Autoimmunity may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Studies have identified disease-specific autoantibodies (DSAAbs) in COPD patients, but natural autoantibodies (NAAbs) may also play a role. Previous studies have concentrated on circulating autoantibodies, but lung-associated autoantibodies may be most important. Our aim was to investigate NAAbs and DSAAbs in the circulation and lungs of COPD smoking (CS) patients compared to smokers (S) without airway obstruction and subjects who have never smoked (NS). Immunoglobulin (Ig)G antibodies that bind to lung tissue components were significantly lower in the circulation of CS patients than NS (with intermediate levels in S), as detected by enzyme-linked immunosorbent assay (ELISA). The levels of antibodies to collagen-1 (the major lung collagen) detected by ELISA were also reduced significantly in CS patients’ sera compared to NS. The detection of these antibodies in NS subjects indicates that they are NAAbs. The occurrence of DSAAbs in some CS patients and S subjects was indicated by high levels of serum IgG antibodies to cytokeratin-18 and collagen-5; furthermore, antibodies to collagen-5 eluted from homogenized lung tissue exposed to low pH (0·1 M glycine, pH 2·8) were raised significantly in CS compared to S and NS. Thus, this study supports a role in COPD for both NAAbs and DSAAbs.

Objective. To investigate the effect of mutations in tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in TNFR-associated periodic syndrome (TRAPS) on the binding of anti-TNFRSF1A monoclonal antibodies (mAb), and to investigate the subcellular distribution of mutant versus wild-type (WT) TNFRSF1A in patients with TRAPS.Methods. HEK 293 cells transfected with WT and/or mutant TNFRSF1A were used to investigate the interaction of anti-TNFRSF1A mAb with the WT and mutant proteins. Monoclonal antibodies that differentially bound to C33Y TNFRSF1A were used to investigate the distribution of WT and mutant TNFRSF1A in TRAPS patients with the C33Y mutation.Results. We identified a mAb whose binding to TNFRSF1A was completely abolished by the C33Y or C52F TRAPS-associated mutations, whereas other mutations (T50M, C88Y, R92Q) had lesser effects on the binding of this mAb. A different mAb was found to bind efficiently to all of the mutant forms of TNFRSF1A examined as well as to the WT receptor. Exploitation of the differential binding properties of these mAb indicated that mutant (as distinct from WT) TNFRSF1A showed abnormal intracellular retention in the neutrophils of TRAPS patients with the C33Y mutation, with little if any expression of mutant TNFRSF1A on the cell surface or as soluble receptor in plasma.Conclusion. TRAPS-associated mutant TNFRSF1A has an antigenically altered structure and shows abnormal retention in the leukocytes of patients with TRAPS, which is consistent with previous findings from in vitro and transgenic model systems. This is consistent with a misfolded protein response contributing to the pathophysiology of TRAPS.