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Frontiers in Immunology 2022The risk to develop ACPA positive rheumatoid arthritis (RA), the most destructive type of autoimmune arthritis, is carried by HLA-DRB1 alleles containing a 5 amino acid... (Review)
Review
The risk to develop ACPA positive rheumatoid arthritis (RA), the most destructive type of autoimmune arthritis, is carried by HLA-DRB1 alleles containing a 5 amino acid motif: the shared epitope (SE). RA is preceded by the emergence of disease specific anti citrullinated protein antibodies (ACPA). SE positive HLA-DRB1 alleles are associated with ACPA and ACPA positive RA, not with ACPA negative RA, suggesting that ACPA contribute to the pathogenesis of RA. Understanding how HLA-DRB1 genotypes influence ACPA could lead to a curative or preventive treatment of RA. The "Shared epitope binds citrullinated peptides " hypothesis suggests that RA associated HLA-DR alleles present citrullinated peptides to T cells that help ACPA producing B cells. The "Hapten carrier model" suggests that PAD4 is the target of the T cells which help ACPA specific B cells through a hapten carrier mechanism in which PAD4 is the carrier and citrullinated peptides are the haptens. Direct binding assay of citrullinated peptides to purified HLA-DR molecules does not support the "shared epitope binds citrullinated peptides" hypothesis. The Odds Ratios to develop ACPA positive RA associated with each of 12 common HLA-DRB1 genotypes match the probability that the two HLA-DR molecules they encode can bind at least one peptide from PAD4, not from citrullinated fibrinogen. Thus, PAD4 tolerization might stop the carrier effect and switch off production of ACPA.
Topics: Arthritis, Rheumatoid; Autoantibodies; Citrullination; Epitopes; HLA-DRB1 Chains; Haptens; Humans; Peptides; Peptides, Cyclic
PubMed: 35774784
DOI: 10.3389/fimmu.2022.930112 -
Journal of Immunology (Baltimore, Md. :... Feb 2011Contact hypersensitivity is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Effector CD8 T cell recruitment into the skin parenchyma to...
Contact hypersensitivity is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Effector CD8 T cell recruitment into the skin parenchyma to elicit the response to hapten challenge requires prior CXCL1/KC-directed neutrophil infiltration within 3-6 h after challenge and is dependent on IFN-γ and IL-17 produced by the hapten-primed CD8 T cells. Mechanisms directing hapten-primed CD8 T cell localization and activation in the Ag challenge site to induce this early CXCL1 production in response to 2,4-dinitrofluorobenzene were investigated. Both TNF-α and IL-17, but not IFN-γ, mRNA was detectable within 1 h of hapten challenge of sensitized mice and increased thereafter. Expression of ICAM-1 was observed by 1 h after challenge of sensitized and nonsensitized mice and was dependent on TNF-α. The induction of IL-17, IFN-γ, and CXCL1 in the challenge site was not observed when ICAM-1 was absent or neutralized by specific Ab. During the elicitation of the contact hypersensitivity response, endothelial cells expressed ICAM-1 and produced CXCL1 suggesting this as the site of CD8 T cell localization and activation. Endothelial cells isolated from challenged skin of naive and sensitized mice had acquired the hapten and the ability to activate hapten-primed CD8 T cell cytokine production. These results indicate that hapten application to the skin of sensitized animals initiates an inflammatory response promoting hapten-primed CD8 T cell localization to the challenge site through TNF-α-induced ICAM-1 expression and CD8 T cell activation to produce IFN-γ and IL-17 through endothelial cell presentation of hapten.
Topics: Adoptive Transfer; Animals; Antigen Presentation; CD8-Positive T-Lymphocytes; Cell Communication; Chemokine CXCL1; Dermatitis, Contact; Endothelial Cells; Female; Haptens; Immunity, Innate; Inflammation Mediators; Interferon-gamma; Interleukin-17; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration
PubMed: 21239709
DOI: 10.4049/jimmunol.1002337 -
ELife Jan 2021Diphenylcyclopropenone (DPC) is an organic chemical hapten which induces allergic contact dermatitis and is used in the treatment of warts, melanoma, and alopecia...
Diphenylcyclopropenone (DPC) is an organic chemical hapten which induces allergic contact dermatitis and is used in the treatment of warts, melanoma, and alopecia areata. This therapeutic setting therefore provided an opportunity to study T cell receptor (TCR) repertoire changes in response to hapten sensitization in humans. Repeated exposure to DPC induced highly dynamic transient expansions of a polyclonal diverse T cell population. The number of TCRs expanded early after sensitization varies between individuals and predicts the magnitude of the allergic reaction. The expanded TCRs show preferential TCR V and J gene usage and consist of clusters of TCRs with similar sequences, two characteristic features of antigen-driven responses. The expanded TCRs share subtle sequence motifs that can be captured using a dynamic Bayesian network. These observations suggest the response to DPC is mediated by a polyclonal population of T cells recognizing a small number of dominant antigens.
Topics: Adolescent; Adult; Aged; Allergens; Child; Cyclopropanes; Female; Haptens; Humans; Male; Middle Aged; Receptors, Antigen, T-Cell; T-Lymphocytes; Young Adult
PubMed: 33432924
DOI: 10.7554/eLife.54747 -
Frontiers in Immunology 2021Allergic reactions to drugs and chemicals are mediated by an adaptive immune response involving specific T cells. During thymic selection, T cells that have not yet... (Review)
Review
Allergic reactions to drugs and chemicals are mediated by an adaptive immune response involving specific T cells. During thymic selection, T cells that have not yet encountered their cognate antigen are considered naive T cells. Due to the artificial nature of drug/chemical-T-cell epitopes, it is not clear whether thymic selection of drug/chemical-specific T cells is a common phenomenon or remains limited to few donors or simply does not exist, suggesting T-cell receptor (TCR) cross-reactivity with other antigens. Selection of drug/chemical-specific T cells could be a relatively rare event accounting for the low occurrence of drug allergy. On the other hand, a large T-cell repertoire found in multiple donors would underline the potential of a drug/chemical to be recognized by many donors. Recent observations raise the hypothesis that not only the drug/chemical, but also parts of the haptenated protein or peptides may constitute the important structural determinants for antigen recognition by the TCR. These observations may also suggest that in the case of drug/chemical allergy, the T-cell repertoire results from particular properties of certain TCR to recognize hapten-modified peptides without need for previous thymic selection. The aim of this review is to address the existence and the role of a naive T-cell repertoire in drug and chemical allergy. Understanding this role has the potential to reveal efficient strategies not only for allergy diagnosis but also for prediction of the immunogenic potential of new chemicals.
Topics: Cross Reactions; Dermatitis, Contact; Drug Hypersensitivity; Epitopes, T-Lymphocyte; Haptens; Humans; Peptides; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 34267746
DOI: 10.3389/fimmu.2021.653102 -
The Journal of Experimental Medicine May 1962The effects of the following parameters on the immunologic specificity of delayed and immediate hypersensitivity reactions were investigated in the guinea pig using the...
The effects of the following parameters on the immunologic specificity of delayed and immediate hypersensitivity reactions were investigated in the guinea pig using the picryl and p-toluenesulfonyl systems: (a) the contribution of the carrier protein, (b) the effect of the number of hapten groups per molecule of the immunizing and challenging antigens, and (c) the effect of interposing a 6 carbon chain (epsilon-aminocaproic acid) between the hapten and its usual attachment to the lysine epsilon-NH(2) groups of the carrier protein. It was found that induction of delayed hypersensitivity was accomplished equally well with both lightly and heavily coupled conjugates. Sensitized animals which gave strong delayed reactions to the immunizing conjugate cross-reacted poorly or not at all to (a) conjugates of the same hapten with a different carrier protein, or (b) conjugates differing from the immunizing conjugate by having an epsilon-aminocaproyl chain interposed between hapten and its attachment onto the carrier protein. Animals sensitized with either lightly or heavily substituted conjugates exhibited strong delayed reactions to both conjugates, but more intense reactions to the immunizing conjugate were always observed. In contrast to the marker carrier specificity exhibited by the delayed hypersensitivity reactions, immediate hypersensitivity reactions, (specific precipitation, Arthus, and PCA reactions) could be elicited equally well with hapten conjugates of all carrier proteins, as well as with conjugates containing epsilon-aminocaproyl chains interposed between hapten and the carrier protein, provided the number of hapten groups per molecule conjugate was sufficiently high. Both in inducing antibody response and in provoking immediate hypersensitivity reactions, heavily substituted conjugates were considerably more effective than were lightly substituted conjugates. Alternative explanations for these observed differences in specificity between immediate and delayed hypersensitivity reactions are discussed.
Topics: Animals; Antibody Formation; Antigens; Carrier Proteins; Guinea Pigs; Haptens; Hypersensitivity; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Immunization
PubMed: 13867017
DOI: 10.1084/jem.115.5.1023 -
Journal of Labelled Compounds &... Nov 2020A deuterated hapten was designed and synthesized that will be essential for a future study of residual hapten and stability of a hapten-protein conjugate. This hapten,...
A deuterated hapten was designed and synthesized that will be essential for a future study of residual hapten and stability of a hapten-protein conjugate. This hapten, 6-AmHap, was chosen for a heroin vaccine that is now slated for a Phase 1 clinical trial. A maleimide-thiol bioconjugation strategy was successfully applied to our heroin vaccine to connect the hapten 6-AmHap with an immunogenic carrier protein (tetanus toxoid, TT) through a trityl-protected 3-mercaptopropanamide linker. The antibodies induced by the vaccine have been found to have activity against several opioids, including heroin and its metabolites, and, importantly, leave alternate pain treatment medications such as methadone untouched. To the best of our knowledge, no other hapten for a heroin vaccine has been deuterated, yet this tool may prove to be of great importance in the study of residual hapten during product release and the long-term stability program of a hapten-protein conjugate as part of FDA regulatory requirements. Hydrocodone was the starting material for the synthesis of the deuterated 6-AmHap, with a stable amide at C6 and a 3-mercaptopropanamide linker attached at C3. The desired deuterated product was prepared as the disulfide, 3,3'-disulfanediylbis(N-((7S,7aR,12bS)-7-acetamido-3-[ H ]methyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)propanamide), that could be easily reduced to form the needed hapten, N-((4aR,7S,7aR,12bS)-7-acetamido-3-[ H ]methyl]-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)-3-mercaptopropanamide.
Topics: Deuterium; Haptens; Heroin; Pharmaceutical Preparations; Reference Standards; Vaccines
PubMed: 32876947
DOI: 10.1002/jlcr.3880 -
Allergology International : Official... Mar 2006Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the... (Review)
Review
Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the immune system. Only after covalently binding to an endogenous protein the immune system reacts to this so called hapten-carrier complex, as the larger molecule (protein) is modified, and thus immunogenic for B and T cells. Consequently, a B and T cell immune response might develop to the drug with very heterogeneous clinical manifestations. In recent years, however, evidence has become stronger that not all drugs need to bind covalently to the MHC-peptide complex in order to trigger an immune response. Rather, some drugs may bind directly and reversibly to immune receptors like the major histocompatibility complex (MHC) or the T cell receptor (TCR), thereby stimulating the cells similar to a pharmacological activation of other receptors. This concept has been termed pharmacological interaction with immune receptors the (p-i) concept. While the exact mechanism is still a matter of debate, non-covalent drug presentation clearly leads to the activation of drug-specific T cells as documented for various drugs (lidocaine, sulfamethoxazole (SMX), lamotrigine, carbamazepine, p-phenylendiamine, etc.). In some patients with drug hypersensitivity, such a response may occur within hours even upon the first exposure to the drug. Thus, the reaction to the drug may not be due to a classical, primary response, but rather be mediated by stimulating existing, pre-activated, peptide-specific T cells that are cross specific for the drug. In this way, certain drugs may circumvent the checkpoints for immune activation imposed by the classical antigen processing and presentation mechanisms, which may help to explain the peculiar nature of many drug hypersensitivity reactions.
Topics: Drug Hypersensitivity; Haptens; Humans; Receptors, Antigen, T-Cell; T-Lymphocytes; Xenobiotics
PubMed: 17075282
DOI: 10.2332/allergolint.55.17 -
ChemMedChem May 2020A click-chemistry-based approach was implemented to prepare peptidomimetics designed in silico and made from aromatic azides and a propargylated GIGI-mimicking platform...
A click-chemistry-based approach was implemented to prepare peptidomimetics designed in silico and made from aromatic azides and a propargylated GIGI-mimicking platform derived from the altered Melan-A/MART-1 antigenic peptide ELAGIGILTV. The Cu -catalyzed Huisgen cycloaddition was carried out on solid support to generate rapidly a first series of peptidomimetics, which were evaluated for their capacity to dock at the interface between the major histocompatibility complex class-I (MHC-I) human leucocyte antigen (HLA)-A2 and T-cell receptors (TCRs). Despite being a weak HLA-A2 ligand, one of these 11 first synthetic compounds bearing a p-nitrobenzyl-triazole side chain was recognized by the receptor proteins of Melan-A/MART-1-specific T-cells. After modification of the N and C termini of this agonist, which was intended to enhance HLA-A2 binding, one of the resulting seven additional compounds triggered significant T-cell responses. Thus, these results highlight the capacity of naturally circulating human TCRs that are specific for the native Melan-A/MART-1 peptide to cross-react with peptidomimetics bearing organic motifs structurally different from the native central amino acids.
Topics: Click Chemistry; HLA-A2 Antigen; Haptens; Humans; MART-1 Antigen; Molecular Structure; Oligopeptides; Peptidomimetics; Receptors, Antigen, T-Cell
PubMed: 32162475
DOI: 10.1002/cmdc.202000038 -
Nature Communications Aug 2018Uptake of tumor antigens by tumor-infiltrating dendritic cells is limiting step in the induction of tumor immunity, which can be mediated through Fc receptor (FcR)...
Uptake of tumor antigens by tumor-infiltrating dendritic cells is limiting step in the induction of tumor immunity, which can be mediated through Fc receptor (FcR) triggering by antibody-coated tumor cells. Here we describe an approach to potentiate tumor immunity whereby hapten-specific polyclonal antibodies are recruited to tumors by coating tumor cells with the hapten. Vaccination of mice against dinitrophenol (DNP) followed by systemic administration of DNP targeted to tumors by conjugation to a VEGF or osteopontin aptamer elicits potent FcR dependent, T cell mediated, antitumor immunity. Recruitment of αGal-specific antibodies, the most abundant naturally occurring antibodies in human serum, inhibits tumor growth in mice treated with a VEGF aptamer-αGal hapten conjugate, and recruits antibodies from human serum to human tumor biopsies of distinct origin. Thus, treatment with αGal hapten conjugated to broad-spectrum tumor targeting ligands could enhance the susceptibility of a broad range of tumors to immune elimination.
Topics: Animals; Antibodies; Dinitrophenols; Haptens; Humans; Immunohistochemistry; Immunotherapy; Mice; Mice, Inbred C57BL; Osteopontin; Receptors, Fc; Vascular Endothelial Growth Factor A
PubMed: 30135425
DOI: 10.1038/s41467-018-05566-x -
Journal of the American Chemical Society Sep 2019Recent trends in methamphetamine (METH) misuse and overdose suggest society is inadvertently overlooking a brewing METH crisis. In the past decade,...
Recent trends in methamphetamine (METH) misuse and overdose suggest society is inadvertently overlooking a brewing METH crisis. In the past decade, psychostimulant-related lethal overdoses and hospitalizations have skyrocketed 127 and 245%, respectively. Unlike the opioid crisis, no pharmaceutical interventions are available for treating METH use disorder or reversing overdose. Herein, we report the first active vaccine that offers protection from lethal (+)-METH challenge in male Swiss Webster mice. This vaccine formulation of ()MLMH-TT adjuvanted with CpG ODN 1826 + alum successfully raised anti-METH antibodies in high titers, reduced (+)-METH distribution to the brain, and lowered (+)-METH-associated stereotypies in a hyperlocomotion assay. A comparison of enantiomeric haptens and the racemate elucidated the importance of employing ()-stereochemistry in METH hapten design for optimal protection.
Topics: Adjuvants, Immunologic; Animals; Antibodies; Haptens; Male; Methamphetamine; Mice; Molecular Conformation; Stereoisomerism; Vaccines
PubMed: 31479256
DOI: 10.1021/jacs.9b07294