Pénfigo Autoinmune (Inglés)

Autoimmunity, February 2012; 45(1): 7–35 q Informa UK, Ltd. ISSN 0891-6934 print/1607-842X online DOI: 10.3109/08916934.2011.606444

Pemphigus autoimmunity: Hypotheses and realities

SERGEI A. GRANDO
Department of Dermatology, University of California, Irvine, CA, USA
(Submitted 25 June 2011; accepted 12 July 2011)

Autoimmunity Downloaded from informahealthcare.com by University Mayor on05/15/12 For personal use only.

Abstract The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocytedetachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies tothe cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatorycytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress indeveloping of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients.

Keywords: Pemphigus vulgaris, Pemphigus foliaceus,autoantigen, autoantibody, apoptolysis, prednisone

Introduction Autoimmune pemphigus is a life-threatening mucocutaneous blistering disease associated with IgG antibodies targeting several types of keratinocyte antigens and eliciting epidermal clefting (acantholysis) via intracellular signaling activating apoptotic enzymes (apoptolysis) [1]. Systemic administration of glucocorticosteroid hormones isessential to establish control of disease during the acute stage [2]. Although glucocorticosteroid treatment is life-saving, it may cause severe side effects, including death [3,4]. Therefore, pemphigus patients need drugs that can replace glucocorticosteroids. The development of non-steroidal treatment has been hampered by a lack of clear understanding of the mechanisms leading to keratinocytedetachment and death in pemphigus. This overview of recent advances in the knowledge of

pemphigus autoimmunity challenges the existing dogmas, helps resolve old controversies, and identifies new perspectives for treatment. It encompasses knowledge on pemphigus vulgaris (PV) and pemphigus foliaceus (PF), but specifically excludes reports on paraneoplastic pemphigus, or PNP, originally described byAnhalt et al. [5], because this disease is not related to PV and PF. The notion that PNP represents a variant of classical pemphigus stems from the facts that patients with PV or PF sometime have concomitant neoplasms [6– 8] and that some patients with PNP develop anti-desmoglein (Dsg) 1 and/or 3 antibodies—the hallmark of classical pemphigus [9]. In fact, PNP represents only one manifestation of...