Direct binding of autoimmune disease related T cell epitopes to purified Lewis rat MHC class II molecules

Abstract Today it is generally accepted that B cells require cognate interactions with CD4+ T cells to develop high-affinity antibodies against proteins. CD4+ T cells recognize peptides (epitopes) presented by MHC class II molecules that are expressed on antigen-presenting cells. Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4+ T cells that can bind to the MHC class II–peptide complex. We used a new humanized hemophilic mouse model to identify FVIII peptides presented by HLA-DRB1*1501. This model carries a knockout of all murine MHC class II molecules and expresses a chimeric murine-human MHC class II complex that contains the peptide-binding sites of the human HLA-DRB1*1501. When mice were treated with human FVIII, the proportion of mice that developed antibodies depended on the application route of FVIII and the activation state of the innate immune system. We identified 8 FVIII peptide regions that contained CD4+ T-cell epitopes presented by HLA-DRB1*1501 to CD4+ T cells during immune responses against FVIII. CD4+ T-cell responses after intravenous and subcutaneous application of FVIII involved the same immunodominant FVIII epitopes. Interestingly, most of the 8 peptide regions contained promiscuous epitopes that bound to several different HLA-DR proteins in in vitro binding assays.

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MHC class II-derived peptides can bind to class II molecules, including self molecules, and prevent antigen presentation.

Journal of Experimental Medicine ◽

10.1084/jem.171.5.1419 ◽

1990 ◽

Vol 171 (5) ◽

pp. 1419-1430 ◽

Cited By ~ 20

Author(s):

E F Rosloniec ◽

L J Vitez ◽

S Buus ◽

J H Freed

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Synthetic Peptides ◽

Molecular Basis ◽

Class Ii ◽

Peptide Antigens ◽

Mhc Molecules ◽

Direct Binding ◽

Mhc Class Ii Molecules ◽

Combined Data

Seven synthetic peptides corresponding to the polymorphic regions of the alpha and beta chains of the I-Ak molecule were examined for their ability to inhibit the presentation of foreign antigens to antigen-specific, I-A-restricted T cell hybridomas. Two of the peptides, representing the sequences found in the first and third polymorphic regions (PMR) of the A alpha k chain (alpha k-1 and alpha k-3) were capable of inhibiting the presentation of three different HEL-derived peptide antigens to their appropriate T cells. In addition, the alpha k-1 peptide inhibited the presentation of the OVA(323-339) immunodominant peptide to the I-Ad-restricted T cell hybridomas specific for it. Prepulsing experiments demonstrated that the PMR peptides were interacting with the APC and not with the T cell hybridomas. These observations were confirmed and extended by the demonstration that the alpha k-1 and alpha k-3 peptides blocked the direct binding of HEL(46-61) to purified I-Ak and that the alpha k-1 peptide blocked the binding of OVA(323-339) to I-Ad. The binding competition experiments suggest that the alpha k-1 peptide binds to the I-Ak molecule from which it was derived with a Kd approximately 10(-5) M, while the alpha k-3 peptide binds slightly less well. These combined data, suggesting that class II-derived peptides can bind to MHC class II molecules, including the autologous molecule from which they are derived, have important implications for the molecular basis of alloreactivity and autoreactivity. Further, they suggest a possible mechanism by which selecting elements, involving only MHC molecules, may be generated in the thymus.

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T cell MHC class II molecules downregulate CD4+ T cell response following LAG-3 binding

Human Immunology ◽

10.1016/0198-8859(96)85066-x ◽

1996 ◽

Vol 47 (1-2) ◽

pp. 69

Author(s):

Frédéric Triebel ◽

Bertrand Huard

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Cell Response ◽

Class Ii ◽

T Cell Response ◽

Cd4 T Cell ◽

Mhc Class Ii Molecules

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Induction and Break of Immune Tolerance to Human FVIII in a HLA-DRB1*1501 Humanized Hemophilic Mouse Model

Blood ◽

10.1182/blood.v118.21.2280.2280 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2280-2280

Author(s):

Katharina Nora Steinitz ◽

Brigitte Binder ◽

Christian Lubich ◽

Rafi Uddin Ahmad ◽

Markus Weiller ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Mouse Model ◽

Mhc Class Ii ◽

Immune Tolerance ◽

Cd4 T Cells ◽

Hemophilia A ◽

Class Ii ◽

T Cell Epitopes

Abstract Abstract 2280 Development of neutralizing antibodies against FVIII is the major complication in the treatment of patients with hemophilia A. Although several genetic and environmental risk factors have been identified, it remains unclear why some patients develop antibodies while others do not. Understanding the underlying mechanisms that drive the decision of the immune system whether or not to make antibodies against FVIII would help to design novel therapeutics. We used a new humanized hemophilic mouse model that expresses the human MHC-class II molecule HLA-DRB1*1501 on the background of a complete knock out of all murine MHC-class II genes. Initial studies had indicated that only a fraction of these mice developed antibodies when intravenously (i.v.) treated with human FVIII. These findings which resemble the situation in patients with severe hemophilia A, evoked the question if the lack of antibody development in non-responder mice reflects the induction of specific immune tolerance after i.v. application of FVIII or represent non-responsiveness for other reasons. We addressed this question by choosing another application route (subcutaneous, s.c.) and by combining i.v. application with a concomitant activation of the innate immune system applying LPS, a well characterized ligand for toll-like receptor 4, together with FVIII. Both strategies resulted in the development of antibodies in all mice included in the study what suggested that non-responsiveness against i.v. FVIII does not reflect an inability to develop antibodies against FVIII. Next, we asked if i.v. FVIII does induce immune tolerance in non-responder mice. We pretreated mice with i.v. FVIII, selected non-responder mice and challenged them with s.c. FVIII. None of the mice developed antibodies what indicated that i.v. pretreatment had induced immune tolerance in non-responder mice. Currently, we test the hypothesis that immune tolerance after i.v. application is induced and maintained by FVIII-specific regulatory T cells. The differences in responder rates after i.v. and s.c. application of FVIII raised the question if there are differences in FVIII T-cell epitopes involved in the initial activation of FVIII-specific CD4+ T cells. We obtained spleen cells from mice treated with either i.v. or s.c. FVIII and generated CD4+ T-cell hybridoma libraries that were tested for peptide specificities. For this purpose we used a FVIII peptide library containing 15 mers with an offset of 3 amino acids. Our results indicate that the pattern of FVIII-specific T-cell epitopes involved in the activation of FVIII-specific CD4+ T cells after i.v. and s.c. application of FVIII is almost identical and represents a small set of FVIII peptides distributed over the A1, A2, B, A3 and C1 domains. Based on our results we conclude that the new HLA-DRB1*1501 hemophilic mouse model represents an interesting opportunity to uncover the mechanisms that drive the decision of the immune system whether or not to develop antibodies against FVIII. Disclosures: Steinitz: Baxter BioScience: Employment. Binder:Baxter BioScience: Employment. Lubich:Baxter BioScience: Employment. Ahmad:Baxter BioScience: Employment. Weiller:Baxter BioScience: Employment. de la Rosa:Baxter BioScience: Employment. Schwarz:Baxter BioScience: Employment. Scheiflinger:Baxter BioScience: Employment. Reipert:Baxter Innovations GmbH: Employment.

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Direct binding of the Mtv7 superantigen (Mls-1) to soluble MHC class II molecules

Immunity ◽

10.1016/s1074-7613(95)80027-1 ◽

1995 ◽

Vol 2 (2) ◽

pp. 149-154 ◽

Cited By ~ 14

Author(s):

David G. Mottershead ◽

Ping-Ning Hsu ◽

Robert G. Urban ◽

Jack L. Strominger ◽

Brigitte T. Huber

Keyword(s):

Mhc Class Ii ◽

Class Ii ◽

Direct Binding ◽

Mhc Class Ii Molecules

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Effects of transgenic mixed-haploptype MHC class II molecules AαdAβz on autoimmune disease in New Zealand mice

International Immunology ◽

10.1093/intimm/8.6.967 ◽

1996 ◽

Vol 8 (6) ◽

pp. 967-976 ◽

Cited By ~ 13

Author(s):

Hiroyuki Nishimura ◽

Ishlkawa Sho ◽

Shingo Nozawa ◽

Masanorl Awaji ◽

Juichi Saito ◽

...

Keyword(s):

New Zealand ◽

Autoimmune Disease ◽

Mhc Class Ii ◽

Class Ii ◽

Mhc Class Ii Molecules

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“Immunoinformatic Identification of T-Cell and B-Cell Epitopes From Giardia lamblia Immunogenic Proteins as Candidates to Develop Peptide-Based Vaccines Against Giardiasis”

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.769446 ◽

2021 ◽

Vol 11 ◽

Author(s):

Thania Garzon ◽

David Ortega-Tirado ◽

Gloria Lopez-Romero ◽

Efrain Alday ◽

Ramón Enrique Robles-Zepeda ◽

...

Keyword(s):

Immune System ◽

T Cell ◽

B Cell ◽

Mhc Class Ii ◽

Giardia Lamblia ◽

Class Ii ◽

Host Immune System ◽

B Cell Epitopes ◽

Immunogenic Proteins ◽

Mhc Class Ii Molecules

Giardiasis is one of the most common gastrointestinal infections worldwide, mainly in developing countries. The etiological agent is the Giardia lamblia parasite. Giardiasis mainly affects children and immunocompromised people, causing symptoms such as diarrhea, dehydration, abdominal cramps, nausea, and malnutrition. In order to develop an effective vaccine against giardiasis, it is necessary to understand the host-Giardia interactions, the immunological mechanisms involved in protection against infection, and to characterize the parasite antigens that activate the host immune system. In this study, we identify and characterize potential T-cell and B-cell epitopes of Giardia immunogenic proteins by immunoinformatic approaches, and we discuss the potential role of those epitopes to stimulate the host´s immune system. We selected the main immunogenic and protective proteins of Giardia experimentally investigated. We predicted T-cell and B-cell epitopes using immunoinformatic tools (NetMHCII and BCPREDS). Variable surface proteins (VSPs), structural (giardins), metabolic, and cyst wall proteins were identified as the more relevant immunogens of G. lamblia. We described the protein sequences with the highest affinity to bind MHC class II molecules from mouse (I-Ak and I-Ad) and human (DRB1*03:01 and DRB1*13:01) alleles, as well as we selected promiscuous epitopes, which bind to the most common range of MHC class II molecules in human population. In addition, we identified the presence of conserved epitopes within the main protein families (giardins, VSP, CWP) of Giardia. To our knowledge, this is the first in silico study that analyze immunogenic proteins of G. lamblia by combining bioinformatics strategies to identify potential T-cell and B-cell epitopes, which can be potential candidates in the development of peptide-based vaccines. The bioinformatics analysis demonstrated in this study provides a deeper understanding of the Giardia immunogens that bind to critical molecules of the host immune system, such as MHC class II and antibodies, as well as strategies to rational design of peptide-based vaccine against giardiasis.

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MHC-class II molecules expression by dendritic cells correlates with activated OPD4+ T cell in of Sentinel and Non-Sentinel nodes from Melanoma patients.

Pigment Cell Research ◽

10.1111/j.1600-0749.2004.00175_52.x ◽

2004 ◽

Vol 17 (4) ◽

pp. 444-444 ◽

Cited By ~ 1

Author(s):

R.-R. Huang ◽

H.-J. Wang ◽

L. L. Lin ◽

D.-R. Wen ◽

E. Itakura ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mhc Class Ii ◽

Class Ii ◽

Sentinel Nodes ◽

Melanoma Patients ◽

Mhc Class Ii Molecules

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Humanized E17 Hemophilic Mice Are a Major Breakthrough in the Design of New Preclinical Models for Developing Factor VIII Products with Reduced Immunogenicity.

Blood ◽

10.1182/blood.v110.11.782.782 ◽

2007 ◽

Vol 110 (11) ◽

pp. 782-782 ◽

Cited By ~ 1

Author(s):

Birgit M. Reipert ◽

Christina Hausl ◽

Maria Sasgary ◽

Maria Schuster ◽

Rafi U. Ahmad ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Factor Viii ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Plasma Cells ◽

Hemophilia A ◽

Class Ii ◽

Mhc Class Ii Molecules

Abstract MHC class II molecules are crucial for regulating adaptive immune responses against self and foreign protein antigens. They determine the antigenic peptides that are presented to CD4+ T cells and are essential for shaping the CD4+ T-cell repertoire in the thymus. Thus, the structure of MHC class II molecules is a major determinant for protein antigen immunogenicity. Structural differences between murine and human MHC class II complexes fundamentally limit the use of conventional murine hemophilia A models for dissecting immune responses to human factor VIII and developing new factor VIII products with reduced immunogenicity. To overcome this limitation, we humanized the murine E17 model of hemophilia A by introducing the human MHC class II haplotype HLA-DRB1*1501 on the background of a complete knockout of all murine MHC class II genes. Any anti-FVIII antibody response in this new humanized hemophilia A model is driven by CD4+ T cells that recognize FVIII-derived peptides that are presented by human HLA-DRB1*1501. The MHC class II haplotype HLA-DRB1*1501 is particularly relevant for the situation in hemophilia A patients because it is found in about 25% of Caucasians and 32% of Africans and has been shown to be associated with an increased risk that patients with severe hemophilia A have for developing FVIII inhibitors. We validated the relevance of this new model by asking the question whether HLA-DRB1*1501 hemophilic E17 mice develop FVIII inhibitors that are similar to those observed in patients with hemophilia A. Furthermore, we wanted to show that anti-FVIII antibody responses in these mice depend on the expression of the human DRB1*1501 molecule. Mice were treated with 8 intravenous doses of human FVIII and tested for anti-FVIII antibodies, anti-FVIII antibody-producing plasma cells and FVIII-specific T cells. About 90% of all humanized hemophilic E17 mice tested developed anti-FVIII antibodies that were similar to FVIII inhibitors found in patients. These antibodies were not restricted isotypically and contained mainly IgG1, IgG2a and IgG2b antibodies. Detection of antibodies in the circulation correlated with the presence of anti-FVIII antibody-producing plasma cells in the spleen. Development of anti-FVIII antibodies depended on the activation of FVIII-specific T cells and strictly depended on the expression of the HLA-DRB1*1501 molecule. Mice that did not express any MHC class II molecules did not develop anti-FVIII antibodies. We conclude that this new humanized E17 model for hemophilia A is a major advance towards developing suitable animal models needed to design future immunomodulatory strategies for patients with FVIII inhibitors and develop new FVIII products with reduced immunogenicity. Furthermore, it provides a tool for identifying T-cell epitopes of human FVIII restricted by MHC class II molecules that can be used for monitoring FVIII-specific T cells in patients who receive replacement therapy with FVIII products.

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