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At least 181 records · Page 10Linked to original sources
PubMed1997

A complementarity-determining region peptide of an anti-desmosome autoantibody may interact with the desmosomal plaque through molecular mimicry with a cytoplasmic desmoglein 1 sequence.

The sera of patients with pemphigus, a group of autoimmune blistering skin diseases, contain autoantibodies directed against components of adhering junctions termed desmosomes. F12, a human monoclonal antibody derived from a pemphigus patient, recognizes an unknown polypeptide of the desmosomal and hemidesmosomal plaques. The third complementarity-determining region of the F12 heavy chain (VH-CDR3) was shown to share a four-amino-acid sequence (GSSG) with the intracellular domains of desmoglein 1 and bullous pemphigoid antigen 2 which interact with components of, respectively, the desmosomal and hemidesmosomal plaques. Computer modeling of F12 showed that the GSSG sequence protudes inside the antigen-combining site and thus might be involved in antigen interactions. The GSSG sequence is essential to F12 function, since a peptide containing the VH-CDR3 inhibited its binding to target antigens while VH-CDR3 peptides with specific modifications of the GSSG sequence did not. These data allow us to hypothesize that certain autoantibodies produced during the course of an autoimmune disease can behave as adhesion molecules, through the molecular mimicry of the motif involved in protein/protein adhesion, and to propose a new self-antigen binding mechanism for some autoantibodies.

Amino Acid Sequence↗
PubMed2004

Lowering the affinity between antigen and the B cell receptor can enhance antigen presentation.

The B cell receptor (BCR) enables antigen-specific B cells to bind, internalize and target antigens for processing into small peptide fragments. These epitopes are then expressed on the plasma membrane in association with MHC class II molecules for recognition by CD4+ T cells. The affinity of the interaction between the BCR and antigen plays an important part in determining T cell epitope generation. In this report we provide evidence that the efficiency of antigen presentation by specific B cells does not need to be directly proportional to antigen/BCR affinity. We show that increased presentation can result from lowering the affinity of the antigen/BCR interaction. This finding suggests a novel mechanism by which B cells can recruit T cell help and obtain survival signals. Activation of these cells may have consequences for the generation of the B cell repertoire.

Animals↗
PubMed2001

Unmasking cryptic epitopes after loss of immunodominant tumor antigen expression through epitope spreading.

The basis of intra-tumoral and systemic T cell reactivity toward cancer remains unclear. In particular the role that peripheral stimuli, whether endogenous or exogenous, play in shaping acquired immune response toward cancer remains poorly understood. In this study we document the surfacing of systemic immune reactivity toward a cryptic epitope from the MAGE-12 gene (MAGE-12:170-178), after temporary regression of a single melanoma metastasis, in response to gp100/PMel17-specific vaccination. This emergence was unlikely related to unusually high expression of MAGE-12 by the tumor, by the influence of analog epitopes to MAGE-12:170-178. Because MAGE-12 was unlikely to be expressed at sites other than the tumor, the demonstration of MAGE-12:170-178 reactivity in post- but not pre-vaccination circulating lymphocytes suggests that the systemically observed immune response was influenced by events induced by the vaccine at tumor site or draining lymph nodal areas. Possibly, as suggested by pre-clinical models, immunologic ignorance is the default response toward cancer in humans unless unusual stimulatory conditions occur in peripheral tissues. Surfacing of MAGE-12 specificity occurred in association with loss of gp100/PMel 17 targeted by the vaccine. This finding suggests that vaccinations might have effects beyond their intrinsic specificity and may trigger broader immune responses through epitope spreading by inducing changes within the tumor microenvironment. This may have important practical implication for the development of immunization strategies. Published 2001 Wiley-Liss, Inc.

Alleles↗
PubMedDate not supplied

Cyclosporin A as a model antigen: immunochemical and structural studies.

The immunosuppressant drug cyclosporin (Cs) A is a cyclic undecapeptide which has been used as a model antigen because structural information and a large number of analogs, modified at each of its 11 positions, were available. This review summarizes immunochemical and crystallographic studies of the interaction between the Fab of monoclonal antibody R45-45-11 and Cs. Three points are discussed: (1) the different conformations of CsA and the question of its biologically active form; (2) the Fab-CsA recognition mechanism; and (3) the relationship between structure and binding properties of CsA analogs.

Animals↗
PubMed2002

Use of statistical models for evaluating antibody response as a correlate of protection against varicella.

In vaccine clinical trials, humoral antibody responses are often used to measure the effect of a vaccine because they correlate with a vaccine's protective efficacy against the target disease. While the concept of a correlate of protection usually refers to establishing a protective level of antibody titre, identifying a clear-cut value is often impossible because vaccine efficacy is not related solely to the antibody titre. We propose examining the relationship between disease protection and the whole distribution of antibody responses rather than a single cut-off level. In particular, we use failure-time models to estimate the relationship between long-term disease breakthroughs and primary antibody responses after vaccination. We apply these models to show that the varicella antibody response measured by glycoprotein enzyme-linked immunosorbent assay 6 weeks after vaccination strongly correlate with protection against varicella (chickenpox); we used 7-year follow-up data from children who received one dose of a live attenuated varicella (Oka/Merck) vaccine. In addition, we explore the potential use of these models to predict long-term disease breakthrough rates and to estimate the predicted vaccine efficacy of a similar varicella vaccine made with a modified manufacturing process.

Antibodies, Viral↗
PubMed2004

Estimating vaccine efficacy from household data observed over time.

Estimation of vaccine efficacy has traditionally focused on the reduction in susceptibility to infection, or the vaccine efficacy for susceptibility (VE(S)). However, a vaccine, such as a prophylactic HIV vaccine, may also lower the infectiousness of a vaccinated person who became infected. The relative reduction in infectiousness due to vaccination is the vaccine efficacy for infectiousness (VE(I)). Estimation of VE(I) is challenging because it requires information on exposure to infection, and gathering this type of information is often expensive and difficult, or even impossible. Household studies are expected to provide more information on who is exposed to whom. In a previous paper, we developed a method for estimating VE(S) and VE(I) from a household study where only the final outbreak data are available. However, the resulting estimates were quite unstable. In this work, we develop a survival model for the estimation of VE(S) and VE(I) from household data where the time of infection is known for every study participant. Using stochastic simulations, we show that the proposed method significantly reduces the bias and mean square error in the estimation of both VE(S) and VE(I) as compared to the method based on final outbreak data. We also show that when time-to-event data are available, a household study produces more robust estimators than a same-size study of unrelated individuals. In addition, we investigate the bias in estimating VE(S) and VE(I) due to misclassification of infection status when only illness data, rather than true infection data, are available.

Computer Simulation↗
PubMed2001

Multinomial analysis of smoothed HIV back-calculation models incorporating uncertainty in the AIDS incidence.

Back-calculation models, developed to reconstruct the past trend of human immunodeficiency virus (HIV) and to project future acquired immunodeficiency syndrome incidence (AIDS), are usually and unrealistically based on the assumption that the observed AIDS counts are independently distributed according to a Poisson process. In contrast, we argue that a multinomial framework is more suitable to this situation, leading to a natural covariance structure. The ill-conditioned nature of the problem is solved by modelling the HIV parameters according to a cubic spline function to reduce the dimensionality of the parameter space and obtain smoother parameter estimates. We applied a regression spline technique which yields to a computationally stable basis incorporating the incubation period in the new design matrix. We directly incorporate the reporting delay distribution in the AIDS incidence data, leading to a more complex formulation of the variance and covariance model that is adapted to the iteratively reweighted least square (IRLS) algorithm. In this case we obtain more accurate estimates of the standard error of the HIV incidence, especially in the most recent time. Our model, which uses a cubic spline reparameterization based on a multinomial probability distribution, is applied to the AIDS epidemic data in Italy.

Acquired Immunodeficiency Syndrome↗
PubMed1996

A structural model for TCR recognition of the HLA class II shared epitope sequence implicated in susceptibility to rheumatoid arthritis.

HLA molecules associated with rheumatoid arthritis (RA) contain a discrete structural element known as the shared epitope, a set of conserved amino acid residues located on the alpha helical portion of the class II beta chain. Each of the different HLA molecules associated with RA contain the same shared epitope sequence, although they may vary markedly in other regions of the class II structure, which also determine peptide-class II interactions. Previous mutagenesis studies and structural modelling indicate that key polymorphic amino acid side chains within the shared epitope sequence are in locations likely to contact the T cell receptor (TCR) during the trimolecular activation reaction between the HLA-peptide complex and TCR. We have evaluated the potential structural basis for such shared epitope recognition by analysing detailed molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor from T cell clone EM025, specific for HLA-DR4 molecules which carry the shared epitope. A likely orientation for the trimolecular complex was deduced in which the EM025 alpha chain interacts with the DR alpha chain and the EM025 beta chain interacts with the DR beta chain; residues Q70 and R71 within the DR beta chain shared epitope region are positioned for hydrogen bond interactions directly with Q97 of the TCR beta CDR3 region, D30 of the TCR beta CDR1 region, and possibly N51 of the TCR beta CDR2 region, indicating a degree of specific selection and interaction which encompasses multiple TCR contacts. These findings suggest a structural basis for the genetic associations with the HLA shared epitope and the potential contribution of this region to oligoclonal T cell selection and expansion in RA.

Arthritis, Rheumatoid↗
PubMed2000

Mimicry of human IgE epitopes by anti-idiotypic antibodies.

According to Jerne's network hypothesis, the binding site of an anti-idiotypic antibody also represents the internal image of an epitope present on a foreign, or even a self antigen. In recent years, antigen mimicry has been defined at the molecular level for some xeno-antigens. However, until now there has been no demonstration of structural mimicry between a human anti-idiotypic antibody and a self structure. To address this question, we used human IgE as the self structure and a well-defined anti-human IgE mAb (BSW17). We describe the isolation of two anti- idiotypic antibodies specific for the anti-IgE antibody BSW17 from a non-immune human Fab phage display library. Interestingly, these two anti-idiotypic antibodies mimic the same molecular surface region as a previously described IgE peptide mimotope isolated by panning on BSW17, but they cover a much larger epitope on the IgE molecule. Accordingly, immunisation of rabbits with the two anti-idiotypic antibodies induced high-affinity antibodies with the same characteristics as BSW17. Thus, our data demonstrate that it is possible to isolate anti-idiotypic antibodies derived from the human genome without the need for hyperimmunization, and confirm Jerne's hypothesis that both foreign antigens and self structures can be mimicked by our own immunoglobulins.

Amino Acid Sequence↗
PubMed1998

Heuristic models of the intermonomeric disulfide bonding process.

The assembly of fully disulfide bonded trout Immunoglobulin M (IgM) was modeled heuristically. The basic mechanism was assumed to be the sequential formation of single disulfide bonds (DSB), linking two monomeric subunits. Biochemical details of the mechanisms of bond formation were not considered. The progression of bonding within each tetramer was described entirely in terms of the rates of bond formation. It was further assumed that the sequence of DSB formation from non-covalently associated tetramers to fully bonded tetramers progressed by the formation of one bond at a time. The experimentally observed ratios of covalently-linked subunits within the tetramers were compared with the values predicted by the models. The results of these analyses suggest that the final stages of trout Ig assembly (the DSB formation between monomeric subunits) must occur in intracellular compartments late in the secretory process itself, thereby yielding incompletely crosslinked tetramers. Further, it would appear that the rate of disulfide bond formation within a tetramer may be accelerated by the presence in that tetramer, of previously incurred, intermonomeric DSBs.

Animals↗
PubMed1999

Dynamics of co-infection with M. Tuberculosis and HIV-1.

Since 1985, there has been a renewed epidemic of tuberculosis (TB) that was previously thought to be in check. There is evidence to believe the main factor for this resurgence has been the human immunodeficiency virus (HIV). Co-infection with HIV and M. Tuberculosis has profound implications for the course of both diseases. This study represents a first attempt to understand how the introduction of an opportunistic infection, namely Mycobacterium tuberculosis, the bacteria that causes TB, affects the dynamic interaction of HIV-1 and the immune system. We create a mathematical model using ordinary differential equations to describe the interaction of HIV and TB with the immune system. It is known that infection with TB can decrease the CD4(+) T cell counts-a key marker of AIDS progression; thus, it shortens survival in HIV infected individuals. Another main marker for HIV progression is the viral load. If this load is increased due to the presence of opportunistic infections, the disease progression is much more rapid. We also explore the effects of drug treatment on the TB infection in the doubly-infected patient.

AIDS-Related Opportunistic Infections↗
PubMed1999

Effects of cytokines on glucocorticoid receptor expression and function. Glucocorticoid resistance and relevance to depression.

Our data indicate that the proinflammatory cytokine, IL-1alpha inhibits GR translocation and hormone-induced GR-mediated gene transcription, and, in conjunction with previous in vivo and in vitro studies, can be interpreted to suggest that cytokines have the capacity to contribute to glucocorticoid resistance and thus the pathophysiology of depression. In addition, data from our mouse viral studies in glucocorticoid deficient animals demonstrate that endogenous glucocorticoids modulate a delicate balance between viral defense and cytokine toxicity. Finally, the antidepressant, DMI, has been found to enhance GR translocation and GR-mediated gene transcription and thus may provide a useful strategy for adjusting neuroendocrine setpoints in vivo. Taken together, these findings suggest that factors which modulate glucocorticoid action (e.g. cytokines and antidepressants) will be relevant contributors to disease expression including behavioral toxicity and sickness behavior.

Animals↗
PubMed1998

Mechanisms of cell death in Alzheimer disease--immunopathology.

Lesions in such chronic neurodegenerative disorders as Alzheimer disease, Parkinson disease, the parkinsonism dementia complex of Guam and amyotrophic lateral sclerosis have associated with them a variety of proteins known to be involved in inflammatory processes. This is particularly true of Alzheimer disease where inflammatory reactions are thought to be important contributors to the neuronal loss. They include complement proteins, complement inhibitors, acute phase reactants, inflammatory cytokines, proteases and protease inhibitors. Studies of cultured human astrocytes and microglia, obtained from postmortem brain, have established that nearly all of these proteins are produced by one or another of these cell types. Human neurons also produce many inflammatory proteins and their inhibitors, creating complex interactions. Accumulations of amyloid and extracellular tangles apparently act as irritants, causing the activation of complement, the initiation of reactive changes in microglia, and the release of potentially neurotoxic products. Such products include the membrane attack complex, oxygen free radicals and excess glutamate. Twenty epidemiological studies that have been published to data indicate that populations taking antiinflammatory drugs have a significantly reduced prevalence of Alzheimer disease or a slower mental decline. One small clinical trial with indomethacin showed arrest of the disease over a 6 month period. Therapeutic intervention in key inflammatory processes holds great promise for the amelioration of Alzheimer disease and possibly other neurodegenerative disorders.

Alzheimer Disease↗
PubMed1993

Humoral immunoresponse of pigeons to Aspergillus fumigatus antigens.

The aim of this study was to develop an immunological model of avian Aspergillosis by studying the humoral response of pigeons to Aspergillus fumigatus antigens. Immunization was performed by administering weekly injections of A. fumigatus extracts for 70 days (10 weeks). A new booster injection was given 270 days (9 months) following the last immunization. Results showed an early Aspergillus-specific humoral immunoresponse which reached a maximum level at 42-63 days (6-9 weeks) post-immunization. Using the ELISA method, it could be observed that A. fumigatus-specific IgG became elevated in the 2nd week and reached a maximum titre at 63rd day (9th week). In contrast, A. fumigatus-specific IgM levels appeared early showing maximum levels at the 2nd week, after which they declined despite the maintenance of antigenic stimulation. Termination of immunization resulted in the decrease of specific humoral immunoresponse with minimal levels of specific antibodies detectable 210 days (7 months) later. A booster injection given at 270 days (9 months) induced a very fast Aspergillus-specific IgM and IgG immunoresponse, reaching levels of antibodies similar to those observed during the immunization period.

Animals↗
PubMed1980

[The role of the complement system in experimental pancreatitis (author's translation)].

Two different experimental procedures were used to induce pancreatitis in rats: distal ligature of the common bile duct and the Pfeffer method in modification of Nevalainen. It could be shown that consumption of complement can be demonstrated even in pancreatitis induced by other than immunological models. Further examination in decomplemented rats showed the possibility of inducing acute pancreatitis by the above-mentioned models, although of less intensity. Therefore, the complement system will be an important factor for the progress and intensity of the inflammation process.

Acute Disease↗
PubMed1996

Inverse analysis of empirical matrices of idiotypic network interactions.

The concept of shape space proposed by Perelson and Oster (1979, J. Theor. Biol. 81, 645-670) has been a useful tool for the theoretical immunologists, who have invoked it to model idiotypic binding, which plays a significant role in mathematical models of immune networks. The actual construction of such a space from its definition requires specialized experimental information, which is not completely available. In this article, we discuss, with illustrative examples, how graphical representations similar to the idea of shape space can be derived by analyzing real affinity matrices, and the relative merits of such representations to approximations that might be obtained by the approach of Perelson and Oster. We also give directions for future research with a view toward applications.

Animals↗
PubMed1995

Dynamical behaviour of biological regulatory networks--II. Immunity control in bacteriophage lambda.

A number of bacterial and viral genes take part in the decision between lysis and lysogenization in temperate bacteriophages. In the lambda case, at least five viral genes (cI, cro, cII, N and cIII) and several bacterial genes are involved. Several attempts have been made to model this complex regulatory network. Our approach is based on a logical method described in the first paper of the series which formalizes the interactions between the elements of a regulatory network in terms of discrete variables, functions and parameters. In this paper two models are described and discussed, the first (two-variable model) focused on cI and cro interactions, the second (four-variable model) considering, in addition, genes cII and N. The treatment presented emphasizes the roles of positive and negative feedback loops and their interactions in the development of the phage. The role of the loops between cI and cro, and of cI on itself (which both have to be positive loops) was discovered earlier; this group's contribution to this aspect mainly deals with the possibility of treating these loops as parts of a more extended network. In contrast, the role of the negative loop of cro on itself had apparently remained unexplained. We realized that this loop buffers the expression of genes cro itself. cII, O and P against the inflation due to the rapid replication of the phage. More generally, negative auto-control of a gene appears an efficient way to render its expression insensitive (or less sensitive) to gene dosage, whereas a simple negative control would not provide this result.

Bacteria↗