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Biomedical subjects

R P Hall

Publications and source records attributed to R P Hall.

At least 19 recordsLinked to original sources
PubMed1999

Characterization of skin cytokines in bullous pemphigoid and pemphigus vulgaris.

The purpose of this study was to determine cytokine and cell marker expression in perilesional skin biopsies from patients with the autoimmune blistering diseases bullous pemphigoid (BP, n = 21) and pemphigus vulgaris (PV, n = 7). Immunohistochemistry and in situ hybridization were used to detect T helper (Th)1 [interleukin (IL)-2, interferon (IFN)-gamma] and Th2 (IL-4, IL-5, IL-13) protein and mRNA. Perilesional skin biopsies from patients with BP were characterized by the deposition of IL-4, IL-13 and IL-5. In patients with BP, IL-4 and IL-13 localized to mononuclear cells within the dermal infiltrate while IL-5 was predominately expressed at the dermal-epidermal junction. BP skin sections also expressed vascular cell adhesion molecule 1 on endothelial cells, not seen in patients with PV. PV biopsies were remarkable for a mixed Th1/Th2 pattern of cytokine expression, including the presence of IL-2, IFN-gamma and IL-4 and the absence of IL-5 and IL-13. In situ hybridization detected mRNA for IL-4 and IL-5 in the cellular infiltrate of BP patients, and IL-2 in a patient with PV. In vitro binding assays demonstrated that normal human eosinophils, activated by coculture in IL-5, bound preferentially to BP skin sections that contained detectable in vivo bound IL-5. The predominance of Th2 cytokines in BP, in association with increased binding of eosinophils in vitro, suggests that Th2 cytokines are relevant in the recruitment and adhesion of eosinophils within the dermal infiltrates of patients with BP, and may play a part in the pathogenesis of blister formation.

Biomarkers↗
PubMed1998

A pilot trial of digital imaging in skin cancer.

We have used inexpensive off-the-shelf equipment for store-and-forward teledermatology and compared the precision and accuracy of digital image consultations with conventional, clinic-based consultations. Thirteen lesions were studied on 12 patients referred to a dermatology clinic for a suspected skin cancer. Patients were examined by two dermatologists. Subsequently, digital images were examined by two different dermatologists. There was almost complete agreement, both among and between the clinical and digital examiners, on different diagnosis and biopsy recommendations. Agreement on the single most likely diagnosis was also good. Digital imaging shows promise in teledermatology.

Diagnosis, Differential↗
PubMed1997

Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune skin diseases caused by autoantibodies against desmoglein (Dsg) 3 and Dsg1, respectively. Routine immunofluorescence testing of skin and serum from patients cannot distinguish between these two severe diseases since both have IgG Abs directed against keratinocyte cell surfaces. In this study, recombinant Dsg3 and Dsg1, produced as secreted proteins by baculovirus expression, have been utilized to develop ELISAs for the specific characterization of their autoantibodies. Of 49 PV sera, 46 were positive in the Dsg3 ELISA and 44 of 46 PF sera were positive in the Dsg1 ELISA, compared with only 3 of 23 sera of bullous pemphigoid, and none of 53 normal control sera in both ELISAs. Both the Dsg3 and Dsg1 ELISAs were more specific and sensitive than conventional immunofluorescence staining. These Ag-specific ELISAs revealed that more than one-half of PV sera (26 of 49) had anti-Dsg1 Abs in addition to anti-Dsg3 Abs. PV patients who had not only oral mucous lesions but also significant skin involvement tended to have higher titers of anti-Dsg1 Abs. Furthermore, the ELISA reactivity correlated well with clinical disease activity in 5 of 6 PV and 5 of 5 PF patients. This ELISA provides a sensitive and highly specific assay for the diagnosis of patients with PV and PF, the correlation of disease activity with serum Ab levels, and a novel tool for investigating the immunopathogenesis of pemphigus.

Autoantibodies↗
PubMed1997

Primary care clinicians' performance for detecting actinic keratoses and skin cancer.

BACKGROUND: If skin cancer screening is to become widely adopted, its effectiveness depends on the ability of primary care clinicians to detect cutaneous malignancies. OBJECTIVE: To assess primary care clinicians' proficiency for detecting skin cancers and actinic keratoses in a clinic population. METHODS: A convenience sample of 190 white male patients aged 40 years or older presenting to a university-affiliated Veterans Affairs general internal medicine or dermatology clinic were included in the study. Each patient was independently examined by a primary care clinician and a dermatologist to measure interobserver agreement. We compared the ability of primary care clinicians to diagnose actinic keratoses and skin cancers using dermatologists' examinations as a pragmatic reference standard. RESULTS: Agreement was moderate as to whether a patient had single actinic keratosis (kappa, 0.36; 95% confidence interval [CI], 0.22-0.50), multiple actinic keratoses (kappa, 0.48; 95% CI, 0.34-0.61), or skin cancer (kappa, 0.48; 95% CI, 0.34-0.62). Agreement decreased when individual lesions were the unit of analysis. When the patient was the unit of analysis, primary care clinicians identified the presence of skin cancer with a sensitivity of 57% (95% CI, 44%-68%), specificity of 88% (95% CI, 81%-93%), positive likelihood ratio of 4.9 (95% CI, 3.0-8.3), and negative likelihood ratio of 0.48 (95% CI, 0.35-0.63). When the lesion was the unit of analysis the sensitivity was 38% (95% CI, 29%-47%), the specificity was 95% (95% CI, 93%-96%), the positive likelihood ratio was 7.1 (95% CI, 4.8-10.3), and the negative likelihood ratio was 0.66 (95% CI, 0.56-0.75). CONCLUSIONS: Examinations performed by primary care clinicians for diagnosing skin cancer lacked sensitivity. Without improved diagnostic skills, primary care clinicians' examinations may be ineffective as a screening test.

Adult↗
PubMed1996

Comparative epitope mapping of sera from United States (US) and Japanese patients with bullous pemphigoid (BP) to fusion proteins encoded by BPAG1.

Sera from patients with bullous pemphigoid (BP) from the United States (US), Japan, and Britain demonstrate similar reactivity to the major target antigens BPAG1 and BPAG2. The purpose of the present study was to determine if the epitope specificity of circulating autoantibodies in patients with BP from the US and Japan is similar as mapped by binding to fusion proteins encoded by BPAG1. Sera from patients and controls with BP from the US and Japan were assayed for reactivity to intact BPAG1 and BPAG2 by immunoblot, and to fusion proteins encoded by BPAG1 by immunoblot and enzyme-linked immunosorbant assay (ELISA). Significant reactivity to fusion proteins encoded by the carboxyl region (FP 16-8) and coiled-coil region (FP3) was seen in sera from the US and Japanese patients, but not from normal controls from the US or Japan. Sera from US and Japanese patients differed in their response to FP7; namely, the reactivity of sera from US patients but not from Japanese patients to FP7 was significantly different from the reactivity of their respective control sera. The reasons for this difference in reactivity are unknown but may reflect genetic or environmental factors relevant in the generation of an autoantibody response to these target antigens.

Aged↗
PubMed1995

The influence of history on interobserver agreement for diagnosing actinic keratoses and malignant skin lesions.

BACKGROUND: Quantifying interobserver diagnostic agreement is necessary to evaluate skin cancer screening programs, but estimates of variability are incomplete. OBJECTIVE: We sought to measure agreement between dermatologists for diagnosing actinic keratoses (AKs) and malignant skin lesions and to determine the way in which blinding examiners to patient history affects agreement. METHODS: We varied the amount of historical information available to examiners in two consecutive patient series (n = 50) presenting to a Veterans Affairs Medical Center dermatology clinic. Two dermatologists examined each patient independently. RESULTS: Assessing historical features increased the kappa statistic for malignancy recognition from -0.04 to 0.76. kappa Statistics for diagnosing single AKs were 0.17 and 0.15, respectively, and 0.62 and 0.55 for multiple AKs. CONCLUSION: Agreement was high for diagnosing malignant skin lesions when history was included in the evaluation. Agreement for multiple AKs was higher than for single AKs, although neither was influenced by inclusion of historical features.

Aged↗
PubMed1994

Peripheral blood mononuclear cells from patients with bullous pemphigoid have an increased frequency of response to synthetic peptides encoded by BPAG1.

We determined the response of peripheral blood mononuclear cells from patients with bullous pemphigoid and normal subjects to synthetic peptides encoded by BPAG1. Peripheral blood mononuclear cells from patients and normal subjects were cocultured in the presence of 15-22-amino-acid-long amphipathic and hydrophilic peptides selected from the BPAG1 sequence. Seven of 10 patients (70%) with bullous pemphigoid had an increased response of peripheral blood mononuclear cells (> 3.25/10(6) cells) when cultured with amphipathic sequences encoded by BPAG1 compared to 3 of 10 (30%) normal subjects. Peripheral blood mononuclear cells from 3 of 15 (20%) patients and 3 of 15 normal subjects (20%) demonstrated an increased response when cultured with hydrophilic peptides. Peptides associated with an increased peripheral blood mononuclear cell response in patients with bullous pemphigoid were adjacent to regions of BPAG1 recently demonstrated to contain epitopes recognized by circulating autoantibodies in the sera of patients with bullous pemphigoid. Increased peripheral blood mononuclear cell responses were more commonly observed in patients with bullous pemphigoid with generalized disease and those who had their disease for longer than 2 months (p < 0.05). The observation that increased duration and generalized disease was associated with increased peripheral blood mononuclear cell responses to peptides encoded by BPAG1 supports the hypothesis that responses to BPAG1 may occur as a consequence of ongoing inflammation at the basement membrane.

Amino Acid Sequence↗
PubMed1994

IgA antibodies against reticulin and endomysium in the serum and gastrointestinal secretions of patients with dermatitis herpetiformis.

Although IgA is present in the skin of patients with dermatitis herpetiformis (DH), the relationship of that IgA to the mucosal immune response is not known. The purpose of this study was to determine if IgA antibodies directed against tissue antigens, which are present in the serum of patients with DH, are also present in the gut secretions of these patients. Serum and gut secretions from 8 patients with DH and 5 control subjects were analyzed by indirect immunofluorescence for the presence of IgA antireticulin and antiendomysium antibodies. IgA antibodies against reticulin (3 of 8 patients) and endomysium (4 of 8 patients) were found in the serum of patients with DH. IgA antibodies were also present in the gut secretions of all of these patients, but not in subjects (patients with DH and controls) that did not have serum IgA antireticulin or antiendomysium antibodies. The presence of IgA antireticulin and antiendomysium in both the serum and gut secretions of DH patients suggests that these antibodies arise as a result of the mucosal immune response and that IgA of mucosal origin can persist in the serum of patients with DH.

Autoantibodies↗
PubMed1994

Cross-reactive idiotypes in the sera of patients with bullous pemphigoid express anti-basement-membrane-zone activity.

We have previously generated a monoclonal anti-idiotypic antibody (antiId 3-17) specific for a cross-reactive idiotype (CRI) present in sera and bound at the basement membrane zone (BMZ) in some patients with bullous pemphigoid (BP). The purpose of the present study was to determine if CRI isolated from sera of patients with BP expressed anti-BMZ activity. CRI, isolated by affinity chromatography from 5 nonrelated patients with BP, bound to the epidermal side of normal human split skin as detected by indirect immunofluorescence. In patients with BP, the presence of the CRI on circulating IgG is associated with anti-BMZ activity.

Antibodies, Anti-Idiotypic↗
PubMed1993

Rabbits immunized with a peptide encoded for by the 230-kD bullous pemphigoid antigen cDNA develop an enhanced inflammatory response to UVB irradiation: a potential animal model for bullous pemphigoid.

Previous attempts to develop an animal model of bullous pemphigoid (BP) have failed to result in inflammatory disease in the skin. P1-2 is an 18-amino acid peptide encoded for by the 230-kD BP antigen cDNA that has been shown to contain an epitope recognized by circulating antibodies from patients with BP. The purpose of this study was to determine if ultraviolet B irradiation of rabbits after immunization with the P1-2 peptide would result in an enhanced inflammatory response in the skin to that injury. Three rabbits were immunized with either P1-2 or a control peptide. All rabbits immunized with P1-2, and none of the control rabbits, developed antibodies against P1-2 that bound in vitro to both human and rabbit skin in a linear pattern at the basement membrane zone. Immunized rabbits were irradiated on the flank with ultraviolet light. Rabbits immunized with P1-2 developed an enhanced inflammatory reaction to ultraviolet B irradiation leading to epidermal necrosis and sloughing of some sites in 6-9 d. Control rabbits showed only mild erythema without sloughing, which healed in 4-6 d. Histology in the P1-2 immunized rabbits at 24 h revealed an inflammatory infiltrate of neutrophils at the dermal-epidermal junction, whereas control rabbits showed only mild edema and a sparse inflammatory infiltrate. All the rabbits immunized with P1-2 had linear deposits of immunoglobulin G and C3 at the basement membrane zone of healed skin compared to none of the controls. These findings demonstrate that antibodies against a synthetic peptide encoded by the BP antigen 1 sequence can lead to an enhanced inflammatory response after epithelial injury in rabbit skin.

Animals↗
PubMed1993

IgG antibodies from patients with bullous pemphigoid bind to fusion proteins encoded by BPAg1 cDNA.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease characterized in part by the presence of circulating and tissue-bound IgG antibodies directed against the epidermal basement membrane zone. IgG from over 95% of patients with BP have been shown to immunoprecipitate a 230-kD epidermal protein, BPAg1, which has been cloned and sequenced. Although sera from almost all patients with BP react with the 230-kD BP antigen the specific epitope(s) of BPAg1 that IgG binds is not known. We have generated fusion proteins from the 230-kD BP antigen cDNA and analyzed sera from patients with BP for binding to these fusion proteins by immunoblot. Sera from 21 of 30 (70%) patients with BP reacted with FP3A (amino acid 873-1193) compared to four of 13 (30%) normal subjects (p < 0.02). Sera from 10 of 30 (33%) patients reacted with FP7 (AA1623-1812) and to FP3 (AA1003-1193), compared to one of 22 (5%) and 0 of 19 (0%) controls, respectively. No significant reactivity was noted against two other fusion proteins (FP6, FP9). Twenty-four of 30 (80%) patients with BP reacted to at least one of three fusion proteins (FP3, FP3A, FP7) compared to three of 11 (27%) of the control subjects (p < 0.003). Fusion proteins FP3, FP3A, and FP7 are at the amino- or carboxyl-terminal regions of the putative central alpha-helical coiled-coil rod domain of BPAg1, which has been postulated to be involved in the self-aggregation of BPAg1. These findings demonstrate that patients with bullous pemphigoid react with multiple regions of BPAg1 and suggest that part of the pathologic consequences of these auto-antibodies in patients with bullous pemphigoid may be by the disruption of the normal self-aggregation of the BPAg1.

Animals↗
PubMed1993

Expression of cross-reactive idiotypes at the basement membrane zone in patients with bullous pemphigoid.

The purpose of the present study was to determine whether tissue-bound anti-basement membrane zone (BMZ) autoantibodies in patients with bullous pemphigoid (BP) express a cross-reactive idiotype. We assayed 34 skin biopsies from 26 patients with BP and nine biopsies from control subjects, including normal subjects and patients with epidermolysis bullosa acquisita for the presence of a cross-reactive idiotype at the BMZ. Perilesional split-skin biopsies were assayed for the presence of immunoreactants, immunoglobulin G, and complement and for reactivity with a monoclonal anti-idiotypic antibody specific for a circulating anti-BMZ antibody, anti-Id 3-17. Anti-Id 3-17 bound in a linear band to the BMZ in 12 of 26 patients with BP (46%) and in 0 of 9 control subjects. In serial biopsy specimens, the presence or absence of cross-reactive idiotype at the BMZ in six patients was stable during the disease course. This cross-reactive idiotype has been previously identified in the serum of 36% of patients with BP; however, in this study, no correlation was noted between the presence of the cross-reactive idiotype in skin and serum of individual patients. Because cross-reactive idiotypes occur as a consequence of restricted variable-region gene utilization, the demonstration of a cross-reactive idiotype at the BMZ previously identified in the serum of patients with BP supports the hypothesis that circulating and tissue-bound autoantibodies in this disease arise from a common genetic origin.

Antibodies, Anti-Idiotypic↗
PubMed1992

Comparison of the intestinal and serum antibody response in patients with dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is an intensely pruritic, blistering skin disease characterized by cutaneous IgA deposits and an associated, most often asymptomatic, gluten-sensitive enteropathy. When patients with DH are placed on a gluten-free diet both the intestinal abnormality and the cutaneous manifestations of the disease are controlled, suggesting that a mucosal immune response is important in the pathogenesis of DH. Although patients with DH continue to ingest gluten only 40-50% have evidence of an ongoing mucosal immune response in their serum. In order to investigate directly the mucosal immune response in patients with DH the antibody response to dietary antigens was analyzed in intestinal secretions and compared to that found in the serum. Intestinal secretions from six patients with DH and five normal subjects were collected using an intestinal lavage solution and analyzed for total IgA, IgG, IgM, and IgA subclasses, and for IgG, IgA, and IgM antibodies against the dietary antigens bovine beta-lactoglobulin and gliadin. Intestinal secretions from patients with DH contained more IgA than those from normal subjects (mean total IgA: DH = 2.3 mg/ml; normal subjects (NL) = 0.143 mg/ml, P = 0.017). This increase in IgA in intestinal secretions from patients with DH was composed primarily of IgA1 (intestinal IgA: 86% IgA1, 14% IgA2; NL gut secretions: IgA1 = 54%; IgA2 = 46%). Increased IgA antibodies directed against beta-lactoglobulin and gliadin were detected in gut secretions of two of six patients with DH and in none of the normal subjects. Serum IgA antibodies against beta-lactoglobulin and gliadin were detected only in the two subjects who had detectable IgA antibodies in their intestinal secretions. Serum and intestinal IgA anti-beta-lactoglobulin antibodies had similar isoelectric spectrotypes (pI 5.0-6.5), IgA subclass composition, and antigenic reactivity by immunoblot analysis, demonstrating the close relationship between the serum and intestinal IgA antibodies. These data demonstrate that in patients with DH an ongoing mucosal immune response is present in the gut as evidenced by a significantly increased concentration of IgA, predominately IgA1. The strong correlation between detectable serum and intestinal IgA antibodies against dietary antigens demonstrates that the lack of serum IgA antibodies against dietary antigens in some patients with DH is not due to the presence of "blocking" IgA anti-dietary antigen antibodies in intestinal secretions.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

Vancomycin-associated linear IgA dermatosis. A report of three cases.

BACKGROUND: Linear IgA dermatosis is an autoantibody-mediated, subepidermal blistering disease that is rarely associated with drug exposure. OBJECTIVE: We report the development of linear IgA dermatosis in three patients associated with the administration of vancomycin and further characterize the immunopathology. METHODS: Direct and indirect immunofluorescence assays were performed to characterize the immunoreactants, determine the subclass of the IgA deposits, and map the site of antibody deposition. RESULTS: A subepidermal blistering disease developed in all patients shortly after vancomycin was initiated, which resolved on discontinuation of the drug. Immunofluorescence studies revealed linear deposits of IgA1 only at the basement membrane zone, below the lamina lucida. Circulating IgA anti-basement membrane zone antibodies were not detected. CONCLUSION: Three patients had linear IgA dermatosis in association with the administration of vancomycin. All patients had linear deposits of IgA1 localized to the sublamina densa zone. Immunophenotypically, the disease in these patients mimics the pattern of IgA deposits seen in the majority of patients with idiopathic linear IgA dermatosis.

Aged↗
PubMed1991

Detection of cross-reactive idiotypes in the serum of patients with bullous pemphigoid.

To further characterize the circulating antibasement membrane zone (antiBMZ) antibodies present in the sera of patients with bullous pemphigoid (BP), we have generated a mouse monoclonal anti-idiotypic antibody (antiId 3-17) specific for an IgG antiBMZ antibody. AntiId 3-17 is specific for an idiotype expressed on antiBMZ IgG in the serum of a patient with BP, and not expressed on pooled normal human IgG or IgG from patients with other autoimmune skin diseases. AntiId 3-17 binds to non-reduced, but not reduced, antiBMZ IgG on immunoblot, suggesting that the idiotype is composed of a conformational epitope expressed on native antibody. By a competitive inhibition ELISA, antiId 3-17 detects a cross-reactive idiotype (CRI) expressed in 18 of 50 (36%) of the sera of patients with BP, but in the sera of only 1 of 50 (2%) normal blood bank controls (p less than 0.001, Fisher's exact test) and 1 of 12 (8%) patients with pemphigus (p = 0.005). Thus, antiId 3-17 recognizes a public idiotype on a native antiBMZ antibody from a patient with BP, which is expressed in the sera of 36% of the unrelated patients with BP studied.

Antibodies, Anti-Idiotypic↗