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Fogo Selvagem (Endemic Pemphigus Foliaceus)
Introduction
The term pemphigus describes a group of autoimmune vesicobullous diseases where autoantibodies are directed against the ectodomains of the desmosomic strutures of the epidermis, culminating in keratinocyte detachment (acantholysis) and intraepithelial blister formation. Autoantibodies against stratified epithelial-specific desmosomal glycoproteins are found in all forms of pemphigus. Two of these transmembrane glycoproteins, known as desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3), are recognized by pemphigus foliaceus (PF) and pemphigus vulgaris (PV) autoantibodies respectively. The pemphigus group is presented in Table 34-1 , including the two variants of immunoglobulin A (IgA) pemphigus.
TABLE 34-1
Types of Pemphigus and Respective Clinical and Laboratorial Aspects
| Pemphigus | Variant | Antibody / Subclass | Antigen / Weight Molecular | Level of the Acantholysis | Mucous Lesions | Localization of the Lesions |
|---|---|---|---|---|---|---|
| Foliaceus (PF) | Classic (Cazenave) | IgG / IgG4 | Desmoglein 1 / 160 kDa | Subcorneal | NO | Seborrhoeic areas Can disseminate |
| Endemic or (FS) Fogo selvage | IgG / IgG4 | Desmoglein 1 / 160 kDa | Subcorneal | NO | Seborrhoeic areas Can disseminate |
|
| Vulgaris (PV) | Mucous | IgG / IgG4 | Desmoglein 3 / 130 kDa | Suprabasilar | YES | Mucous sores |
| Muco cutaneous | IgG / IgG4 | Desmoglein 3 / 130 kDa Desmoglein 1 / 160 kDa | Suprabasilar | YES | Mucous and any cutaneous areas | |
| Vegetans | IgG / IgG4 | Suprabasilar | YES | Intertriginous and mucous areas | ||
| Drug-induced | PF type PV type |
IgG | Desmoglein 1 / 160 kDa Desmoglein 3 / 130 kDa |
NO YES |
PF like PV like |
|
| Paraneoplastic | Desmoglein 3 / 130 kDa Desmoglein 1 / 160 kDa Members of plakin family * |
Suprabasilar acantholysis, erythema multiforme-like, lichen planus like | YES | Severe mucositis | ||
| IgA Pemphigus | Subcorneal dermatoses | IgA | Desmocolin 1 / 110 / 100 kDa | Subcorneal pustules | Rare | Axilla and groin vesico pustules |
| Intraepidermal neutrophilic | IgA | ? | Suprabasilar pustules | Rare | Axilla and groin vesico pustules |
* Members of plakin family: Plektin (500 kD); Desmoplakin I (250 kD); Desmoplakin II (210 kD); BPAg1: bullous pemphigoid antigen 1 (230 kD); Envoplakin (210 kD); Periplakin (190 kD), A2ML1: α-2-macroglobulin-like-1 protease inibidor (q70 kD).
The endemic variant of PF is known as fogo selvagem (FS). FS is distinguished by its epidemiologic features, since the disease shares the same clinical, histopathologic, and immunologic characteristics of the classical form of PF. FS has several unique and remarkable epidemiologic features, such as the geographic and temporal clustering of cases, the higher frequency of cases among children and young adults, the higher frequency of familial cases, and an association with certain distinct human leukocyte antigen (HLA)-DR alleles.
History
The endemic form of PF was reported in 1903 by Paes-Leme in Brazil, when he thought to present a clinical blistering variant of tinea corporis – that is, tinea imbricata or “Tokelau.” Vieira found that this illness exhibited the same clinical features of PF as reported by Cazenave (1844). Vieira established the salient clinical and histologic features of this endemic form of PF. Most of the patients came from rural or wild areas, and the symptoms are similar – of skin feeling as if burned by fire – so this disease was denominated fogo selvagem (wildfire). Before 1940s, the diagnosis was based only on clinical aspects. After that time, with the contribution of the pathology, FS became recognized as an acantholytic bullous disease. In 1964, Beutner and Jordon found circulating antibodies on the intercellular space of the epidermis, so pemphigus was redefined as an autoimmune acantholytic bullous disease. Desmoglein 1 (Dsg1) is the autoantigen recognized by PF and FS autoantibodies and it is a member of the desmosomal cadherin family of cell adhesion molecules. Therefore, FS is now known to be an anticadherin autoimmune bullous disease.
Etiopathogenesis
Epidemiologic and Environmental Factors
Pemphigus can be found rarely all over the world (incidence = 0.76–5 new cases per million per year). In most countries, PV is more common than PF; exceptions to this include Finland, Tunisia, and Brazil. In rural Brazil, the ratio of endemic PF to PV is a remarkable 17 : 1. Unlike classical pemphigus foliaceus, which is a disease of mostly middle-aged and older patients, FS affects young adults and children of either sex or any race exposed to the local ecology in rural areas, and its incidence gradually decreases as the area is developed.
FS occurs in colonization regions of South America, mainly in impoverished rural areas of certain midwestern and northwestern states of Brazil. A cutaneous disease with similar features to FS has also been described in other countries, including Colombia, Tunisia, and Peru. The ecological systems of FS share similarities with insect-vector-borne diseases Chagas disease and leishmaniasis.
The Limão Verde reservation is a Terena Amerindian settlement located in the state of Mato Grosso do Sul (Brazil); it has a population of about 1300 individuals with a prevalence of FS of 3.4%. A case–control study performed in this reservation suggested that individuals living in this endemic area might be at risk of developing FS if they lived in rustic houses with thatched roofs and adobe walls; furthermore, the risk might be increased if these individuals were exposed to hematophagous insect bites (black flies, kissing bugs, or bed bugs). A predominant black fly species, Simulium nigrimanum , was found in this reservation, and this species is rarely seen in non-endemic areas of Brazil.
Salivary antigens from the sand fly Lutzomyia longipalpis , and specifically the LJM11 salivary protein, were recognized by FS antibodies. Anti-Dsg1 monoclonal autoantibodies derived from FS patients also cross-reacted with LJM11. Mice immunized with LJM11 generated anti-Dsg1 antibodies. Thus, insect bites may deliver salivary antigens that initiate a cross-reactive IgG4 antibody response in genetically susceptible individuals that leads to subsequent development of FS.
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