (IL-2) and interferon-γ, whereas a Th2 response is associated with secretion of interleukin type 4(IL-4). mRNA extracted from peripheral blood mononuclear nuclear cells (PBMC) showed significantly increased levels of IL-2 and interferon-γ expression in 24 autistic subjects relative to 19 normal controls. IL-4 mRNA was undetectable in the same group of autistic subjects. These results indicate that a CD4+ T cell-mediated immune response is associated with autism.
The expression of V-β chain mRNA was used as a marker or particular T cell clone expression. The expression of V-β 13 was significantly elevated in the study group of 11 autistic subjects, but not in 9 normal subjects. This suggests that T cell-mediated autoimmunity is a factor in the disease. Two types of human leukocyte antigens (HLA) alleles, DR4 and DR1, are associated with autism. The association between V-β 13 expressing T cell clones and autism was shown even more strongly in the subgroups expressing HLA DR4 or DR1. This result suggests a link between antigen presentation by HLA DR4 or DR1 and expansion of V-β 13 T cell clones.
The potential involvement of pathogens suspected to trigger autism was investigated by examining T cell proliferation responses to peptide epitopes. As a group, the 24 autistic subjects did not show a decreased response to peptides derived from rubella virus, influenza A virus, herpes simplex virus type 1, cytomegalovirus, and Clostridium tetani. Another model of autism postulates that autism is induced by pathogens that possess epitopes identical to the hypervariable region 3 (HVR-3) of the HLA DR4 or DR1 alleles. Two antigens derived from the Escherichia coli dna J protein and the Epstein-Barr virus glycoprotein 110 peptides that contain sequences identical to the HVR-3 of the DR4 and DR1 alleles were examined for their ability to induce T cell proliferation in autistic and normal subjects. No effect of the DR4 or DR1 alleles on the response to these two antigens was detected. Therefore, both types of results do not support the model of immune tolerance in autism. However, average T cell proliferative activity was significantly lower in the same autistic subjects. This confirms many prior reports that reduced T-cell responses may shape susceptibility to autism.
Further understanding of how immune abnormalities and infectious agents lead to autism should guide development of preventative and therapeutic strategies for this disease. (152 pages)
Hu, Yong, "Altered T Cell-Mediated Immunity and Infectious Factors in Autism" (2000). All Graduate Theses and Dissertations. 6846.
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