The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis.

The human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

El dolor alarma y el dolor como carga / The soul pain soul and the pain like load

Respecto del tratamiento con fármacos opioides se discuten algunas de las dificultades que tienen los médicos para valorar los síntomas en pacientes con dolor moderado a severo, y para implementar estrategias terapéuticas para aliviarlos. Dentro de las conductas médicas englobadas como ôopiofobiaõ se describen el miedo a que el paciente desarrolle depresión respiratoria (que no llega al 1% de riesgo de ocurrencia luego de la vía parenteral) y a que se vuelva adicto. Se repasan los conceptos de adicción, dependencia, tolerancia y se resumen las principales series de pacientes que proveen evidencia científica sobre la seguridad de los opioides utilizados en forma apropiada y en el marco de cuidados médicos.

A specific antibody response to HCV E2 elicited in mice by intramuscular inoculation of plasmid DNA containing coding sequences for E2.

As the chimpanzee, the only reliable animal model for hepatitis C virus (HCV) infection, is impractical for early stage testing of HCV vaccine candidates, we have evaluated the immune response in mice to an experimental plasmid based HCV vaccine. We used this system because DNA vaccines can be rapidly constructed without the necessity of large scale protein production and purification. In this preliminary study we tested the immune response in mice to HCV envelope glycoprotein, E2, induced by a eukaryotic expression plasmid. Protein expression was monitored by immunofluorescence in transfected tissue culture cells. Each mouse was inoculated intramuscular with 100 microg plasmid DNA and some mice were boosted after 5 weeks. Among 12 BALB/C mice inoculated, 10 developed antibody to E2 by the second week. The antibody levels increased steadily before reaching a plateau in mice receiving the booster, but in the nonboosted mice the antibody declined over time. The serum from one mouse was tested against a series of overlapping peptides covering most of E2. This serum contained antibodies recognizing two distinct epitopes beginning at amino acid 57 and amino acid 113 but no antibody was directed against peptides representing the hypervariable region of E2, antibody to which is thought to be important in HCV neutralization. We have shown that the use of plasmid based vaccines can induce a specific immune response in mice against HCV antigens. This system should be useful as the first step in vaccine development.

Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features. The Hepatitis C Study Group.

OBJECTIVE: To assess the clinical significance of antibody to hepatitis C virus (anti-HCV) in volunteer blood donors. DESIGN: Prospective cohort study. SETTING: National Institutes of Health Clinical Center, a tertiary referral research hospital. PATIENTS: 60 anti-HCV-positive blood donors, divided into three groups of 20 persons each: Group I had normal alanine aminotransferase levels, group II had levels elevated to values less than twice the normal range, and group III had levels elevated to values greater than twice the normal range. MEASUREMENTS: Medical history, results of laboratory and virologic testing, and percutaneous liver biopsy findings. RESULTS: Participants with normal alanine aminotransferase levels were older and more often female than those with abnormal levels. The source of infection, duration of disease, symptom score, and amount of alcohol consumed were similar in the three groups. Hepatitis C virus RNA was detectable in 85% of participants, more commonly in the groups with elevated alanine aminotransferase levels (95%) than in the group with normal levels (65%); however, titers were similar in all groups. Examination of liver biopsy specimens showed chronic hepatitis in 54 participants (90%) and cirrhosis in 1 participant. The only normal liver biopsy specimens (n = 3) were those from participants who were HCV RNA negative and had normal alanine aminotransferase levels. CONCLUSIONS: Most blood donors with anti-HCV have chronic hepatitis C regardless of their serum alanine aminotransferase levels. Donors with normal alanine aminotransferase levels and no HCV RNA in their serum generally have normal liver histologic findings or minimal changes and have probably recovered from HCV infection.

The Tay-Sachs disease prevention program in Australia: Sydney pilot study.

OBJECTIVES: To determine the frequency of heterozygous carriers of the Tay-Sachs disease gene in an asymptomatic Ashkenazi Jewish population and to compare the acceptability of different community testing strategies. DESIGN: Pilot survey of carrier rates and community attitudes. SETTING: Sydney, February 1993 to November 1994. PARTICIPANTS: 147 self- or medically referred people of Ashkenazi Jewish origin were tested. Jewish religious, medical and community organisations and leaders were consulted. OUTCOMES: Prevalence of HEXA mutations, client and community preference for different testing and reporting strategies. RESULTS: Frequency of heterozygous carriers was 1 in 18, with a relative frequency of the three major allelic variants similar to that in overseas studies. Most subjects were medically referred and preferred individual reporting of their carrier status. Community representatives had serious reservations about this strategy and few orthodox Jews participated in the study. An alternative strategy was developed for future testing. CONCLUSIONS: Frequency of heterozygous carriers of the Tay-Sachs disease gene was higher than found among Ashkenazi Jews in other countries, possibly because of ascertainment bias. A testing strategy with medical referral and individual reporting of carrier status may not be appropriate for all the community at risk and a modified strategy is necessary.

Genotypic analysis of hepatitis C virus in American patients.

We examined hepatitis C virus genotypes in 98 American patients with chronic hepatitis C virus infection by means of two methods; restriction fragment length polymorphism analysis and line probe assay, which is based on type-specific sequence variations in the 5' untranslated region. Type 1 was present in 73 patients (74%), type 2 in 15 (15%), type 3 in 6 (6%) and type 4 in 1 (1%). Line probe assay further subdivided type 1 into 1a (n = 35) and type 1b (n = 37) and type 2 into type 2a (n = 6) and 2b (n = 9). Two patients (2%) had both restriction fragment length polymorphism and line probe assay evidence of dual infection (with types 1 and type 2) while another case had both type 1a and 1b by line probe assay. One patient was untypable by either technique. There was no correlation between infecting genotype and presumed cause, serum indexes of necroinflammatory activity, or age or sex of the patients studied or known duration of infection. Patients with type 2 hepatitis C virus had more severe liver disease histologically (p = 0.0027) compared with other genotypes but, paradoxically, had significantly lower levels of circulating hepatitis C virus RNA (12.1 +/- 12.8 x 10(5) genome equivalents/ml) than other types (36.4 +/- 44.8 x 10(5) genome equivalents/ml, p < 0.001). Response to interferon was less likely to be sustained in patients infected with type 1 than in those infected with other types (7% vs. 40%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Partial characterization of hepatitis A viruses from three intermediate passage levels of a series resulting in adaptation to growth in cell culture and attenuation of virulence.

Viruses from passages 9/10, 21, and 32 of a serially passaged human isolate of hepatitis A virus, strain HM-175, were partially sequenced and compared for their abilities to grow in cell cultures and to cause disease in primates. Viruses from all passages grew more efficiently in cell culture than did the wild-type virulent virus from which they were derived, and all displayed some degree of attenuation of virulence for primates. Within the 5' noncoding region and the 2B2C region of the HAV genome, passage 9/10 virus differed in sequence from wild-type at a single and novel position in the 2C gene, while the sequence of the passage 32 virus was almost identical to that of a fully attenuated passage 35 virus. Passage 21 viruses were found to consist of a mixture of viruses which included all but two of the 13 mutations present in the sequenced regions of the virus from passage 32.