Towards a better understanding of pemphigus autoimmunity
Authors: M. Amagai
Journal: British Journal of Dermatology (2000)

Among the many autoimmune diseases, pemphigus has, at a remarkable pace, become one of the best characterized tissue-specific autoimmune diseases. The identification of the desmosomal cadherins, desmoglein 3 (Dsg3) and Dsg1, as the target antigens of pemphigus vulgaris (PV) and pemphigus foliaceus (PF), respectively, has provided the basic pathophysiological mechanism for the blister formation in pemphigus.1-3 IgG autoantibodies inhibit the adhesive function of desmogleins and disrupt cell-to-cell adhesion of keratinocytes, with resultant intraepidermal blister formation. However, the actual clinical pictures of patients with pemphigus are more heterogeneous and complex than this basic concept. Recently, several independent groups, including Harman et al. in this issue, have reported on the association of autoantibody profile and clinical phenotype.4-7 When PV is divided into two subtypes, the mucosal dominant and mucocutaneous types, the mucosal dominant PV has only anti-Dsg3 IgG, but no anti-Dsg1 IgG, while the mucocutaneous PV has both anti-Dsg3 and anti-Dsg1 IgG autoantibodies. There is a logical explanation why the anti-Dsg autoantibody profile defines the clinical phenotype.8, 9 In the skin, Dsg3 is expressed in the lower part of the epidermis, mainly in the basal and immediate suprabasal layers, while Dsg1 is expressed throughout the epidermis, but more intensely in the superficial layers.10 In mucous membranes, Dsg3 is highly expressed throughout the mucosa, while expression of Dsg1 is much less than that in the skin.11 In the skin, sera containing only anti-Dsg3 IgG interfere with the function of Dsg3; however, Dsg1 compensates for the lost Dsg3 function and manages to hold the keratinocytes together, resulting in no apparent skin blisters or limited skin lesions. In contrast, in mucous membranes, Dsg1 cannot compensate for the lost Dsg3 function because of its low expression. Therefore, anti-Dsg3 IgG alone is able to lead to mucous membrane blisters, and thus, PV sera containing only anti-Dsg3 IgG causes mucosal dominant PV with minimal skin involvement. When sera contain both anti-Dsg3 and anti-Dsg1 IgG, they interfere with the function of both Dsg3 and Dsg1, resulting in extensive blister formation in the skin as well as in the mucous membranes. Thus, PV sera containing both anti-Dsg3 and anti-Dsg1 IgG cause mucocutaneous PV. There is another interesting finding in the manuscript by Harman et al.7 Anti-Dsg1 IgG autoantibodies were detectable even early in the course in patients with mucocutaneous PV, while anti-Dsg1 IgG was not detectable in patients with mucosal dominant PV, including two patients who received very little or no systemic treatment over periods of 5 and 26 years. This finding suggests that patients with mucocutaneous PV may produce both anti-Dsg3 IgG and anti-Dsg1 IgG from the beginning of the disease and that epitope spreading from Dsg3 to Dsg1 is not a common phenomenon. This finding is not consistent with the previous observation by others that typical PV patients start with oral lesions and then develop skin lesions later.12, 13 Although such cases with antibody profile changes do exist, we may need to reconsider whether this is a natural course of PV or not. If patients with mucocutaneous PV develop from those with mucosal dominant PV by epitope spreading from Dsg3 to Dsg1, why is it so rare to see conversion from PF to PV by epitope spreading from Dsg1 to Dsg3? As suggested by Harman et al., genetic susceptibility may play an important role in determining the basic autoantibody profile in patients with pemphigus. Further studies are necessary to confirm this hypothesis. Talking about the genetic susceptibility, it is also interesting to see the finding that first-degree relatives of patients with PV have antibodies that react with Dsg3 as reported by Kricheli et al.,15 in this issue, and others.16, 17 There has been a paradox that, although the relatives have antibodies reacting with Dsg3, it is extremely rare to see a familial case of pemphigus except in the endemic form of PF, fogo selvagem, in Brazil. Kricheli et al. explained that one of the reasons may be the absence of IgG4 subclass against Dsg3 among the relatives. Although this may be further confirmed, one of our next common major goals is to clarify the mechanism of the tolerance break against desmogleins in patients with pemphigus. In the past, we dermatologists gained much of our understanding of disorders in dermatology from general medicine or basic science. Now we have pemphigus in our hands as one of the best characterized autoimmune diseases. The precise mechanism of autoimmunity and tolerance is still vague despite a tremendous amount of effort by many investigators in the last century. It may be our turn to provide to them knowledge of the basic mechanisms through studies on pemphigus.