Identified the pathogenic effects of GM-CSF autoantibodies in different diseases

Abstract

Abstract Pathogenic GM-CSF autoantibodies are found in over 90% of people with pulmonary alveolar proteinosis (PAP), a rare pulmonary autoimmune disease with surfactant lipoprotein accumulating in alveoli spaces. However, more and more people with GM-CSF autoantibodies have also been identified without PAP phenotype but underlying severe central nervous system (CNS)-involved Cryptococcus gattii or Nocardia spp. infection since 2013, highlighting the pathogenic mechanisms that might differ between individual diseases. We developed single B cell cloning to isolate GM-CSF monoclonal antibodies from cryptococcosis patients aiming to investigate the pathogenic effects. GM-CSF autoantibodies in cryptococcosis bound GM-CSF through three non-overlapping epitopes, and formed a high-molecular-weight immune complex similar to the research of GM-CSF mAbs in PAP patients. Surprisingly, GM-CSF mAbs isolated from cryptococcosis revealed potentially binding to GM-CSF when the V gene reversed to the germline. GM-CSF autoantibodies underwent somatic hypermutation to enhance their binding ability and neutralizing activities. We analyzed whether the mAbs binding sites interfere with cytokine-specific receptor interaction, and only one epitope showed the receptor blockade. The GM-CSF mAbs from the other two epitopes remained inhibition effects, indicating another neutralizing mechanism independent of interfering receptor binding. The neutralizing pathway and biological impact of GM-CSF autoantibodies from cryptococcosis is still worthy of further investigation. These works might help know the anti-GM-CSF autoantibodies cause different clinical manifestations and find a novel pave for better diagnosis and treatments.