Generalized essential telangiectasia in the presence of gastrointestinal bleeding.

Generalized essential telangiectasia was well defined more than 30 years ago. There have been no reported cases of associated gastrointestinal (GI) bleeding. Recurrent hemorrhage in the setting of telangiectases, including GI bleeding, is more typically associated with hereditary hemorrhagic telangiectasia. We report a unique case of a woman with generalized essential telangiectasia and GI bleeding from a watermelon stomach. We include a brief review of the literature of watermelon stomach, generalized essential telangiectasia, and hereditary hemorrhagic telangiectasia.

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.

Pathogenesis of psoriasis.

The information summarized in this article supports the "framework hypothesis." The details of cells of the immune system in the pathogenesis are covered elsewhere in this issue. We believe the observations reported herein allow the following conclusions. The entire epidermis of any individual with the psoriatic phenotype has the capacity to express overt clinical disease. Control of expression is linked to a complex interaction of cells of the epidermis, cells of the dermis, cells of the immune system, and possibly other noncellular humoral elements. The keratinocytes of psoriatic patients are unique in that the inherent phenotype has a capacity for hyperproliferation and altered differentiation. Proliferation and differentiation are controlled at the level of the gene. Thus, it is important to consider not only cytokines and growth factors released by the various cell types, but also the role of regulators of transcription, translation, and the modification of the cytokines and growth factors. The large number of alterations of cytokine and growth factor profiles within psoriasis cause us to postulate that the genetic aberration in psoriasis is quite basic, that is, it is proximal to the common element in the cascade of inflammatory events that lead to a lesion of psoriasis. We speculate that such a defect may be in transcription regulatory elements associated with one or more cytokines (or growth factors). This mutation could occur (1) in the regulatory element itself; (2) in the receptor, which binds both ligand and regulatory element; (3) in the ligand (cytokine or growth factor); or (4) in a gene responsible for the control of proliferation that is under the influence of the sites mentioned in 1, 2, and 3. A mutation within a key regulatory element for a gene controlling proliferation could produce the following scenario of lesional expression. Such a mutation will probably result in less affinity for a receptor/ligand complex. Because this regulatory element in interaction with the receptor/ligand complex normally suppresses gene expression of a promoter of proliferation, the result is a phenotype that tends to be more proliferative and less differentiative. Conversely, if such a mutation produced a regulatory element that has increased affinity for a promoter receptor/ligand complex, then the same phenotype can evolve. Because a wide variety of receptor/ligand complexes can modulate each regulatory element, such a genetic defect could have wide-ranging effects on phenotypic expression. Moreover, as this change in affinity for binding the receptor/ligand complexes only represents a change in sensitivity, not total unresponsiveness, one can expand on the scenario to conclude that the clinical phenotype is only expressed once the system is overwhelmed. This scenario fits the information presented. Both keratinocytes and fibroblasts from psoriatic subjects are hyperproliferative, but only under specific culture conditions. Furthermore, psoriatic keratinocytes appear to be relatively resistant to the antiproliferative and prodifferentiative effects of retinoids or the vitamin D analogues that have antipsoriatic activity. If a genetic defect decreases the affinity of a suppressive receptor/ligand complex for the regulatory element of IL-6 or TGF-alpha, for example, then these cells could be relatively resistant to homeostatic regulation by indigenous corticosteroids, vitamin D, and retinoids. This would result in a situation in which any trigger phenomenon that releases a cytokine, whose receptor/ligand complex upregulates this regulatory element, would overwhelm the defective counterregulatory signal. Subsequently, cells in the skin generate additional cytokines that invoke an inflammatory cascade that eventuates in the egress of immune cells into the skin and the evolution of a lesion of psoriasis. Similar scenarios could be derived from mutations in the other pathways described in this article.

Inhibition of neutrophil adherence to antibody by dapsone: a possible therapeutic mechanism of dapsone in the treatment of IgA dermatoses.

Dapsone is frequently effective in cutaneous diseases characterized by antibody deposition and accumulation of neutrophils. We hypothesized that this mechanism of action of dapsone may involve the inhibition of neutrophil adherence to antibody. The neutrophil adherence assay, which measures the binding of neutrophils to basement membrane zone-bound antibody on skin sections, was used to evaluate the effect of dapsone on neutrophil adherence to immunoglobulin A and immunoglobulin G. We evaluated the effect of dapsone on adherence of normal neutrophils to immunoglobulin A and immunoglobulin G from sera of linear immunoglobulin A bullous dermatosis and bullous pemphigoid patients, respectively. Linear immunoglobulin A bullous dermatosis or bullous pemphigoid antibody were bound to the basement membrane zone of normal skin sections as a substrate for the neutrophil adherence assay. Dapsone was added directly to the neutrophils or to the antibody source in concentrations of 0-50 micrograms/ml (pharmacologic range). Addition of dapsone to neutrophils produced an incremental inhibition of neutrophil adherence up to 75% at 50 micrograms/ml. Dapsone produced similar inhibition when added directly to the antibody itself, despite washing prior to usage in the neutrophil-adherence assay. Control specimens including irrelevant fractions of patient sera failed to demonstrate binding. Serum from a patient on dapsone therapy also showed inhibition of neutrophil adherence compared to the same patient on no therapy. We conclude that dapsone inhibits the adherence of neutrophils to basement membrane zone antibody in a dose-dependent manner. This may be related to an effect directly on antibody. This inhibition may contribute to the clinical efficacy of dapsone in antibody-mediated diseases.

The effect of an elemental diet with and without gluten on disease activity in dermatitis herpetiformis.

Elemental diets are reported to decrease activity of patients with dermatitis herpetiformis. We tested the hypothesis that gluten, given in addition to an elemental diet, is responsible for the intestinal abnormalities, cutaneous immunoreactant deposition, and skin disease activity in dermatitis herpetiformis. At entry eight patients with dermatitis herpetiformis, who were consuming unrestricted diets, were stabilized on their suppressive medications at dosage levels that allowed individual lesions to erupt. Six patients were then given an elemental diet plus 30 of gluten for 2 weeks, followed by the elemental diet alone for 2 weeks. Conversely, two patients received an elemental diet alone for 2 weeks followed by an elemental diet plus gluten during the final 2 weeks. Small bowel biopsies, skin biopsies, and clinical assessments were done at 0, 2, and 4 weeks. Suppressive medication dose requirement decreased over the 4 weeks by a mean of 66%. Six of eight subjects significantly improved clinically during the gluten-challenge phase of the elemental diet and all were improved at the end of the study. The amount of IgA in perilesional skin did not change significantly, but the amount of C3 increased in five of seven evaluable subjects after gluten challenge. Circulating anti-gluten and anti-endomysial antibodies were not significantly affected by the diets. All subjects completing evaluable small bowel biopsies (seven of seven) demonstrated worsening of their villus architecture (by scanning electron microscopy and intraepithelial lymphocyte counts) during gluten challenge and improvement (six of six subjects) after 2 weeks of elemental dietary intake. We conclude that 1) there is a significant improvement in clinical disease activity on an elemental diet, independent of gluten administration, 2) small bowel morphology improves rapidly on an elemental diet, and 3) complement deposition but neither IgA deposition nor circulating antibody levels correlate with gluten intake. It seems likely that dietary factors other than gluten are important in the pathogenesis of the skin lesions in dermatitis herpetiformis.

Bullous pemphigoid antigens: extraction and degradation of antigens during epidermal preparation.

Although two groups of bullous pemphigoid antigens have been well characterized, different research groups have shown strikingly different prevalence rates of antibodies to these antigens in their patients. Potential explanations for this phenomena include a patient population that has different prevalence of antibodies, or that the antigen preparations used by the different groups contain different relative amounts of these antigens. We have compared the relative concentration of the different bullous pemphigoid antigens in epidermal extract preparations made by three different procedures commonly used to separate dermis from epidermis: NaCl, ethylenediaminetetraacetic acid (EDTA), and heat. We have found that the amount of the 180-kD antigen present in extracts is dependent on the techniques involved in separation of the epidermis from dermis. NaCl- and EDTA-separation procedures result in partial proteolysis of the 180-kD antigen to smaller forms, including major brands at 160 kD and 97 kD in the EDTA preparation. Fragments of the 180-kD antigen are present in both the separation and wash fluids, associated with a significant reduction of the 180-kD form in the extract of the NaCl-separated skin. We conclude that the native molecular weight of the previously described minor bullous pemphigoid antigen is 180 kD, and that the apparent difference in patient reaction to the 180-kD antigen may be due to different preparations of the antigen rather than underlying differences in seropositivity in the patient population.

Cigarette smoking: risk factor for premature facial wrinkling.

OBJECTIVE: To determine if cigarette smoking is a risk factor for the development of premature facial wrinkling. DESIGN: Cross-sectional study. SETTING: Smoking cessation clinic and community. PATIENTS: Convenience sample of 132 adult smokers and non-smokers in 1988. MEASUREMENTS: A questionnaire was administered to quantify cigarette smoking and to obtain information about possibly confounding factors such as skin pigmentation, sun exposure, age, and sex. Wrinkling was assessed using photographs of the temple region, and a severity score based on predetermined criteria was assigned. A logistic regression model, which controlled for confounding variables, was developed to assess the risk for premature wrinkling in response to pack-years of smoking. MAIN RESULTS: The prevalence of premature wrinkling was independently associated with sun exposure and pack-years of smoking. After controlling for age, sex, and sun exposure, premature wrinkling increased with increased pack-years of smoking. Heavy cigarette smokers (greater than 50 pack-years) were 4.7 times more likely to be wrinkled than nonsmokers (95% CI, 1.0 to 22.6; P value for trend = 0.05). Sun exposure of more than 50,000 lifetime hours also increased the risk of being excessively wrinkled 3.1-fold (CI, 1.2 to 7.1). When excessive sun exposure and cigarette smoking occurred together, the risk for developing excessive wrinkling was multiplicative (prevalence ratio of 12.0; CI, 1.5 to 530). CONCLUSION: Cigarette smoking is an independent risk factor for the development of premature wrinkling.

Persistent melanocytic lesions associated with cosmetic tanning bed use: "sunbed lentigines".

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.

Two groups of bullous pemphigoid antigens are identified by affinity-purified antibodies.

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.

Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis.

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.

IgA class antibodies in dermatitis herpetiformis: reaction with tissue antigens.

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.