肺胞蛋白症（自己免疫性又は先天性）

BACKGROUND: Lung disease associated with systemic juvenile idiopathic arthritis (SJIA-LD) remains poorly understood. Evaluation of bronchoalveolar lavage fluid (BALF) may better reflect disease pathogenesis. The objectives of our study were to measure levels of cytokines and chemokines in BALF and their associations with clinical features and treatment in patients with SJIA-LD. METHODS: Children with SJIA-LD undergoing clinically indicated diagnostic bronchoscopy were enrolled. Comparator BALF was collected from patients with other chronic inflammatory and non-inflammatory lung diseases. BALF was assayed for IL-6, 8 and 18, S100A8/9, S100A12, sCD25, CCL11, CCL17, CCL25, MMP7, and CXCL9. RESULTS: BALF was obtained from 21 patients with SJIA-LD and 54 comparator patients with other lung diseases. Compared to all controls, children with SJIA-LD had a significant elevation of IL-18 (median (IQR) 1406 (722.3-2812) vs 37.2 (25.3-70) pg/mL, p < 0.0001), S100A8/9 (4745.3 (3003-11506) vs. 1297.5 (260-7755) ng/mL, p = 0.02), sCD25 (31.6 (19-50.3) vs. 13.6 (8.6-37.3) pg/mL, p = 0.04), MMP-7 (18,466.7 (10,462.2-33,516.1) vs. 13.645 (8.6-37.3) pg/mL, p = 0.0384), and CCL17 (0 (0-63.1; p = 0.038) vs 0 (0-0) pg/mL. BALF IL-18 was significantly higher in children with SJIA-LD compared to all control subgroups (inflammatory and non-inflammatory airway disease, autoimmune pulmonary alveolar proteinosis, and poorly controlled asthma), in patients who were actively treated with anti-cytokine biologics (N = 9), and in patients who ultimately underwent hematopoietic stem cell transfer (N = 8). Patients receiving anti-cytokine biologics also had significant elevations in several other cytokines compared to patients without such treatments, while profiles in those treated with JAKi (N = 14) were largely similar. Linear regression analysis showed an association between BALF level of IL-18 and the number of immunosuppressive medications utilized (p = 0.0167), but not with O2 requirement, dose of anakinra or prednisone, plasma IL-18, ferritin, CRP or ESR. CONCLUSIONS: Patients with SJIA-LD showed a distinct BALF cytokine profile, including significant IL-18, S100A8/9 protein, sCD25, and CCL-17 elevation. The level of IL-18 was higher in patients who required more immunosuppressive medications and were actively treated with anti-cytokine biologics. The relationship between BALF cytokine profiles and anti-cytokine biologics and JAK inhibitors is unclear and should be evaluated further.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by impaired surfactant clearance due to alveolar macrophage dysfunction. Leuprorelin acetate, a gonadotropin-releasing hormone agonist, is widely used in the treatment of ovarian endometriosis; however, pulmonary findings associated with this therapy have not been well characterized. We report a case of PAP diagnosed during leuprorelin acetate therapy for ovarian endometrioma and describe its temporal relationship with treatment. CASE PRESENTATION: A 29-year-old woman underwent laparoscopic surgery for an ovarian endometrioma in August 2025 and initiated leuprorelin acetate therapy three days postoperatively. A routine chest computed tomography (CT) performed one month later revealed scattered bilateral ground-glass opacities (GGOs), which persisted on repeat CT in November 2025. Although the patient remained asymptomatic, video-assisted thoracoscopic surgery (VATS) lung biopsy was performed to obtain a histopathological diagnosis and confirmed PAP. Serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody testing was negative (3.2 µg/mL; reference range, ≤ 5 µg/mL), not supporting autoimmune PAP. During treatment, the patient developed transient Common Terminology Criteria for Adverse Events (CTCAE) grade 2 leukopenia (white blood cell nadir, 2.94 × 10⁹/L), which resolved spontaneously after completion of leuprorelin acetate therapy without intervention. Hematological evaluation did not suggest an underlying clonal disorder, including myelodysplastic syndrome. Because baseline chest imaging was unavailable, pre-existing subclinical PAP could not be excluded. Follow-up CT performed three months after completion of therapy showed regression of GGOs. CONCLUSION: This case shows a temporal relationship between leuprorelin acetate therapy and non-autoimmune PAP. However, causality cannot be inferred in the absence of baseline imaging. Only a temporal association can be observed. This observation is hypothesis-generating and highlights a potential rare pulmonary finding observed in the context of gonadotropin-releasing hormone agonist therapy.

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare lung disease caused by impaired surfactant clearance resulting in lipoproteinaceous material accumulation in the alveoli often causing progressive dyspnea and respiratory failure. Autoimmune PAP (aPAP), accounting for ~90% of cases with a prevalence of 6.7-6.9 per million, disrupts granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via neutralizing autoantibodies. AREAS COVERED: This article explores the role of GM-CSF in the pathogenesis and treatment of PAP. GM-CSF autoantibodies block signaling essential for alveolar macrophage function. Therapeutic whole lung lavage (WLL) remains the gold standard of treatment for PAP. While WLL is an effective and safe treatment, and can indeed complement GM-CSF therapy, it is labor intensive and often requires repeated procedures. GM-CSF augmentation represents a new era of therapeutic advancement targeting the pathogenesis of PAP to ensure sustained, efficacious results. Inhaled GM-CSF shows superior efficacy over subcutaneous treatment. Trials through recent decades including IMPALA-2 show improvements in symptoms physiology, radiology with a favorable safety profile. These studies have helped inform the much-needed European Respiratory Society guidelines for the diagnosis and management of PAP in 2024. EXPERT OPINION: Despite our greater understanding of this ultra-rare disease, further studies are required to explore the mechanistic and logistical aspects of treatment with GM-CSF. We explore some of these aspects in our expert opinion section.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare, diffuse lung disease characterized by surfactant accumulation in the alveoli, leading to impaired gas exchange and progressive respiratory insufficiency. It is caused by neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), which disrupts the GM-CSF signaling required for alveolar macrophage maturation and surfactant clearance. Whole-lung lavage (WLL), the standard treatment for aPAP, improves oxygenation by removing accumulated surfactants, but is invasive and often must be repeated. An improved understanding of disease pathogenesis has shifted therapy toward restoring GM-CSF signaling, rather than simply removing alveolar material. Thus, inhaled recombinant human GM-CSF is a promising disease-directed therapeutic agent for aPAP. Direct delivery to the alveolar compartment is intended to restore GM-CSF signaling, while minimizing systemic exposure. Randomized controlled trials have demonstrated improvements in oxygenation, pulmonary function, and radiographic findings. Despite these advances, important questions remain unresolved because aPAP is rare and clinical studies have been limited, including the optimal dose, treatment duration, maintenance strategy, and the role of device-dependent drug delivery to the distal lung. This review summarizes the pathogenesis of aPAP, biological rationale for GM-CSF replacement, available formulations and aerosol delivery strategies, and clinical evidence supporting inhaled GM-CSF therapy. This review also discusses unresolved issues and future directions, including the potential contributions of quantitative models of aerosol deposition and pharmacokinetics to optimize treatment.

Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.