Severe acute respiratory syndrome-related coronavirus: the species and its viruses-a statement of the Coronavirus Study Group. bioRxiv 2020; published online Feb 11.

Secreted IgM and complement are important mediators in the optimal initiation of primary T-dependent humoral immune responses. Secreted IgM serves as a natural adjuvant by enhancing the immunogenicity of protein antigens, perhaps as a result of IgM's ability to facilitate antigen deposition onto follicular dendritic cells (FDCs) and promote rapid germinal center (GC) formation. To understand how IgM enhances adaptive immune responses, we investigated the mechanism by which IgM-containing immune complexes (IgM-IC) are transported to FDCs as a first step in GC formation. We demonstrate that IgM-IC localize first to the splenic marginal zone (MZ) where the IgM-IC bind MZ B cells in a complement and complement receptor (CR1/2) dependent process. MZ B cells then transport the IgM-IC into the follicle for deposition onto FDCs. Mice with reduced numbers of MZ B cells trap IgM-IC on FDC less efficiently, whereas mice with reduced numbers of follicular B cells trap IgM-IC normally. The functional elimination of MZ B cells abrogates the ability of FDCs to trap IgM-IC. Transfer of B cells with associated IgM-IC into naive mice results in deposition of IgM-IC onto FDC by MZ B cells. The results demonstrate an IgM and complement-dependent role for MZ B cells in the fate of antigen early in the initial phases of T-dependent immune responses. The data also establish an important role for CR1/2 on MZ B cells in the efficient binding and transport of IgM-IC to FDCs, which we suggest is an important first step in initiating adaptive immune responses.

Marburg and Ebola viruses cause a severe hemorrhagic disease in humans with high fatality rates. Early target cells of filoviruses are monocytes, macrophages, and dendritic cells. The infection spreads to the liver, spleen and later other organs by blood and lymph flow. A hallmark of filovirus infection is the depletion of non-infected lymphocytes; however, the molecular mechanisms leading to the observed bystander lymphocyte apoptosis are poorly understood. Also, there is limited knowledge about the fate of infected cells in filovirus disease. In this review we will explore what is known about the intracellular events leading to virus amplification and cell damage in filovirus infection. Furthermore, we will discuss how cellular dysfunction and cell death may correlate with disease pathogenesis.

In systemic lupus erythematosus (SLE), immune complexes (ICs) containing mammalian DNA activate dendritic cells (DC) at least in part through Toll‐like receptor 9 (TLR9). However, the DNA sequence required for this TLR9 activation is unclear because, unlike bacterial or viral DNA, mammalian DNA contains very few of the classical unmethylated CpG motifs believed to be important for TLR9 activation. To address this question, we treated mouse DC with immune complexes containing DNA fragments of defined sequence, including sequences obtained from CpG islands within the mammalian genome, and measured cytokine production and co‐stimulatory molecule upregulation. We found that although the strongest activation was elicited by classical unmethylated CpG motifs, effective activation was also elicited by methylated classical CpG motifs and by unmethylated non‐classical CpG motifs. The activation was entirely TLR9‐dependent. In contrast, no activation was elicited by DNA lacking CG sequences. Overall, the data indicate that IC containing DNA sequences found in mammalian DNA are able to activate DC, providing a possible explanation for how DNA‐containing IC might cause immune system activation in patients with SLE. This research is supported by a NIH (NIAMS) program project grant.

We have investigated the roles of IgM and complement (C) in the enhancement of primary immune responses and the localization of protein antigen (Ag) in the spleen. Pentameric but not monomericIgM enhances antibody (Ab) responses in both wild‐type and secretory μ‐deficient (μs–/–) mice, indicating that a single IgM clone is sufficient as long as it activates C. Ag localizes on follicular dendritic cells (FDC) within 16 h after injection of immune complexes (IC) containing pentameric but not monomeric IgM. Surprisingly, pentameric IgM‐containing IC were trapped in spleens of C3‐depleted and Cr2‐deficient mice. However, the IC were found only in the marginal zone (MZ), associated predominantly with MZ macrophages. IC were also detected in the MZ in normal mice within 1 h after injection, but associated with other cells in addition to MZ macrophages. The results demonstrate an important role for pentameric IgM in the initiation of Ag trapping, a step independent of C3 activation and of the interaction of IC with CR1 and CR2. The data also provide direct evidence that C3 activation is required for the next phase of localization, in which Ag moves from the MZ to FDC, with consequent enhancement of specific immune responses.