Factors Supporting Intrathecal Humoral Responses following Viral Encephalomyelitis

Abstract

Central nervous system (CNS) infections and autoimmune inflammatory disorders are often associated with retention of antibody-secreting cells (ASC). Although beneficial or detrimental contributions of ASC to CNS diseases remain to be defined, virus-specific ASC are crucial in controlling persistent CNS infection following coronavirus-induced encephalomyelitis. This report characterizes expression kinetics of factors associated with ASC homing, differentiation, and survival in the spinal cord, the prominent site of coronavirus persistence. Infection induced a vast, gamma interferon (IFN-␥)-dependent, prolonged increase in chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11 mRNA, supporting a role for chemokine (C-X-C motif) receptor 3 (CXCR3)-mediated ASC recruitment. Similarly, CD4 T cell-secreted interleukin-21, a critical regulator of both peripheral activated B cells and CD8 T cells, was sustained during viral persistence. The ASC survival factors B cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferatinginducing ligand (APRIL) were also significantly elevated in the infected CNS, albeit delayed relative to the chemokines. Unlike IFN-␥-dependent BAFF upregulation, APRIL induction was IFN-␥ independent. Moreover, both APRIL and BAFF were predominantly localized to astrocytes. Last, the expression kinetics of the APRIL and BAFF receptors coincided with CNS accumulation of ASC. Therefore, the factors associated with ASC migration, differentiation, and survival are all induced during acute viral encephalomyelitis, prior to ASC accumulation in the CNS. Importantly, the CNS expression kinetics implicate rapid establishment, and subsequent maintenance, of an environment capable of supporting differentiation and survival of protective antiviral ASC, recruited as plasmablasts from lymphoid organs.Virus-specific antibodies (Ab) play an important role in the control of many viral infections of the central nervous system (CNS) (17). Ab are delivered to the CNS either by diffusion across a compromised blood brain barrier (18, 53) or actively by Ab-secreting cells (ASC) which have infiltrated the CNS or differentiated locally in the inflamed tissue. Passage of Ab from serum is inefficient under steady-state conditions, making ASC-mediated Ab secretion at the site of CNS infection a more effective strategy of viral control. For example, Ab production by invading B cells is required to clear rabies virus from the CNS, as passively administered Ab do not mediate virus clearance (22). Furthermore, B cells in the CNS of Sindbis virus-infected mice continue to secrete Ab during viral RNA persistence, supporting the idea that ASC play a role in preventing viral recrudescence (71). In addition, prolonged intrathecal antiviral Ab production and ASC accumulation within the CNS occur following control of Semliki Forest virus (43, 53-55), measles virus (9, 48), and Theiler's murine encephalomyelitis virus (50, 51) infections.The concept of an ASC survival niche in the CNS during chronic infl...

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

“…The expression of CXCL13 and CXCL12 is essential for follicle formation in the CNS (22,23). CXCL13 mRNA was not elevated in the brains of JHMV-infected mice (48). In response to SINV, CXCL13 and CCL19 mRNAs were induced in the brain, but CXCR5 ϩ and CCR7 ϩ B cells did not appear to be infiltrating the brain, and other investigators have shown that CXCL13 Ϫ/Ϫ mice infected with SINV have normal B-cell infiltration and virus clearance (51).…”

“…Astrocytes in the CNS constitutively produce BAFF, and microglial cells secrete BAFF in vitro (24,49). In JHMV infection, the long-term maintenance of ASCs in the CNS after clearance of infectious virus and during persistence of viral RNA in glial cells coincides with astrocyte production of BAFF mRNA (16,48).…”

“…In GCs, IL-21 is produced by CD4 ϩ follicular helper T cells (47). CD4 ϩ T cells in the CNS also produce IL-21 (48), and T cells shift from CD8 ϩ to CD4 ϩ T cells after the clearance of infectious virus. Therefore, SINV-specific ASCs are likely maintained through interaction with SINV-specific IL-21-producing CD4 ϩ T cells that provide a signal for further differentiation and retention while nonspecific B-cells exit or undergo apoptosis.…”

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

“…To ascertain that CD19 deficiency affected overall ASC CNS migration independent of specificity, we monitored accumulation of ASC via expression of mRNAs encoding IgG and IgM heavy chains, which are highly expressed in ASC compared to non-Absecreting B cells (8). Both brains and spinal cords of infected WT mice exhibited a significant increase in IgG heavy chain mRNA by 14 days p.i., which was further elevated at days 21 through 28 p.i.…”

“…Following CNS infection with a glial-tropic sublethal variant of mouse hepatitis virus (MHV), designated JHMV-v2.2-1, both T and B cell priming occurs in draining cervical lymph nodes (CLN) (5)(6)(7). While virus-specific CD4 and CD8 T cells are essential to clear infectious virus, virus-specific antibody (Ab)-secreting cells (ASC) and sustained neutralizing IgG Ab are required for long-term control of persisting virus, which is detectable only by the ongoing presence of low levels of viral RNA (5,8,9). Virus-specific ASC in CLN are CD4 dependent (10) and reach peak frequencies at ϳ14 days postinfection (p.i.)…”