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Blood, 1 October 2000, Vol. 96, No. 7, pp. 2613-2620
RED CELLS
Abnormal T-cell repertoire is consistent with immune process
underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria
Anastasios Karadimitris,
John S. Manavalan,
Howard T. Thaler,
Rosario Notaro,
David J. Araten,
Khedoudja Nafa,
Irene A.G. Roberts,
Marc E. Weksler, and
Lucio Luzzatto
From the Department of Human Genetics and Department of
Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center,
New York, NY; the Department of Medicine, Joan and Sanford I. Weill
Medical College of Cornell University, New York, NY; and the Department
of Hematology, Imperial College School of Medicine, Hammersmith
Hospital, London, UK.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal
disorder of the hematopoietic stem cell (HSC). Somatic mutations in the
PIG-A gene result in the deficiency of several
glycosylphosphatidylinositol-linked proteins from the surface of blood
cells. This explains intravascular hemolysis but does not explain the
mechanism of bone marrow failure that is almost invariably seen in PNH.
In view of the close relationship between PNH and idiopathic aplastic
anemia (IAA), it has been suggested that the 2 disorders might have a
similar cellular pathogenesis, namely, that autoreactive T-cell clones
are targeting HSCs. In this paper, we searched for abnormally expanded
T-cell clones by size analysis of the complementarity-determining
region 3 (CDR3) in the beta variable chain (BV) messenger RNA (mRNA) of
the T-cell receptor (TCR) in 19 patients with PNH, in 7 multitransfused
patients with hemoglobinopathy. and in 11 age-matched healthy
individuals. We found a significantly higher degree of skewness in the
TCR BV repertoire of patients with PNH, compared with controls
(R2 values 0.82 vs 0.91, P < .001). The mean frequency of skewed families per
individual was increased by more than 2-fold in patients with PNH,
compared with controls (28% ± 19.6% vs 11.4% ± 6%,
P = .002). In addition, several TCR BV families were
significantly more frequently skewed in patients with PNH than in
controls. These findings provide experimental support for the concept
that PNH, like IAA, has an immune pathogenesis. In addition, the
identification of expanded T-cell clones by CDR3 size analysis will
help to investigate the effect of HSC-specific T cells on normal and
PNH HSCs.
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