Use of MHC II Structural Features in the Design of Vaccines for Organ-Specific Autoimmune Diseases

Moustakas, Antonis K.; Papadopoulos, George K.

doi:10.2174/138161209789105117

Cited by 10 publications

(8 citation statements)

References 137 publications

(210 reference statements)

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“…In the case of the TCR recognition site, both non-MHC class II binding sites (P2, P3, P5 and P8) and amino acids outside the nonamer core region are important. In addition, some exceptions and anchor residues are recognized by the TCR [52][53][54].…”

Section: Mhc Class II and Apl Contact Sitesmentioning

confidence: 99%

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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SummaryBoth CD4 + and CD8 + T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4 + T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells.

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Section: Mhc Class II and Apl Contact Sitesmentioning

confidence: 99%

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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“…[12][13][14][15] Protein antigens are taken up by antigen-presenting cells that process and present peptides that bind to a polymorphic groove on major histocompatibility complex class II (MHCII) proteins. 16 The MHCII alleles 17 carried by an individual determine which peptides can be presented to his or her immune system. The peptide-MHCII complex may (or may not) then be recognized by 1 of millions of T-cell receptors (TCRs) on T-helper (Th) cells.…”

Section: Introductionmentioning

confidence: 99%

T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire

Ettinger

Paz

James³

et al. 2016

Blood

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• An HA subject with a multiexon F8 deletion showed a highly clonal response to 1 FVIII epitope via an immunodominant TCR.• The same HLA-DRA*01-DRB1*01:01-restricted FVIII epitope was recognized by T cells from 3 HA subjects.Factor VIII (FVIII)-neutralizing antibodies ("inhibitors") are a serious problem in hemophilia A (HA). The aim of this study was to characterize HLA-restricted T-cell responses from a severe HA subject with a persistent inhibitor and from 2 previously studied mild HA inhibitor subjects. Major histocompatibility complex II tetramers corresponding to both of the severe HA subject's HLA-DRA-DRB1 alleles were loaded with peptides spanning FVIII-A2, C1, and C2 domains. Interestingly, only 1 epitope was identified, in peptide FVIII [2194][2195][2196][2197][2198][2199][2200][2201][2202][2203][2204][2205][2206][2207][2208][2209][2210][2211][2212][2213] , and it was identical to the HLA-DRA*01-DRB1*01:01-restricted epitope recognized by the mild HA subjects. Multiple T-cell clones and polyclonal lines having different avidities for the peptide-loaded tetramer were isolated from all subjects. Only high-and medium-avidity T cells proliferated and secreted cytokines when stimulated with FVIII 2194-2213 . T-cell receptor b (TCRB) gene sequencing of 15 T-cell clones from the severe HA subject revealed that all high-avidity clones expressed the same TCRB gene. High-throughput immunosequencing of high-, medium-, and low-avidity cells sorted from a severe HA polyclonal line revealed that 94% of the high-avidity cells expressed the same TCRB gene as the high-avidity clones. TCRB sequencing of clones and lines from the mild HA subjects also identified a limited TCRB gene repertoire. These results suggest a limited number of epitopes in FVIII drive inhibitor responses and that the T-cell repertoires of FVIII-responsive T cells can be quite narrow. The limited diversity of both epitopes and TCRB gene usage suggests that targeting of specific epitopes and/or T-cell clones may be a promising approach to achieve tolerance to FVIII. (Blood. 2016; 128(16):2043-2054

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“…The specificity of this pocket is dictated by the Gly/Val dimorphism at b86. [11][12][13][60][61][62] HLA-DR alleles with b86Gly, including DRB1*01:01, allow primarily large hydrophobic aromatic residues at position 1 and large aliphatic residues secondarily, whereas HLA-DR alleles with b86Val have the reverse specificities. Accordingly, F2196 was found to be critical for DRB1*01:01 affinity and for the CD4 1 T-cell response.…”

Section: Org Frommentioning

confidence: 99%

“…Peptide side chains at relative "anchor" positions 1, 4, 6, 7, and 9 bind to these pockets, with size, shape, and charge or hydrophobic complementarity determining their affinity. [11][12][13] Recognition of MHCII-peptide complexes by specific TCR, in the context of costimulatory engagement, results in T-cell activation and proliferation. Activated T-effectors traffic to B-cell follicles where they engage with B cells via MHCII-peptide-TCR interactions and induce germinal center formation, wherein activated B cells proliferate and terminally differentiate into anti-FVIII antibody-secreting plasma cells.…”

Section: Introductionmentioning

confidence: 99%

FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity

Ettinger¹,

Liberman

Gunasekera

et al. 2018

Blood Advances

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Use of MHC II Structural Features in the Design of Vaccines for Organ-Specific Autoimmune Diseases

Cited by 10 publications

References 137 publications

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire

FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity

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