B cells going viral in the CNS: Dynamics, complexities, and functions of B cells responding to viral encephalitis

Abstract

Summary A diverse number of DNA and RNA viruses have the potential to invade the central nervous system (CNS), causing inflammation and injury to cells that have a limited capacity for repair and regeneration. While rare, viral encephalitis in humans is often fatal and survivors commonly suffer from permanent neurological sequelae including seizures. Established treatment options are extremely limited, predominantly relying on vaccines, antivirals, or supportive care. Many viral CNS infections are characterized by the presence of antiviral antibodies in the cerebral spinal fluid (CSF), indicating local maintenance of protective antibody secreting cells. However, the mechanisms maintaining these humoral responses are poorly characterized. Furthermore, while both viral and autoimmune encephalitis are associated with the recruitment of diverse B cell subsets to the CNS, their protective and pathogenic roles aside from antibody production are just beginning to be understood. This review will focus on the relevance of B cell responses to viral CNS infections, with an emphasis on the importance of intrathecal immunity and the potential contribution to autoimmunity. Specifically, it will summarize the newest data characterizing B cell activation, differentiation, migration, and localization in clinical samples as well as experimental models of acute and persistent viral encephalitis.

CD6 Regulates CD4 T Follicular Helper Cell Differentiation and Humoral Immunity During Murine Coronavirus Infection

“…Therefore, accelerated and enhanced CD4 TFH cell differentiation was followed by increased B cell activation and GC responses. We further confirmed that GC structures were properly forming within CD6 KO cLNs at day 14PI, a time when GCs were easily discernable in WT cLNs, by examining the accumulation of GL7 + B cells within the cLN B cell follicle 20,35,36 (Figure 3D). Consistent with accelerated GC somatic hypermutation, mCoV-specific IgG antibodies with increased affinity for mCoV were selectively detected in CD6 KO sera at day 14PI (Figure 3E).…”

“…Importantly, the opposing functions of CD6 in CD4 T cell activation are not easily attributed to murine intrinsic factors, as the CD6 KO mice used herein were generated from the same colony and housed in the same facility as in the above mentioned autoimmune studies [15][16] . Unfortunately, further comparison between autoimmune and virus models is complicated by numerous factors; In the autoimmune encephalomyelitis and uveitis models T cell activation is dependent on immunization with self-peptide or antigen in adjuvant resulting in the induction of both Th1 and Th17 CD4 T cells 15,46 , whereas virus-specific T cells are activated by replicating virus and presentation of viral antigen generating an exclusive Th1 response [17][18][19][20] . These models also utilize distinct innate immune scavenging, pattern recognition receptors, and antigen presenting cells, all of which also contribute to the outcome of T cell activation [48][49][50] .…”

“…The total number of B cells in the CD6 KO mCoV infected brains was also elevated at day 7PI (Figure 5F). This was notable as most of the B cells in the brain at this early timepoint are IgD + IgM + B cells that migrate to the CNS in response to the inflammation [20][21] . More surprisingly, analysis of supernatants from dissociated WT and CD6 KO brain and spinal cord tissue revealed similar levels of virus-specific IgG antibodies across multiple dilutions as well as comparable mCoV affinity at day 21PI (Figure 5G-H).…”

“…Given the opposing functions of CD6 in different disease and clinical settings, we sought to determine how CD6 regulates T cell activation in an established model of viral encephalomyelitis. The attenuated recombinant neurotropic murine beta coronavirus MHV-A59 (mCoV), was chosen for this study as both the CD4 T helper 1 (TH1) cells and cytotoxic CD8 T cells are essential for the control of infectious virus within the CNS [17][18][19][20] . Furthermore, the generation of mCoV-specific antibodies is dependent on the CD4 follicular helper (TFH) cells, which mediate both germinal center (GC) formation as well as somatic-hypermutation of the B cell immunoglobulin variable chain, thus enabling the generation of high-affinity class switched antigen-specific B cells [20][21][22] .…”

An introduction to neuroimmunology

“…Another very timely review by Dr. Bergmann and colleagues highlights other pathogens that have the potential to inflict permanent CNS damage: DNA and RNA viruses 7. Although viral infections of the CNS are rare, treatment options are severely limited and often neurological sequelae are permanent and present a lifelong threat to hosts.…”