Understanding the Pathophysiology of Immunobullous Skin Disorders
BULLETIN FOR MEDICAL PRACTITIONERS
Dr Patricia Ng
National Skin Centre
Among the immunobullous skin diseases, pemphigus and bullous pemphigoid are the two most frequently encountered ones. Although both present with blistering and erosions and both are known to be immunologically-mediated, there are important differences between them. Apart from the age-group affected (middle-aged versus elderly) and level of blister formation (intraepidermal versus subepidermal), there are also significant differences in terms of pathophysiology between pemphigus and bullous pemphigoid. A proper understanding of the pathophysiology of these conditions will enable us to use therapeutic agents in a rational way.
I Mechanisms of autoantibody-induced blistering
Between the two diseases, pemphigus is more severe with a mortality rate of 5-10%. The antibodies in pemphigus have been shown to be directly pathogenic. In laboratory studies when pemphigus antibodies were infused into neonatal mice, the mice developed blisters  . This blistering occurred even if the mice were pretreated with high doses of corticosteroids which eliminates plasminogen activity  . Complement depletion was also unable to prevent the antibody-induced blistering.
In contrast, the blistering induced by bullous pemphigoid antibodies in passive transfer mouse models did not occur in the absence of complement  and proteases secreted by neutrophils  . This suggests that the antibodies in BP are not directly pathogenic and that blistering is due to the inflammatory cascade that occurs following antibody binding.
The clinical implication is that in pemphigus, one needs to suppress antibody production with corticosteroids and/or immunosuppressives in order to control the blistering. In severe pemphigus, physically removing the antibodies by plasmapheresis may be necessary to achieve control of the disease. Anti-inflammatory drugs such as dapsone and tetracycline/ nicotinamide which are often used in bullous pemphigoid have no role in the therapy of pemphigus as they do not suppress antibody production. In the light of the pathophysiology, topical steroids also have no role in the treatment of pemphigus as they do not affect the circulating autoantibody levels.
On the other hand, bullous pemphigoid may be treated with anti-inflammatory drugs such as dapsone, nicotinamide/tetracycline and methotrexate. Corticosteroids may be used as anti-inflammatory agents at doses lower than that required for antibody suppression. Topical steroids having a local anti-inflammatory effect may be useful.
II Target antigens
Blistering occurs at different levels in the skin because the autoantibodies in pemphigus and bullous pemphigoid target different antigens. There have been significant advances in the understanding of these target antigens.
Pemphigus vulgaris presents clinically with mucosal lesions or with mucocutaneous lesions while pemphigus foliaceus is confined to the skin alone. It has been well established in the past decade that autoantibodies are produced against transmembrane desmosomal proteins, desmoglein 3 and desmoglein 1, in pemphigus vulgaris and pemphigus foliaceus, respectively. However, in recent years, the development of desmoglein 3 knockout mice has greatly increased our understanding of the role of desmogleins in maintaining epidermal cell adhesion. These genetically-engineered mice with targeted disruption of desmoglein 3 gene developed oral lesions but surprisingly, did not develop skin lesions  . It was later observed that pemphigus vulgaris patients with only mucosal involvement had antibodies against desmoglein 3 alone while those with both mucosal and cutaneous involvement had antibodies against desmoglein 3 and desmoglein 1 (pemphigus foliaceus antigen)[6,7] . It is believed that this may represent an example of "epitope spreading", a phenomenon observed in autoimmune diseases in which an immune response to a specific epitope is slowly followed by an immune response to a neighbouring epitope/ molecule. Desmoglein 3 appears to be essential to the integrity of the mucosal epithelium but not the skin because of co-expression of desmoglein 1 in the skin. If desmoglein 1 is also affected in addition to desmoglein 3, then skin involvement becomes apparent.
In pemphigus foliaceus where antibodies are targeted only against desmoglein 1, blister formation in the skin is superficial compared to pemphigus vulgaris as desmoglein 1 is critical in maintaining cell adhesion in the upper epidermis where there is no expression of desmoglein 3.
The target antigens in bullous pemphigoid have been identified as bullous pemphigoid antigen 1 (BPAG1), a 230 kDa intracellular protein within the basal cell hemidesmosome plaque, and bullous pemphigoid antigen 2 (BPAG2), a 180 kDa transmembrane protein that has domains within the hemidesmosome plaque, the basement membrane and the lamina lucida. Although both antigens are recognized by the autoantibodies, of late, evidence points to anti-BP180 antibodies being the cause of blistering  . It is presently believed that antibodies to BP230Ag are secondary, non-pathogenic and also result from the phenomenon of "epitope spreading", which has been described above  .
Understanding the target antigens will be useful in novel immunotherapies for pemphigus. Research is ongoing to define precisely which desmoglein 3 peptides are bound by the major histocompatibility complex (MHC) molecules associated with the disease, with the hope of developing a peptide-based vaccine that can reinduce tolerance to desmoglein 3 or an anti-idiotype vaccine to block the pathogenic idiotype PV and PF antibodies  .
- Anhalt GJ, Labib RS, Vorhees J, et al. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Eng J Med 1982;306:1189-96.
- Anhalt GJ, Patel HP, Labib RS, et al. Dexamethasone inhibits plasminogen activator activity in experimental pemphigus in vivo but does not block acantholysis. J Immunolog 1986;135:113-17.
- Liu Z, Guidice GJ, Swartz SJ, et al. The role of complements in experimental bullous pemphigoid. J Clin Invest 1995;95:1539-44.
- Liu Z, Guidice GJ, Zhou X, et al. A major role for neutrophils in experimental bullous pemphigoid. J Clin Invest 1997;100:1256-63.
- Koch PJ, Mahoney MG, Ishikawa H, et al. Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol 1997;137:1091-102.
- Ding X, Aoki V, Mascaro JM, et al. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J Invest Dermatol 1997;109:592-96.
- Amagai M, Tsunoda K, Zillikens D, et al. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol 1999;40:167-70.
- Liu Z, Diaz LA, Troy JL, et al. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest 1993;92:2480-88.
- Mutasim DF. Levels of antibodies to BP180 correlate with disease activity in bullous pemphigoid. Arch Dermatol 2000;136:253-4.
- Anhalt GJ, Diaz LA. Research advances in pemphigus. JAMA 2001;285:652-54.
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By National Skin Centre (Singapore)
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