Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES natural killer (NK) cells, interferon gamma-positive (IFN-γ) ILC1s, interleukin (IL)-13 ILC2s, and for IL-22, but not for IL-17A ILC3s. Our results support a model of tissue ILC differentiation ("ILC-poiesis"), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.
The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of
OTP
expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.
Autoimmune pancreatitis (AP) is one manifestation of a systemic, steroid-responsive disease with elevated serum IgG4 and characteristic histopathology, including increased IgG4-positive (+) plasma cells in the tissue. The histopathology of pulmonary IgG4 disease has not been well established. Six lung biopsies from patients with documented AP were studied, along with 12 additional cases showing similar pulmonary histopathology. For comparison, we examined Erdheim-Chester disease (n=3), pulmonary Sjögren syndrome (n=19), inflammatory myofibroblastic tumor (n=10), various inflammatory and interstitial lung disease (n=61), and nodal or extranodal Rosai-Dorfman disease (RD) in adults (n=8). All cases were stained for IgG4 and scored as 1, 2, and 3 as described in AP according to the following criteria: 0, <5 (per high power field); 1, 5 to 10; 2, 11 to 30; and 3, >30. Five lung biopsies from AP patients showed IgG4 score of 3, and 1 had a score of 2. Consistent findings in lung biopsies of AP patients included endothelialitis of pulmonary vessels, active fibrosis, lymphangitic inflammatory infiltrates rich in plasma cells and histiocytes with or without nodule formation, and fibrinous pleuritis. Prominent lymphatic dilatation with histiocytes showing emperipolesis of lymphocytes was also seen. All 12 additional cases showing these histologic features also had the IgG4 score of 2 or 3. Among other conditions, an IgG4 score of 2 or 3 was seen in 6 of 8 RD, 4 of 10 inflammatory myofibroblastic tumors, and 8 of 61 inflammatory and interstitial lung disease, but in none of the rest. In conclusion, distinctive pulmonary histopathology was associated with increased IgG4+ cells in both AP patients and those unknown for AP status. The significance of increased IgG4+ cells in high proportion of RD cases merits further study as does overlap of RD and IgG4 disease.
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