Several studies reported enhanced pathology after a heterologous

Several studies reported enhanced pathology after a heterologous challenge of adult mice with CVB3 after an initial infection with CVB2 (Beck et al., 1990; Yu et al., 1999; Michels & Tiu, 2007). In these studies, a heterologous challenge was crucial for enhanced pathology, suggesting an effect of cross-reactivity and enhanced immunopathology which may be due to the

phenomenon of original antigenic sin (Morens et al., 2010) or to antibody-dependent Torin 1 purchase enhancement (ADE) (Beck et al., 1990; Girn et al., 2002; Kishimoto et al., 2002; Takada & Kawaoka, 2003; Sauter & Hober, 2009). Our data have more similarity to those of Horwitz et al. (2003), who showed that in adult mice homologous challenge with CVB4-E2 resulted in hyperglycemia. The authors showed that the effect was not directly T-cell-mediated although T cells were still essential for survival of infection. We hypothesize on

the basis of our data that preexisting immunity is responsible for the enhanced pathology in the offspring and that the observed effects are thus immune-mediated. There are several Nivolumab options: (1) maternal antibodies, passively transferred to offspring; (2) T-cell-mediated immunity, and (3) triggering of autoimmunity. Implications of these options are the following: (1) maternal antibodies are expected to be of the neutralizing type being able to protect pups from infection with the homologous strain; however, low antibody levels may fail to neutralize the virus and cause an adverse effect by means of ADE as has been

reported before (Beck et al., 1990; Girn et al., 2002; Horwitz et al., 2003; Takada & Kawaoka, 2003; Sauter & Hober, 2009). Indeed, antibodies were present in the 9 (+/−) control pups and in the infected dams. Assuming that the offspring were not infected antenatally as we believe, the antibodies must have been of maternal origin; (2) intrauterine infection of the pups may raise a cellular immune response which, because of a gradual maturation of the fetal immune system, may be more vigorous in the 3rd week of gestation than in earlier stages. The latter can explain the more severe course upon challenge after maternal infection at day 17; (3) autoimmunity, being actually a variant of option (2), may be triggered by infection of pancreatic islets of the mother, thus presenting islet auto-antigens in a context of (infectious) danger signaling during BCKDHB the development of the fetus. For the latter two options, an antenatal infection may probably not be needed, as recently was shown by Jubayer et al. (2010), who demonstrated that postnatal immunity can be specifically raised by immunization of the mother during gestation. Hence, all three mechanisms (passive transfer of antibody and induction of cellular immunity against viral and/or auto-antigens) may thus occur in the absence of antenatal infection. Further studies are required to investigate which of these possibilities are responsible for the enhanced pathology.

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