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Mechanism(s) of immunodeficiency consequent to inactivation of the ATM gene which might enhance tumorigenesis in A-T patients

Ataxia telangiectasia (A-T) is an autosomal recessive multisystem disorder characterized by cerebellar ataxia, conjunctival and cutaneous telangiectasias, immune deficiency, chromosome aberrations, radiation hypersensitivity, and a high incidence of tumors, mainly of lymphoid origin. The mechanism(s) of the immunodeficiency consequent to inactivation of the ATM gene, which might underlie both impaired lymphocyte development and enhanced lymphomagenesis, have not yet been fully elucidated.

In the course of this project we reported that the T-cell receptor (TCR) variable beta (BV)–chain repertoire of 9 A-T patients was restricted by diffuse expansions of some variable genes prevalently occurring within the CD4 subset and clustering to certain TCRBV genes (eg, 5.1,11, 14, and 23). In addition, the study of the third complementarity-determining region (CDR3) showed, in all patients, significantly altered profiles in most BV genes examined suggesting diffuse oligoclonal expansions.

The sequencing of TCR CDR3 regions revealed completely normal V(D)J coding joints and confirmed a reduced diversity of the antigen-receptor repertoire. The B-cell repertoire was similarly restricted and skewed by diffuse oligoclonal expansions with normal V(D)J joints. Thymic output, evaluated by measuring TCR rearrangement excision circles, was extremely low. The majority of peripheral T cells had the phenotype and the function of effector memory cells, indicating that in vivo they are able to respond normally by terminal differentiation to antigenic stimulation. These results indicate that ATM mutation limits the generation of a wide repertoire of normally functioning T and B cells.

Reported by

Istituto Dermopatico dell'Immacolata IDI - IRCCS
Via dei Monti di Creta 104
00167 Rome
Italy
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