Bullous pemphigoid (BP) represents an autoimmune blistering disorder that may coexist with acquired hemophilia A (AHA), a rare autoimmune condition arising from the formation of circulating autoantibodies directed against factor VIII (FVIII). The underlying pathomechanisms of BP-AHA remain elusive. This study conducted a retrospective analysis of data from 196 BP patients admitted to our hospital. We have collected serum samples from a recently admitted BP-AHA patient and healthy controls to isolate, screen and identify the potential FVIII inhibitors. The expression and function of lipopolysaccharide-binding protein (LBP) in BP-AHA were further validated by a series of biochemical experiments. The retrospective analysis showed that the activated partial thromboplastin time (APTT) values of seven patients exceeded 33.8 s (normal value) in 196 BP patients. FVIII: C (%) and FVIII inhibitors in the plasma of partial prolonged-APTT patients were significantly altered compared with control group or non-prolonged-APTT group. LBP was identified as a potential inhibitory protein of FVIII. Consistently, a notable alteration in LBP expression was observed in the plasma of BP patients with prolonged-APTT. Moreover, the amount of LBP bound to FVIII in the BP-AHA patient was notably higher than that in control group, which was also markedly reversed after treatment. In vitro experiments finally confirmed that exogenous LBP directly bound to FVIII and significantly inhibited FVIII activity. In conclusion, the incidence of AHA in BP patients may be substantially underestimated, which needs more vigilance towards indicators such as APTT, LBP, and FVIII. LBP emerges as an inhibitory protein of FVIII, indicating the potential involvement in the progression of BP-AHA.
Yajing You,Zhijun Lin,Jiazhen Chen,Jiahui Liu,Yuwu Luo,Xingdong Ye,Jiang Yang
Pemphigus vulgaris (PV) is a chronic, often fatal autoimmune blistering disorder that affects the skin and body-wide mucous membranes, imperatively urging for accurate detection of characteristic autoantibodies. To overcome the sensitivity constraint, we report here a serological avidity test for complex PV autoantibodies, relying on cell-based plasmonic biolayer interferometry (cpBLI) with two-tiered enhancement of light interference by gold nanostars (AuNSs). High-surface-area, clean-surface AuNSs with abundant tips and grooves can enhance interference patterns and promote intrinsic and extrinsic catalysis of 3,3′-diaminobenzidine by themselves and conjugated peroxidase, enabling a dual hierarchical signal amplification of 26.8-fold over conventional BLI at a limit of detection of 0.36 pM. The cpBLI responses correlate well with diagnostic ELISA from clinical laboratories, precisely differentiating PV from normal and other epithelial antibody-associated immunobullous cutaneous diseases such as bullous pemphigoid. In a simple dip-and-read format with real-time readouts, the efficacy was verified in a masked validation cohort and multicenter patient samples. The cpBLI effectively assesses PV prognosis and precisely stratifies severity in good association with the Pemphigus Disease Area Index (PDAI). Notably, live cells on the biosensor surface facilitate drug screening by responding to PV therapeutics. Therefore, the cpBLI immunodiagnostic assay is promising for diagnosing, staging, and therapeutic monitoring PV in clinical settings and can be generalized for other autoimmune diseases.
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