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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
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↗
PubMed1991

DNA sequence analysis and restriction fragment length polymorphism (RFLP) typing of the HLA-DQw2 alleles associated with dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is a blistering autoimmune skin disease associated with a 95-100% incidence of the HLA class II antigen HLA-DQw2. Although the precise role of this antigen in the pathogenesis of DH is unclear, one theory proposes that patients with DH possess a molecularly unique subtype of the HLA-DQw2 antigen that causes immune abnormalities eventuating in the clinical manifestations of DH. To test this hypothesis, we performed DNA sequence analysis on the highly polymorphic HLA-DQB1 and HLA-DQA1 loci of eight patients with dermatitis herpetiformis. All DQB1 alleles sequenced were identical to the previously described HLA-DQB*0201 allele from HLA-DQw2 normal subjects. In addition, DQA1 alleles sequenced were identical to those alleles previously associated with HLA-DQw2 (DQA*0201, DQA*0501). These data document that although HLA-DQw2 appears to be a necessary element in the pathogenesis of DH, the development of DH is not dependent on the presence of a unique HLA-DQw2 antigen. HLA-DQ allelic typing by restriction fragment length polymorphism analysis of PCR-amplified HLA-DQA1 and HLA-DQB1 fragments was also performed in ten patients with DH to determine the allelic distribution among both HLA-DR3 (eight patients) and non-DR3 (two patients) DH patients. At the HLA-DQ beta chain locus, all patients possessed the DQB1*0201 allele. At the HLA-DQ alpha chain locus, all HLA-DR3 patients and one non-DR3 patient displayed a pattern consistent with the DQA1*0501 allele, whereas one non-DR3 patient displayed a pattern consistent with the DQA1*0201 allele. These data document that patients with DH do not express a unique HLA-DQw2 heterodimer, that the HLA-DQw2 molecules present in patients with DH have no DNA sequence differences from those found in normal HLA-DQw2 subjects and therefore that susceptibility to DH is not due to a unique HLA-DQw2 molecule.

Alleles↗
PubMed1991

Soluble interleukin-2 receptor levels in patients with dermatitis herpetiformis.

To determine the role of T-cell activation in dermatitis herpetiformis (DH), soluble IL-2R levels were measured by enzyme-linked immunosorbent assay (ELISA) in the sera of 30 patients with DH. Levels of this shed receptor are considered to be a measure of in vivo T-lymphocyte activation, and are elevated in the sera of many patients with inflammatory and immune-mediated diseases. Fifteen of the thirty (50%) patients with DH had elevated levels of soluble IL-2R compared to one of 31 (3%) healthy HLA-B8 or HLA-DR3 control subjects (p less than 0.00001) and one of 10 (10%) healthy non-HLA-B8/-DR3 subjects (p less than 0.0018). In addition, the mean soluble IL-2R level in the patients with DH (744 +/- 381 U/ml) was also significantly higher than that seen in 31 healthy HLA B8 or HLA DR3 individuals (388 +/- 160 U/ml, p = 0.0001) and 10 healthy non-HLA-B8/DR3 individuals (397 +/- 201 U/ml, p = 0.002). Only two of the 30 patients with DH had active skin lesions at the time of serum sampling, one of whom had elevated levels of IL-2R. Measurement of soluble IL-2R levels in sequential serum samples, available in four patients with DH at times of active and inactive skin disease, demonstrated a temporal association between soluble IL-2R level elevations and active skin disease in two patients and no association in two patients. In one patient a marked elevation in soluble IL-2R levels occurred with the onset of gastrointestinal symptoms, which decreased by 14% with institution of a gluten-free diet. In order to determine if soluble IL-2R levels are related to the mucosal immune response, the IL-2R levels were compared to the level of IgA antibodies directed against the dietary antigen beta-lactoglobulin. Ten of eleven (91%) patients with circulating IgA anti-beta lactoglobulin antibodies were also found to have elevated levels of IL-2R. In contrast, in the patients with no detectable IgA anti-beta lactoglobulin antibodies, only four of 16 (25%) had elevated levels of IL-2R (p = 0.001). Because IL-2R levels are not related to activity of the skin disease in patients with DH but are associated with the presence of IgA antibodies against the dietary antigen beta-lactoglobulin, these results suggest that some of the T-cell activation commonly present in DH reflects an ongoing immune response in the gastrointestinal tract.

Antibodies↗
PubMed1991

IgA-binding structures in dermatitis herpetiformis skin are independent of elastic-microfibrillar bundles.

Dermatitis herpetiformis (DH) is characterized in part by the presence of granular deposits of IgA in the papillary dermis just beneath the dermal-epidermal junction. The nature of the structures to which IgA binds in DH skin, however, has not been clearly demonstrated. Previous immunoelectron-microscopy studies using the peroxidase-antiperoxidase technique have concluded that the IgA may bind to abnormal elastic microfibrillar bundles. Recently, antibodies have been developed against a major component of the elastic microfibril bundles, fibrillin. In addition, another dermal matrix protein, hexabrachion, has been characterized and found in normal human skin in a distribution similar to the IgA deposits of DH. Utilizing antibodies against fibrillin, hexabrachion, and human IgA and immunoelectronmicroscopy with immunogold staining techniques, we have examined the skin from patients with DH in order to localize the IgA deposits. Normal-appearing skin from five patients with DH exhibited electron-dense patches within the dermis, which were not seen in skin from normal subjects. These structures were sometimes adjacent to the basement membrane zone, but appeared amorphous and without a well-defined fibrillar structure. The electron-dense patches were labeled with anti-human IgA, but not with antibodies to fibrillin or hexabrachion. The anti-IgA antibody did not label the normal basement membrane. These studies confirm the presence of abnormal electron-dense, amorphous structures in the skin of patients with DH. Due to this lack of association with the elastic microfibril bundles and the lack of labeling with antibodies against fibrillin, we suggest that these deposits are distinct from the microfibrillar bundles of elastic tissue and may represent IgA bound to degraded basement membrane or isolated dermal deposits of IgA.

Actin Cytoskeleton↗
PubMed1991

Immunogenetics of dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is a pruritic, papulovesicular skin disease characterized in part by the presence of granular deposits of IgA at the dermal-epidermal junction, an associated gluten sensitive enteropathy (GSE), and a strong association with specific human histocompatibility leukocyte antigens (HLA). Initial investigations revealed that 60% to 70% of patients with DH expressed the HLA antigen B8 (normal subjects = 21%). Further investigation of the HLA associations seen in patients with DH has revealed an even higher frequency of the HLA class II antigens HLA-DR3 (DH = 95%; normal = 23%), HLA-DQw2 (DH = 100%; normal = 40%), and HLA-DPw1 (DH = 42%; normal = 11%). Analysis of the genetic linkage of HLA antigens has revealed that the strongest HLA association in patients with DH is with the HLA class II antigens DR3 and DQw2. This article will discuss current studies regarding the role of HLA associations and DH and the role this strong HLA association may play in the pathophysiology of DH.

Dermatitis Herpetiformis↗
PubMed1990

IgG antibodies from patients with bullous pemphigoid bind to localized epitopes on synthetic peptides encoded by bullous pemphigoid antigen cDNA.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized in part by the presence of tissue-bound and circulating antibodies specific for basement membrane zone proteins, the BP Ag. The purpose of the present study was to determine seroreactivity of patients with BP to six nonoverlapping synthetic peptides representing sequences in the carboxyl domain of the recently cloned 230-kDa BP Ag. Sera from 40 patients with BP, 57 normal subjects, and 18 patients with other autoimmune blistering skin diseases were examined in an ELISA for binding to six synthetic peptides varying between 17 and 19 amino acids in length. The binding of IgG from patients with BP to three synthetic peptides, P1-2, P1-1, and P3-1, was significantly different from that seen in the normal controls (p less than 0.001, Fisher's exact test). Affinity-purified anti-P1-2 antibody from a patient with BP bound in a characteristic linear band to the epidermal side of 1 M NaCl split skin and immunoprecipitated the native 230-kDa BP Ag. Serum IgG antibodies from a rabbit immunized with a BP fusion protein that contains the sequences for P1-1 and P1-2, bound on ELISA to P1-2 but not to P1-1. These data suggest that multiple epitopes on the 230-kDa BP Ag are recognized by circulating autoantibodies in patients with this disease, and that an epitope encoded within the synthetic peptide P1-2 is expressed on the native molecule and may be relevant in the generation of an immune response both in man and in an animal model.

Amino Acid Sequence↗
PubMed1990

Serum interleukin-2 receptor responses to immunization.

Serum interleukin-2 receptor (sIL-2R) levels have been used to assess immune activation in inflammatory and infectious illnesses, although the cellular origin of these receptors and the dynamics of their production are not well defined. To investigate the relationship between sIL-2R levels and the degree of immune activation in antigen-specific responses, sIL-2R were measured in healthy individuals after both primary and secondary immunization with keyhole limpet hemocyanin (KLH). Despite induction of strong antibody responses, KLH immunization did not result in consistent elevations of sIL-2R levels, with only one of six subjects developing a substantial (twofold) increase in sIL-2R levels. The absence of sIL-2R elevation after a discrete antigenic stimulus suggests that inflammatory illnesses in which elevated sIL-2R levels have been noted involve more extensive stimulation of immune cells, either in number or in degree, than that present after simple immunization in healthy individuals.

Adult↗
PubMed1990

Dermatitis herpetiformis in two American blacks: HLA type and clinical characteristics.

Dermatitis herpetiformis is a rare blistering skin disease characterized in part by granular IgA deposits at the dermoepidermal junction, an associated gluten-sensitive enteropathy, and a strong association with the human histocompatibility leukocyte antigen (HLA)-A1 (74% of patients with dermatitis herpetiformis), -B8 (88%), -DR3 (95%), and -DQw2 (100%). Dermatitis herpetiformis is rarely seen in American blacks and some investigators have postulated that this finding may be due to the decreased frequency of HLA-A1 and -B8 in American blacks compared with Caucasians (American blacks: HLA-A1 = 15.3%, HLA-B8 = 10.7%; Caucasian: HLA-A1 = 26.4%, HLA-B8 = 18.3%). This report describes two American blacks with dermatitis herpetiformis and reports the results of HLA typing of these subjects for HLA-A, -B, -C, -DR, and -DQ antigens. HLA typing revealed that neither patient expressed HLA-A1 or -B8; however, both patients did express the class II antigens most frequently seen in dermatitis herpetiformis, HLA-DR3 and -DQw2. Comparison of HLA class II antigen frequency in normal American blacks and Caucasians reveals a similar frequency of HLA-DR3 and -DQw2 (American blacks: HLA-DR3 = 27.6%, HLA-DQw2 = 40.9%; Caucasian: HLA-DR3 = 22.6%, HLA-DQw2 = 32.9%). These data confirm the importance of the HLA class II region in the pathogenesis of dermatitis herpetiformis. In addition, these data suggest that the rare occurrence of dermatitis herpetiformis in American blacks is not due to the decreased frequency of the HLA class I antigens -A1 and/or -B8 but rather is related to differences in the HLA class II region not detected by routine HLA typing.

Biopsy↗
PubMed1990

An HLA class II region restriction fragment length polymorphism (RFLP) in patients with dermatitis herpetiformis: association with HLA-DP phenotype.

Dermatitis herpetiformis (DH) is characterized in part by an associated gluten-sensitive enteropathy (GSE), and a strong association with the HLA antigens HLA-A1, -B8, -DR3, and -DQw2, essentially identical to that seen in patients with isolated GSE (celiac disease). A 4.0-kb RsaI RFLP has been identified using a DQ beta-chain cDNA and localized to the HLA-DP beta-chain region. This RFLP has been found more frequently in patients with isolated GSE than in normal HLA matched controls. We have analyzed genomic DNA from 24 patients with DH and 15 HLA-matched controls to determine if this 4.0-kb RsaI RFLP was present in patients with DH. Twenty-one of 24 (87%) of patients with DH were found to have this RFLP as compared to 7 of 10 (70%) HLA-DR3, -DQw2 matched control subjects (p = 0.23). Thus, the 4.0-kb RsaI RFLP detected in patients with isolated GSE is also present in patients with DH; however, its frequency in DH patients does not differ significantly from that of HLA matched controls. Family studies of patients with DH revealed that although the 4.0-kb RsaI RFLP segregated with the HLA-A1, -B8, -DR3, -DQw2 haplotype in one family, it did not segregate with this disease-associated haplotype in two other families. In both patient and control populations, this RFLP was associated with HLA-DPw1 or -DPw3 phenotypes; 25 of 26 (96%) HLA-DPw1 or -DPw3 subjects were found to have this RFLP compared to only 1 of 6 (17%) who did not express HLA-DPw1 or -DPw3 (pc = 0.0009). These population and family data suggest that this 4.0-kb RsaI RFLP is primarily associated with the HLA-DPw1, -DPw3 phenotype, rather than the clinical manifestations of DH. These data further document that the strongest association of DH with HLA antigens remains with HLA-DQw2 and HLA-DR3 antigens.

Cell Line↗
PubMed1990

Dermatitis herpetiformis.

The state of our understanding of the pathogenesis of DH relies on the integration of several key characteristics: (1) a high frequency of the HLA antigens HLA-B8, HLA-DR3, and HLA-DQw2, (2) an associated GSE, (3) the resolution of both the skin lesions and gut abnormalities in response to a gluten-free diet, and (4) the presence of granular deposits of IgA in normal and perilesional skin. The role of the HLA class II antigens expressed in patients with DH most likely relates to the afferent or initiating arm of the immune system. The association of the HLA-A1, -B8, -DR3, -DQw2 haplotype with Sjogren's syndrome, chronic hepatitis, Graves' disease, and other presumably immunologically mediated diseases, as well as the evidence that some normal HLA-B8, -DR3 individuals have an abnormal in vitro lymphocyte response to wheat protein and mitogens and have abnormal Fc-IgG receptor-mediated functions, suggests that this HLA haplotype or genes linked closely to it may confer a generalized state of immune susceptibility on its carrier, the exact phenotypic expression of which depends on other genetic or environmental determinants. It also is clear, from the association of DH with GSE and the ability to control the cutaneous manifestations of DH with a gluten-free diet, that the gut disease is a critical factor in the pathogenesis of DH. Several pathogenetic theories about the origin of the cutaneous IgA deposits in DH have been proposed, one of which states that the IgA is produced in the gut mucosa as a response to a dietary antigen or gut epithelial antigen and then cross-reacts with the skin of patients with DH. A second hypothesis is that the IgA produced in the gut binds to an antigen and is deposited in skin as an antigen-antibody complex. Finally, it could be that the gut mucosal abnormality simply allows an unknown antigen access to the central immune system where an IgA antibody is produced that binds to skin. The failure to detect circulating IgA anti-basement membrane zone antibodies in patients with DH suggests that either the structures to which the IgA binds are not present in normal skin without DH, that IgA cannot bind to these structures in vitro, or that the circulating IgA is too scant for detection with conventional methods. Finally, it must be considered that the IgA deposited in DH skin may bind as a result of non-antigen-antibody interactions that cannot be duplicated in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

Celiac Disease↗
PubMed1989

Alterations in HLA-DP and HLA-DQ antigen frequency in patients with dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is associated with a markedly increased frequency of the HLA class II antigens DR3 and DQw2. To investigate a possible role of HLA-DP (or closely associated genes) in the pathogenesis of DH as well as to confirm the previously described alterations of HLA-DR3 and HLA-DQw2 antigen frequency, we have typed 43 patients with DH for HLA-DP, HLA-DQ, and HLA-DR antigens. All patients with DH had typical clinical and histologic features, as well as granular deposits of IgA at the dermal-epidermal junction by direct immunofluorescence. HLA-DR3 was expressed in 41 of 43 (95%) DH patients, whereas HLA-DQw2 was expressed in all 43 (100%). The overall distribution of HLA-DP antigens in patients with DH was significantly different from that seen in all controls and in HLA-DR3 and HLA-DQw2 controls (p less than 0.02). Examination of the frequency of individual DP antigens revealed that HLA-DPw1 was increased (42% of patients with DH vs 11% of all controls and 26% of DR3 positive controls), but this increase was not statistically greater than that expected due to the disequilibrium linkage of DPw1 with DR3/DQw2. Patients with DH, however, did have a statistically significant decreased frequency of DPw2 (14% of patients vs 31% of all controls and 41% of DR3 positive controls) (pc less than 0.05). Studies of three informative families demonstrated that the DPw2 genes of the DH patients were not present on the haplotype thought to carry a DH susceptibility gene (HLA-A1, HLA-B8, HLA-DR3, HLA-DQw2). A role of HLA-DP region genes in the pathogenesis of DH is further suggested by the observation that HLA-DPw1 was expressed in 82% (9 of 11) of DH patients with IgA antibodies against dietary antigens as compared with only 33% (4 of 12) of patients without IgA antibodies. HLA-DP genes or genes closely linked to them may be important in DH either as markers of the disease haplotype or by direct involvement in its pathogenesis.

Antigens↗
PubMed1989

Epidermal keratinocytes express the adhesion molecule intercellular adhesion molecule-1 in inflammatory dermatoses.

Using indirect immunofluorescence assays on frozen tissue sections of skin from healthy subjects and subjects with inflammatory skin diseases, we found that intercellular adhesion molecule-1 (ICAM-1) was expressed in a cell surface pattern on epidermal keratinocytes at the site of lymphoid infiltration in cutaneous dermatoses. ICAM-1 was not expressed on epidermal keratinocytes in noninflamed skin. Its expression was not related solely to epidermal hyperproliferation, as hyperproliferative, tape-stripped epidermis did not express ICAM-1. We have reported previously that ICAM-1 expression on epidermal keratinocytes was upregulated by treatment with interferon gamma and that activated T lymphocytes bound to cultured epidermal keratinocytes in vitro by lymphocyte function associated-1 (LFA-1) molecules on T cells and ICAM-1 on epidermal keratinocytes. Taken together, these data suggest that upregulation of expression of ICAM-1 is an important feature of cutaneous inflammation.

Antigens, Surface↗
PubMed1989

Anti-idiotypic antibodies as vaccine candidates. The immune network.

Antibodies specific for determinants within the variable region of an antibody molecule are known as anti-idiotypic antibodies. Anti-idiotypic antibodies specific for determinants within the antigen binding site of the antibody may mimic the original antigen and are said to bear an "internal image" of the antigen. These anti-idiotypic antibodies have been shown in animal studies to function as surrogate antigens in stimulating an immune response and may ultimately be useful therapeutically as vaccines to prevent infectious diseases, to enhance the immune response to neoplasms, and to modulate autoantibody production in autoimmune diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Idiotypes, anti-idiotypes, and autoimmunity.

Over the past two decades it has become clear that the ability of a host to generate antibodies against a wide variety of potential antigens is due to structural diversity in the antibody molecule within the variable region. This diversity results in sites within the molecule that are themselves immunogenic. These immunogenic sites are called idiotopes, and the collection of idiotopes on a single antibody molecule determines that antibody's idiotype. The idiotype of an antibody molecule is defined serologically by a second antibody termed an anti-idiotype. Anti-idiotypic antibodies can recognize antibody molecules bearing similar or identical structures within the variable regions, which are often on or near sites of antigen binding. Investigation into the nature of idiotype and anti-idiotype interactions has increased our knowledge of antibody structure, antigen-antibody interactions, the regulation of antibody production, and the nature of autoimmune disorders. This review will discuss the nature of idiotypes and anti-idiotypes and their potential role in the diagnosis, management, and treatment of autoimmune, infectious, and malignant diseases.

Antibodies, Anti-Idiotypic↗