Pemphigus vulgaris (PV) is a potentially fatal blistering disease caused by autoantibodies against desmoglein 3 (Dsg3). Here, we clone anti-Dsg3 antibodies from four PV patients and identify pathogenic VH1-46 autoantibodies from all four patients. Unexpectedly, VH1-46 autoantibodies had relatively few replacement mutations. We reverted antibody somatic mutations to their germline sequences to determine the requirement of mutations for autoreactivity. Three of five VH1-46 germline-reverted antibodies maintain Dsg3 binding, compared to zero of five non-VH1-46 germline-reverted antibodies. Site-directed mutagenesis of VH1-46 antibodies demonstrate that acidic amino acid residues introduced by somatic mutation or heavy chain VDJ recombination are necessary and sufficient for Dsg3 binding. Our data suggest that VH1-46 autoantibody gene usage is commonly found in PV because VH1-46 antibodies require few to no mutations to acquire Dsg3 autoreactivity, which may favor their early selection. Common VH gene usage indicates common humoral immune responses, even among unrelated patients.
Pemphigus vulgaris is a blistering disease associated with autoantibodies to the desmosomal adhesion protein, desmoglein 3. Genetic deficiency of desmoglein 3 in mice mimics autoimmunity to desmoglein 3 in pemphigus vulgaris, with mucosal-dominant blistering in the suprabasal layer of the epidermis. Mice with an epidermal-specific deletion of desmocollin 3, the other major desmosomal cadherin isoform expressed in the basal epidermis, develop suprabasal blisters in skin that are histologically identical to those observed in pemphigus vulgaris, suggesting that desmocollin 3 might be a target of autoantibodies in some pemphigus vulgaris patients. We now demonstrate that desmocollin 3 is an autoantigen in pemphigus vulgaris, illustrated in a patient with mucosaldominant blistering. Six of 38 pemphigus vulgaris and one of 85 normal serum samples immunoprecipitate desmocollin 3 (P ؍ 0.003). Incubation of patient IgG with human keratinocytes causes loss of intercellular adhesion, and adsorption with recombinant desmocollin 3 specifically prevents this pathogenic effect. Additionally, anti-desmocollin 3 sera cause loss of keratinocyte cell surface desmocollin 3, but not desmoglein 3 by immunofluorescence , indicating distinct cellular pathogenic effects in anti-desmocollin and antidesmoglein pemphigus , despite their identical clinical presentations. These data demonstrate that desmocollin 3 is a pathogenic autoantigen in pemphigus vulgaris and suggest that pemphigus vulgaris is a histological reaction pattern that may result from autoimmunity to desmoglein 3, desmocol-
IMPORTANCE Dermatologists, pulmonologists, and rheumatologists study and treat patients with sarcoidosis with cutaneous manifestations. The validity of cutaneous sarcoidosis outcome instruments for use across medical specialties remains unknown.OBJECTIVE To assess the reliability and validity of cutaneous sarcoidosis outcome instruments for use by dermatologists and nondermatologists treating sarcoidosis. DESIGN, SETTING, AND PARTICIPANTSWe performed a cross-sectional study evaluating the use of the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) and Sarcoidosis Activity and Severity Index (SASI) to assess cutaneous sarcoidosis disease severity and the Physician's Global Assessment (PGA) as a reference instrument. Four dermatologists, 3 pulmonologists, and 4 rheumatologists evaluated facial cutaneous sarcoidosis in 13 patients treated at a cutaneous sarcoidosis clinic in a 1-day study on October 24, 2014; data analysis was performed from November through December 2014. MAIN OUTCOMES AND MEASURES Interrater and intrarater reliability and convergent validity, with correlation with quality-of-life measures as the secondary outcome. RESULTS All instruments demonstrated excellent intrarater reliability. Interrater reliability (reported as intraclass correlation coefficient [95% CI]) was good for the CSAMI Activity scale (0.69 [0.51-0.87]) and PGA (0.66 [0.47-0.85]), weak for the CSAMI Damage scale (0.26 [0.11-0.52]), and excellent for the modified Facial SASI (0.78 [0.63-0.91]). The CSAMI Activity scale and modified Facial SASI showed moderate correlations (95% CI) with the PGA (0.67 [0.57-0.75] and 0.57 [0.45-0.66], respectively). The CSAMI Activity scale but not the modified Facial SASI showed significant correlations (95% CI) with quality-of-life instruments, such as the Dermatology Life Quality Index (Spearman rank correlation, 0.70 [0.25-0.90]) and the Skin Stigma raw score of the Sarcoidosis Assessment Tool (Pearson product moment correlation, 0.56 [0.01-0.85]). CONCLUSIONS AND RELEVANCEThe CSAMI and SASI were reliable and valid in assessing cutaneous sarcoidosis among our diverse group of specialists. The CSAMI Activity score also correlated with quality-of-life measures and suggested construct validity. These results lend credibility to expand the use of the CSAMI and SASI by dermatologists and nondermatologists in assessing cutaneous sarcoidosis disease activity.
Cryptococcosis is a fungal infection that typically occurs in severely immunocompromised patients. Here, we report the case of a heart transplant recipient who presented with cutaneous lesions and was diagnosed with disseminated cryptococcosis and then cryptococcal meningitis on the basis of positive Tzanck smear of the lesions, confirmed by culture, highlighting the importance of the skin as a window to systemic disease.
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