Identification of a Novel Non-desmoglein Autoantigen in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is an autoimmune bullous disease of the skin and mucous membranes characterized by the presence of circulating and tissue-bound autoantibodies against keratinocyte cell surface antigens, specifically desmoglein (Dsg) 1 and 3. The pathogenic role of anti-Dsg antibodies is well-established, while the mechanism of blister formation is only partly defined. We have applied a previously developed method for the efficient immortalization of IgG+ memory B cells to identify novel target antigens in PV.

Epidermolysis Bullosa (EB) Acquisita in an Adult Patient with Previously Unrecognized Mild Dystrophic EB and Biallelic COL7A1 Mutations.

Circulating anti-type VII collagen autoantibodies are frequently detected in patients with recessive dystrophic epidermolysis bullosa (RDEB). However, evidence supporting their pathogenic role in inducing epidermolysis bullosa acquisita (EBA) has been provided for only one individual with dominant dystrophic epidermolysis bullosa (DDEB). We describe here a patient who presented with dystrophic toenails since early childhood and developed trauma-induced skin blisters and oral erosions at age 26 years.

Childhood epidermolysis bullosa acquisita during squaric acid dibutyl ester immunotherapy for alopecia areata.

Epidermolysis bullosa acquisita (EBA) is a rare acquired subepidermal blistering disease associated with autoantibodies against type VII collagen. Although EBA manifests more frequently in adults, it can occur in childhood. We describe a 6-year-old boy who developed the inflammatory variant of EBA shortly after initiation of immunotherapy with squaric acid dibutyl ester (SADBE) for scalp alopecia areata.

Autoantibody Profile of a Cohort of 78 Italian Patients with Mucous Membrane Pemphigoid: Correlation Between Reactivity Profile and Clinical Involvement.

Direct diagnosis of mucous membrane pemphigoid (MMP) is not easy. Circulating autoantibodies targeting bullous pemphigoid antigens of 180 kDa and 230 kDa (BP180 and BP230), α6β4 integrin, laminin 332 and type VII collagen (Col VII) are not always present. The aims of this study were to characterize the humoral immune response of a cohort of Italian patients with MMP, its association with clinical involvement and severity, and to design an algorithm for efficient serological diagnosis.

The pathogenic activity of anti-desmoglein autoantibodies parallels disease severity in rituximab-treated patients with pemphigus vulgaris.

Background: Pemphigus vulgaris (PV) is an autoimmune blistering disease mediated by IgG autoantibodies targeting desmogleins (Dsgs). The anti-CD20 monoclonal antibody rituximab is increasingly used in corticosteroid-resistant PV patients. In a subset of rituximab-treated patients in remission, high ELISA index values have been reported; however, their significance remains so far unclear.

A truncating mutation in the laminin-332α chain highlights the role of the LG45 proteolytic domain in regulating keratinocyte adhesion and migration.

Background: Altered function of laminin-332 (α3β3γ2) consequent to mutations in the LAMA3, LAMB3 and LAMC2 genes causes junctional epidermolysis bullosa non-Herlitz (JEB-nH). JEB-nH patients suffer from skin blistering and have an increased risk of developing aggressive skin carcinomas in adulthood. Laminin-332 is proteolytically processed and its extracellular mature form lacks the α3 chain C-terminal globules 4 and 5 (LG45).

Sensitivity of different assays for the serological diagnosis of epidermolysis bullosa acquisita: analysis of a cohort of 24 Italian patients.

Background: Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease characterized by tissue-bound and circulating autoantibodies to the dermal-epidermal junction. The autoantibody target is type VII collagen (Col VII) which is involved in dermal-epidermal adhesion. Diagnosis is made by clinical and histopathological findings, linear deposition of autoantibodies at the dermal-epidermal junction detected by direct immunofluorescence, and binding to the dermal side of salt-split skin by indirect immunofluorescence (IIF).

Are clinical phenotype and autoantibody profile always concordant in pemphigus? A study in a cohort of pemphigus patients.

Background: The clinical phenotype of different forms of pemphigus is reportedly defined by the anti-desmoglein (Dsg) autoantibody profile. In routine practice, however, this is not always the case.

Objectives: To verify the relationship between the anti-Dsg1 and -3 autoantibody profiles and titers on the one hand and the clinical phenotype and disease activity on the other.

Detection of IgG and IgE reactivity to BP180 using the ISAC® microarray system.

Background: Bullous pemphigoid (BP) is an autoimmune skin disease in which patient autoantibodies react with BP180 and BP230 proteins. In addition to IgG, IgE has been shown to play a role in the disease.

Objectives: To evaluate the feasibility of detecting IgE and IgG against the immunodominant BP180 NC16A domain (BP180) using a microarray system.

Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface.

Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice.

Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study.

Bullous pemphigoid (BP), the most common autoimmune subepidermal bullous disease, is associated with an autoantibody response to BP180 and BP230, two components of junctional adhesion complexes in human skin promoting dermo-epidermal cohesion. Retrospective analyses demonstrated that these autoantigens harbor several epitopes targeted by autoaggressive B and T cells. The aim of this prospective multicenter study was to assess the evolution of IgG autoantibodies in 35 BP patients over a 12-month observation period.

Efficiency of translation termination in humans is highly dependent upon nucleotides in the neighbourhood of a (premature) termination codon.

Background: Spontaneous read-through of a premature termination codon (PTC) has so far not been observed in patients carrying nonsense mutations. This report describes a patient with junctional epidermolysis bullosa who was expected to die because of compound heterozygous nonsense mutations in the gene LAMA3 (R943X/R1159X), but was rescued by spontaneous read-through of the R943X allele.

Results And Conclusion: FACS analysis of cells carrying various PTCs surrounded by their natural neighbouring codons revealed significant reporter gene expression despite the PTC only for this patient's genetic context.

Anti-desmoplakin antibodies in erythema multiforme and Stevens-Johnson syndrome sera: pathogenic or epiphenomenon?

The pathophysiology of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) is unclear. Whether autoantibodies against desmoplakin (Dp) I and II play a pathogenic role or result from an epitope spreading phenomenon is uncertain. Our aim was to characterize the keratinocyte antigens recognized in EM, TEN and SJS.

Paraneoplastic pemphigus presenting as mild cutaneous features of pemphigus foliaceus and lichenoid stomatitis with antidesmoglein 1 antibodies.

Herein, we report a case of paraneoplastic pemphigus with mild skin features of pemphigus foliaceus and lichenoid stomatitis associated with B-cell lymphoma. A 49-year-old man presented with scattered blisters and erosions on the trunk along with mucosal blisters and erosions. Skin biopsy showed subcorneal acantholytic bulla and oral mucosal biopsy demonstrated lichenoid dermatitis.

Sequential intramolecular epitope spreading of humoral responses to human BPAG2 in a transgenic model.

Bullous pemphigoid (BP) is a subepidermal autoimmune disease characterized by a humoral response to an epidermal basement membrane (BM) component, BP antigen 2 (BPAG2). BP patients have IgG autoantibodies against an immunodominant BPAG2 extracellular domain termed NC16A as well as additional epitopes located both in the intracellular and extracellular domains (ICD and ECD, respectively) of this autoantigen. To study the evolution of humoral responses to BPAG2, sequential serum samples obtained from C57BL/6Ncr mice grafted with otherwise syngeneic skin from transgenic mice expressing human BPAG2 (hBPAG2) in epidermal BM were studied for IgG reactivity to seven ECD and ICD hBPAG2 epitopes.

Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune bullous disease, associated with autoantibodies directed against the hemidesmosomal components BP180 and BP230. In this study for the first time different laboratories have analyzed the autoantibody profile in the same group of 49 prospectively recruited BP patients. The results show that: 1) disease severity and activity correlated with levels of IgG against the BP180-NC16A domain, but also against a COOH-terminal epitope of BP180, 2) distinct epitopes of the BP180 ectodomain other than BP180-NC16A were recognized by 96% of the BP sera; and 3) the combined use of BP180 and BP230 ELISA led to the detection of IgG autoantibodies in all the BP sera.

Oral pemphigoid autoantibodies preferentially target BP180 ectodomain.

Mucous membrane pemphigoid (MMP) comprises a heterogenous group of autoimmune subepithelial bullous diseases very frequently having oral involvement. Very few studies have investigated the immunological status of a subset of MMP, termed oral pemphigoid (OP), presenting with exclusive oral lesions. In this study we show that 75% of 20 OP patients without scarring phenotype possessed circulating autoantibodies against the BP180 molecule, indicating a prominent role of this protein as a target antigen in OP.

The intracellular and extracellular domains of BP180 antigen comprise novel epitopes targeted by pemphigoid gestationis autoantibodies.

Pemphigoid gestationis (PG) is an autoimmune sub-epidermal bullous dermatosis of pregnancy associated with circulating autoantibodies targeting the extracellular non-collagenous (NC) 16A domain of bullous pemphigoid (BP) 180 antigen. In order to determine whether BP180 regions other than NC16A are recognized by PG autoantibodies, we have analyzed the reactivity of 15 PG patient sera against several BP180 antigenic sites by sensitive methods such as immunological screening and ELISA. Most PG sera tested (13 of 15) reacted with an epitope (amino acid 508-541) mapped in the NC16A domain.

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro.

Spinocerebellar ataxia type 1 is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population.

A fine physical map of the CACNA1A gene region on 19p13.1-p13.2 chromosome.

The P/Q-type Ca(2+) channel alpha(1A) subunit gene (CACNA1A) was cloned on the short arm of chromosome 19 between the markers D19S221 and D19S179 and found to be responsible for Episodic Ataxia type 2, Familial Hemiplegic Migraine and Spinocerebellar Ataxia type 6. This region was physically mapped by 11 cosmid contigs spanning about 1. 4Mb, corresponding to less than 70% of the whole region.

Population variation analysis at nine loci containing expressed trinucleotide repeats.

The polymorphisms of nine loci containing reiterated CAG repeats were examined in four populations from three continents. Their normal variation was analysed across populations or in subsets of loci grouped according to either the presence/absence of disease-associated expansions or CAG interruptions. A unifying feature of the allele distributions of all loci in all populations was the marked non-normality.