Regulation of the Immune Response

Sinclair, Nicholas

doi:10.1084/jem.129.6.1183

Cited by 169 publications

(28 citation statements)

References 20 publications

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“…A detailed analysis of the cellular mechanism of antibody-mediated immune suppression is the subject of a forthcoming communication. Studies of suppression of the immune response by antibody fragments in vivo have yielded conflicting results (26,(32)(33)(34), partly due to the increased catabolism of these fragments (35). The effect of antibody fragments on the immune response in vitro, without the drawback of increased catabolism, should be of interest.…”

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Suppression of the Immune Response in Vitro

Feldmann

Diener

1970

The Journal of Experimental Medicine

124

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Antibody-mediated suppression of the in vitro immune response to polymerized flagellin of Salmonella adelaide and to sheep erythrocytes was studied at the cellular level. Normal mouse spleen cells, preincubated in vitro with mixtures of antigen and antibody for short periods of time before being washed, did not respond to an optimal antigenic challenge in vitro, whereas similar cells treated with antibody alone gave a normal response. The degree of immune suppression was found to depend on the time of preincubation. Significant immune suppression could be induced in as short a time as 15 min, whereas profound suppression (90%) required the incubation of cells with mixtures of antigen and antibody for 4–6 hr. Mouse spleen cells treated similarly were also unable to respond subsequently to the antigen upon transfer to lethally irradiated hosts, as measured at both the level of the antigen-reactive cell and that of serum antibody production. These results were taken as evidence that in vitro an effect of antibody-mediated suppression occurred at the level of the immunocompetent cell. Similarities between immune tolerance and antibody-mediated suppression in vitro were described, and the significance of the findings discussed in the light of current concepts of the mechanism of antibody-mediated suppression.

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Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Suppression of the Immune Response in Vitro

Feldmann

Diener

1970

The Journal of Experimental Medicine

124

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“…19,[41][42][43] In addition, the inhibitory potential of an antibody is markedly reduced if its interaction with Fc␥RIIB is abolished by deglycosylation. 44 However, inhibition through Fc␥RIIB has been dismissed as a possible mechanism based on 3 observations: an IgG3 isotype antibody, which in the mouse does not bind to Fc␥RIIB, can be inhibitory 18,19 ; in some studies, F(abЈ) 2 fragments can also inhibit B-cell responses 17,20,21 ; and IgG is inhibitory in Fc-receptor knockout mice.…”

Section: Mechanism Of Maternal Antibodies 6147mentioning

confidence: 99%

Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies

Kim

Huey

Oglesbee

et al. 2011

Blood

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The inhibition of vaccination by maternal antibodies is a widely observed phenomenon in human and veterinary medicine. Maternal antibodies are known to suppress the B-cell response. This is similar to antibody feedback mechanism studies where passively transferred antibody inhibits the B-cell response against particulate antigens because of epitope masking. In the absence of experimental data addressing the mechanism underlying inhibition by maternal antibodies, it has been suggested that epitope masking explains the inhibition by maternal antibodies, too. Here we report that in the cotton rat model of measles virus ( IntroductionMaternal antibodies of the immunoglobulin G (IgG) antibody class are transferred from mother to child and protect children against infectious diseases. Over time, passively transferred maternal antibody titers decline and are not protective any longer but interfere with successful vaccination. A well-documented example of this is measles vaccination. 1 Inoculation of seronegative children with a live-attenuated vaccine measles virus (MV) leads first to the development of antibodies specific for the nucleocapsid (MV-N) protein (which is released by infected cells) and subsequently to protective neutralizing antibodies specific for the hemagglutinin (MV-H) and fusion (MV-F) proteins. 2 Neutralizing antibodies recognize at least 15 nonoverlapping neutralizing epitopes on MV-H and 3 on MV-F. 3 Vaccination in the presence of maternal antibodies, however, does not lead to development of protective neutralizing antibodies, 4 whereas the T-cell response is readily detectable. [5][6][7][8][9][10] These findings indicate a specific inhibition of B-cell responses by maternal antibodies. In the absence of experimental data, inhibition of B cells has been postulated to be the result of physical blockage of epitopes by maternal antibodies (epitope masking 11 ). This model is based on antibody feedback mechanism studies. 11,12 In these studies, passive transfer of IgG suppresses the B-cell response against sheep red blood cells. Epitope masking leads to epitope-specific suppression at lower antibody concentrations, whereas at higher antibody concentrations also nonepitopespecific inhibition was observed and explained by steric hindrance. 13 A proposed alternate mechanism is based on the only inhibitory receptor of the IgG binding Fc receptor family, Fc␥-IIB receptor (Fc␥RIIB). On B cells, cross-linking of Fc␥RIIB to the B-cell receptor (BCR) through antigen/antibody complexes leads to inhibition of activation and antibody secretion. 12,[14][15][16] This mechanism was dismissed for the antibody feedback model because IgG is inhibitory in Fc-receptor knockout mice, 17 an IgG3 isotype antibody that in the mouse does not bind to Fc␥RIIB can be inhibitory, 18,19 and in some studies F(abЈ) 2 fragments can also inhibit B-cell responses. 17,20,21 In summary, these studies provide evidence for epitope masking as the main mechanism of inhibition of antibody responses in the antibody feedback model. Whether the...

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“…A number of laboratories have demonstrated that the removal of the oligosaccharide chain from the IgG molecule affects several Fc effector functions, especially the ability to bind to Fc receptors (FcR) [14][15][16]. Although there are a number of factors that affect the clearance of IgG (either monomeric, or as part of an immune complex), the ability to bind to FcRs expressed on a number of different cell types influences not only the degradation of the molecule [17], but, in some cases, even the subsequent synthesis [18]. In general, the high-affinity FcRI appears to be important for binding monomeric IgG, whereas immune complexes, containing IgG, interact with FcRII and FcRIII [19].…”

Section: Introductionmentioning

confidence: 99%

Differential clearance of glycoforms of IgG in normal and autoimmune-prone mice

Newkirk

Novick

Stevenson

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIn order to understand better the origins of the elevated levels of the glycoform of IgG that lacks galactose on both arms of the oligosaccharide chain (G0%) located in the Fc, which occurs in man and mouse with age, and in particular in autoimmune disease, we investigated the clearance of two glycosylated forms of IgG2a and IgG1 in normal (BALB/c) and autoimmune-prone (MRL/lpr, MRL/, and non-obese diabetic (NOD)) mice. To investigate the possibility of different rates of catabolism, enzymatically generated glycoforms of monomeric IgG1 and IgG2a (fully glycosylated or G0%), were iodinated and injected into the tail vein of the mice. We found that the G0% IgG2a remained in circulation significantly longer than the fully glycosylated variants, in all of the mouse strains tested. In contrast, the two forms of IgG1 had similar kinetics in all the autoimmune-prone mice, whereas in BALB/c, there was a longer half-life (t 1/2 ) for G0% IgG1. These data suggest that there may be differences in the ability of the IgG glycoforms to bind to the Fc°receptors, in particular Fc°RI. The clearance rates were found to vary among the strains studied, with MRL/lpr having the fastest catabolic rates for all glycoforms and IgG subclasses tested. This appeared to be due to the presence of circulating IgG and IgM rheumatoid factors (RF). There were significantly increased frequencies and titres for both IgM and IgG RF in MRL/lpr mice compared with the other strains. In contrast, interferon-gamma, known to induce the Fc°RI, was found to be similar in the sera, in all of the strains of mice examined. These results suggest that RF probably play an important biological function in the MRL/lpr mice and aid in the clearance of circulating IgG. Our study shows that the state of glycosylation of IgG affects the t 1/2 in vivo, and that by removing the terminal sugars (sialic acid and galactose), the antibody (IgG2a) will remain in circulation significantly longer. These observations may thus provide a partial explanation for the increase in relative percentage of this glycoform that occurs with age.

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Regulation of the Immune Response

Cited by 169 publications

References 20 publications

Antibody-Mediated Suppression of the Immune Response in Vitro

Antibody-Mediated Suppression of the Immune Response in Vitro

Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies

Differential clearance of glycoforms of IgG in normal and autoimmune-prone mice

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