Recruitment Kinetics and Composition of Antibody-Secreting Cells Within the Central Nervous System Following Viral Encephalomyelitis

Abstract

Infection by the neurotropic JHM strain of mouse hepatitis virus produces an acute demyelinating encephalomyelitis. While cellular immunity initially eliminates infectious virus, CNS viral persistence is predominantly controlled by humoral immunity. To better understand the distinct phases of immune control within the CNS, the kinetics of humoral immune responses were determined in infected mice. Early during clearance of the JHM strain of mouse hepatitis virus, only few virus-specific Ab-secreting cells (ASC) were detected in the periphery or CNS, although mature B cells and ASC without viral specificity were recruited into the CNS concomitant with T cells. Serum antiviral Ab and CNS virus-specific ASC became prominent only during final elimination of infectious virus. Virus-specific ASC peaked in lymphoid organs before the CNS, suggesting peripheral B cell priming and maturation. Following elimination of infectious virus, virus-specific ASC continued to increase within the CNS and then remained stable during persistence, in contrast to declining T cell numbers. These data comprise three novel findings. Rapid recruitment of B cells in the absence of specific Ab secretion supports a potential Ab-independent effector function involving lysis of virus-infected cells. Delayed recruitment relative to viral clearance and subsequent maintenance of a stable CNS ASC population demonstrate differential regulation of T and B lymphocytes within the infected CNS. This supports a critical role of humoral immunity in regulating viral CNS persistence. Lastly, altered antiviral ASC specificities following clearance of infectious virus suggest ongoing recruitment of peripheral memory cells and/or local B cell differentiation.

Alphavirus-Induced Encephalomyelitis: Antibody-Secreting Cells and Viral Clearance from the Nervous System

“…However, in the current study, infectious virus was cleared by day 8, even though infiltrating ASCs did not produce antiviral IgG until day 10 (54). The appearance of virus-specific IgG and IgA ASCs after the clearance of infectious virus was also observed in the CNS of mice infected with mouse hepatitis virus (52). Extrafollicularly derived SINV-specific IgM ASCs were the first to arrive in the brain and were detectable by day 5.…”

“…Long-term maintenance of antiviral ASCs is essential for continued local Ab production and is likely to be important for the prevention of viral recrudescence. Retention of antiviral ASCs has been observed following other neurotropic virus infections, such as those caused by measles virus (38), West Nile virus (48), rabies virus (17), and mouse hepatitis virus (52,53). Clinical evidence of the importance of sustained suppression of virus replication in the CNS comes from experience with rituximab (anti-CD20) for the elimination of B cells and with natalizumab (anti-VLA-4) for prevention of the entry of inflammatory cells into the CNS, where a major complication has been reactivation of CNS virus infection (8,20).…”

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

“…IgG therapy (53)(54)(55)(56). Especially in the case of neurotropic viruses, Abs have been shown to limit or prevent virus spread to the CNS system or restrict virus expression (57)(58)(59)(60). Other viruses infecting epithelia such as pulmonary influenza virus can be cleared by application of Abs after establishment of infection (61).…”

Recruitment and Retention of B Cells in the Central Nervous System in Response to Alphavirus Encephalomyelitis

“…The presence of antiviral ASCs in the CNS has been observed following other neurotropic virus infections, such as those caused by measles virus (7)(8)(9), West Nile virus (10), rabies virus (11), Semliki Forest virus (12,13), Theilers murine encephalomyelitis virus (14), and the JHM strain of mouse hepatitis virus (JHMV) (15,16). There is also substantial evidence that entry and retention of ASCs in the CNS are important for virus clearance and prevention of reactivation (17,18).…”