Follicular dendritic cell dysfunction contributes to impaired antigen-specific humoral responses in sepsis-surviving mice
Minakshi Rana, Andrea La Bella, Rivka Lederman, Bruce T. Volpe, Barbara Sherry, Betty Diamond
Minakshi Rana, Andrea La Bella, Rivka Lederman, Bruce T. Volpe, Barbara Sherry, Betty Diamond
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Research Article Immunology Infectious disease

Follicular dendritic cell dysfunction contributes to impaired antigen-specific humoral responses in sepsis-surviving mice

Abstract

Sepsis survivors exhibit impaired responsiveness to antigen (Ag) challenge associated with increased mortality from infection. The contribution of follicular dendritic cells (FDCs) in the impaired humoral response in sepsis-surviving mice is investigated in this study. We demonstrated that mice subjected to sepsis from cecal ligation and puncture (CLP mice) have reduced NP-specific high-affinity class-switched Ig antibodies (Abs) compared with sham-operated control mice following immunization with the T cell–dependent Ag, NP-CGG. NP-specific germinal center (GC) B cells in CLP mice exhibited reduced TNF-α and AID mRNA expression compared with sham-operated mice. CLP mice showed a reduction in FDC clusters, a reduced binding of immune complexes on FDCs, and reduced mRNA expression of CR2, ICAM-1, VCAM-1, FcγRIIB, TNFR1, IKK2, and LTβR compared with sham-operated mice. Adoptive transfer studies showed that there was no B cell–intrinsic defect. In summary, our data suggest that the reduced Ag-specific Ab response in CLP mice is secondary to a disruption in FDC and GC B cell function.

Authors

Minakshi Rana, Andrea La Bella, Rivka Lederman, Bruce T. Volpe, Barbara Sherry, Betty Diamond

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Figure 7

B cell transfer from either sham or CLP mice into Rag1-KO mice leads to normal anti-NP Ab response and restoration of FDC clusters.

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B cell transfer from either sham or CLP mice into Rag1-KO mice leads to ...
B cells isolated from sham or CLP mice at 4 weeks after surgery together with CD4+ T cells from WT mice were transferred into Rag1-KO mice. After 21 days of reconstitution, mice were immunized with NP-CGG in alum and serially bled up to day 21 of immunization. Time-dependent (A) low-affinity anti-NP23 IgG and (B) high-affinity anti-NP2 IgG response in Rag1-KO mice (n = 10, Sham+NP-CGG; n = 10, CLP+NP-CGG). Data represent mean ± SEM from 2 independent experiments. Sham+NP-CGG vs. CLP+NP-CGG (2-way repeated-measures ANOVA). Spleens were harvested at day 21 following immunization, and frozen sections were stained for CD3, B220, and CD35. (C) Representative whole spleen sections from Rag1-KO mice receiving B cells from sham or CLP mice. Whole spleen images acquired by stitching tiled images. Original magnification, ×20; scale bar: 500 μm. (D) Quantification of FDC clusters in Rag1-KO mice (n = 6, Sham+NP-CGG; n = 5, CLP+NP-CGG). Data represent mean ± SEM from 1 of 2 independent experiments. Sham+NP-CGG vs. CLP+NP-CGG (Mann-Whitney U test).