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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3468-3478
Intrathymic Restriction and Peripheral Expansion of the T-Cell
Repertoire in Omenn Syndrome
Simona Signorini,
Luisa Imberti,
Silvia Pirovano,
Anna Villa,
Fabio Facchetti,
Marco Ungari,
Fabio Bozzi,
Alberto Albertini,
Alberto
G. Ugazio,
Paolo Vezzoni, and
Luigi D. Notarangelo
From the Terzo Servizio Analisi, Spedali Civili, the Institute of
Chemistry, the Department of Pathology, and the Istituto di Medicina
Molecolare "Angelo Nocivelli," Department of Pediatrics,
University of Brescia, Brescia, Italy; and the Department of Human
Genome and Multifactorial Disease Research, I.T.B.A. CNR, Segrate (MI),
Italy.
Mutations in the human RAG genes that impair, but do not
abolish, recombination activity lead to Omenn syndrome, a severe primary immune deficiency that is associated with clinical and pathological features of graft-versus-host disease and oligoclonal expansion of activated, autologous T cells. We have analyzed the mechanisms accounting for peripheral oligoclonality of the T-cell repertoire. Predominance of few T-cell receptor clonotypes (both within
TCRAB- and within TCRGD-expressing lymphocytes) is already detectable in the thymus and is further selected for in the
periphery, with a different distribution of clonotypes in different
tissues. These data indicate that oligoclonality of the T-cell
repertoire in Omenn syndrome is due both to intrathymic restriction and
to peripheral expansion. Moreover, the RAG genes defect that
causes Omenn syndrome directly affects early stages of V(D)J
recombination, but does not alter the process of double-strand-break
DNA repair, including N and P nucleotide insertion.
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