Phenotypically aberrant clonal T cells in the lungs of patients with type II refractory celiac disease

To the editor:

Type II refractory celiac disease (RCD II) is a rare condition characterized by a massive accumulation of intraepithelial lymphocytes with a natural killer/T phenotype and containing clonal T-cell rearrangements.¹  Its severe prognosis is largely due to the development of an aggressive enteropathy-type–associated T-cell lymphoma (EATL). RCD II is a diffuse digestive but also extradigestive disease.²  Various pulmonary manifestations have been reported in celiac patients^3-6  but little, if anything, is known about their mechanisms, even though the presence of a T lymphoid alveolitis had been described. One study has shown the presence of aberrant T cells in the lungs of some celiac patients.⁷  We confirm and extend these data by reporting here 7 patients with RCD II in whom the presence of specific aberrant T lymphocytes and clonal T-cell receptor gamma (TCR-γ) rearrangements were detected in bronchoalveolar lavage (BAL), and/or in bronchial biopsies, or in mediastinal lymph nodes, all of which argue for the lung as an overt extradigestive site of the disease.

All patients exhibited a massive digestive intraepithelial infiltration by cCD3⁺, CD3^–, CD4^–, CD8^–, and CD103⁺ T cells containing clonal TCR-γ rearrangements associated in some way with the presence of similar T cells in skin and/or bone marrow (Table 1). Five of the 7 also exhibited the same phenotypically aberrant cells in BAL and/or bronchial biopsy T cells, accounting by fluorescence-activated cell sorter analysis for 0.5% to 74% of total BAL lymphocytes. Lung cells also contained rearranged TCR-γ T-cell clones, which were not always identical to those detected in the digestive mucosa and/or in blood.

EATL developed in 4 of 7 patients. Two of them died of cutaneous lymphoma and 2 from digestive lymphoma.

Various clinical respiratory manifestations (chronic cough, hemoptysis, organized pneumonia) can occur in celiac patients, including the intrapulmonary location of RCD II–specific T cells in clinically asymptomatic patients.⁷  We confirm and extend the latter observation by showing the presence of clonal T cells in the lungs of 7 patients with RCD II in alveolar and/or bronchial epithelium or mediastinal lymph nodes. Interestingly, these clonal T-cells in some instances harbored different TCR-γ rearrangements from those detected in the digestive mucosa or in circulating blood, ruling out their detection in the lung as mere blood contamination. Taken together, these data strongly argue for airway epithelium as an additional specific target of RCD II with its potentially most severe complication—aggressive local EATL. This should alert the clinicians in charge of such patients about the importance of including pulmonary evaluation in their routine workups. Indeed, these patients can be clinically and/or radiologically asymptomatic and yet exhibit abnormal T cells, with a potential for transformation into aggressive malignant cells.