Clinicopathological features of aggressive large granular lymphocyte leukaemia resemble Fas ligand transgenic mice

Fas ligand triggers cell death after interaction with its receptor Fas. Alt ered expression of Fas has been associated with lymphoproliferation and aut oimmune disorders in both mice and man. Apoptosis of lung and liver tissue is seen in Fas ligand transgenic mice. It is not known whether constitutive expression of Fas ligand can cause a similar human disease, Four patients with aggressive large granular lymphocyte (LGL) leukaemia involving lung an d liver were studied. All four patients were severely ill with pulmonary in volvement. Two patients presented with hypoxia and were oxygen dependent; t he other two patients had severe pulmonary hypertension. Lung biopsies show ed interstitial infiltration by leukaemic LGL. The infiltrating lymphocytes expressed both Fas and Fas ligand, whereas normal pneumocytes expressed on ly Fas. Similar findings were observed in liver biopsies from these patient s. Features mimicking the pathological changes of graft-versus-host disease were observed, including pneumocyte apoptosis. All four patients had high levels of circulating Fas ligand. Successful treatment with oral methotrexa te or 2-chlorodeoxyadenosine was associated with disappearance or marked re duction of circulating Fas ligand, These results suggest that dysregulated expression of Fas ligand can lead to human disease with pathological featur es resembling graft-versus-host disease.