Topic Article:
The IgM Anti-Desmoglein 1 Response Distinguishes Brazilian Pemphigus Foliaceus (Fogo Selvagem) from Other Forms of Pemphigus
Luis A. Diaz, Phillip S. Prisayanh, David A. Dasher, Ning Li, Flor Evangelista, Valeria Aoki, Gunter Hans-Filho, Vandir dos Santos, Bahjat F. Qaqish and Evandro A. Rivitti for the Cooperative Group on Fogo Selvagem Research
Journal of Investigative Dermatology (2008) 128, 667-675; doi:10.1038/sj.jid.5701121

Antibody Response in Endemic Pemphigus Foliaceus

Nancy Kim^1^, Aparche Yang^1^ and Robert S. Kirsner^1^

Journal of Investigative Dermatology (2008) 128, 498; doi: 10.1038/jid.2008.17

Antibodies against desmoglein proteins account for intraepidermal immunobullous disorders in the pemphigus family of diseases. Antibodies against desmoglein 3 are responsible for the blisters seen in patients with pemphigus vulgaris, whereas antibodies against desmoglein 1 lead to the more superficial separation seen in pemphigus foliaceus. Similar in both clinical and histologic features to pemphigus foliaceus (PF), an endemic form of the disease, fogo selvagem (FS) is found in high prevalence in certain regions of Brazil (Diaz et al., 1989). The endemic nature of the condition is thought to be precipitated by an immune response to an environmental antigen(s), currently not yet identified. This unique epidemiologic phenomenon provides researchers with an opportunity to study the differences between endemic and sporadic forms of this disease.

Diaz et al. (2008) studied early immunologic responses among patients with FS to determine whether the IgM response differs from that seen in patients with the sporadic disease. In a comprehensive assessment of immune responses, they evaluated sera from patients with FS in rural endemic and urban areas of Brazil, patients with PF in the United States and Japan, and control subjects in these locations. Detection of desmoglein 1 IgM varied, with the highest levels (58%) in FS patients in endemic regions and control subjects (>50%) from the same areas. The desmoglein 1 IgM response was considerably lower (12–18%) in FS patients from urban areas of Brazil and still lower in patients from the United States (10%) and Japan (0%). Less variability was found in IgG responses in patients, with markedly lower responses in control subjects, apart from control subjects from rural areas of Brazil. The investigators hypothesize that an environmental agent responsible for the development of FS may cause an early IgM response that predates clinical disease.

Through the following questions we will examine this paper in greater detail.

QUESTIONS

1. What is the role of desmoglein 1 IgG in the development of PF and FS?

2. What is the role of desmoglein 1 IgM in FS?

3. Although the investigators suggest that desmoglein 1 IgM is the earliest finding in patients destined to develop FS, do any other possible explanations explain the data?

4. What is the significance of and the rationale for performing studies with and without calcium and glycosylated desmoglein 1?

5. What clinical implications may be drawn from this report?

6. What additional studies would be useful to test the investigators’ hypothesis?

ANSWERS

1. Desmoglein 1 (Dsg1) is a keratinocyte adhesion protein that plays an important role in maintaining the structure of epidermis. Compared with other desmoglein proteins, such as Dsg 3, Dsg1 is located relatively high in the epidermis and as a result has limited expression in mucosa. It is well established that anti-Dsg1 IgG is pathogenic in the development of PF and FS. Pathogenic anti-Dsg1 IgG binds to the N-terminus of Dsg 1; however, the exact sequence of events that follows antibody binding is not completely understood. One theory is that, by binding to the N-terminus of desmoglein 1, the pathogenic antibody interferes with the adhesion of desmogleins, leading to disadhesion of keratinocytes. Another theory posits that the binding of pathogenic IgG anti-Dsg1 to Dsg1 leads to a signal transduction cascade that leads to cellular disadhesion.

Studies involving patients with PF and FS have shown an evolution of IgG epitopes during progression of the disease from preclinical to clinically active. Warren et al. (2003) and Li et al. (2003) noted that 10 individuals with preclinical PF had IgG1 antibodies directed against the EC5 domain of Dsg1. As these patients progressed to clinically active disease, IgG4 autoantibodies against Dsg1 EC1-2 domains became predominant.

There are several plausible explanations for the variability in IgG autoantibodies found in the sera of patients with FS. First, the investigators had not excluded patients who were undergoing treatment with immunosuppressant therapy. Steroids and other immunosuppressant medications decrease the production of autoantibodies in some patients. Other patients under immunosuppressant treatment for FS/PF continue to have circulating autoantibodies. The reason for this is not entirely clear, but inhibition of antibody formation may take time, and even after antibody production is inhibited, antibodies will continue to circulate for some time. Immunosuppressant medications may also work by decreasing cytokines and decreasing inflammation, as opposed to affecting antibody production.

2. Because of the geographic distribution of FS, it has long been thought that the condition may be caused by a response to an environmental antigen. The investigators therefore hypothesized that anti-Dsg1 IgM may reflect exposure to potential antigens that may induce FS within an endemic area, and that these antibodies would be the earliest response during the sensitization process that eventually leads to FS (Diaz et al., 2008). However, it is not clear that this conclusion is supported by all the data presented. The investigators found that anti-Dsg1 IgM was highest in people living in Limao Verde (LV). For it to be a risk factor for the development of FS, anti-Dsg1 IgM should be found in greater prevalence in FS patients than in the general population from that region. However, anti-Dsg1 IgM was highly prevalent in patients both with and without FS. Therefore, our conclusion from this data is that living in LV is a risk factor for having high levels of anti-Dsg1 IgM. The link between anti-Dsg1 IgM and the subsequent development of pathogenic anti-Dsg1 IgG was not demonstrated unequivocally.

It should be pointed out that anti-Dsg1 IgM is not in and of itself pathogenic. Pathogenic IgG anti-Dsg1 autoantibodies from PF and FS patients attack conformational and Ca2+-dependent epitopes on Dsg1 (Olague-Alcala and Diaz, 1993; Amagai et al., 1995). In this study the binding of IgM autoantibodies to Dsg1 was found to be independent from calcium and N-glycosylation (Diaz et al., 2008). From this we can intuit that the epitopes recognized by anti-Dsg1 IgM and pathogenic IgG are different. This also confirms that IgG anti-Dsg1 autoantibodies do not competitively inhibit the binding of IgM anti-Dsg1 autoantibodies. Furthermore, in this study anti-Dsg1 IgM did not bind to epidermal cell surfaces by indirect IF.

3. It is thought that the high prevalence of anti-Dsg1 IgM in certain regions of Brazil, including the region of LV, might represent a response to an environmental antigen. In fact, Diaz et al. (2004) have discovered that patients with leishmaniasis, onchocerciasis, and Chagas disease carry significant levels of anti-Dsg1 autoantibodies specific for the EC5 domain. While this suggests cross-reactivity and while molecular mimicry might play a role in the development of FS in these regions, other possibilities exist. For example, anti-Dsg1 IgM levels may be coincidental and only indicate exposure to these arthropod-borne diseases, which are also endemic in LV.

4. Pathogenic IgG1 anti-Dsg1 autoantibodies from PF/FS patients have been shown to identify conformational and Ca2+-dependent epitopes on Dsg1 (Olague-Alcala and Diaz, 1993; Amagai et al., 1995). The significance of studying anti-Dsg1 IgM autoantibodies and binding to Dsg1 with and without calcium and glycosylated Dsg1 is another method to demonstrate that anti-Dsg1 IgM autoantibodies bind to a different epitope on Dsg1 than do IgG anti-Dsg1 autoantibodies. This is important for several reasons. First, it demonstrates that the percentage of reactive patients described is accurate. (If competitive binding had occurred, it would need to be accounted for in considering antibody positivity in these patients.) Second, it substantiates the concept that anti-Dsg IgM is not pathogenic.

5. The implications of this article are conceptual rather than being related to clinical management. The article illustrates the concept that blistering autoimmune disorders may be caused by exogenous exposures to antigens. Drawing from emerging data in patients with other diseases, such as lupus erythematosus, the investigators propose the hypothesis that in patients in endemic areas of Brazil, having high levels of anti-Dsg1 IgM is a risk factor for subsequently developing more pathogenic anti-Dsg1 IgG autoantibodies and thus FS. Although this is not fully supported by the data presented, it is clear that individuals who live in LV have a much higher level of anti-Dsg1 IgM autoantibodies than patients who live some distance away from this endemic area. In either case, this suggests that measures to prevent exposure to environmental antigens might play a role in the local community or for visitors to the area.

6. First, one might attempt to follow patients in LV with high levels of IgM anti-Dsg1 over time to monitor potential disease progression, For example, they could be monitored for the development of IgG1 and IgG4 antibodies as well as for the development of clinical symptoms of FS. Additional differences—either clinical or immunologic—between persons in endemic areas with and without the disease might help to define further both the epidemiology and the pathophysiology of the disease.

Second, it might be useful to study other populations also at risk for FS, such as in Colombia, El Salvador, Paraguay, Peru, and Tunisia. In a similar fashion, collecting data on anti-Dsg1 IgM, anti-Dsg1 IgG, and HLA types may provide additional insight.

Finally, a focus of study has been the endemic population in LV, but an additional group to study would be persons who migrated to the endemic area, by monitoring their IgM and IgG levels and following them for clinical signs of disease. Conversely, it would be of interest to determine whether patients with FS who emigrated away from endemic areas have improvement in their symptoms and a decrease in IgM and/or IgG levels.

REFERENCES

Amagai M, Ishii K, Hashimoto T, Gamou S, Shimizu N, Nishikawa T (1995) Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent. J Invest Dermatol 105:243–7.

Diaz LA, Sampaio SAP, Rivitti EA, Martins CR, Cunha PR, Lombardi C et al. (1989) Endemic pemphigus foliaceus (fogo selvagem): II. Current and historic epidemiologic studies. J Invest Dermatol 92:4–12

Diaz LA, Arteaga LA, Hilario-Vargas J, Valenzuela JG, Li N, Warren S et al. (2004) Anti-desmoglein-1 antibodies in onchocerciasis, leishmaniasis and Chagas disease suggest a possible etiological link to Fogo selvagem. J Invest Dermatol 123:1045–51

Diaz LA, Prisayanh PS, Dasher DA, Li N, Evangelista F, Aoki V et al. (2008) The IgM anti-desmoglein response distinguishes Brazilian pemphigus foliaceus (fogo selvagem) from other forms of pemphigus. J Invest Dermatol 128:667–75

Li N, Aoki V, Hans-Filho G, Rivitti EA, Diaz LA (2003) The role of intramolecular epitope spreading in the pathogenesis of endemic pemphigus foliaceus (fogo selvagem). J Exp Med 197:1501–10

Olague-Alcala M, Diaz LA (1993) The epitopes on bovine pemphigus foliaceus antigen are calcium dependent and located on the peptide backbone of this glycoprotein. Chron Dermatol 2:189–209

Warren SJ, Arteaga LA, Rivitti EA, Aoki V, Hans-Filho G, Qaqish BF et al. (2003) The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus. J Invest Dermatol 120:104–8

^1^Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA