CLONAL EXPANSION OF CD45RO⁺ T LYMPHOCYTES IN OMENN SYNDROME.• 52

Omenn Syndrome (OS) is a catastrophic form of combined immunodeficiency characterized by FTT, erythrodermatitis, lymphadenopathy, hepatosplenomegaly, lymphocytosis, and eosinophilia. Antigen-specific T lymphocyte responses and antibody (Ab) production are absent. IgE can be elevated, so that a primary T_H2-type process has been hypothesized. We investigated the pathogenesis of OS and the basis of the lymphocytosis, by flow cytometric analyses (including monoclonal-Ab's to 5 T-cell receptor (TCR) Vβ families in patient 1) and by RT-PCR (primer sets from each of the 25 known TCR Vβ families and 21 cytokine primer sets, examining for a T_H2-type pattern, in patient 2). Blood mononuclear cells were studied prior to initiation of therapy, without in vitro culturing. Patient 1: Of gated CD3⁺ cells, CD45RO⁺=100% (nl=47±14%), CD45RA⁺=3% (nl=53±12%), Vβ17⁺=33% (nl=5±2%), and CD4:CD8=1.5. Patient 2: Of gated CD3⁺ cells, CD45RO⁺=100%, CD45RA⁺=1%, and CD4:CD8=0.8. All 25 Vβ families were detected by RT-PCR, but 12 exhibited prominent oligoclonality of 2 to 4 intense bands each. Vβ12 and Vβ21 amplicons were sequenced, with noted repetition of 3 and 4 separate sequences, respectively. No CDR3 amino acid motif could be discerned. Inflammatory (TNF-α and IL-1β) and T_H1-type(IFN-γ and IL-2) cytokine mRNA's were found to be increased, in comparison to normal control specimens. IL-4 and IL-5 mRNA's were not increased and were actually somewhat less in patient 2 than normal control specimens. CONCLUSIONS: T lymphocytes (single positive for CD4 or CD8) with the activation/memory marker, CD45RO⁺, are clonally-expanded in OS. An inflammatory, T_H1-type cytokine response, consistent with the overall clinical features, predominates in OS. Defective regulation of T lymphocyte proliferation could lead to these findings. Because of recent examples of apoptotic defects (mutations in Fas or the Fas-ligand), which exhibit clinical features of lymphoproliferation, lymphadenopathy, and hepatosplenomegaly, we propose to study for apoptotic lesions in OS.