Ectopic Expression of Epidermal Antigens Renders the Lung a Target Organ in Paraneoplastic Pemphigus

Abstract

Paraneoplastic pemphigus (PNP) is an autoimmune disease of the skin and mucous membranes that can involve fatal lung complications. IgG autoantibodies target the cell adhesion molecules desmoglein (Dsg)3 and plakins, but the nature and targets of infiltrating T cells are poorly characterized. Moreover, the lung involvement in this skin Ag-specific autoimmune condition represents a paradox. To mimic autoimmunity in PNP, we grafted wild-type skin onto Dsg3−/− mice, which resulted in graft rejection and generation of anti-Dsg3 IgG and Dsg3-specific T cells. Transfer of splenocytes from these mice into Rag2−/− mice induced a combination of suprabasilar acantholysis and interface dermatitis, a histology unique to PNP. Furthermore, the recipient mice showed prominent bronchial inflammation of CD4+ and CD8+ T cells with high mortality. Intriguingly, ectopic Dsg3 expression was observed in the lungs of PNP mice, mirroring the observation that squamous metaplasia is often found in the lungs of PNP patients. Dsg3 and other epidermal Ags were ectopically expressed in the lungs after pulmonary injuries by naphthalene, which was sufficient for recruitment of Dsg3-specific CD4+ T cells. These findings demonstrate that squamous metaplasia after pulmonary epithelial injury may play a crucial role in redirecting the skin-specific autoimmune reaction to the lungs in PNP.

Pemphigus

“…Notably, bronchiolitis obliterans (an inflammation and fibrotic change that cause the obstruction of bronchioles), which shows pulmonary T cell infiltration, occurs as a complication of paraneoplastic pemphigus but not in pemphigus vulgaris or pemphigus foliaceus 101,102 . Desmoglein 3-specific CD4 + T cells could induce pulmonary inflammation probably due to ectopic expression of desmoglein 3 by squamous metaplasia in the lung, as has been observed in patients with paraneoplastic pemphigus 101,103 . Ectopic expression of epidermal autoantigens might help to explain the multiple organ involvement in paraneoplastic pemphigus.…”

Desmosomes in acquired disease

“…Also differing from the other forms of pemphigus, simple squamous epithelia can be involved, with 30–40% of patients developing pulmonary symptoms (Amagai, 2010). A recent study utilizing the PNP model mouse suggests that the fatal pulmonary symptoms in patients are most likely due to ectopic expression of Dsg3 and other epidermal antigens (Hata, et al, 2013). Autoantibodies in PNP are directed against multiple desmosomal proteins, including Dsgs, Dscs, desmoplakin and plakophilins (Futei, et al, 2003, Gallo, et al, 2014, Hashimoto, et al, 1995a, Lambert, et al, 2010, Seishima, et al, 2004).…”

Paraneoplastic pemphigus: A trait d’union between dermatology and oncology

“…The death is usually caused by severe complications including sepsis, gastrointestinal bleedings and BO [4][5][6]11] . At this regard, a link between anti-DSG-3 antibodies and BO has been reported [58] . Thus, it is important to evaluate accurately the respiratory symptoms in patients with a positivity to anti-DSG-3 antibodies.…”

“…Furthermore, the link between anti-DSG-3 antibodies and bronchiolitis obliterans (BO) [58] has been reported as one of the most important complications of PNP patients. The detection of antibodies against A2ML1 using IP and IB is also useful for the diagnosis of PNP [31,57] .…”