p38 mitogen activated protein kinase (p38 MAPK) signaling plays a major role in the modulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. The extent of the involvement of p38 MAPK in the pathogenesis of autoimmune blistering diseases has started to emerge, but whether it pays a critical role is a matter of debate. The activity of p38 MAPK has been studied in great detail during the loss of keratinocyte cell-cell adhesions and the development of pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These diseases are characterised by autoantibodies targeting desmogleins (Dsg). Whether autoantibody-antigen interactions can trigger signaling pathways (such as p38 MAPK) that are tightly linked to the secretion of inflammatory mediators which may perpetuate inflammation and tissue damage in pemphigus remains unclear. Yet, the ability of p38 MAPK inhibitors to block activation of the proapoptotic proteinase caspase-3 suggests that the induction of apoptosis may be a consequence of p38 MAPK activation during acantholysis in PV. This review discusses the current evidence for the role of p38 MAPK in the pathogenesis of pemphigus. We will also present data relating to the targeting of these cascades as a means of therapeutic intervention. 1. Introduction The skin represents the first organ of the body exposed to the external environment and thus serves as the primary barrier of the immune defense system. Its key role is to maintain protection against hazardous environmental threats such as microorganisms and viruses [1, 2]. The epidermis is the outmost cellular tissue of the skin and expresses several proteins that orchestrate the essential protective functions. Inflammatory mediators such as prostaglandins, histamines, cytokines, and chemokines are synthesized and secreted from keratinocytes regulating the skin’s immune responses [3, 4]. When this epithelial barrier is compromised due to the deterioration of skin tissue integrity, patients are at high risk of fluid and electrolyte loss, as well as infection. If left untreated, conditions can be fatal. Even though the mechanisms of skin damage are essentially the same as the ones that control protective immunity and despite the evolution of sophisticated anti-inflammatory and tissue repair mechanisms, the formation of immune complexes against self-antigens (a hallmark of autoimmunity) initiates a sustained inflammatory response characterized by autoreactive immune cells, cytokines, and autoantibody production [5–8]. Pemphigus signifies a distinctive
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