Clinical significance of serum anti-granulocyte–macrophage colony-stimulating factor autoantibodies in patients with sarcoidosis and hypersensitivity pneumonitis

Abstract

Background Anti-granulocyte–macrophage colony-stimulating factor autoantibody (GMAb) has been recognized as a diagnostic biomarker for autoimmune pulmonary alveolar proteinosis (aPAP). The aims of this study were to know the incidence of increased level of serum GMAb in granulomatous lung diseases (sarcoidosis and hypersensitivity pneumonitis [HP]) and to clarify the role of GMAb. Consecutive individuals diagnosed with sarcoidosis (n = 92) and HP (n = 45) at National Hospital Organization Kinki-Chuo Chest Medical Center were retrospectively analyzed. We measured serum GMAb levels at the diagnosis. Cut-off values of GMAb discriminating aPAP (n = 110) from healthy controls (n = 31) were determined by receiver operating characteristic (ROC) curve analysis. We compared the clinical features of sarcoidosis and HP patients with GMAb levels above the cut-off value (“Elevated-GMAb”) with those of patients whose GMAb levels below the cut-off value (“Low-GMAb”). Radiological and pathological findings in elevated-GMAb patients were re-evaluated to elucidate the role of GMAb in granulomatous lung diseases. Results Analysis of ROC indicated a sensitivity and specificity of 100% at GMAb level of 3.33 μg/mL for discriminating aPAP from healthy controls (area under curve = 1.000, p < 0.0001). The percentages of elevated-GMAb sarcoidosis and HP patients were 5.4% (n = 5) and 11.1% (n = 5), respectively. The number of comorbid sarcoidosis and HP patients with aPAP was two and one, respectively. Elevated-GMAb sarcoidosis patients presented with significantly higher serum levels of Krebs von den Lungen (KL)-6, surfactant protein-D (SP-D), lactate dehydrogenase, and the requirement of systemic corticosteroid therapy. Elevated-GMAb HP patients demonstrated older age, higher serum KL-6, SP-D, carcinoembryonic antigen, and cytokeratin fragment 21-1 levels, and a higher percentage of lymphocytes in bronchoalveolar lavage than low-GMAb patients. A subset of patients presented with radiological and pathological findings characteristic of aPAP. Conclusions We demonstrated the percentage of elevated-GMAb sarcoidosis and HP patients who presented with several features suggestive of aPAP. Elevated-GMAb sarcoidosis and HP patients without definitive aPAP diagnosis may have subclinical or early-stage aPAP and may not necessarily indicate false positives. Upon diagnosis of sarcoidosis or HP, measurement of GMAb may be useful in detecting possible comorbidity of subclinical or early-onset aPAP.

Expression profiles and potential functions of long noncoding RNAs and mRNAs in autoimmune pulmonary alveolar proteinosis patients

“…Generally, APAP is considered to be an autoimmune disease characterized by high serum and lung levels of GM-CSF autoantibodies, which prevent alveolar macrophages from clearing pulmonary surfactants. Interestingly, our microarray results did not reveal any significant changes in immune processes, possibly because the mean GM-CSF antibody level in our APAP group (110.44 ng/mL) was significantly lower than the levels reported in previous studies of APAP patients (40.5 μg/mL [ 30 ], 66.8 ± 71.7 μg/mL [ 5 ] and 102 μg/mL [ 31 ]). For this reason, we also did not identify any lncRNA molecules involved in immune processes.…”

The Role of GM-CSF Autoantibodies in Infection and Autoimmune Pulmonary Alveolar Proteinosis: A Concise Review

“…Anti-cytokine AAbs have been described for many other autoimmune diseases including rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Felty’s syndrome, systemic lupus erythematosus, and sarcoidosis; however, their frequency and role have been extensively debated ( 20 , 21 ). Recently, AAbs to various cytokines, including GM-CSF, were identified in some patients with postherpetic neuralgia, which were hypothesized to cause an autoimmune immunodeficiency syndrome leading to uncontrolled varicella zoster virus reactivation and nerve damage ( 22 ).…”

Autoimmune pulmonary alveolar proteinosis and sarcoidosis in the same patient

“…[ 9 ] In fact, elevated GM-CSF autoantibodies have been detected in the serum of a few patients with sarcoidosis. [ 18 ] Immunosuppressants cause a disproportionate reduction in GM-CSF level than anti-GM-CSF antibodies,[ 9 ] possibly leading to a relative excess of the antibody causing macrophage dysfunction and surfactant accumulation. [ 9 ] Had this phenomenon been common, considering the large number of patients being treated with immunomodulatory therapy for inflammatory and autoimmune diseases, one would expect PAP to be much more frequent than what is currently observed.…”