The etiology and pathogenesis of KS remain unknown. We recently reported the unusual finding that IgA-producing plasma cells are prominent in vascular tissue from KS patients (J Immunol 1997;159:5946). To determine whether this unusual IgA immune response is antigen-driven, we have sequenced CDR3 regions of the immunoglobulin α heavy chain genes in a primary, unamplified, oligo dT-primed λZAP cDNA library made from vascular tissue at the aorto-iliac junction of a patient with fatal acute KS (illness day 13). If the IgA response were the result of a superantigen or were a non-specific, polyclonal response, clonally related IgA sequences would not be expected. However, if the response were antigen-driven, clonally related sequences would likely be present in the library. α clones were detected in the primary, unamplified library using an α probe, and clones containing variable region were plaque-purified and excised for DNA sequencing. Use of the primary, unamplified library ensured that the clones identified represented unique individual α sequences in the vascular tissue; no amplification process with its potential to skew the clonal representation was performed. Of 20 α clones sequenced to date, we found that 2 (10%) were members of the VH1 family, 9 (45%) were of the VH3 family, 7 (35%) were of the VH4 family, 1(5%) was of the VH5 family, and 1 (5%) was of the VH6 family. The 9 VH3 clones have different CDR3 sequences. In striking contrast, 4 of the 7 VH4 clones have clonally related CDR3 sequences; 3 are identical and one has one amino acid substitution. Thus, overall 4/20 (20%) α sequences in the vascular library are clonally related. The presence of such clonally related sequences indicates that they are derived from an original B-cell which bound antigen and underwent proliferation. Our results strongly suggest that an antigen-driven IgA immune response is present in the vascular tissue in acute KS. Synthesis of these VH4 IgA antibodies in vitro should enable identification of their target antigens in KS tissues, and provide data regarding the etiology and pathogenesis of the illness.