A lymphocyte-mediated cause of secondary PAP

In this issue of Blood, Iriguchi et al report that T-lymphocyte–restricted overexpression of T-bet causes a maturational arrest in mononuclear phagocyte lineage cells and severe secondary pulmonary alveolar proteinosis (PAP).¹ 

PAP is a rare syndrome characterized by pulmonary surfactant accumulation and hypoxemic respiratory failure for which the current treatment is whole lung lavage, an invasive and inefficient procedure to physically remove the excess pulmonary surfactant. It occurs in a heterogeneous group of diseases usefully subdivided into primary PAP, secondary PAP, and disorders of surfactant production.²  Surfactant is normally comprised of a thin phospholipid/protein layer that stabilizes alveoli by reducing alveolar wall surface tension and is maintained by balanced secretion by alveolar epithelial cells, and clearance by these cells and alveolar macrophages. In PAP, however, progressive surfactant accumulation eventually fills alveoli, thus displacing inhaled air and compromising gas exchange.

While significant research advances have elucidated the pathogenesis of primary PAP and led to the development of novel diagnostics and therapeutics,^3,4  other than its association with myelodysplastic syndromes, the pathogenesis of secondary PAP remains obscure, its prognosis is poor, and therapeutic options are limited.⁵  In primary PAP, the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling causes alveolar macrophages to undergo maturational arrest, which impairs their ability to clear surfactant. From a mechanistic perspective, the disruption of the GM-CSF→PU.1→PPARγ signaling axis reduces the expression of a critical macrophage lipid exporter, ABCG1, which results in foamy, lipid-laden alveolar macrophages with impaired surfactant clearance capacity, intraalveolar surfactant accumulation, and PAP.^6-9  The loss of GM-CSF signaling also increases pulmonary levels of monocyte chemoattractant protein-1 (MCP-1), a biomarker of primary PAP. It is thought that secondary PAP is caused by a reduction in either the functional capacity or absolute numbers of alveolar macrophages, but data supporting this hypothesis are limited.² 

Although expression of T-bet, a “master” T_H1 transcription factor, is increased in inflammatory, autoimmune, and hematologic disorders including myelodysplastic syndromes, its precise role in disease pathogenesis is unknown. To address this question and determine the contribution made by increased expression of T-bet to the pathogenesis of inflammatory diseases, Iriguchi et al studied wild-type (wt) and transgenic mice heterozygous or homozygous for a human CD2–T-bet transgene (tg) (wt/wt, tg/wt, or tg/tg mice, respectively). Unexpectedly, the results identified a novel mechanism by which increased expression of T-bet, exclusively in T lymphocytes, spontaneously drives the pathogenesis of both myelodysplasia and secondary PAP in a dose-dependent manner.¹ 

Prior studies with these mice had shown that T-bet overexpression increased interferon-γ (IFNγ) production in CD4⁺ cells, enhanced T_H1 and suppressed T_H2 antibody responses, and caused dermatitis.¹⁰  The present report shows that compared with wt/wt mice, tg/wt mice spontaneously developed maturational arrest in the mononuclear phagocytic lineage, while tg/tg mice also spontaneously developed severe lung inflammation including perivascular/peribronchiolar lymphocytic infiltration, secondary PAP, and had increased mortality correlating with the presence and severity of the lung disease.

These results identify a previously unsuspected mechanism in which T-bet expression in T_H1 cells regulates myeloid lineage progression that, when activated constitutively, causes maturational arrest of mononuclear phagocytes, dose-dependent tissue inflammation, and secondary PAP. These findings are important because they provide a molecular explanation for the association between PAP and myelodysplastic syndromes, and confirm the leading hypothesis about the pathogenesis of secondary PAP (see figure). Nonetheless, the precise mechanism by which T-bet overexpression results in maturational arrest of myeloid lineage cells or the accumulation of functionally impaired alveolar macrophages remains to be determined. Future studies are needed to determine the pathogenic mechanism and to explore the clinical implications of these findings for myelodysplasia and secondary PAP.