Biomedical subjects
Publications and source records attributed to J J Zone.
A patient with persistent melanocytic lesions after tanning bed use is described. A review of the literature provides two additional examples of similar clinical and histologic presentations after UVA exposure without psoralen. To our knowledge, this is the first reported case of "sunbed lentigines" in the United States.
The bullous pemphigoid antigen was originally described as a 240-kD protein extracted from human epidermis, but a subsequent report has described patients' sera which react with epidermal proteins of molecular masses 240, 200, 180, 97, and 77 kD. We have evaluated the heterogeneity of the pemphigoid antigens identified by the sera of 10 patients with clinically typical bullous pemphigoid. We used indirect immunofluorescence and Western immunoblots of epidermal extracts prepared from epidermis separated by either 1 M salt or 20 mM EDTA to characterize the reactivity of both crude sera and affinity-purified antibodies. Affinity purification of antibodies was performed with either normal human epidermis or protein bands blotted onto nitrocellulose as immunoabsorbents. The anti-basement membrane antibody titers determined by indirect immunofluorescence on the saline- and EDTA-separated epidermis were identical. Despite this, Western blots of extracts prepared from EDTA-separated epidermis demonstrated greater amounts of the 240-kD antigen than saline split skin. Multiple antigens were recognized in epidermal extracts on Western blots by most crude BP sera, including bands at 240, 200, 160, and 100 kD. Different sera reacted with these antigens with a markedly different intensity, falling into two major groups, those bearing antibodies to the 240-200-kD antigens and those with antibodies to the 160-100-kD components. When epidermis was used as a substrate for affinity purification of bullous pemphigoid antibodies, the eluted antibodies reacted with multiple bands on Western blots, demonstrating the reactivity of anti-basement membrane zone antibodies with multiple proteins. Antibodies eluted from several individual bands of immunoblots were found to react with the basement membrane on indirect immunofluorescence. When these nitrocellulose-purified antibodies were reapplied to Western blots, they cross-reacted within two groups, the 240-200 kD antigens and the 160-100 kD antigens. We conclude that pemphigoid antigens are best demonstrated when EDTA-split skin is used for extraction and that different pemphigoid sera may contain antibodies to two separate groups of basement membrane zone antigens.
Linear IgA bullous dermatosis and dermatitis herpetiformis are inflammatory subepidermal blistering diseases characterized by IgA deposits at the cutaneous epithelial basement membrane and in dermal papillae, respectively. Inflammation in both disorders localizes to sites of IgA deposition and is characterized by a predominance of neutrophils. From these observations we postulate that IgA deposits in both diseases may contribute to the recruitment and/or localization of neutrophils. In this study we examined the ability of in vitro and in vivo bound IgA anti-basement membrane autoantibodies from patients with linear IgA bullous dermatosis and in vivo bound IgA deposits in dermal papillae from patients with dermatitis herpetiformis to mediate adherence of neutrophils stimulated by granulocyte macrophage colony-stimulating factor. The study showed that stimulated neutrophils adhered to basement membranes and dermal papillae containing IgA deposits. Adherence was IgA anti-basement membrane antibody concentration dependent and correlated with the immunofluorescence staining intensity of IgA deposits in dermal papillae. Adherence to IgA deposits but not IgG deposits could be inhibited by purified exogenous secretory IgA but not IgG and adherence to IgG deposits could be inhibited by purified exogenous IgG but not secretory IgA. These results provide direct experimental evidence that cutaneous IgA deposits in linear IgA bullous dermatosis and dermatitis herpetiformis can function as ligands for neutrophil adherence and have a role in the localization of inflammation in these disorders.
Linear IgA bullous dermatosis (LABD) is a rare blistering skin disease characterized by basement membrane zone deposition of IgA. This study identifies a tissue antigen detected by patient serum and then isolates the autoantibody using epidermis and protein bands blotted on nitrocellulose as immunoabsorbents. Sera from 10 patients (9 with cutaneous disease and 1 with cicatrizing conjunctivitis) were evaluated. Indirect immunofluorescence revealed an IgA anti-basement membrane antibody in 6 of 10 sera with monkey esophagus substrate and 9 of 10 sera with human epidermal substrate. Immunoblotting was performed on epidermal and dermal extracts prepared from skin separated at the basement membrane zone with either sodium chloride or EDTA. Saline-separated skin expressed a 97-kD band in dermal extract alone that was recognized by 4 of 10 sera. EDTA-separated skin expressed the 97-kD band in both epidermal (4 of 10 sera) and dermal (6 of 10 sera) extract. Immunoabsorption of positive sera with epidermis purified an IgA antibody that reacted uniquely with the 97-kD band. In addition, IgA antibody bound to nitrocellulose was eluted from the 97-kD band and found to uniquely bind basement membrane zone. It is likely that the 97-kD protein identified by these techniques is responsible for basement membrane binding of IgA in LABD.
The reported linkage between cutaneous melanoma and the dysplastic nevus syndrome (CM/DNS) to markers located on the distal portion of the short arm of chromosome 1 was examined in three Utah kindreds ascertained for multiple cases of melanoma. Family members in these kindreds were genotyped for the two markers reported to be most closely linked in the Bale study, PND and D1S47. Both melanoma alone and a combined melanoma/DNS phenotype were analyzed; no evidence for linkage was found. By multipoint linkage analysis the CM/DNS locus was excluded from an area of 55 cM containing the PND-D1S47 region. Diagnostic or genetic heterogeneity are alternate explanations for the discrepancy between our observations and those of Bale et al.
Studies of dysplastic melanocytic nevi (DMN) have suggested that lesions from patients with a personal or family history of malignant melanoma are histologically more atypical than are those from control populations without such histories. To evaluate this possibility, we examined histologic sections of DMN that had been removed from patients in three groups. Group A consisted of 17 subjects with a past history of melanoma; group B comprised 79 subjects with DMN and a family history of melanoma in first-degree relatives; group C consisted of 64 subjects who were unrelated spouses of members of groups A and B. For each group, sections of DMN were initially selected on the basis of architectural atypia as defined by the National Institutes of Health Consensus Conference. All biopsy material was then further evaluated for four histologic features suggested to be discriminatory for DMN associated with increased melanoma risk; the features are degree of junctional activity, irregularity of melanocytic nests, presence of dusty melanin, and size of melanocytic nuclei. A subjective rating was given for each on a 0 to 3 scale of increasing severity. Three pathologists individually rated the specimens without knowledge of the patient group. The means of the individual observer cumulative scores of the four histologic criteria for each biopsy specimen and the average of these means from the three observers exhibited a trend to increasing values from groups C to A, but none of the differences reached statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
We estimated the prevalence of persons with histologic dysplasia in at least one of two nevi examined by biopsy to be 53% in Utah's caucasians. This apparently high prevalence indicates that such lesions may represent a normal variant of a melanocytic nevus, perhaps those in the process of active proliferation. Regardless of the apparent ubiquity of these lesions, examination of biopsy specimens led to a grading scheme of histologic dysplasia that may reflect chronologic stages in the neoplastic development of melanocytic nevi. Comparison of these histologic findings with the clinical examination yielded the unexpected result that dysplasia and lesion size are independent of each other. Lesions 3 mm in diameter or smaller were as likely to be dysplastic as those much larger. There was, however, a statistically significant relationship between histologic dysplasia of a nevus examined by biopsy and the person's total number of melanocytic lesions. This finding indicates that the pathology grading scheme may be useful. The high prevalence of dysplastic nevi dilutes the clinical significance of a dysplastic nevus as an isolated finding and thereby lessens the importance of pathologic findings in the diagnosis of dysplastic nervus syndrome.
The mechanism for deposition of IgA in dermatitis herpetiformis (DH) remains unclear. To test the hypothesis that a circulating IgA class antibody in DH patients binds to constituents of normal human skin, we employed the highly sensitive methods of immunoblotting and indirect immunofluorescence. Sera from 64 DH patients, 67 randomly selected normal control subjects, 29 histocompatibility locus antigen (HLA) B8/DR3/DQw2 controls, and 12 psoriatic patients were tested for IgA binding to various substrates, including dermal and epidermal extracts, fibroblast and keratinocyte supernatants, monkey esophagus sections, and whole and saline-split normal human skin sections. Significant differences observed among the groups in the frequency of detectable IgA antibodies reacting with various substrates were as follows: 1) IgA antibodies in 30% of both DH and HLA B8/DR3/DQw2 sera bound to a 60-Kd protein in dermal extracts (p less than 0.25 versus non-HLA matched controls); 2) IgA antiendomysial antibodies were present in 38% of DH patients (predominantly those not on gluten-free diets), whereas both normal control groups had frequencies of 5-10% (p less than 0.025); 3) there was more nonspecific IgA antibody-binding to dermal, epidermal, and bovine proteins in DH and HLA control sera than in normal sera; and 4) IgA antibodies directed against the basement membrane were present with an increased frequency of 25% in both DH and HLA B8/DR3/DQw2 sera (p less than 0.1 versus non-HLA matched controls). Therefore, these results do not support the hypothesis that there is an unique antigen within normal human skin to which IgA antibodies from DH sera bind.
Explore the source record for details and available documents.
Herpes gestationis (HG) is a putative autoimmune bullous dermatosis of pregnancy which shares many findings with bullous pemphigoid (BP), a disease of the elderly. This study identifies for the first time the antigen detected by HG autoantibodies and compares it with that recognized by BP autoantibodies. Sera from 16 HG and 17 BP patients, and from normal pregnant women were evaluated by immunofluorescent (IF) studies and immunoblotted against human epidermal extracts. 89% of HG sera with circulating antibodies by IF recognized a 180-kD protein by immunoblotting. 71% of BP sera recognized a 240-kD band, but 47% detected a 180-kD protein that comigrated with the antigen detected by HG sera. None of the control sera recognized any specific bands. These findings suggest that the 180-kD epidermal protein may be the antigen detected by the HG factor and they also define immunologic similarities between HG and BP.
Dermatitis herpetiformis and gluten-sensitive enteropathy are diseases in which exposure to gluten results in an inflammatory response. Both diseases are associated with certain human lymphocyte antigen alleles, and gluten-sensitive enteropathy is well known to cluster in families. Gluten-sensitive enteropathy has also been reported in families of patients with dermatitis herpetiformis. Despite this evidence that dermatitis herpetiformis is a genetic disease, reports of the familial occurrence of dermatitis herpetiformis are rare. We have obtained family histories from 92 patients with dermatitis herpetiformis with 740 first-degree relatives. Six of these relatives have dermatitis herpetiformis. Comparison of these data with the expected prevalence of dermatitis herpetiformis shows this incidence to be highly significant (p less than 0.0001), strongly suggesting that dermatitis herpetiformis is a familial disease, presumably because of shared genetic factors but possibly because of a shared environment.
Dermatitis herpetiformis (DH) is characterized by the granular deposition of IgA in the dermal papillary tips. The source and antigenic specificity of this IgA are unknown, largely because of the previous inability to isolate it for study. These granular IgA deposits, pathognomonic of DH, have been specifically isolated from 4-mm punch biopsies. Specific isolation was achieved by removing contaminating serum IgA by a combination of washes in saline and sodium dodecyl sulfate without a reducing agent present and mechanical isolation of papillary dermis. The tissue IgA was then solubilized by a buffer containing 1% sodium dodecyl sulfate and 0.2 mM dithiothreitol, a reducing agent. Immunoreactive alpha chains were recovered in eluates of DH skin in 6-fold greater amounts than in eluates of normal skin, coincident with disappearance of immunofluorescent-staining granular deposits of IgA. Extracted specific IgA was recovered in sufficient quantity for detection by immunoenzymatic stain, was partially composed of a native (165 Kd) molecular mass, and had alpha and kappa staining material, all indicating that the extracted immunoglobulin was in part intact.
A patient with classical hypostatic dermatitis-related autoeczematization was found to have an elevated ratio of helper to suppressor T lymphocytes and increased circulating activated T cells in the absence of detectable levels of circulating interferon. Despite the high levels of activated T cells, peripheral blood mononuclear leukocytes did not produce interferon spontaneously in culture. These findings suggest that autoeczematization is a form of cell-mediated autoimmunity and that activated T cells and interferon production may be unrelated in vivo.
A 45-year-old woman with cutaneous urticaria-like lesions subsequently developed polyarthritis, glomerulonephritis, and chronic obstructive pulmonary disease. Biopsy of skin showed leukocytoclastic vasculitis of superficial capillaries. Biopsy of the kidney revealed mesangioproliferative glomerulonephritis, and lung biopsy revealed severe emphysema and thick-walled blood vessels with immunoglobulin deposition. Therapy with dapsone produced dramatic improvement of the patient's cutaneous vasculitis and arthritis. This case uniquely demonstrates the efficacy of dapsone for both the urticarial vasculitic and the arthritic components of this syndrome and reemphasizes the potentially severe pulmonary and renal complications.
Proteolytic enzymes may be involved in blister formation in dermatitis herpetiformis (DH). We have examined collagenase, gelatinase and elastase-like enzyme activities in fluids collected from spontaneous blisters and from suction blisters raised on developing DH-lesions induced by application of potassium iodide. Control suction blisters were raised on unaffected DH-skin and on healthy volunteers. High enzyme activities were found in spontaneous blisters, and suction blister fluids obtained from developing lesions showed increased levels of gelatinase and elastase-like enzymes. Inhibitor studies revealed that a part of the elastase-like enzyme activity might be derived from inflammatory cells. Gel filtration chromatography disclosed two separate elastase-like enzymes which, as they had high molecular weights, could be either enzyme-inhibitor complexes or aggregates.
Elevated levels of circulating HLA-DR bearing (activated) T cells have been reported in a variety of conditions. The role played by these cells in the pathogenesis of disease is not established. We found elevated levels of activated T lymphocytes in patients with rheumatoid arthritis (RA), dermatitis herpetiformis, gluten sensitive enteropathy, as well as presumed healthy persons with HLA-B8 antigen. We could not show any change in the concentration of these cells with disease activity, therapy, or in a case of dermatitis herpetiformis, challenge with the presumed antigen, gluten. Our studies do not suggest an apparent causal relationship between activated T lymphocytes and the above disorders.
20 patients with dermatitis herpetiformis maintained on once daily dosing of dapsone were studied to investigate the pharmacodynamics of dapsone in suppressing clinical disease. Multiple correlation analysis was performed on variables including dosage requirements, serum concentration of dapsone and monoacetyl dapsone, acetylation ratio, IgA-containing circulating immune complexes, adherence to a gluten-free diet, and clinical disease severity. It was found that: 1. dapsone exhibits good bioavailability in dermatitis herpetiformis with absorption being unaffected by presumed gluten-sensitive enteropathy; 2. there is wide variation in serum concentrations of dapsone and monoacetyl dapsone with no specific "therapeutic level"; 3. acetylator phenotype was unrelated to dapsone dose requirement; 4. serum dapsone concentration had only a weak correlation with disease severity; and 5. there was poor correlation between IgA circulating immune complexes and dapsone serum concentration. The use of daily dapsone dose requirements or dapsone serum concentration necessary for disease suppression as an indicator of disease severity in the research setting is inappropriate. Measurements of serum concentration of the parent drug (dapsone) or principal metabolite (monoacetyl dapsone) do not serve as a useful guide to therapeutic management.
Pyostomatitis vegetans is a rarely occurring disorder of the oral mucosa, which has a dramatic clinical picture and a striking histopathologic pattern. Moreover, the condition is a highly specific oral mucosal marker for inflammatory bowel disease, particularly ulcerative colitis. Our findings in two cases and a review of the literature emphasize the relationship of pyostomatitis vegetans to inflammatory bowel disease and the vegetating dermatoses.