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. 2006 Mar;36(3):603-12.
doi: 10.1002/eji.200535123.

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

Shuen-Ing Tschen  1 , Stephen A Stohlman, Chandran Ramakrishna, David R Hinton, Roscoe D Atkinson, Cornelia C Bergmann
Affiliations

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

Shuen-Ing Tschen et al. Eur J Immunol. 2006 Mar.

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 ASC-supporting environment, even after resolution of viral infection and in the absence of chronic ongoing inflammation.

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Figures

Figure 1
Figure 1
Kinetics of serum and neutralizing Ab responses. (A) Virus‐specific IgG (solid circle) and IgM (open circle) and neutralizing Ab (B) in sera of infected mice are shown. Data are representative of pooled sera from three to five mice per time point from at least three experiments.
Figure 2
Figure 2
JHMV‐specific IgG and IgM ASC in peripheral lymphoid organs. Frequencies of JHMV‐specific IgG (solid circle) and IgM (open circle) ASC in spleen (A) and BM (B) measured by ELISPOT. Data represent the average of three to five separate experiments per time point ± SEM.
Figure 3
Figure 3
JHMV‐specific IgG and IgM ASC within the CNS. Frequencies of JHMV‐specific IgG (solid circle) and IgM (open circle) ASC in CNS measured by ELISPOT. Data represent the average of two to five separate experiments per time point ± SEM.
Figure 4
Figure 4
Plasma cell retention in the CNS following JHMV infection. Distribution of CD138+ plasma cells in spinal cord at day 35 p.i (A) and day 90 p.i. (B, C) as detected by immunohistochemistry. IgG+ cells (D, E) and IgM+ cells (F) in spinal cord at day 90 p.i. as detected by immunohistochemistry.
Figure 5
Figure 5
Total JHMV‐specific IgG (A) and IgM (B) ASC in CNS, spleen (SP) and BM. Numbers derived from frequencies were converted to total cell numbers in each tissue.
Figure 6
Figure 6
Recruitment kinetics of CD138+CD19+ B cells and differentiation during viral persistence. CNS mononuclear cells isolated from JHMV‐infected mice were stained for CD45, CD19, CD138 and class II expression and analyzed by 4‐color flow cytometry at the indicated time points after infection. (A) Density plots depicting CD138 and class II expression on CD45hi cells from brains throughout infection (gated on CD45hi cells). (B) Density plots gated on CD45hi cells from spinal cords depicting CD138 expression together with CD19 (left) and class II (right) at day 70 after infection. Numbers indicate percentages of cells in the respective quadrants.
Figure 7
Figure 7
Comparison of ASC frequencies and total numbers per tissue following CNS and peripheral infection. Frequencies and total numbers of virus‐specific ASC per tissue 90 days following CNS (A, C) or peripheral (B, D) JHMV infection are shown (SP: spleen). Frequencies and total numbers represent a combination of IgG and IgM ASC. Data are representative of three separate experiments.
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