Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders.

BACKGROUND: Retroviruses have been implicated in the aetiology of various autoimmune diseases. We used immunoblots as a surrogate test to find out whether retroviruses play a part in the development of primary biliary cirrhosis. METHODS: We did western blot tests for HIV-1 and the human intracisternal A-type particle (HIAP), on serum samples from 77 patients with primary biliary cirrhosis, 126 patients with chronic liver disease, 48 patients with systemic lupus erythematosus, and 25 healthy volunteers. FINDINGS: HIV-1 p24 gag seroreactivity was found in 27 (35%) of 77 patients with primary biliary cirrhosis, 14 (29%) of 48 patients with systemic lupus erythematosus, 14 (50%) of 28 patients with chronic viral hepatitis, and nine (39%) of 23 patients with either primary sclerosing cholangitis or biliary atresia, compared with only one (4%) of 24 patients with alcohol-related liver disease or alpha1-antitrypsin-deficiency liver disease, and only one (4%) of 25 healthy volunteers (p=0.003). Western blot reactivity to more than two HIAP proteins was found in 37 (51%) of patients with primary biliary cirrhosis, in 28 (58%) of patients with systemic lupus erythematosus, in 15 (20%) of patients with chronic viral hepatitis, and in four (17%) of those with other biliary diseases. None of the 23 patients with either alcohol-related liver disease or alpha1-antitrypsin deficiency, and only one of the healthy controls showed the same reactivity to HIAP proteins (p<0.0001). Our results showed a strong association between HIAP seroreactivity and the detection of autoantibodies to double-stranded DNA. HIAP seroreactivity was also strongly associated with the detection of mitochondrial, nuclear, and extractable nuclear antigens. INTERPRETATION: The HIV-1 and HIAP antibody reactivity found in patients with primary biliary cirrhosis and other biliary disorders may be attributable either to an autoimmune response to antigenically related cellular proteins or to an immune response to uncharacterised viral proteins that share antigenic determinants with these retroviruses.

Reactivity of sera from systemic lupus erythematosus and Sjögren's syndrome patients with peptides derived from human immunodeficiency virus p24 capsid antigen.

We have previously demonstrated that about one-third of patients with either Sjögren's syndrome (SS) or systemic lupus erythematosus (SLE) react to human immunodeficiency virus (HIV) p24 core protein antigen without any evidence of exposure to, or infection with, HIV itself. Herein, we further characterize the specificity of this reaction using enzyme-linked immunosorbent assay to peptides representing fragments of p24. Characteristic epitope-specific profiles were seen for SS and SLE patients. SS patients had significantly increased responses to peptides F (p24 amino acids 69 to 86) and H (amino acids 101 to 111) and diminished reactivity to peptides A (amino acids 1 to 16) and P (amino acids 214 to 228). SLE patients had increased reactivity to peptides E (amino acids 61 to 76), H, and P. Utilization of peptide P hyporeactivity as the criterion to select for SS patients results in a screen that is moderately sensitive (64%) and specific (79.3%). Adding hyperreactivity to one other peptide (F or H) as an additional criterion yields an expected decrease in sensitivity (to 41%) while increasing specificity (to 93.1%). All sera-reactive peptides from regions of known structure of HIV p24 were located in the apex of the p24 molecule. Thus, the specificity of the peptide reactivities described here indicates a specific pattern of a nonrandom cross-reactivity between HIV type 1 p24 and autoimmune sera which may be partially syndrome specific. The future focus of our work will be to optimize assays of the peptide as diagnostic tools.

Use of antipolymer antibody assay in recipients of silicone breast implants.

BACKGROUND: Local complications (encapsulation, rashes, rupture, and leakage) can occur after placement of silicone gel-containing breast implants (SBI). Whether SBI exposure results in systemic manifestations in some recipients is controversial. We have carried out a blinded study to assess whether there is any difference between SBI recipients and non-exposed controls in the proportions positive for serum antibodies directed against polymeric substances. METHODS: We recruited female SBI recipients (including those without symptoms) who presented to a single rheumatology clinic. A physician global assessment was used to classify SBI recipients who did not meet criteria for specific autoimmune diseases according to the severity of local and systemic signs and symptoms. Controls were recruited from among clinic staff and their acquaintances. Results of the antipolymer antibody (APA) assay were compared with those of an assay for antinuclear antibodies (ANA) and with the severity of the signs and symptoms. FINDINGS: Positive APA results were found in one (3%) of 34 SBI recipients with limited symptoms, two (8%) of 26 with mild symptoms, seven (44%) of 16 with moderate symptoms, and 13 (68%) of 19 with advanced symptoms. Four (17%) of 23 healthy non-SBI-exposed controls and two (10%) of 20 non-exposed women with classic autoimmune diseases were positive for APA. Thus, women with moderate or advanced symptoms were significantly more likely than those with limited or mild symptoms, or non-exposed controls to have APA (p < 0.001). The proportion with positive ANA results was higher for women with classic autoimmune diseases 14 (70%) of 20 than for any SBI-exposed subgroup (0-33%). INTERPRETATION: The APA assay can objectively contribute to distinguishing between SBI recipients with limited or mild signs and symptoms. SBI recipients with more severe manifestations, and patients with specific autoimmune diseases. Further studies will be needed to define the signs and symptoms associated with exposure to SBI.

The interaction of a type A retroviral particle and class II human leukocyte antigen susceptibility genes in the pathogenesis of Graves' disease.

We have previously reported that over 85% of patients with Graves' disease have detectable serum antibodies against a human intracisternal type A retroviral particle (HIAP), which are not present in age- and gender-matched controls, suggesting a role for HIAP in triggering the autoimmune process leading to Graves' disease. To investigate the interaction of this viral particle with genetic factors, 35 members of 3 kindreds, selected because of a high family prevalence of Graves' disease (a total of 11 members affected), were examined for clinical signs of thyroid dysfunction, goiter, and opthalmopathy. Thyroid function tests and autoimmune serological profiles were also obtained. In addition, subjects were tested for the presence of antibodies against HIAP by means of immunoblot analysis of their sera, and their human leukocyte antigen (HLA) class II alleles were determined by DNA methodology. Molecular genetic analyses enabled the detection of postulated HLA susceptibility haplotypes in each family. These families had 8, 4, and 5 members, respectively, with such apparent susceptibility genes and 11, 5, and 9 members, respectively, with immunological evidence of retroviral exposure. In the presence of both factors (codetected in a total of 15 members of the 3 kindreds), the incidence of Graves' disease was 100%, 67%, and 80%, respectively. One additional member of family B and 3 in family C with both viral and genetic susceptibility factors were found to have serological abnormalities and/or goiter and ocular signs consistent with evolving or preclinical Graves' disease. In families A and C, tight linkage between HLA haplotypes and Graves' disease was demonstrated in a manner consistent with recessive inheritance. The association between the occurrence of both anti-HIAP-I antibody positivity and HLA susceptibility and the presence of Graves' disease was highly significant (P < 0.001). The pathogenesis of Graves' disease in these families appears to be attributable to the interaction between the immune response to an intracisternal type A retroviral particle and immunogenetic susceptibility, leading to the autoimmune processes that underlie Graves' disease, with subsequent development of the characteristic features of the illness. Data from these families suggest that both of these factors are necessary for final disease expression. These results imply that serological evidence of retroviral exposure together with genetic HLA susceptibility are the two major predisposing factors underlying the pathogenesis of Graves' disease. Further studies will establish whether prospective identification of persons at risk for Graves' disease is possible by this means.

Genetic diversity in clinical isolates of the dimorphic fungus Blastomyces dermatitidis detected by a PCR-based random amplified polymorphic DNA assay.

Blastomyces dermatitidis is a dimorphic fungus causing localized or systemic infection in areas where the organism is endemic in the central and southeastern United States. In this study, 19 independent isolates of B. dermatitidis from Little Rock, Ark., were grouped into three classes based on restriction fragment length polymorphism patterns in mitochondrial DNA with a heterologous probe from Histoplasma capsulatum. One large class of 15 isolates and two smaller classes (classes 2 and 3), each consisting of two isolates, were observed in BglII digests. Strain-specific arrays of PCR-amplified DNA products were obtained with arbitrarily selected primers (18 to 29 nucleotides long; G+C contents, 33 to 56%). In the large class 1 group, 13 isolates could be differentiated by the random amplified polymorphic DNA (RAPD) method with various primers. The two remaining class 1 isolates were obtained from the same patients and produced identical RAPD arrays. Dissimilar RAPD patterns were obtained from the smaller class 2 group but not from the class 3 isolates. Significant genetic diversity in clinical isolates of B. dermatitidis was observed; this may underscore a similar environmental diversification. Further application of the typing techniques may provide significant insight into the epidemiology of blastomycosis and aid in the assessment of specific virulence phenotypes.

Evidence for a retroviral trigger in Graves' disease.

An apparently high frequency of Graves' disease encountered in New Orleans, Louisiana, prompted an investigation for a possible infectious agent that might be triggering the disease in genetically susceptible individuals. We studied 40 patients with Graves' disease, and compared them to the following groups of controls: age and gender matched healthy subjects; patients with multinodular goiter (non-autoimmune thyroid controls); patients with chronic lymphocytic thyroiditis (autoimmune thyroid disease controls) and additional organ or tissue specific autoimmune controls exclusive of thyroid autoimmunity, including patients with Type I diabetes and other endocrine autoimmune complex disorders. Serum antibodies against a prototypic strain of a human intracisternal A-type retroviral particle type 1 (HIAP-1) were detected by a sensitive and specific immunoblotting assay. In 87.5% (35/40) of the Graves' disease patients there was a positive reaction against several HIAP-1-associated proteins, predominantly 97 Kd and 80 Kd, with only 5 showing no reactivity to any. In contrast, 2% (2/105) of sera from normal controls showed positive reactivity. Furthermore, only 10% (1/10) of sera from multinodular goiter control patients and 10% (1/10) of Hashimoto's patients showed reactivity (p < 0.0005). Sera from 3 of 20 (15%) of Type I diabetic patients none of whom had Graves' disease, showed reactivity but there was no reactivity in 9 other patients with one or more of the endocrine autoimmune complex disorders, including Addison's disease, vitiligo, myasthenia gravis and pernicious anemia. In addition we studied two individuals with Graves' disease from each of two families residing outside Louisiana, all of whom were positive for these antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)