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Protective T cell-independent antiviral antibody responses are dependent on complement.

Ochsenbein AF, Pinschewer DD, Odermatt B, Carroll MC, Hengartner H, Zinkernagel RM - J. Exp. Med. (1999)

Bottom Line: In contrast, immunizations with nonreplicating antigens revealed an important role of B cell stimulation via CR2 in the switch to IgG.The complement cascade was activated after infection with VSV via the classical pathway, and active complement cleavage products augmented the effector function of neutralizing IgM and IgG antibodies to VSV by a factor of 10-100.Absence of the early neutralizing antibody responses, together with the reduced efficiency of neutralizing IgM in C3(-/-) mice, led to a drastically enhanced susceptibility to disease after infection with VSV.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Immunology, University Hospital, CH-8091 Zurich, Switzerland. aochsenb@pathol.unizh.ch

ABSTRACT
Complement is part of the innate immune system and one of the first lines of host defense against infections. Its importance was evaluated in this study in virus infections in mice deficient either in soluble complement factors (C3(-/-), C4(-/-)) or in the complement signaling complex (complement receptor [CR]2(-/-), CD19(-/-)). The induction of the initial T cell-independent neutralizing immunoglobulin (Ig)M antibody response to vesicular stomatitis virus (VSV), poliomyelitis virus, and recombinant vaccinia virus depended on efficient antigen trapping by CR3 and -4-expressing macrophages of the splenic marginal zone. Neutralizing IgM and IgG antibody responses were largely independent of CR2-mediated stimulation of B cells when mice were infected with live virus. In contrast, immunizations with nonreplicating antigens revealed an important role of B cell stimulation via CR2 in the switch to IgG. The complement cascade was activated after infection with VSV via the classical pathway, and active complement cleavage products augmented the effector function of neutralizing IgM and IgG antibodies to VSV by a factor of 10-100. Absence of the early neutralizing antibody responses, together with the reduced efficiency of neutralizing IgM in C3(-/-) mice, led to a drastically enhanced susceptibility to disease after infection with VSV.

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Long-term antibody and B cell memory in complement-deficient mice. C3−/− (A), C4−/− (B), CR2−/− (C), and CD19−/− (D) mice were immunized with 2 × 106 pfu VSV, and long-term antibody titers were compared with controls. Three of six C3−/− and two of five C4−/− animals died between day 8 and 12 after immunization. Antibody titers in surviving and dying mice were comparable until day 8. Antibody titers in surviving animals were followed up to day 120. 120 d after infection, VSV-specific AFCs in the spleen (F) and bone marrow (E) were assessed in an enzyme-linked immunospot assay. Results are given as mean ± SD of three mice per group. Experiments were repeated twice with comparable results.
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Figure 5: Long-term antibody and B cell memory in complement-deficient mice. C3−/− (A), C4−/− (B), CR2−/− (C), and CD19−/− (D) mice were immunized with 2 × 106 pfu VSV, and long-term antibody titers were compared with controls. Three of six C3−/− and two of five C4−/− animals died between day 8 and 12 after immunization. Antibody titers in surviving and dying mice were comparable until day 8. Antibody titers in surviving animals were followed up to day 120. 120 d after infection, VSV-specific AFCs in the spleen (F) and bone marrow (E) were assessed in an enzyme-linked immunospot assay. Results are given as mean ± SD of three mice per group. Experiments were repeated twice with comparable results.

Mentions: Complement has been shown to be involved in targeting antigen to CD21 and CD35 on FDCs in GCs, where the survival of GC B cells is dependent on the expression of CRs 232447. To assess antiviral B cell memory, C3−/−, C4−/−, CR2−/−, or CD19−/− mice were infected with 2 × 106 pfu VSV, and antibody titers were followed up to 150 d. C3−/−, C4−/−, and CR2−/− mice maintained IgG antibody titers comparably to control mice (Fig. 5A–C). In contrast, CD19−/− mice lost memory antibody titers within 90 d (Fig. 5 D), confirming earlier results 33. On day 120 after the initial infection, the number of AFCs was assessed in the bone marrow (Fig. 5 E) and spleen (Fig. 5 F). C3−/− and control mice had similar numbers of AFCs in the bone marrow and spleen, a finding that correlated with the observed antibody titers. The AFCs in C4−/− and CR2−/− mice in the bone marrow were reduced by 80–90% and in the spleen by ∼50% compared with the number of AFCs present in control mice. The AFCs in CD19−/− mice were reduced by >99.9% in the bone marrow and the spleen, confirming earlier results analyzing B cell memory in CD19−/− mice 33. The reduced numbers of AFCs in C4−/− and CR2−/− mice by a factor of 5 or 2 in spleen or bone marrow, respectively, were still sufficient to maintain long-term antibody titers after immunization with VSV. However, in CD19−/− mice, where AFCs are reduced by a factor of 100–1,000, neutralizing antibody titers could not be maintained. B cell memory was also assessed in C3−/− mice 150 d after infection with Vacc VSV G, VSV G protein, and LCMV. Long-term antibody titers after these different immunization protocols were comparably maintained in C3−/− and control mice (not shown).


Protective T cell-independent antiviral antibody responses are dependent on complement.

Ochsenbein AF, Pinschewer DD, Odermatt B, Carroll MC, Hengartner H, Zinkernagel RM - J. Exp. Med. (1999)

Long-term antibody and B cell memory in complement-deficient mice. C3−/− (A), C4−/− (B), CR2−/− (C), and CD19−/− (D) mice were immunized with 2 × 106 pfu VSV, and long-term antibody titers were compared with controls. Three of six C3−/− and two of five C4−/− animals died between day 8 and 12 after immunization. Antibody titers in surviving and dying mice were comparable until day 8. Antibody titers in surviving animals were followed up to day 120. 120 d after infection, VSV-specific AFCs in the spleen (F) and bone marrow (E) were assessed in an enzyme-linked immunospot assay. Results are given as mean ± SD of three mice per group. Experiments were repeated twice with comparable results.
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Related In: Results  -  Collection

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Figure 5: Long-term antibody and B cell memory in complement-deficient mice. C3−/− (A), C4−/− (B), CR2−/− (C), and CD19−/− (D) mice were immunized with 2 × 106 pfu VSV, and long-term antibody titers were compared with controls. Three of six C3−/− and two of five C4−/− animals died between day 8 and 12 after immunization. Antibody titers in surviving and dying mice were comparable until day 8. Antibody titers in surviving animals were followed up to day 120. 120 d after infection, VSV-specific AFCs in the spleen (F) and bone marrow (E) were assessed in an enzyme-linked immunospot assay. Results are given as mean ± SD of three mice per group. Experiments were repeated twice with comparable results.
Mentions: Complement has been shown to be involved in targeting antigen to CD21 and CD35 on FDCs in GCs, where the survival of GC B cells is dependent on the expression of CRs 232447. To assess antiviral B cell memory, C3−/−, C4−/−, CR2−/−, or CD19−/− mice were infected with 2 × 106 pfu VSV, and antibody titers were followed up to 150 d. C3−/−, C4−/−, and CR2−/− mice maintained IgG antibody titers comparably to control mice (Fig. 5A–C). In contrast, CD19−/− mice lost memory antibody titers within 90 d (Fig. 5 D), confirming earlier results 33. On day 120 after the initial infection, the number of AFCs was assessed in the bone marrow (Fig. 5 E) and spleen (Fig. 5 F). C3−/− and control mice had similar numbers of AFCs in the bone marrow and spleen, a finding that correlated with the observed antibody titers. The AFCs in C4−/− and CR2−/− mice in the bone marrow were reduced by 80–90% and in the spleen by ∼50% compared with the number of AFCs present in control mice. The AFCs in CD19−/− mice were reduced by >99.9% in the bone marrow and the spleen, confirming earlier results analyzing B cell memory in CD19−/− mice 33. The reduced numbers of AFCs in C4−/− and CR2−/− mice by a factor of 5 or 2 in spleen or bone marrow, respectively, were still sufficient to maintain long-term antibody titers after immunization with VSV. However, in CD19−/− mice, where AFCs are reduced by a factor of 100–1,000, neutralizing antibody titers could not be maintained. B cell memory was also assessed in C3−/− mice 150 d after infection with Vacc VSV G, VSV G protein, and LCMV. Long-term antibody titers after these different immunization protocols were comparably maintained in C3−/− and control mice (not shown).

Bottom Line: In contrast, immunizations with nonreplicating antigens revealed an important role of B cell stimulation via CR2 in the switch to IgG.The complement cascade was activated after infection with VSV via the classical pathway, and active complement cleavage products augmented the effector function of neutralizing IgM and IgG antibodies to VSV by a factor of 10-100.Absence of the early neutralizing antibody responses, together with the reduced efficiency of neutralizing IgM in C3(-/-) mice, led to a drastically enhanced susceptibility to disease after infection with VSV.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Immunology, University Hospital, CH-8091 Zurich, Switzerland. aochsenb@pathol.unizh.ch

ABSTRACT
Complement is part of the innate immune system and one of the first lines of host defense against infections. Its importance was evaluated in this study in virus infections in mice deficient either in soluble complement factors (C3(-/-), C4(-/-)) or in the complement signaling complex (complement receptor [CR]2(-/-), CD19(-/-)). The induction of the initial T cell-independent neutralizing immunoglobulin (Ig)M antibody response to vesicular stomatitis virus (VSV), poliomyelitis virus, and recombinant vaccinia virus depended on efficient antigen trapping by CR3 and -4-expressing macrophages of the splenic marginal zone. Neutralizing IgM and IgG antibody responses were largely independent of CR2-mediated stimulation of B cells when mice were infected with live virus. In contrast, immunizations with nonreplicating antigens revealed an important role of B cell stimulation via CR2 in the switch to IgG. The complement cascade was activated after infection with VSV via the classical pathway, and active complement cleavage products augmented the effector function of neutralizing IgM and IgG antibodies to VSV by a factor of 10-100. Absence of the early neutralizing antibody responses, together with the reduced efficiency of neutralizing IgM in C3(-/-) mice, led to a drastically enhanced susceptibility to disease after infection with VSV.

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Related in: MedlinePlus