Epidermal LCs but not dermal DCs take up skin surface protein through intact tight junctions and mediate IgG1 antibody responses to bacterial antigen, conferring protective immunization.

Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC1) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB): EB simplex with muscular dystrophy (EBS-MD), and EB simplex with pyloric atresia (EBS-PA). Here, we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin. We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients. In EBS-PA, expression of all plectin domains was found to be markedly attenuated or completely lost; in EBS-MD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD, and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype. These results also clearly account for the majority of EBS-MD PLEC1 mutation restriction within the large exon 31 that encodes the plectin rod domain, whereas EBS-PA PLEC1 mutations are generally outside exon 31.

Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.

We have recognized in recent years that some cases with idiopathic bilateral sensorineural hearing loss which showed acute progression in either ear responded to steroid and that the improved hearing level could be maintained by longterm administration of steroid only. Forty cases of bilateral sensorineural hearing loss were selected for study. In most of these cases hearing deterioration of either ear was confirmed by audiometry. Eight of fifteen cases with marked improvement have been proved to respond to steroid treatment. These eight cases include three cases with syphilitic deafness and one case with aortitis syndrome. In four other cases the causes are still unknown, but could be due to autoimmune mechanisms. In four of 25 cases the immune complexes (IC) value was higher than normal and three among them responded to steroid. Since a high IC value has been reported in lupus nephritis, immunologic examinations are necessary for patients over 30 years of age with bilateral sensorineural hearing loss.

Peptidylarginine deiminase, which catalyzes the deimination of arginyl residues in protein, was identified and partially purified from rabbit skeletal muscle. The specific activity of the crude extract from the muscle was aboutt 120 times that of the extract from newborn rat epidermis. The enzyme was purified abou 250-fold over the initial extract of rabbit skeletal muscle in a yield of about 53%. The enzyme requires Ca2+ as an essential cofactor and the activity was not inhibited by monoiodoacetate or PCMB. The molecular weight of the enzyme was found to be about 115,000 by gel chromatography on Bio-Gel P-300. The enzyme catalyzed the deimination of arginyl residue when both the alpha-amino and alpha-carboxyl groups were substituted, and showed low activity when substrates had either a free alpha-amino or a free alpha-carboxyl group. The action of the enzyme on free L-arginine was negligible. Proteins such as protamine, histone, and ribonuclease A were better substrates than the other small synthetic peptides tested.