Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem)

Abstract

We have shown that although the IgG response in fogo selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limão Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease.

Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus

“…Pemphigus foliaceus patients have higher serum immunoglobulin G (IgG) levels against desmocollins 1 and 2 and all four desmogleins ( 32 ). Most pathogenic antibodies, able to induce acantholysis in vitro and in vivo ( 33 – 35 ), are of the IgG4 subclass ( 36 – 38 ), directed against the DSG1 N-terminal ectodomains ( 39 , 40 ). Anti-DSG1 IgG1 are common in asymptomatic individuals of endemic regions, but can be the only pathogenic antibodies in a subset of PF patients ( 19 ).…”

Impact of structural modifications of IgG antibodies on effector functions

“…IgG4 is therefore generally regarded as less important subclass in the autoimmune setting. However, IgG4 can still be highly pathogenic, for example in the form of (blocking) autoantibodies in pemphigus ( 64 ), primary membranous nephropathy ( 65 , 66 ), or in IgG4-related disease ( 67 ). Elevated levels of serum IgG4 have also been associated with asthma ( 68 ) and tissue eosinophilia ( 69 ).…”

From Insect Bites to a Skin Autoimmune Disease: A Conceivable Pathway to Endemic Pemphigus Foliaceus

“…Remarkably, a significant number (55%) of healthy individuals from LV possess nonpathogenic IgG anti-Dsg1 antibodies (42) . FS possess predominantly IgG4 pathogenic anti-Dsg1 autoantibodies and a few mixed with non-pathogenic IgG1-IgG3 as well (21) (43)(44)(45)(46). Moreover, a highly sensitive and specific "IgG4 predictor" of FS was developed by serological analysis of the IgG isotypes of the anti-Dsg1 response from 214 FS patients and 261 normal individuals from endemic areas (46).…”