Pediatric AIDS-associated lymphocytic interstitial pneumonia and pulmonaryarterio-occlusive disease - Role of VCAM-1/VLA-4 adhesion pathway and human herpesviruses

Because the mechanisms of lymphocyte accumulation in the lungs of children with AIDS-associated lymphocytic interstitial pneumonia (LIP) are unknown, we studied the relative contributions of known adhesion pathways in mediati ng lymphocyte adherence to endothelium and the potential role of human herp esviruses in the expansion of these lesions. LTP was characterized by lymph oid hyperplasia of the bronchus-associated lymphoid tissue (BALT) and infil tration of the pulmonary interstitium with CD8(+) T lymphocytes, In some in dividuals there was expansion of the alveolar septae with dense aggregates of B lymphocytes, many containing the Epstein-Barr viral (EBV) genome. Pati ents with concurrent EBV infection also demonstrated large-vessel arteriopa thy characterized by thickening of the intimae with collagen and smooth mus cle. Venular endothelium from the lung of children with LIP, but not uninfl amed lung from other children with ADDS or lung from children with nonspeci fic pneumonitis, expressed high levels of vascular cell adhesion molecule-1 (VCAM-1) protein. In turn, inflammatory cells expressing very late activat ion antigen-4 (VLA-4), the leukocyte ligand for VCAM-1, were the predominan t perivascular infiltrate associated with vessels expressing VCAM-1. Expres sion of other endothelial adhesion molecules, including intracellular adhes ion moleucle-1 and E-selectin, was not uniformly associated with LIP. Using a tissue adhesion assay combined with immunohistochemistry for VCAM-1, we show that CD8(+) T cell clones that express VLA-4 bind preferentially to pu lmonary vessels in sites of LIP: vessels that expressed high levels of VCAM -1, When tissues and cells were pretreated with antibodies to VCAM-1 or VLA -4, respectively, adhesion was inhibited by greater than or equal to 80%. T hus, infiltration of alveolar septae with CD8(+) T cells was highly correla tive with VCAM-1/VLA-4 adhesive interactions, and focal expansion of B cell s was coincidental to co-infection with EBV.