Human parvovirus B19 : studies on the pathogenesis of infection

Sammanfattning: Human parvovirus B19 (B19) causes the common childhood disease erythema infectiosum. The virus is transmitted by the respiratory route, infects erythroid progenitor cells, and thereby inhibits erythropoiesis. The seroprevalence in the adult population is 50-70%, rising to over 80% among the elderly. Primary infection in adults may cause arthritis of long duration and lead to aplastic crisis patients with underlying haemolytic disorder. In immunocompromised individuals, the infection can establish persistency in the bone marrow resulting in severe anaemia. Persistent B 19 infection has also been observed in immunocompetent individuals, even though B19-neutralising antibodies can be detected, giving rise to a wide array of symptoms. Primary B19 infection in pregnant women has been linked to the development of hydrops fetalis, spontaneous abortion and intrauterine fetal death (IUFD), most commonly during the second trimester of pregnancy. We prospectively collected placental and fetal tissue from cases of late second and third trimester lUFD, during the years 1992-99, and found 7.5% and 15%, respectively, to be B19 DNA positive. These findings indicate that B 19 may be more commonly associated to lUFD in the late stages of pregnancy than earlier appreciated. The majority of cases did not exhibit hydrops fetalis, lacked clinical signs of acute infection, and may thus have been infected long before clinical presentation. We therefore suggest that sensitive methods for detection of B 19 DNA should be included in the routine investigation of IUFD Previous reports have indicated that the viral genotype may determine the course of B 19 infection with regard to development of persistent infection. When comparing full-length sequences from B 19 viral isolates derived from inummocompromised and immunocompetent persistently infected individuals with previously published sequences, no significant difference was found. This indicates that variations in the B 19 genotype may not be important in the development of persistent infection. It has been suggested that antibodies to the B 19 non-structural (NS) dominate in patients with persistent B 19 infection, reflecting an altered humoral response in these individuals. However, by linear epitope mapping the anti-B 19 NS-specific antibody reactivity was found to be conserved among healthy subjects and patients suffering from various B 19 related complications. Neither was any specific region commonly recognised by all individuals. Deficient cytotoxic cellular immune response against B 19 may contribute to the development of viral persistence. This entity of the immune system has not previously been investigated in B 19 infection. By screening overlapping peptides, an HLA B35 restricted B19-specific cytotoxic T cell epitope was found contained within the NS protein. Using interferon-gamma detection and tetrameric complex binding we found that approximately 65% of all HLA-matched individuals possess functional epitope-specific cytotoxic T cells to this epitope, however in immunocompromised individuals these cells exhibit lower cytolytic function ex vivo. We have thus investigated factors involved in the pathogenesis of persistent B 19 infection in immunocompetent individuals, inummocompromised patients and pregnant women.