Boxes span the interquartile range (IQR) with the 25th and the 75th percentiles

Boxes span the interquartile range (IQR) with the 25th and the 75th percentiles. normalization improved overall performance and reduced discordance. The interlaboratory interassay assessment between Basel3 and Helsinki1 exposed only 15 discordant results, 14 (93%) of which were close to the cutoff. Preadsorption recognized specificities of 99.44% and 97.78% and sensitivities of 99.54% and 95.87% for Basel3 and Helsinki1, respectively. Therefore, normalization to a preferably WHO-approved research serum, duplicate testing, and preadsorption for samples round the cutoff may be necessary for reliable JCPyV serology and PML risk stratification. INTRODUCTION Seroprevalence studies show that by early adulthood, JC polyomavirus (JCPyV) offers infected approximately half of the general human population (1, 2). Thereafter, JCPyV asymptomatically persists in renourinary tract and is intermittently shed into the urine (2,C4). In immunocompromised individuals, JCPyV can cause progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, with typically fatal end result (5, 6). PML results from lytic JCPyV replication in subcortical oligodendrocytes that generate neuronal myelin sheaths. Progressive demyelination followed by neuronal Madecassic acid dysfunction and cell death underlies the radiological and medical features Madecassic acid of PML (1, 5, 6). Despite some encouraging data (7), there is currently no specific antiviral therapy, and the outcome of PML depends mainly on mounting JCPyV-specific immune functions that suppress JCPyV replication (1, 6, 8, 9). PML had been a frequent complication of HIV and AIDS individuals in the era before combination antiretroviral therapy, influencing 1% to 8% of the individuals at risk (10, 11). The availability of combination antiretroviral therapy (cART) offers decreased the incidence of PML and significantly improved PML end result (10, 12). Recently, an increasing quantity of PML instances were observed among multiple sclerosis (MS) individuals treated with natalizumab. Natalizumab is definitely a monoclonal antibody obstructing 41 integrin and therefore homing of inflammatory cells to MS lesions (13,C15). Practically all MS individuals were found to be JCPyV seropositive at the time of Madecassic acid natalizumab treatment, indicating that most, Madecassic acid if not all, instances of PML were in fact caused by JCPyV reactivation (16). Therefore, the risk of PML after 24 months of natalizumab therapy can be as high as 1:100 in JCPyV-seropositive individuals but less than 1:10,000 in JCPyV-seronegative MS individuals compared to less than 1:500,000 in the general population per year (1). Consequently, testing of MS individuals for JCPyV antibodies may provide a relevant PML risk stratification tool and inform decisions concerning follow-up and treatment modalities (17, 18). JCPyV antibodies can be recognized by different techniques, including disease neutralization, hemagglutination inhibition of reddish blood cells, indirect immunofluorescence using JCPyV protein-expressing cells, and the enzyme-linked immunosorbent assay (ELISA) (1, 19). Ctsl However, neutralization, while being functionally important, has some limitations, including the absence of a defined cutoff and the inability to detect specific, nonneutralizing antibodies. Hemagglutination inhibition assays generally display low sensitivity and don’t allow reliable measurement of low antibody titers and detection of antibodies against JCPyV with standard PML-associated mutations in the sialic acid-binding region of the mutant VP1 gene (20, 21). While ELISA is the most widely used technique, the different assays vary in overall performance, serum dilutions, empirically derived cutoffs, and antigen preparations. Even though major viral capsid protein VP1 is frequently used, preparations of monomer, pentamer, or virus-like particles (VLPs) have been reported, which together with variations in serum dilutions and cutoffs are likely to affect reliability and commutability of results (1, 19). We previously investigated the seroprevalence of JCPyV antibodies in 400 healthy blood donors from Basel, Switzerland. Although our overall results corresponded well to reports from other studies (22), including those on MS individuals (23), as examined in research 1, the interpretation of results round the cutoff is usually hard. Particularly the implications of a false-negative result for patient counseling concerning the PML risk under natalizumab therapy or conversely the withholding of therapy for a patient having a false-positive result.