Neutrophil extracellular traps contribute to immune dysregulation in bullous pemphigoid via inducing B‐cell differentiation and antibody production

Abstract

Bullous pemphigoid (BP), an autoimmune skin disease, is characterized by autoantibodies against hemidesmosomal proteins in the skin and mucous membranes. Neutrophils infiltrate BP skin lesions, however, their role in immune dysregulation remains unclear. We investigated whether BP involves aberrant neutrophil extracellular traps (NETs) formation in skin lesions and circulation; and examined the triggers and deleterious immuno‐inflammatory consequences. In the present study, we found that circulating NET‐related biomarker levels increased in serum and blister fluid of BP patients and significantly correlated with disease severity. Additionally, circulating neutrophils from BP patients displayed enhanced spontaneous NETs formation than healthy controls. In vitro, BP180‐NC16A immune complexes‐induced NETosis in neutrophils from BP patients, which was abrogated by Fcγ receptor and/or NADPH pathway blockade. Furthermore, the elevated levels of NETs from BP patients boosted autoantibody production by inducing B‐cell differentiation into plasma cells, mediated by MAPK P38 cascade activation. Together, our findings provide strong evidence that NETs are involved in a pathogenic loop, causing excessive differentiation of B cells and promotion of autoantibody production. Hence, targeting aberrant neutrophil responses will provide novel potential targets for the treatment of BP.

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

“…Using immunodetection of patient skin biopsies, NET formation has been shown to be associated with BP ( 101 ). Additionally, levels of NET biomarkers are correlated to BP disease activity ( 102 ). Thus, it is likely that these complexes play a role in the tissue damage involved in this disease.…”

The cytokine milieu of bullous pemphigoid: Current and novel therapeutic targets

“…Neutrophils and eosinophils also regulate different aspects of BP inflammation. As an example, NET release from neutrophils acts systemically by inducing B-cell differentiation into plasma cells via activation of the MAPK/p38 cascade (109). Eosinophils mediate specific IgE pathogenicity, release cytokines which enhance Th2 cell recruitment and stimulate peripheral nerve terminals, e.g., by releasing IL-31 (88,(110)(111)(112).…”

Neutrophils: Musketeers against immunotherapy

“…The antitumor response mainly depends on APCs to prime naïve T cells ( 171 ). Various studies have reported that the cDC1 subset is associated with the induction of tumor-controlling immunity and improved overall survival in many tumor types ( 172 , 173 ). The activation of neutrophils releases the granule content neutrophils elastase (NE) that induces the polarization of the DC-mediated development of T cells into Th 17 cells, while the blocking of neutrophil activation or NE prevents the production of Th 17 cells ( 174 ).…”