ABSTRACT
The etiology and pathogenesis of Kawasaki syndrome (KS) remain unknown. Clinical and epidemiologic features of KS are consistent with an infectious cause. To search for an etiologic agent of KS, a phage cDNA expression library was constructed from the aorto-iliac junction of a patient with fatal acute KS and screened with convalescent KS serum followed by anti-human Ig. Unexpectedly, 0.1% of the clones in the library react with anti-human Ig, indicating the presence of many Ig-producing B lymphocytes in the vasculitic tissue. To confirm this finding and to determine the isotypes produced, frozen vascular tissue sections from the patient and paraffin sections from coronary arteries from six additional patients with fatal acute or subacute KS were incubated with Abs to Ig isotypes. Histopathology of the tissues revealed the presence of many plasma cells in the inflammatory infiltrate. IgA was the predominant isotype produced in vascular tissue in all seven KS patients. IgM- and IgG-producing cells were less often detected. We conclude that there is a marked plasma cell response within the vasculitic tissue in KS, with unusual IgA production locally in this nonlymphoid, nonmucosal tissue. We suggest that the prominence of IgA plasma cells in the vascular infiltrate in the early, acute, and subacute stages of KS indicates an Ag-driven immune response to an etiologic agent with a respiratory or gastrointestinal portal of entry and speculate that this unusual immune response is integral to the pathogenesis of the illness.
Subject(s)
Aorta/immunology , Iliac Artery/immunology , Immunoglobulin A/biosynthesis , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/pathology , Plasma Cells/chemistry , Adolescent , Aorta/pathology , Child , Child, Preschool , DNA, Complementary/isolation & purification , Female , Fluorescent Antibody Technique, Direct , Gene Library , Humans , Iliac Artery/pathology , Immunoglobulin A/analysis , Immunohistochemistry , Infant , Infant, Newborn , Male , Middle Aged , Mucocutaneous Lymph Node Syndrome/genetics , Nucleic Acid Hybridization , Plasma Cells/metabolism , Polymerase Chain ReactionABSTRACT
The MHC-linked hsp70 locus consists of duplicated genes, hsp70.1 and hsp70.3, which in primary mouse embryo cells are highly heat shock-inducible. Several mouse cell lines in which hsp70 expression is not activated by heat shock have been described previously, but the basis for the deficiency has not been identified. In this study, genomic footprinting analysis has identified a common basis for the deficient response of the hsp70.1 gene to heat shock in four such cell lines, viz., the promoter is inaccessible to transcription factors, including heat shock transcription factor. Southern blot analyses reveal extensive CpG methylation of a 1.2-kilobase region spanning the hsp70.1 transcription start site and hypermethylation of the adjacent hsp70.3 gene, which is presumably also inaccessible to regulatory factors. Of four additional, randomly chosen mouse cell lines, three show no or minimal hsp70.3 heat shock responsiveness and CpG methylation of both hsp70 genes, and two of the three lines exhibit a suboptimal hsp70.1 response to heat shock as well. In all three lines, the accessibility of the hsp70.1 promoter to transcription factors is detectable but clearly diminished (relative to that in primary mouse cells). Our results suggest that the tandem hsp70 genes are concomitantly methylated and transcriptionally repressed with high frequency in cultured mouse cells.
