John E. Fitzgerald

Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10−8); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10−6). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ∼7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

Identification of Anti-Plasmin Antibodies in the Antiphospholipid Syndrome That Inhibit Degradation of Fibrin

The combined presence of anti-phospholipid Ab (aPL) and thrombosis is recognized as the antiphospholipid syndrome (APS). The aPL represent a heterogeneous group of Ab that recognize various phospholipids (PL), PL-binding plasma proteins, and/or PL-protein complexes. Recently, we found the presence of antithrombin Ab in some APS patients and that some of these anti-thrombin Ab could inhibit thrombin inactivation by antithrombin. Considering that thrombin is homologous to plasmin, which dissolves fibrin, we hypothesize that some APS patients may have Ab that react with plasmin, and that some anti-plasmin Ab may interfere with the plasmin-mediated lysis of fibrin clots. To test this hypothesis, we searched for anti-plasmin Ab in APS patients and then studied those found for their effects on the fibrinolytic pathway. The results revealed that seven of 25 (28%) APS patients have IgG anti-plasmin Ab (using the mean OD plus 3 SD of 20 normal controls as the cutoff) and that six of six patient-derived IgG anti–thrombin mAb bind to plasmin with relative Kd values ranging from 5.6 × 10−8 to 1 × 10−6 M. These Kd values probably represent affinities in the higher ranges known for human IgG autoantibodies against protein autoantigens. Of these mAb, one could reduce the plasmin-mediated lysis of fibrin clots. These findings suggest that plasmin may be an important driving Ag for some aPL B cells in APS patients, and that the induced anti-plasmin Ab may act either directly, by binding to plasmin and inhibiting its fibrinolytic activity, or indirectly, by cross-reacting with other homologous proteins in the coagulation cascade to promote thrombosis.

Case Report: Allergic Bronchopulmonary Aspergillosis and Allergic Fungal Sinusitis Successfully Treated with Voriconazole

Allergic bronchopulmonary aspergillosis and allergic fungal sinusitis are closely related disorders that rarely present in the same individual. The mainstay of treatment for allergic bronchopulmonary aspergillosis is systemic corticosteroids. Itraconazole is used as adjunctive therapy in refractory cases. Allergic fungal sinusitis requires initial sinus surgery followed by systemic steroids. Antifungal therapy has not proven to be beneficial in allergic fungal sinusitis. We report a case of concomitant allergic bronchopulmonary aspergillosis and allergic fungal sinusitis that was refractory to standard therapy but had dramatic clinical response following treatment with voriconazole.

Sinonasal manifestations of sarcoidosis: a single institution experience with 38 cases

Sarcoidosis is a chronic disease process characterized by non‐caseating granulomatous inflammation, usually involving the lower respiratory tract. Given the rarity of rhinologic involvement, the objectives of the present study were (1) to describe clinical features, and (2) to review outcomes of rhinologic surgery for sinonasal sarcoidosis.