CNS viral infection diverts homing of antibody‐secreting cells from lymphoid organs to the CNS

Abstract

Neurotropic coronavirus infection of mice results in acute encephalomyelitis followed by viral persistence. Whereas cellular immunity controls acute infection, humoral immunity regulates central nervous system (CNS) persistence. Maintenance of serum Ab was correlated with tissue distribution of virus-specific Ab-secreting cells (ASC). Although virus-specific ASC declined in cervical lymph node and spleen after infectious virus clearance, virus-specific serum Ab was sustained at steady levels, with a delay in neutralizing Ab. Virus-specific ASC within the CNS peaked rapidly 1 wk after control of infectious virus and were retained throughout chronic infection, consistent with intrathecal Ab synthesis. Surprisingly, frequencies of ASC in the BM remained low and only increased gradually. Nevertheless, virus-specific ASC induced by peripheral infection localized to both spleen and BM. The data suggest that CNS infection provides strong stimuli to recruit ASC into the inflamed tissue through sustained up-regulation of the CXCR3 ligands CXCL9 and CXCL10. Irrespective of Ag deprivation, CNS retention of ASC coincided with elevated BAFF expression and ongoing differentiation of class II + to class II -CD138 + CD19 + plasmablasts. These results confirm the CNS as a major ASCsupporting environment, even after resolution of viral infection and in the absence of chronic ongoing inflammation. IntroductionThe preeminent goal of the immune system is to eliminate pathogens and establish immunological memory [1]. Both T cells and Ab participate in eliminating a variety of pathogens; however, sustained serum Ab is an important criteria for many vaccination strategies, as they provide the first line of defense against re-infection [2]. Upon Ag encounter in regional lymph nodes, B cells undergo clonal expansion in extrafollicular foci and within germinal centers [3,4].Rapidly activated B cells secrete low-affinity Ab but can undergo isotype switching and limited BCR hypermutation as they differentiate into plasmablasts [3]. In the milieu of accessory cells and cytokines, germinal center B cells undergo affinity maturation and ultimately differentiate into both Ab-secreting cells (ASC) and memory B cells. As Ag is depleted, ASC and memory B cells are detected with increasing frequency in BM [2], where both stromal cells and other resident cells provide soluble as well as contact-dependent survival signals, including CXCL12 and BAFF [5]. Ab secretion by terminally differentiated plasma cells is independent of both Ag and T cell regulation [2,6]. Long-lived ASC in BM and spleen maintain serum Ab, thus providing protective immunity to re-infection, sometimes for the [4,6]. In contrast to Ag encountered in the periphery, the regulation of B cell activation by Ag sequestered within the central nervous system (CNS) is less clear. The absence of dedicated lymphatic drainage and the presence of the blood brain barrier (BBB) limits Ag transport from the CNS into secondary lymphoid tissue as well as trafficking of both cells and macromolecule...

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

“…The late detection of SINV-specific IgA in the bone marrow could be due to the trafficking of these cells from the brain or further differentiation within the bone marrow. Ongoing differentiation of PBs was also observed in the brains of mouse hepatitis virusinfected mice (53).…”

“…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).…”

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

“…This again suggests that CXCR3 ligands play a role in recruitment of effector cells to infection sites. Because both CXCL9 and CXCL10 are important for recruitment of ASCs to inflamed tissues (54), it is possible that CXCL9 is able to compensate for the CXCL10 deficiency by recruiting ASCs in CXCL10 2/2 mice following DENV infection. Other chemokines, such as CXCL12, may also be involved in ASC recruitment (38).…”

Efficacy of Intracerebral Immunization against Pseudorabies Virus in Mice

“…The elevated CSF antibody titers detected only in SA immunized and not in SC immunized rabbits suggest IT synthesis as the most likely source of the excess immunoglobulin. Antibody production in the CSF has been reported in normal brain (8) as well as in animals and humans with increased blood-brain barrier permeability or other pathologies of the CNS (3,12,(43)(44)(45). Immunologic processing with drainage and retention of brain-derived antigens is an important factor in the initiation and regulation of immune responses in the CNS.…”