Autoimmunity to Keratinocyte Acetylcholine Receptors in Pemphigus

Abstract

Pemphigus autoimmunity is not limited to antides- moglein antibodies. Nondesmoglein antibodies induce pemphigus-like lesions in neonatal mice. Acantholytic activity of pemphigus IgG harbors pharmacologic effects on keratinocyte shape and adhesion. Acantholytic antireceptor autoantibodies target: (1) a novel human α9 acetylcholine receptor regulating keratinocyte adhesion, and (2) pemphaxin, a novel keratinocyte annexin-like molecule binding acetylcholine. A ‘multiple-hit’ hypothesis reconciles recent findings of anti-acetylcholine-receptor autoimmunity in pemphigus and the fact that pemphigus patients also develop autoantibodies to adhesion molecules. The antiacantholytic activity of cholinergic agonists suggests a novel avenue for the development of a nonhormonal treatment of pemphigus.

Autoimmune diseases involving nicotinic receptors

“…Neuronal AChRs have been detected in several non-neuronal tissues (Grando, 2001;Corriveau et al, 1995;Wang et al, 2001;Sekhon et al, 1999;Kawashima et al, 2000). Recently an autoimmune response to ␣9 AChRs has been found in the skin disease pemphigus (Grando, 2000). Autoimmune diseases to AChRs involving other neuronal and non-neuronal tissues are likely to be found.…”

“…Immunosuppressive steroids have reduced mortality from 90 to 10%. A variety of autoantigens have been identified, including desmoglian, pemphaxin, and ␣9 AChR subunits (Grando, 2000;Nguyen et al, 2000). Pemphaxin is a 75 kDa protein reported to bind ACh (Nguyen et al, 2000).…”

“…This review will briefly consider what is known about the autoimmune response to ␣1 muscle AChRs in MG (Drachman, 1994;Lindstrom, 2000aLindstrom, , 2002a and compare this with what is being discovered about recently recognized autoimmune responses to ␣3 neuronal AChRs in some forms of dysautonomia (Vernino et al, 1998(Vernino et al, , 2000(Vernino et al, , 2001 and to ␣9 neuronal AChRs in pemphigus (Grando, 2000). It will end with some speculation about what other diseases might result from autoimmune responses to neuronal AChRs that remain to be discovered.…”

“…Nicotinic acetylcholine receptors (AChRs) are the targets of both autoimmune and genetic diseases (Drachman, 1994;Lindstrom, 2000aLindstrom, , 2002aVernino et al, 2000;Grando, 2000;Engel et al, 1999Engel et al, , 2002aSteinlein, 2000;Kuryatov et al, 1997;De Fusco et al, 2000;Phillips et al, 2001). For both types of pathologies, initially myasthenias rather than neuronal AChR diseases were discovered because we better understand the functional role of muscle AChRs and most easily recognized the effects on neuromuscular transmission of pathologies resulting from decreasing or increasing AChR function.…”

“…Neuronal AChRs have more recently been discovered to be the objects of both autoimmune and genetic diseases (Vernino et al, 2000;Grando, 2000;Steinlein, 2000;Kuryatov et al, 1997;DeFusco et al, 2000;Phillips et al, 2001). The major barrier to recognizing the pathological bases of diseases resulting from altered neuronal AChR function is that we know so little about the normal functional roles of the many subtypes of neuronal AChRs (Lindstrom, 2000b).…”