A Complement C3-Specific Nanobody for Modulation of the Alternative Cascade Identifies the C-Terminal Domain of C3b as Functional in C5 Convertase Activity.

The complement system is an intricate cascade of the innate immune system and plays a key role in microbial defense, inflammation, organ development, and tissue regeneration. There is increasing interest in developing complement regulatory and inhibitory agents to treat complement dysfunction. In this study, we describe the nanobody hC3Nb3, which is specific for the C-terminal C345c domain of human and mouse complement component C3/C3b/C3c and potently inhibits C3 cleavage by the alternative pathway. A high-resolution structure of the hC3Nb3-C345c complex explains how the nanobody blocks proconvertase assembly. Surprisingly, although the nanobody does not affect classical pathway-mediated C3 cleavage, hC3Nb3 inhibits classical pathway-driven hemolysis, suggesting that the C-terminal domain of C3b has an important function in classical pathway C5 convertase activity. The hC3Nb3 nanobody binds C3 with low nanomolar affinity in an SDS-resistant complex, and the nanobody is demonstrated to be a powerful reagent for C3 detection in immunohistochemistry and flow cytometry. Overall, the hC3Nb3 nanobody represents a potent inhibitor of both the alternative pathway and the terminal pathway, with possible applications in complement research, diagnostics, and therapeutics.

Chronic hepatitis caused by persistent parvovirus B19 infection.

BACKGROUND: Human infection with parvovirus B19 may lead to a diverse spectrum of clinical manifestations, including benign erythema infectiosum in children, transient aplastic crisis in patients with haemolytic anaemia, and congenital hydrops foetalis. These different diseases represent direct consequences of the ability of parvovirus B19 to target the erythroid cell lineage. However, accumulating evidence suggests that this virus can also infect other cell types resulting in diverse clinical manifestations, of which the pathogenesis remains to be fully elucidated. This has prompted important questions regarding the tropism of the virus and its possible involvement in a broad range of infectious and autoimmune medical conditions. CASE PRESENTATION: Here, we present an unusual case of persistent parvovirus B19 infection as a cause of chronic hepatitis. This patient had persistent parvovirus B19 viraemia over a period of more than four years and displayed signs of chronic hepatitis evidenced by fluctuating elevated levels of ALAT and a liver biopsy demonstrating chronic hepatitis. Other known causes of hepatitis and liver damage were excluded. In addition, the patient was evaluated for immunodeficiency, since she had lymphopenia both prior to and following clearance of parvovirus B19 infection. CONCLUSIONS: In this case report, we describe the current knowledge on the natural history and pathogenesis of parvovirus B19 infection, and discuss the existing evidence of parvovirus B19 as a cause of acute and chronic hepatitis. We suggest that parvovirus B19 was the direct cause of this patient's chronic hepatitis, and that she had an idiopathic lymphopenia, which may have predisposed her to persistent infection, rather than bone marrow depression secondary to infection. In addition, we propose that her liver involvement may have represented a viral reservoir. Finally, we suggest that clinicians should be aware of parvovirus B19 as an unusual aetiology of chronic hepatitis, when other causes have been ruled out.