Across the animal kingdom, multivalency discriminates antibodies from all other immunoglobulin superfamily members. The evolutionary forces conserving multivalency above other structural hallmarks of antibodies remain, however, incompletely defined. Here, we engineer monovalent either Fc-competent or -deficient antibody formats to investigate mechanisms of protection of neutralizing antibodies (nAbs) and non-neutralizing antibodies (nnAbs) in virus-infected mice. Antibody bivalency enables the tethering of virions to the infected cell surface, inhibits the release of virions in cell culture, and suppresses viral loads in vivo independently of Fc gamma receptor (Fc gamma R) interactions. In return, monovalent antibody formats either do not inhibit virion release and fail to protect in vivo or their protective efficacy is largely Fc gamma R dependent. Protection in mice correlates with virus-release-inhibiting activity of nAb and nnAb rather than with their neutralizing capacity. These observations provide mechanistic insights into the evolutionary conservation of antibody bivalency and help refining correlates of nnAb protection for vaccine development.

Passive antibody therapy and vectored antibody gene delivery (VAGD) in particular offer an innovative approach to combat persistent viral diseases. Here, we exploit a small animal model to investigate synergies of VAGD with the host's endogenous immune defense for treating chronic viral infection. An adeno-associated virus (AAV) vector delivering the lymphocytic choriomeningitis virus (LCMV)-neutralizing antibody KL25 (AAV-KL25) establishes protective antibody titers for >200 days. When therapeutically administered to chronically infected immunocompetent wild-type mice, AAV-KL25 affords sustained viral load control. In contrast, viral mutational escape thwarts therapeutic AAV-KL25 effects when mice are unable to mount LCMV-specific antibody responses or lack CD8(+) T cells. VAGD augments antiviral germinal center B cell and antibody-secreting cell responses and reduces inhibitory receptor expression on antiviral CD8(+) T cells. These results indicate that VAGD fortifies host immune defense and synergizes with B cell and CD8 T cell responses to restore immune control of chronic viral infection.

Significance Vaccines against persisting viruses such as HIV or hepatitis C virus remain a significant unmet global need. Long-lived memory B cells can be induced by vaccination to form an important pillar of antiviral immunity, yet persisting viruses subvert both primary B cell responses and memory B cell protection. Studying a mouse model of persistent viral infection, we found that CD4 T memory cells averted the deletion of antiviral B cells upon chronic virus challenge. Memory T help promoted germinal center reactions, preventing the B cells’ untimely, interferon-induced end differentiation. These observations indicate that B cell–based vaccination should be paired with potent memory CD4 T cell induction for memory B cells to prevail when confronted with a chronic viral intruder.

Raw data underlying the publication by Narr et al. entitled "Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection".

Systemic sclerosis (SSc) is a rare, difficult to treat disease with profound effects on quality of life and high mortality. Complex and incompletely understood pathophysiologic processes and greatly heterogeneous clinical presentations and outcomes have hampered drug development.This review summarizes the currently available immunosuppressive and antifibrotic therapies and discusses novel approaches for the treatment of SSc. We reviewed the literature using the MEDLINE and ClinicalTrial.gov databases between May and September 2020.Available immunosuppressive and antifibrotic drugs only modestly impact the course of the disease. Most drugs are currently only investigated in the subset of patients with early diffuse cutaneous SSc. In this patient population, hematopoietic stem-cell transplantation is currently the only treatment that has demonstrated reversal of lung involvement, enhanced quality of life and reduced long-term mortality, but carries the risk of short-term treatment-related mortality. A great need to provide better therapeutic options to patients exists also for those patients who have limited cutaneous skin involvement. A better understanding of SSc pathophysiology has enabled the identification of numerous new therapeutic targets. The progress made in the design of clinical trials and outcome parameters will likely result in the improvement of effective management options.

Over 4 million cases of Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been confirmed worldwide. Up to 20% of cases develop severe disease and the fatality rate are high.[1] Little is known however on the course of the infection in immunosuppressed patients. We therefore report the case of a patient with COVID-19 under immunosuppression with rituximab. This 77-year-old woman was admitted to the hospital with a 5-week history of unclear fever (up to 38.5°C), hypotension (80 mmHg systolic on self-measurement), occasional mild shortness of breath and intermittent dry cough.

Introduction Systemic sclerosis (SSc) is a rare, difficult to treat disease with profound effects on quality of life and high mortality. Complex and incompletely understood pathophysiologic processes and greatly heterogeneous clinical presentations and outcomes have hampered drug development. Areas covered This review summarizes the currently available immunosuppressive and antifibrotic therapies and discusses novel approaches for the treatment of SSc. We reviewed the literature using the MEDLINE and ClinicalTrial.gov databases between May and September 2020. Expert opinion Available immunosuppressive and antifibrotic drugs only modestly impact the course of the disease. Most drugs are currently only investigated in the subset of patients with early diffuse cutaneous SSc. In this patient population, hematopoietic stem-cell transplantation is currently the only treatment that has demonstrated reversal of lung involvement, enhanced quality of life and reduced long-term mortality, but carries the risk of short-term treatment-related mortality. A great need to provide better therapeutic options to patients exists also for those patients who have limited cutaneous skin involvement. A better understanding of SSc pathophysiology has enabled the identification of numerous new therapeutic targets. The progress made in the design of clinical trials and outcome parameters will likely result in the improvement of effective management options.

Persistent viral infections subvert key elements of adaptive immunity. To compare germinal center (GC) B cell responses in chronic and acute lymphocytic choriomeningitis virus infection, we exploit activation-induced deaminase (AID) fate-reporter mice and perform adoptive B cell transfer experiments. Chronic infection yields GC B cell responses of higher cellularity than acute infections do, higher memory B cell and antibody secreting cell output for longer periods of time, a better representation of the late B cell repertoire in serum immunoglobulin, and higher titers of protective neutralizing antibodies. GC B cells of chronically infected mice are similarly hypermutated as those emerging from acute infection. They efficiently adapt to viral escape variants and even in hypermutation-impaired AID mutant mice, chronic infection selects for GC B cells with hypermutated B cell receptors (BCRs) and neutralizing antibody formation. These findings demonstrate that, unlike for CD8(+) T cells, chronic viral infection drives a functional, productive, and protective GC B cell response.

Arenaviruses such as Lassa virus (LASV) cause hemorrhagic fever. Terminal shock is associated with a systemic cytokine storm, but the mechanisms are ill defined. Here we used HLA-A2-expressing mice infected with a monkey-pathogenic strain of lymphocytic choriomeningitis virus (LCMV-WE), a close relative of LASV, to investigate the pathophysiology of arenavirus hemorrhagic fever (AHF). AHF manifested as pleural effusions, edematous skin swelling, and serum albumin loss, culminating in hypovolemic shock. A characteristic cytokine storm included numerous pro-inflammatory cytokines and nitric oxide (NO) metabolites. Edema formation and terminal shock were abrogated in mice lacking inducible nitric oxide synthase (iNOS), although the cytokine storm persisted. iNOS was upregulated in the liver in a T cell- and interferon-γ (IFN-γ)-dependent fashion. Accordingly, blockade of IFN-γ or depletion of T cells repressed hepatic iNOS and prevented disease despite unchecked high-level viremia. We identify the IFN-γ-iNOS axis as an essential and potentially druggable molecular pathway to AHF-induced shock.

Interferon-driven inflammation in chronic viral infection blocks generation of sustained B cell responses. See related Research Articles by Moseman et al. and Sammicheli et al. and a Focus by Laidlaw et al.

Antibodies are critical for protection against viral infections. However, several viruses, such as lymphocytic choriomeningitis virus (LCMV), avoid the induction of early protective antibody responses by poorly understood mechanisms. Here we analyzed the spatiotemporal dynamics of B cell activation to show that, upon subcutaneous infection, LCMV-specific B cells readily relocate to the interfollicular and T cell areas of the draining lymph node where they extensively interact with CD11b+Ly6Chi inflammatory monocytes. These myeloid cells were recruited to lymph nodes draining LCMV infection sites in a type I interferon-, CCR2-dependent fashion and they suppressed antiviral B cell responses by virtue of their ability to produce nitric oxide. Depletion of inflammatory monocytes, inhibition of their lymph node recruitment or impairment of their nitric oxide-producing ability enhanced LCMV-specific B cell survival and led to robust neutralizing antibody production. In conclusion, our results identify inflammatory monocytes as critical gatekeepers that prevent antiviral B cell responses and suggest that certain viruses take advantage of these cells to prolong their persistence within the host.

Immune subversion represents a hallmark of persistent infection, but microbial suppression of B cell responses remains mechanistically ill-defined. Adoptive transfer experiments in a chronic viral infection model evidenced the rapid and profound decimation of B cells that responded to virus or to concomitantly administered protein. Decimation affected naive and memory B cells and resulted from biased differentiation into short-lived antibody-secreting cells. It was driven by type I interferon (IFN-I) signaling to several cell types including dendritic cells, T cells and myeloid cells. Durable B cell responses were restored upon IFN-I receptor blockade or, partially, when depleting myeloid cells or key IFN-I-induced cytokines. B cell decimation represents a molecular mechanism of humoral immune subversion and reflects an unsustainable “all-in” response of B cells in IFN-I-driven inflammation.