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J J Zone

Publications and source records attributed to J J Zone.

At least 37 records · Page 2Linked to original sources
PubMed1999

The immunoglobulin A antibody response in clinical subsets of mucous membrane pemphigoid.

BACKGROUND: Mucous membrane pemphigoid (MMP) is an immunobullous disease. In MMP there is frequently a mixed antibody response with the presence of IgA and/or IgG antibodies directed toward basement membrane zone antigens. The IgG antibody response in MMP has been studied, but the antigens to which the IgA antibodies react have not been studied. OBJECTIVE: To determine the IgA autoantibody reactivity profiles in patients with MMP. METHODS: Patients who had both ocular and oral MMP were compared with patients who had ocular or oral MMP and with patients who had cutaneous linear IgA disease (LABD) by Western immunoblot studies. RESULTS: Five of 15 MMP patients and 1 of 5 LABD patients had IgA antibodies reactive with the 180-kD bullous pemphigoid antigen. Seven of 15 MMP patients had IgA antibodies reactive with the 97-kD LABD antigen. CONCLUSION: Major antigens in IgA MMP are the 180-kD bullous pemphigoid antigen and the 97-kD LABD antigen.

Autoantibodies↗
PubMed1998

Epitope spreading: lessons from autoimmune skin diseases.

Autoimmune diseases are initiated when patients develop aberrant T and/or B cell responses against self proteins. These responses presumably are directed to single immunogenic epitopes on these proteins. Recent data in animal models of autoimmune diseases suggest that the targets of immune responses in autoimmunity do not remain fixed, but can be extended to include other epitopes on the same protein or other proteins in the same tissue, a phenomenon termed "epitope spreading." The "epitope spreading" phenomenon also applies to situations in which tissue damage from a primary inflammatory process causes the release and exposure of a previously "sequestered" antigen, leading to a secondary autoimmune response against the newly released antigen. In experimental autoimmune animal diseases, "epitope spreading" seems to have significant physiologic importance in determining the course and duration of disease. In this paper, we review the current concepts in animal models of autoimmune diseases in order to define the "epitope spreading" phenomenon, and we then propose how this phenomenon might play a significant role in the development and the course of autoimmune skin diseases. Hopefully, an understanding of "epitope spreading" will help the dermatology community to better understand the pathogenesis of autoimmune skin diseases and to rationally fashion disease-specific immune therapy in the future.

Animals↗
PubMed1998

The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2.

IgA autoantibodies from the sera of some patients with linear IgA bullous dermatosis (LABD) recognize a 97 kDa antigen (LABD97) located in the lamina lucida of the basement membrane zone. As LABD autoantibodies do not react with the 180 and 230 kDa proteins recognized by bullous pemphigoid autoantibodies, LABD97 has been thought to represent a separate lamina lucida protein. In this study, we purified LABD97 from the extract of human epidermis using a monoclonal antibody immunoaffinity column and analyzed the amino acid sequence of the N terminus of purified LABD97. This revealed a 16 amino acid sequence that was identical to a previously reported sequence of the 180 kDa antigen in bullous pemphigoid (BPAg2). The N terminus was located 41 amino acids downstream from the carboxyl end of the transmembrane domain of BPAg2 and 11 amino acids downstream from the MCW-1 domain, the predominant bullous pemphigoid epitope. Purified LABD97 was subsequently enzymatically digested with endoproteinase Arg C and separated by chromatography, which resulted in multiple peptide fractions. Fourteen of these fractions were subjected to amino acid sequencing. The amino acid sequence of the peptide fractions, totaling 205 amino acids, were identical to sequences contained within the extracellular domain of BPAg2. Whereas the predominant epitope identified with bullous pemphigoid sera is located in the noncollagenous region of this protein, the epitope recognized by LABD sera is either within or adjacent to the collagenous portion. We conclude that LABD97 represents a portion of the extracellular domain of BPAg2 and that the IgA autoantibodies are directed against an epitope within or adjacent to a collagenous domain.

Amino Acid Sequence↗
PubMed1998

97 kDa linear IgA bullous dermatosis antigen localizes in the lamina lucida between the NC16A and carboxyl terminal domains of the 180 kDa bullous pemphigoid antigen.

Linear IgA bullous dermatosis is an autoimmune blistering disease characterized by circulating IgA anti-basement membrane autoantibodies. A 97 kDa protein (97-LAD), which localizes at the basement membrane zone of normal human skin, is one of the major autoantigens associated with this disease and possesses multiple regions of amino acid identity with the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAG2. To investigate further the relationship between 97-LAD and BPAG2, immunogold electron microscopy was performed on cryo-ultrathin sections of normal human skin using a series of polyclonal and monoclonal antibodies. Gold particles immunolabeling two newly developed monoclonal antibodies against 97-LAD were localized to the lamina lucida. This immunolabeling pattern was associated with hemidesmosomes and localized at a mean distance of 28 nm beneath the plasma membrane of basal keratinocytes. In contrast, polyclonal antibodies against a fusion protein containing the NC16A domain of BPAG2 immunolabeled the plasma membrane of the hemidesmosomal complex, whereas polyclonal antibodies against the carboxyl terminus mainly immunolabeled the lower lamina lucida with a mean distance of 42 nm beneath the plasma membrane. By double immunolabeling, 97-LAD was localized as if being sandwiched between the NC16A and the carboxyl terminal domains of BPAG2. These results clearly demonstrated the co-localization of 97-LAD and the extracellular portion of BPAG2 in the lamina lucida, and suggested that 97-LAD is closely related to, and/or forms a complex with, the extracellular domain of BPAG2.

Autoantibodies↗
PubMed1998

The 97 kDa linear IgA bullous dermatosis antigen is not expressed in a patient with generalized atrophic benign epidermolysis bullosa with a novel homozygous G258X mutation in COL17A1.

The nature and expression pattern of the 97 kDa linear IgA bullous dermatosis antigen (LAD-1) and its role in epidermolysis bullosa have not been fully elucidated. In this study, we examined the expression of LAD-1 in the skin specimens of 70 patients with the various subtypes of epidermolysis bullosa, including simplex (n = 23), junctional (n = 15), and dystrophic variants (n = 32). For immunolabeling, we used two recently developed monoclonal antibodies to LAD-1 whose epitopes were ultrastructurally localized in the lamina lucida between NC16A and carboxyterminal domains of BPAG2, as well as autoantibodies against LAD-1 from the sera of two patients with linear IgA dermatosis. Among the 70 patients, only one patient with generalized atrophic benign epidermolysis bullosa failed to demonstrate LAD-1 expression. Although other major basement membrane components, including laminin 5, BPAG1, plectin, alpha6 and beta4 integrins, as well as type IV and type VII collagens were normally expressed, BPAG2/type XVII collagen was absent from the skin of this patient. Mutation analysis on COL17A1 using polymerase chain reaction amplification, heteroduplex scanning, and direct nucleotide sequencing revealed that this patient was homozygous for a novel nonsense mutation G258X in exon 11, and her parents were heterozygous carriers for this mutation. This is the first mutation located in the intracellular domain of BPAG2, and resides 817 bp upstream from the N-terminal amino acid sequence of LAD-1. These findings indicate that the absent expression of LAD-1 is observed in a BPAG2-deficient generalized atrophic benign epidermolysis bullosa patient with mutations in both alleles of COL17A1, and not in other epidermolysis bullosa subtypes. These findings also support the notion that LAD-1 is a degradation product of BPAG2.

Antigens↗
PubMed1996

Interobserver concordance in discriminating clinical atypia of melanocytic nevi, and correlations with histologic atypia.

BACKGROUND: The clinical features attributed to atypical (formerly ¿dysplastic") nevi and to the atypical multiple mole melanoma syndrome have been used in clinical practice, as well as experimentally, to assign melanoma risk. Little information is available, however, on the interobserver reliability in assessing those features. OBJECTIVE: Our purposes were to quantify interobserver and intraobserver concordances in recognizing certain atypical characteristics of nevi and to correlate the clinical assessments with the histologic characteristics. METHODS: Three observers evaluated clinical photographs of 100 pigmented lesions (predominantly melanocytic nevi, with some lentigines and seborrheic keratoses) from 95 subjects, of whom 85 were family members of four multiple melanoma kindreds and 10 were spouses. Each lesion was rated for border irregularity, color variegation, surface contour irregularity, pigment diffusion, and macularity versus papularity. Predictions were made as to the histologic diagnoses and presence of melanocytic atypia for those lesions judged to be nevi. RESULTS: The pair-wise concordances before agreement on specific criteria were quantified by kappa statistics, which indicated slight to fair agreement in judging the atypical clinical characteristics; concordances increased to moderate levels after consensus development of criteria for color variegation and assessment of macularity, but agreement on the other features remained limited. Whereas macularity and color variegation did correlate somewhat with higher grades of histologic atypia, correlations were generally low between the clinical and histologic diagnoses. CONCLUSION: There is limited interobserver reliability in the clinical assessment of nevus atypia, although correlations do exist between some atypical characteristics and grades of histologic atypia. Because of the low concordances, the clinical discrimination of the melanoma-associated atypical nevus phenotype should rely more on quantitative aspects of the trait, such as total numbers or maximal sizes of nevi, rather than on the subjective determinations of atypia.

Dermatitis, Seborrheic↗
PubMed1996

LAD-1, the linear IgA bullous dermatosis autoantigen, is a novel 120-kDa anchoring filament protein synthesized by epidermal cells.

This study characterizes a novel basement membrane component that is the target of autoantibodies in patients with linear IgA bullous dermatosis. Tissue surveys showed that this protein localized to the epidermal side of 1 M NaCl split skin and to basement membranes in cornea, oral mucosa, esophagus, intestine, kidney collecting ducts, ureter, bladder, urethra, and thymus, but was absent in lung, blood vessels, skeletal muscle, and nerve. Monoclonal antibody 123, which recognizes this protein, induced dermal-epidermal separation of human skin in situ, and this protein was found, by immunoelectron microscopy, to localize exclusively to anchoring filaments. This protein was secreted as as a 120-kDa peptide from primary cultures of keratinocytes as determined by radioimmunoprecipitation. Monoclonal antibody 123 recognized this protein as a 120-kDa band from conditioned cell culture medium and a 97-kDa band from human skin extracts as shown by immunoblot. Serum from five patients with the autoimmune blistering disorder linear IgA bullous dermatosis specifically recognized bands of 120 and 97 kDa from culture medium and skin extracts, respectively, that were of identical electrophoretic migration to the bands recognized by monoclonal antibody 123. In summary, this study characterizes a novel anchoring filament protein that is the target of linear IgA bullous dermatosis autoantibodies. Because monoclonal antibody 123 induces blistering of human skin, we hypothesize that this protein functions to maintain dermal-epidermal cohesion and that autoantibodies in this disease are themselves pathogenic. We propose LAD-1 as the name for this protein.

Animals↗
PubMed1996

IgA antibodies in chronic bullous disease of childhood react with 97 kDa basement membrane zone protein.

Chronic bullous disease of childhood (CBDC) is an autoimmune blistering disease occurring in prepubertal children. Both CBDC and its adult counter-part, linear IgA bullous dermatosis (LABD), are characterized by linear deposition of IgA along the cutaneous basement membrane zone (BMZ). Circulating IgA antibody in LABD has been found to bind to a 97-kDa BMZ antigen, whereas the antigen in CBDC has not been well characterized. The purpose of this study was to evaluate the immunoreactivity of BMZ IgA antibodies in a series of CBDC patients. We evaluated 12 sera from patients with CBDC with circulating IgA anti-BMZ antibodies on indirect immunofluorescence (IIF), which stained the epidermal side of split skin with titers ranging from 1:20 to 1:640. Immunoblotting was performed against two preparations of BMZ proteins: one enriched with the two bullous pemphigoid antigens (BP230, BP180) and one enriched with the LABD antigen (LABD97). Eight of the twelve sera reacted with a 97-kDa protein that co-migrated with the protein detected in many LABD sera. The intensity of the reaction on immunoblot correlated with serum antibody titers. There was no consistent pattern of reactivity of the IgA anti-BMZ antibodies with either the BP230 or BP180 antigens, although two sera reacted with several higher molecular mass proteins (160-200 kDa). The significance of this reactivity was examined with immunoblotting using BMZ-affinity-purified antibodies, and ELF using nitrocellulose-eluted antibodies. One serum also contained anti-BMZ IgA antibodies that reacted with a 180-kDa protein, corresponding to BP180. We conclude that IgA antibodies in CBDC sera recognize a 97-kDa BMZ antigen present on the epidermal side of BMZ split skin that co-migrates with the antigen previously identified in LABD. These findings suggest that CBDC and LABD are the immunologically related disorders occurring in different age groups.

Antibodies↗
PubMed1996

Deposition of granular IgA relative to clinical lesions in dermatitis herpetiformis.

OBJECTIVE: To compare the deposition of IgA and C3 in the skin of patients with active dermatitis herpetiformis relative to the sites of disease. DESIGN: In the phase 1 study, skin biopsy specimens were obtained from erythematous perilesional skin, nonerythematous perilesional skin, and never-involved skin. In the phase 2 study, specimens from the nonerythematous perilesional and uninvolved skin from the same anatomic region were sampled. SETTING: The Dermatology Clinic at the University of Utah Health Sciences Center, Salt Lake City. PATIENTS: Patients with known dermatitis herpetiformis: 19 patients in the phase 1 study and 15 patients in the phase 2 study. Suppressive medications were stopped for 48 to 72 hours after biopsy specimens were obtained. All patients had active disease at the time that biopsy specimens were taken. MAIN OUTCOME MEASURE: The intensity of IgA and C3 immunofluorescent staining in 6 sections from each skin biopsy specimen was graded by using a semiquantitative scale (0 to 3+) in a blinded fashion by a single observer. RESULTS: Deposition of IgA was more intense in noninflamed perilesional skin in 11 of 19 patients compared with that in erythematous skin (P < .05). Erythematous skin was negative for IgA in 16% (3/19) of the specimens. Noninflamed perilesional skin showed more intense IgA deposition in 18 of 19 specimens compared with that in never-involved skin (P < .01); C3 was more intense in erythematous skin (P < .01). In the phase 2 study, skin from the same anatomic region revealed greater deposition of IgA near lesions in 12 of 15 patients (P < .001). CONCLUSIONS: In patients with dermatitis herpetiformis, IgA is not uniformly distributed throughout the skin, and IgA is present in greater amounts near active lesions. The preferred biopsy site for the diagnosis of dermatitis herpetiformis is normal-appearing skin that is adjacent to an active lesion.

Adolescent↗
PubMed1995

Linear IgA bullous dermatosis. Characterization of a subset of patients with concurrent IgA and IgG anti-basement membrane autoantibodies.

BACKGROUND AND DESIGN: The term linear IgA bullous dermatosis defines an immune-mediated blistering skin disease characterized by pruritic blisters, subepidermal separation with neutrophilic infiltration, and linear IgA antibody deposition at the basement membrane zone (BMZ). However, some patients with linear IgA bullous dermatosis demonstrate both IgA and IgG anti-BMZ autoantibodies on immunofluorescence. We describe four such patients and attempt to define this group of patients by studying their clinical, histopathologic, immunopathologic, immunoultrastructural, and immunochemical characteristics. RESULTS: Clinically, all four patients had a generalized pruritic blistering skin disease consistent with linear IgA bullous dermatosis. Histopathologically, all four cases demonstrated subepidermal blister formation with a predominantly neutrophilic dermal infiltrate. Immunopathologically, tissue-bound IgA (in four of four patients) and IgG (in three of four patients) antibodies were detected at the BMZ. Circulating IgA (in four of four patients) and IgG (in four of four patients) labeled the epidermal BMZ of normal human skin fractured at the lamina lucida and did not label the dermal BMZ. By immunoblot analyses, IgA (in three of three patients) and IgG (in one of three patients) circulating antibodies labeled the 97-kd linear IgA bullous dermatosis antigen. By direct immunoelectron microscopy, IgA and IgG antibodies were localized (in two of two patients) exclusively within the upper lamina lucida of the BMZ. CONCLUSIONS: Four cases of an immune-mediated blistering skin disease typical for linear IgA bullous dermatosis demonstrated both IgA and IgG anti-BMZ autoantibodies against the linear IgA bullous dermatosis antigen within the upper lamina lucida. We conclude that linear IgA bullous dermatosis should include a subgroup of patients with both IgA and IgG anti-BMZ autoantibodies.

Adult↗
PubMed1995

A Japanese case of the fibrillar type of dermatitis herpetiformis.

BACKGROUND: Although dermatitis herpetiformis (DH) is a relatively common disease in Caucasian populations, this disease is very rare in Asian populations including the Japanese. METHODS AND RESULTS: We present a Japanese DH patient, who showed a fibrillar pattern of deposition of IgA, IgG, IgM and C3. The HLA typing revealed no B8/DR3. The survey of the Japanese literature and the comparison to studies on American or European DH revealed several interesting differences: high frequency of the fibrillar pattern, relatively high incidence of deposits of immunoglobulins other than IgA, rarity of gluten-sensitive enteropathy and HLA-B8/DR3 in Japanese DH. CONCLUSION: The present study suggests that there may be a significant difference in pathophysiology between Caucasian and Japanese DH patients.

Complement C3↗
PubMed1995

A child with antibodies targeting both linear IgA bullous dermatosis and bullous pemphigoid antigens.

BACKGROUND: Some patients with subepidermal blistering diseases show clinical, histologic, and immunopathologic features of both linear IgA bullous dermatosis and bullous pemphigoid. Such patients can be further characterized by defining the target of their circulating autoantibodies. We present the first case report of a child with linear deposits of IgA and IgG with circulating autoantibodies characteristic of both linear IgA bullous dermatosis and bullous pemphigoid. OBSERVATIONS: Widely distributed subepidermal vesicles showing neutrophils in the dermal papillae developed in a 3-year-old boy. Direct immunofluorescence microscopy of perilesional skin revealed linear deposits of IgA, IgG, and C3 in the epidermal basement membrane. The patient responded to therapy with dapsone, and after 6 months, it was possible to discontinue treatment. Circulating IgA antibodies from this child bound the epidermal side of 1-mol/L saline-split skin and immunoblotted the 97-kd linear IgA bullous dermatosis antigen. Circulating IgG antibodies bound the epidermal and, at low titer, dermal sides of split skin. These IgG antibodies immunoblotted and immunoprecipitated bullous pemphigoid antigens 1 and 2. CONCLUSIONS: Linear deposits of IgA and IgG in the epidermal basement membrane of patients with subepidermal bullous lesions may signify the coexistence of circulating autoantibodies directed against linear IgA bullous dermatosis and bullous pemphigoid antigens.

Autoantibodies↗
PubMed1994

Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM).

A susceptibility locus for familial melanoma has been localized to the short arm of chromosome 9. Penetrance of melanoma was estimated by calculating the Kaplan-Meier function and fitting a log normal hazard function in 124 gene carriers in three 9p-linked kindreds. The penetrance of the gene for melanoma was estimated to be 53% by age 80. Additionally, nevus counts, skin type, and sun exposure histories were gathered for 119 individuals in two kindreds. Gene carriers were found to have higher nevus counts and nevus densities than non-gene carriers. Among gene carriers, individuals with melanoma were found to have more sun exposure within each skin type than gene carriers without melanoma. These analyses suggest that the 9p melanoma susceptibility is related to total number of nevi and that it interacts with other genetic and environmental factors to produce melanoma.

Adult↗