Lymphoid Follicle Transcriptome Reveals Maladaptive Immune Responses In Severe Chronic Obstructive Pulmonary Disease (COPD).

Abstract

Abstract Rationale: Increases in the number and size of lymphoid follicles (LFs) are present in severe stages of COPD and have not been fully characterized. HLA complex is crucial in enabling the immune system to recognize “self” versus “non-self” antigens and plays a major role in immune responses to cigarette smoke exposure. Methods: Lung follicles from COPD patients with milder (GOLD I–II) and more severe (GOLD III–IV) COPD were sampled using GeoMX® Digital Spatial Transcriptional Profiling. Data were analyzed and normalized using GeoMx® DSP Analysis Suite. Results: Pathway analysis showed that B cell activation pathways had the highest fold enrichment. GOLD I–II compared to GOLD III–IV COPD patients had the highest expression of HLA-Cand its ligands (KIR2DS2, KIR2DS1, KIR3DL1; p<0.0001) which facilitate CD8-mediated cytotoxicity, and HLA-Gand its receptor LILRB4(p=0.01) which are key modulators of immune tolerance. GOLD III–IV COPD patients had the highest HLA enrichment in LFs, with upregulation of transcription factors (HIF1A, IRF1, NFYBand NFYC) and assembly components (CALR, TAPBP, ERP27, MARCHF1, B2M, and CIITA) of HLA (p<0.01). Compared to GOLD I–II, LFs from GOLD III–IV COPD patients had much higher expression of HLAs involved in autoimmune responses to self-antigens and adaptive immune evasion, such HLA-DRA, HLA-DRB1, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-Eand HLA-B(p<0.0001). Conclusions: We show for the first time that LFs from patients with severe COPD are characterized by expression of HLAs associated with immune evasion and autoimmune responses, whereas LFs in milder stages of COPD are characterized by induction of immune responses controlled by tolerance mechanisms R01 HL 149744-04/06