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[Study of influenza virus hemagglutinin H3 avidity using monoclonal antibodies].

The results of a comparative study of the features of antigenic determinants of avid and non-avid variants of influenza virus hemagglutinin H3 and of the influence of the mode of antigen presentation on the degree of its avidity are presented. The avidity of influenza virus hemagglutinin was shown to be determined by the capacity of individual antigenic determinants to interaction with antibodies. The antigenic determinants of avid hemagglutinin possessing a high functional activity in interaction with antibodies may have the spatial configuration which does not change in different modes of the antigen presentation. Isolation of hemagglutinin from virions of non-avid virus variants may lead to increased functional activity of individual antigenic determinants (and the antigen molecule as a whole) probably due to an increased degree of exposure and/or complementarity of the determinants for active centres of antibody.

Animals↗
PubMed1984

Avidities of hapten-specific antibodies when the responses are modulated by anti-carrier antibodies.

Either alone or in combination with antibodies having specificity for the carrier erythrocyte, TNP-ORBC were injected i.p. into CBA/J mice. Five days later, their spleens were removed and evaluated for TNP-specific PFC. The spleens from animals receiving 19S antibody (IgM) with carrier specificity displayed 3-4-fold more direct and indirect hapten-specific PFC than control animals receiving the TNP-erythrocyte conjugate only. Animals receiving 7S antibodies (IgG) with carrier specificity displayed very little change in their direct PFC response to the hapten. However, the indirect response to the hapten was suppressed as much as 16-fold by carrier specific IgG. Evaluation by haptenic inhibition of the relative avidity of the antibodies being secreted by these cells revealed the following: the relative avidity of antibodies secreted by indirect PFC in the spleens of animals receiving TNP-ORBC only was approximately 20-fold higher than antibodies secreted by the direct PFC. The 3-4-fold potentiation of the hapten-specific PFC response by carrier-specific IgM antibody did not result in a change in relative avidity of direct or indirect PFC. IgG with carrier specificity did not change the relative avidity of the antibodies secreted by direct PFC having specificity for the hapten. However, evaluation of the remaining PFC in spleens from animals whose indirect hapten-specific PFC response had been suppressed by carrier-specific IgG revealed that the remaining PFC had a lower avidity than indirect PFC from animals receiving TNP-ORBC only. In other words, carrier-specific IgG selectively induced suppression of high avidity hapten-specific IgG antibody secreting cells.

Animals↗
PubMed1994

Cell surface distribution of high-avidity LFA-1 detected by soluble ICAM-1-coated microspheres.

Murine recombinant soluble ICAM-1 (sICAM-1) was immobilized on polystyrene microspheres. The binding of sICAM-1-coated microspheres to splenic T cells required previous activation of the cells and was inhibited by antibody to LFA-1 (CD11a/CD18), indicating that sICAM-1-coated microspheres bind exclusively to high-avidity LFA-1. The cytoskeleton inhibitor cytochalasin B did not inhibit the binding of sICAM-1-coated microspheres to PMA-activated splenic T cells, whereas their adhesion to sICAM-1 immobilized on microtiter wells was almost completely inhibited. The murine T hybridoma T28 cells on activation with PMA also bound sICAM-1-coated microspheres, and the binding sites on the cell surface seemed localized on some of the cells, whereas fluorescence staining showed an even distribution of LFA-1 on the cell surface. In contrast, the murine B cell line A20A8 and monocytic line P388 showed a more even distribution of sICAM-1 binding sites. To further investigate the distribution of high-avidity LFA-1, murine fibroblast L cells expressing LFA-1 were generated by gene transfer. The transfected L cells constitutively expressed high-avidity LFA-1 and bound sICAM-1-coated microspheres without previous activation. Interestingly, the binding sites seemed highly localized on most cells. In contrast, the binding sites for anti-LFA-1 Ab-coated microspheres were randomly distributed on the transfected L cells. Furthermore, fluorescence staining also revealed a uniform punctate distribution of LFA-1 on the surfaces of these cells. These results show that 1) sICAM-1-coated microspheres represent a useful tool in identifying high-avidity LFA-1, 2) the binding of sICAM-1-coated microspheres to high-avidity LFA-1 does not require an intact cytoskeleton, and 3) the cell surface distribution of high-avidity LFA-1 can be different from that of LFA-1 in general, and the former seems highly localized on some cells.

Animals↗
PubMed2026

Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions.

In signaling cascades, signaling proteins often encode multiple domains or motifs, which presents the possibility for avidity -- where multivalent binding drastically increases interaction strength and duration. However, predicting and validating multivalent interactions that interact with avidity is a challenge. Here, we integrate mechanistic modeling, structure-based analysis, and experimental approaches as a framework for defining the conditions under which avidity plays a role. We explore the tandem SH2 domain family of interactions with bisphosphorylated partners as a multivalent archetype, which encompasses key secondary messengers in tyrosine kinase signaling networks. Theoretical modeling suggests that maximum avidity occurs with closely spaced tyrosine phosphorylation sites combined with moderate monovalent affinities - exactly around the innate range of SH2 domain affinity - or with phosphorylation sites separated by sufficiently flexible linkers. Surprisingly, despite sequence diversity, structure-based analysis showed relatively conserved three-dimensional spacing between SH2 domains across all tandem SH2 families, which we corroborate experimentally, suggesting evolutionary optimization for avidity interactions. The combination of structure-based analysis of domain spacing with available monovalent experimental data appears, along with iterative experimental refinement of biophysical parameters, can identify high affinity interactions of tandem SH2 domain recruitment to the EGFR C-terminal tail. Using these principles, we extended bivalent predictions into the full phosphoproteome space and structural parameterization of other partners of SH2 domain binding, providing resources and methods for more rapid expansion of bivalent analysis. These approaches lay the groundwork for larger utility in multivalent prediction and testing to help better understand protein interactions that drive cell signaling.

BLI↗
PubMed2025

Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions.

In signaling cascades, where domain-motif interactions tend to interact with relatively low affinity (allowing for reversibility), signaling proteins often encode multiple domains or motifs, which present the possibility of avidity - drastically increasing the interaction strength and duration as a result of multivalent binding. However, given the large combinatorial space, predicting and validating multivalent interactions that interact with avidity is a challenge. Here, we integrate mechanistic modeling, structure-based analysis, and experimental approaches as a framework for defining the conditions under which avidity plays a role. We explore the tandem SH2 domain family of interactions with bisphosphorylated partners as a multivalent archetype, which encompasses key secondary messengers in tyrosine kinase signaling networks. While certain multivalent interactions have been shown to be necessary in immune receptor recruitment of partners, bivalent recruitment of tandem SH2 domains more broadly is poorly understood. Theoretical modeling suggests that maximum avidity occurs with closely spaced or flexibly linked phosphotyrosine sites, combined with moderate monovalent affinities - exactly around the innate range of SH2 domain affinity. Surprisingly, despite sequence diversity, structure-based analysis showed remarkably conserved three-dimensional spacing between SH2 domains across all tandem SH2 families, which we corroborate experimentally, suggesting evolutionary optimization for avidity interactions. The combination of structure-based analysis of domain spacing with available monovalent experimental data appears to be sufficiently accurate to predict and rank order high affinity interactions of tandem SH2 domain recruitment to the EGFR C-terminal tail. These approaches lay the groundwork for larger utility in multivalent prediction and testing to help better understand protein interactions that drive cell signaling.

BLI↗
PubMed1996

Cytomegalovirus antibody avidity in allogeneic bone marrow recipients: evidence for primary or secondary humoral responses depending on donor immune status.

The reconstitution of the human cytomegalovirus (CMV) antibody response in CMV seropositive bone marrow transplant patients was investigated by comparing 11 patients whose donors were CMV seropositive with 8 whose donors were CMV seronegative. Evidence for primary or secondary responses to CMV was sought by determining IgG antibody avidity using an avidity index method, and antibody titre over a period of up to 3 years after transplant. For the patients whose donors were CMV seropositive, the results showed the characteristics of a secondary response, i.e., rising antibody titres of high avidity immediately after transplant. In contrast, the patients with CMV seronegative donors showed evidence of a primary antibody response usually occurring at about 250 days after transplant, i.e., rising antibody levels initially of low avidity maturing to high avidity over the following 100 to 200 days. It is concluded that a secondary response and hence transfer of humoral immunity had occurred in those patients whose donor was CMV seropositive, whereas a delayed primary response occurred in those patients whose donor was CMV seronegative.

Antibodies, Viral↗
PubMed1999

Serum antibody levels and avidities to Escherichia coli O antigens and poliovirus type 1 antigen are increased in children treated for malignant disease.

BACKGROUND: Treatment of malignant disease in children is often associated with low serum immunoglobulin and reduced specific antibody levels. The aim of this study was to investigate if the functional affinity of specific antibodies in serum and saliva is reduced as well and to evaluate if antigenic exposure or treatment duration affects this antibody avidity. PROCEDURE: Serum samples were obtained from 45 children and salivary specimens from 30 children with malignant disease. The children were tested either prior to, during, or after chemotherapy. Levels of antibody to E. coli O and to poliovirus type 1 antigens were determined using an ELISA and isotype-specific relative antibody avidity was measured using thiocyanate to elute antibodies from solid-phase immobilized antigens. RESULTS: Children with malignant disease had higher levels and relative avidity indexes of serum antibodies to both antigens as compared to controls. The duration of treatment and type of malignant disease were unrelated to these parameters. In saliva, the level of antibodies to E. coli O antigens, but not to poliovirus type 1 antigen, increased during treatment. CONCLUSIONS: Both the amount and avidity of serum antibodies to these antigens are increased in children with malignant disease. This may be due to a dysregulation of the immune system caused by the malignancy and seems not to be dependent on exposure. In contrast, the avidity and levels of these antibodies in saliva seem to correlate with the presence of antigenic exposure.

Adolescent↗
PubMed2000

Decrypting the spectrum of antigen-specific T-cell responses: the avidity repertoire of MBP-specific T-cells.

Myelin basic protein (MBP) is a well-characterized autoantigen potentially involved in the pathogenesis of the most common human demyelinating disease of the central nervous system (CNS), multiple sclerosis (MS). It is known that MBP-specific T-cell responses differ widely among different individuals and also within a single donor in terms of fine specificity and functional characteristics including the avidity in antigen recognition. In this report, we demonstrate that the in vitro selection of MBP-reactive T-cell repertoire is strictly dependent upon the antigen dose used in the primary cultures. MBP-specific T-cell lines (TCLs) were generated from MS patients and healthy donors using different antigen concentration in cultures (0.1 to 50 microg/ml). In both MS patients and controls, the number of obtained T-cell lines was affected by the antigen concentration. In addition, low and high antigen concentrations selected in vitro different T-cell populations in terms of peptide specificity patterns and different functional avidities in antigen recognition. Low concentrations of MBP in the primary cultures yielded a small number of TCLs recognizing the specific antigen with higher avidity whereas high antigen concentrations allowed the in vitro expansion of a higher numbers of T-cells recognizing MBP with lower avidity. The use of different antigen concentrations in the primary cultures can be applied as a simple experimental system to investigate the overall avidity repertoire of antigen-specific T-cell response in humans.

Antibody Affinity↗
PubMed1985

A longitudinal study of high and low avidity antibodies to double-stranded DNA in systemic lupus erythematosus.

The role of avidity in the pathogenicity of double-stranded DNA/anti-double-stranded DNA immune complexes in systemic lupus erythematosus (SLE) has been controversial. We used polyethylene glycol to identify low avidity antibodies and the standard Farr assay to detect high avidity antibodies against double-stranded DNA in a longitudinal study of sera from 19 patients with SLE. We found that high and low avidity antibodies to double-stranded DNA did not move independently, but instead, rose and fell in a parallel and relatively fixed manner in these patients. The mechanisms responsible for the changes in titer of anti-double-stranded DNA antibody appeared nondiscriminatory in regard to avidity. In addition, the humoral immune response in SLE depicted by these antibody measurements appeared atypical, lacking maturational features.

Adolescent↗
PubMed1991

Differentiation of primary cytomegalovirus infection from reactivation using the urea denaturation test for measuring antibody avidity.

Cytomegalovirus (CMV) is probably the most common agent of prenatal infection of the newborn, and one of 20 congenitally infected newborns shows serious symptoms. It was therefore considered important to be able to differentiate primary CMV from reactivation in pregnant females. A urea denaturation test was used to distinguish primary from secondary rubella infection in which the urea is included in the wash step of the standard IgG ELISA. This resulted in the removal of low-avidity antibodies, which are the antibodies produced early in infection. A group of CMV IgM-negative and -positive sera were tested, and all but one showed moderate to high avidity, with an avidity index reading of more than 30%. Among a group of babies 3-12 months of age, who were CMV IgM positive, 55% (16 of 29) showed low-avidity CMV antibodies. A small group of renal transplant patients and patients with clinically and laboratory-confirmed CMV gave more or less predicted avidity index results. It appears that, with the method used at this laboratory, the urea denaturation test can be applied to CMV to determine primary infection or reactivation in the majority of cases.

Antibodies, Viral↗
PubMed1991

Antibody avidity following varicella-zoster virus infections.

The avidity of IgG antibodies following varicella-zoster virus (VZV) infections was investigated using urea treatment of antigen-bound serum antibody by indirect radioimmunoassay (RIA) and immunoblotting techniques. Sequential sera from 16 patients with varicella and 17 patients with zoster were tested, as well as sera from 80 seropositive individuals without a recent history of VZV disease. Both types of assay showed that low-avidity antibodies predominate early after primary infection, but that antibody avidity increases markedly during convalescence. Using RIA, all sera taken up to 12 weeks after the onset of varicella showed greater than 50% reduction in antibody titre after treatment with 8 M urea but thereafter the proportion of urea resistant antibody increased with time. In contrast, after recurrent infection, high avidity antibodies were found to predominate at all times. Only 6 of 47 sera tested from zoster cases showed greater than 30% reduction after urea treatment and all these were taken within 2 weeks after onset of rash. Immunoblotting also showed that the highly immunogenic p32/p36 nucleoproteins appear to induce predominantly low avidity antibodies, even after recurrent VZV infection. The results of this study indicate that treatment with 8 M urea in RIA for IgG antibodies may be a simple and reliable method for distinguishing primary and anamnestic antibody responses against VZV.

Antibodies, Viral↗
PubMed2000

Differential expansion and survival of high and low avidity cytotoxic T cell populations during the immune response to a viral infection.

The importance of high avidity CTL for the effective clearance of viral infections is now well established. Thus one would predict that the preferential activation and expansion of high avidity CTL following viral challenge and retention of these cells in the memory pool would be optimal for the immune response. However, whether this actually occurs during the immune response to viral infection is unknown. In this report I have analyzed the avidity of the CTL specific for the OVA(257-264) peptide during acute infection with a recombinant vaccinia expressing ovalbumin and in the memory population. I have found that the relative ratio of high and low avidity CTL varies over the course of an immune response. Thus CTL avidity is an important factor in the expansion and survival of CTL in vivo.

Animals↗
PubMed1993

T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2.

While the T cell receptor (TcR) recognizes cell bound, peptide antigens embedded within major histocompatibility complex (MHC) proteins, this interaction is not sufficient for T cell activation and function. A number of other cell surface molecules, termed co-receptors or accessory molecules, cooperate with the TcR by participating in T cell adhesion to antigen presenting cells (APC) and/or by contributing to T cell signaling. In addition, recent evidence suggests that T cell activation can, in turn, increase the avidity of several of these co-receptors for their ligands. One such co-receptor molecule is CD2, a T cell glycoprotein that not only participates in T cell activation but also provides the T cell with a major adhesion pathway whose avidity is regulated by TcR triggering. Using both cellular and molecular biological approaches, we have mapped the portions of CD2 involved in CD2-dependent signaling and in the regulation of avidity for its ligand CD58 (lymphocyte function associated antigen-3, LFA-3) to structurally distinct portions of the cytoplasmic domain. This delineation of function has allowed us to analyze the contribution of co-receptor basal adhesion, signaling, and avidity regulation in antigen-dependent T cell interactions. The signal transduction pathways recruited for the regulation of CD2 avidity for its ligand differ from those used by other co-receptors such as LFA-1 and CD8 for their respective ligands. Taken together, the multiplicity of co-receptors, their interplay, and their differential regulation contribute to the control and the sensitivity of antigen-dependent immune responses.

Animals↗
PubMed1998

Estimation of the avidity of immunoglobulin G for routine diagnosis of chronic Toxoplasma gondii infection in pregnant women.

Present serological methods differentiate poorly between acute and chronic toxoplasmosis in pregnant women, particularly when immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to Toxoplasma gondii are present simultaneously. In the present study, a simple test for discriminating between high-avidity antibodies, which are usually present in chronic infections, and low-avidity antibodies, typical of acute infection, was evaluated. Sera were evaluated for Toxoplasma gondii antibodies using a commercial enzyme immunoassay, but a duplicate well was washed in 6M urea to disrupt low-avidity complexes. Results are expressed as the percentage of antibodies resisting elution by urea. Equivocal sera (n = 493) containing both IgG and IgM Toxoplasma gondii antibodies from 309 pregnant women whose status as chronically or acutely infected had been independently determined using standard methods were evaluated for antibody avidity. A value of > 35% elution-resistant antibodies was always associated with chronic infection and could absolutely exclude a recent (< 3 months) infectious incident. Values of < 35% require repeat testing four weeks later to confirm the patient's status, since a proportion of individuals with chronic toxoplasmosis maintain low-avidity antibodies over long periods. This inexpensive, simple method can provide reassurance to clearly chronically infected individuals and avoids the need for repeated testing in these cases.

Acute Disease↗
PubMed2003

Immunodiagnosis of primary Toxoplasma gondii infection in sheep by the use of a P30 IgG avidity ELISA.

Toxoplasma gondii is a protozoan parasite with a worldwide distribution. In both sheep and humans, if the parasite is encountered during pregnancy, fetal infection and abortion can occur. Therefore, Toxoplasma infection in sheep has a major economic impact upon sheep farming. Clinically, there is a need to distinguish recent (acute) infections from longstanding (chronic) infections. However, current serological techniques, such as detection of anti-T. gondii IgG, cannot discriminate between acute and chronic infections. Increasing immunoglobulin avidity is a good determining factor of how recent an infection is. In this study, we describe the application and validation of a T. gondii IgG avidity ELISA, based on the use of an affinity-purified, native T. gondii P30 antigen. The assay was used to examine sera from eight sheep experimentally infected with T. gondii and found that all seroconverted within 21 days post-infection (p.i.), beginning with avidities that were initially low but that increased over time, with all sheep reaching high IgG avidity within 10 weeks p.i. In addition, sera from clinically healthy but T. gondii-seropositive lambs and ewes and seropositive ewes with a history of abortion were also subjected to a preliminary serological investigation. High IgG avidities were found in 80% of the seropositive lambs, in 90% of the clinically healthy ewes and in 97% of the ewes with abortion problems. These findings indicate that the animals had most likely contacted the parasite a longer time ago.

Abortion, Veterinary↗
PubMed1991

Memory T cells enhance the expression of high-avidity naive B cells.

The secondary immune response classically differs from the primary response in magnitude, avidity, and isotype of the antibodies produced. Cell transfer studies to assess the contribution of memory B and memory T cells to each of these parameters are described. Avidities of the anti-DNP plaque-forming cells (PFC) generated in lethally irradiated recipients of naive B cells and keyhole limpet hemocyanin (KLH)-primed T cells, followed by immunization with soluble DNP-KLH, are medium to high, and do not differ significantly from the avidities of anti-DNP PFC in recipients of DNP-primed B cells and KLH-primed T cells. However, the number of indirect (I)-PFC and the ratio of I-PFC to direct (D)-PFC are significantly greater in the recipients of primed B and primed T cells. The results suggest that carrier primed T cells can selectively activate virgin B cells which are committed to produce medium- and high-avidity antibodies, and/or enhance the generation of somatic mutation which leads to antibodies of higher avidity. Priming of B cells is necessary for the increased magnitude of the I-PFC.

Animals↗
PubMed1983

Disparity in antiserum avidity as measured by nephelometry, radial immunodiffusion, and column-binding strength.

When antiserum potency is being assessed, avidity is often inferred from affinity measurements or from measurements obtained from completely unrelated immunoassay techniques. The present experiments describe an instance where antibodies that have very high column-binding strength, obtained by elution from immobilized antigen with dissociating agents, have low avidity in nephelometry and radial immunodiffusion. This low avidity appears not to be due to molecular damage since the eluted antibodies do not contain molecular aggregates and retain their column-binding strength when reapplied to the immobilized antigen. We theorize that in nephelometry and radial immunodiffusion, lattice formation may require a heterogeneous population of antibodies and that the low avidity fractions may have too limited a specificity. We support this theory by combining two different populations of low avidity antibodies and finding that the combination produces a nephelometric response greater than that of either fraction alone.

Antibody Affinity↗
PubMed1992

Avid AL, a synthetic ligand affinity gel mimicking immobilized bacterial antibody receptor for purification of immunoglobulin G.

Avid AL is an affinity gel designed for the purification of immunoglobulin G (IgG). The gel was prepared by first reacting Sepharose with 3,5-dichloro-2,4,6-trifluoropyridine and 4-dimethylaminopyridine and then with 2-mercaptoethanol. The IgG purified by Avid AL is about 95% pure. The binding parameters of Avid AL for the whole IgG, Fab and Fc fragment and the stability of gel were investigated. The IgG bound to Avid AL can be eluted with an acidic buffer or with a novel neutral buffer containing electron donors. The development of such a mild neutral elution buffer is described. Application of Avid AL in a rapid gram-scale IgG purification was demonstrated. The possible mechanism of IgG binding is discussed.

Animals↗