Role of Complement in the Induction of Immunological Responses

Pepys, Mark B.

doi:10.1111/j.1600-065x.1976.tb00230.x

Cited by 67 publications

(62 citation statements)

References 60 publications

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“…Antigens are trapped and retained on the surface of FDCs through interactions between complement components and cellular complement receptors (47,50). The loss of expression FIG.…”

Section: Discussionmentioning

confidence: 99%

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Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

Mabbott

Young

McConnell

et al. 2003

J Virol

141

178

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“…Antigens are trapped and retained on the surface of FDCs through interactions between complement components and cellular complement receptors (47,50). The loss of expression FIG.…”

Section: Discussionmentioning

confidence: 99%

“…10 4.5 intracerebral [i.c.] ID 50 [50% infectious dose] units). For oral inoculation, mice were fed individual food pellets doused with 50 l of a 1.0% scrapie brain homogenate.…”

Section: Methodsmentioning

confidence: 99%

Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

Mabbott

Young

McConnell

et al. 2003

J Virol

141

178

View full text Add to dashboard Cite

“…However, C also plays a crucial role in the generation of Ab responses (reviewed in [1][2][3]. This was first demonstrated by Pepys (4), who found that C3 depletion of mice by treatment with cobra venom factor abrogated Ab responses to sheep erythrocytes (SRBCs).…”

Section: Igm Mutation | Natural Igmmentioning

confidence: 99%

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Rutemark

Alicot

Bergman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen–Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.

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“…Each shot of CVF should deplete complement activity for up to 4 days. 18 For NK cell depletion, ASGM1 Ab (Wako, Neuss, Germany) was injected intraperitoneally (10 L in 200 L PBS) on day 5 and day 9 after tumor inoculation. Depletion was assessed in the tail blood of 2 treated versus 2 control mice on day 7 using FSC/side scatter (SSC) criteria and staining with DX5 and Ly-49c mAb (both from Pharmingen, San Diego, CA) by flow cytometry.…”

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confidence: 99%

Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents

Cragg

Glennie

2004

Blood

314

249

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Despite the success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about their mechanism(s) of action. Here, we show that certain of these reagents (rituximab and 1F5), which redistribute CD20 into membrane rafts, are bound efficiently by C1q, deposit C3b, and result in complement-dependent cytotoxicity (CDC). This activity is important in vivo, because complement depletion using cobra venom factor (CVF) markedly reduced the efficacy of rituximab and 1F5 in 2 lymphoma xenograft models. However, complement depletion had no effect on the potent therapeutic activity of B1, a mAb that does not redistribute CD20 into membrane rafts, bind C1q, or cause efficient CDC. Equivalent immunotherapy also occurred in the presence or absence of natural killer (NK) cells. Perhaps most surprising was the observation that F(ab) 2 fragments of B1 but not 1F5 were able to provide substantial immunotherapy, indicating that non-Fc-dependent mechanisms are involved with B1. In accordance with this, B1 was shown to induce much higher levels of apoptosis than rituximab and 1F5. Thus, although complement is important for the action of rituximab and 1F5, this is not so for B1, which more likely functions through its ability to signal apoptosis. ( IntroductionPrevious studies have suggested that several mechanisms might be involved in providing therapeutic efficacy through anti-CD20 reagents, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and the induction of growth arrest or apoptosis. Currently, the bulk of the experimental evidence indicates that rituximab operates through conventional effector mechanisms measured by CDC and ADCC assays, the most conclusive data coming from work in primates showing that an immunoglobulin G4 (IgG4) variant of rituximab, unlike the chimeric IgG1 monoclonal antibody (mAb), was unable to deplete normal B cells. 1 The evidence that ADCC and Fc␥R are important in the therapeutic activity of rituximab comes from several sources, both clinical and experimental. In the former, it has been shown that patients with non-Hodgkin lymphoma (NHL) expressing the high-affinity 158V variant of the Fc␥RIIIa gene have better response rates after rituximab treatment than those carrying the low-affinity allotype. 2 Similar results have now been shown for the depletion of B cells with rituximab in systemic lupus erythematosus (SLE). 3 The importance of Fc␥R in vivo is also supported by elegant work from Clynes et al 4 that used Fc␥R-deficient mice, which indicated that Fc␥R on macrophages are critical to the ability of mAb to control subcutaneous B-cell lymphoma. Thus, there are clearly data to support a role for Fc␥R-bearing effectors in mediating the activity of anti-CD20 mAb. Although these experiments seem to indicate the importance of Fc␥R-expressing cells as cytotoxic effectors, the possible role of these cells in enhancing mAb and receptor cross-linking should not be ignored, as in vitro experiments show tha...

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Role of Complement in the Induction of Immunological Responses

Cited by 67 publications

References 60 publications

Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents

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