The IgM Anti-Desmoglein 1 Response Distinguishes Brazilian Pemphigus Foliaceus (Fogo Selvagem) from Other Forms of Pemphigus

Abstract

Fogo selvagem (FS) and pemphigus foliaceus (PF) possess pathogenic IgG anti-desmoglein 1-(Dsg1) autoantibodies. Although PF occurs sporadically, FS is endemic in Limao Verde (LV), Brazil (3.4% prevalence). IgM anti-Dsg1 were detected in 58% FS LV patients (n=31), 19% of FS patients from Hospital-Campo Grande (n=57), 19% from Hospital-Goiania (n=42), 12% from Hospital-Sao Paulo (n=56), 10% of PF patients from United States (n=20), and 0% of PF patients from Japan (n=20). Pemphigus vulgaris (n=40, USA and Japan), bullous pemphigoid (n=40, USA), and healthy donors (n=55, USA) showed negligible percentages of positive sera. High percentages of positive IgM anti-Dsg1 were found in healthy donors from four rural Amerindian populations (42% of 243) as compared with urban donors (14% of 81; P<0.001). More than 50% of healthy donors from LV (n=99, age 5-20 years) possess IgM anti-Dsg1 across ages, whereas IgG-anti-Dsg1 was detected in 2.9% (age 5-10 years), 7.3% (age 11-15 years), and 29% of donors above age 16. IgM anti-Dsg1 epitopes are Ca2+ and carbohydrate-independent. We propose that IgM anti-Dsg1 are common in FS patients in their native environment and uncommon in other pemphigus phenotypes and in FS patients who migrate to urban hospitals. Recurrent environmental antigenic exposure may lead to IgM and IgG responses that trigger FS. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub.

Profile of Trypanosoma cruzi Reactivity in a Population at High Risk for Endemic Pemphigus Foliaceus (Fogo Selvagem)

“…8 In this study, we detected 22% of reactivity against Dsg1 in non-FS individuals, indicating a possible environmental stimulus in the development of autoantibody formation. Some findings concerning the nonpathogenic response towards Dsg1 are relevant to reinforce the environmental hypothesis in FS, as follows: the lower prevalence of the IgG anti-Dsg1 response in normal subjects that live far away from the endemic sites (13%), 32 the predominance of a certain black fly species, Simulium nigrimanum, in FS regions, 24 an enhanced IgM or IgE anti-Dsg1 immune response in FS, 19,20 and finally, the epidemiological data emphasizing the relevance of housing conditions and exposure to hematophagous insects, such as bedbugs and kissing bugs of patients with the disease. 16 Individuals with parasitic diseases that are vector-mediated, such as onchocerciasis, cutaneous leishmaniasis, and Chagas disease, often possess circulating nonpathogenic anti-Dsg1 autoantibodies.…”

“…In those genetic predisposed individuals, intra-molecular spreading may occur, leading to an EC1-2-oriented IgG4 response, and therefore precipitating FS onset. 6,18 There is also evidence of other immunoglobulin classes in FS pathogenesis: circulating IgM autoantibodies directed against Dsg1 are found in FS patients and in healthy individuals living in endemic areas, indicating a role as serological markers for the disease 19 ; moreover, an IgE-based immune response to Dsg1 was detected in the sera of 81% of FS patients. 20 These findings lead to the hypothesis of continuous exposure to an environmental antigen that may share epitopes to Dsg1, and become a strong stimulus to nonpathogenic anti-Dsg1 IgM and IgG production in areas at high risk for FS.…”

Pathogenic Relevance of IgG and IgM Antibodies against Desmoglein 3 in Blister Formation in Pemphigus Vulgaris

“…12 This anti-Dsg1 IgM was shown, by ELISA and immunoprecipitation, to bind to recombinant Dsg1, but it did not bind to human skin sections in indirect immunofluorescence studies, in which AK23 IgM also failed to yield a positive signal. Our findings suggest that the anti-Dsg1 IgM is most likely nonpathogenic and unable to cause blisters, because of the inaccessibility of Dsg1 integrated within desmosomes.…”

“…Recently, an anti-Dsg1 IgM autoantibody typically found in fogo selvagem patients was also detected in several healthy individuals. 12 Nonetheless, the pathophysiological role of anti-Dsg3 IgM in PV remains unclear. In the present study, we used transgenic techniques to generate an IgM isotype of an IgG mAb that recognizes a critical Dsg3 epitope located on the functionally important amino-terminal adhesive interface and then examined its pathogenic role in PV.…”

“…11 Although IgM autoantibodies are not found in the sporadic form of pemphigus, high levels of IgM autoantibodies against desmoglein 1 (Dsg1) were recently detected in sera from patients with fogo selvagem, a form of pemphigus foliaceus endemic in certain areas of Brazil (notably in Limão Verde), as well as healthy individuals. 12 Nonetheless, the pathogenic relevance of IgM autoantibodies in PV remains to be elucidated.…”