A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03: 01 by a murine TCR

Research output: Contribution to journalArticle

Benjamine Arellano, Rehana Hussain, William A. Miller-Little, Emily Herndon, Doris Lambracht-Washington, Todd N. Eagar, Robert Lewis, Don Healey, Steven Vernino, Benjamin M. Greenberg, Olaf Stüve

Background Aquaporin 4 (AQP4) is considered a putative autoantigen in patients with Neuromyelitis optica (NMO), an autoinflammatory disorder of the central nervous system (CNS). HLA haplotype analyses of patients with NMO suggest a positive association with HLA-DRB1∗ 03:01.We previously showed that the human (h) AQP4 peptide 281-300 is the dominant immunogenic determinant of hAQP4 in the context of HLA-DRB1∗03:01. This immunogenic peptide stimulates a strong Th1 and Th17 immune response. AQP4281-300-specific encephalitogenic CD4+ T cells should initiate CNS inflammation that results in a clinical phenotype in HLA-DRB1∗03:01 transgenic mice. Methods Controlled study with humanized experimental animals. HLA-DRB1∗03:01 transgenic mice were immunized with hAQP4281-300, or whole-length hAQP4 protein emulsified in complete Freund's adjuvant. Humoral immune responses to both antigens were assessed longitudinally. In vivo T cell frequencies were assessed by tetramer staining. Mice were followed clinically, and the anterior visual pathway was tested by pupillometry. CNS tissue was examined histologically post-mortem. Flow cytometry was utilized for MHC binding assays and to immunophenotype T cells, and T cell frequencies were determined by ELISpot assay. Results Immunization with hAQP4281-300, resulted in an in vivo expansion of antigen-specific CD4+ T cells, and an immunoglobulin isotype switch. HLA-DRB1∗03:01 TG mice actively immunized with hAQP4281-300, or with whole-length hAQP4 protein were resistant to developing a neurological disease that resembles NMO. Experimental mice show no histological evidence of CNS inflammation, nor change in pupillary responses. Subsequent analysis reveals that a single amino acid substitution from aspartic acid in hAQP4 to glutamic acid in murine (m)AQP4 at position 290 prevents the recognition of hAQP4281-300, by the murine T cell receptor (TCR). Conclusion Induction of a CNS inflammatory autoimmune disorder by active immunization of HLADRB1∗ 03:01 TG mice with human hAQP4281-300, will be complex due to a single amino acid substitution. The pathogenic role of T cells in this disorder remains critical despite these observations.

Original languageEnglish (US)
Article numbere0152720
JournalPLoS ONE
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2016

PMID: 27054574

Altmetrics

Cite this

Standard

A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03 : 01 by a murine TCR. / Arellano, Benjamine; Hussain, Rehana; Miller-Little, William A.; Herndon, Emily; Lambracht-Washington, Doris; Eagar, Todd N.; Lewis, Robert; Healey, Don; Vernino, Steven; Greenberg, Benjamin M.; Stüve, Olaf.

In: PLoS ONE, Vol. 11, No. 4, e0152720, 01.04.2016.

Research output: Contribution to journalArticle

Harvard

Arellano, B, Hussain, R, Miller-Little, WA, Herndon, E, Lambracht-Washington, D, Eagar, TN, Lewis, R, Healey, D, Vernino, S, Greenberg, BM & Stüve, O 2016, 'A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03: 01 by a murine TCR' PLoS ONE, vol. 11, no. 4, e0152720. https://doi.org/10.1371/journal.pone.0152720

APA

Arellano, B., Hussain, R., Miller-Little, W. A., Herndon, E., Lambracht-Washington, D., Eagar, T. N., ... Stüve, O. (2016). A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03: 01 by a murine TCR. PLoS ONE, 11(4), [e0152720]. https://doi.org/10.1371/journal.pone.0152720

Vancouver

Arellano B, Hussain R, Miller-Little WA, Herndon E, Lambracht-Washington D, Eagar TN et al. A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03: 01 by a murine TCR. PLoS ONE. 2016 Apr 1;11(4). e0152720. https://doi.org/10.1371/journal.pone.0152720

Author

Arellano, Benjamine ; Hussain, Rehana ; Miller-Little, William A. ; Herndon, Emily ; Lambracht-Washington, Doris ; Eagar, Todd N. ; Lewis, Robert ; Healey, Don ; Vernino, Steven ; Greenberg, Benjamin M. ; Stüve, Olaf. / A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03 : 01 by a murine TCR. In: PLoS ONE. 2016 ; Vol. 11, No. 4.

BibTeX

@article{6e506491cd924723845172b52772844e,
title = "A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03: 01 by a murine TCR",
abstract = "Background Aquaporin 4 (AQP4) is considered a putative autoantigen in patients with Neuromyelitis optica (NMO), an autoinflammatory disorder of the central nervous system (CNS). HLA haplotype analyses of patients with NMO suggest a positive association with HLA-DRB1∗ 03:01.We previously showed that the human (h) AQP4 peptide 281-300 is the dominant immunogenic determinant of hAQP4 in the context of HLA-DRB1∗03:01. This immunogenic peptide stimulates a strong Th1 and Th17 immune response. AQP4281-300-specific encephalitogenic CD4+ T cells should initiate CNS inflammation that results in a clinical phenotype in HLA-DRB1∗03:01 transgenic mice. Methods Controlled study with humanized experimental animals. HLA-DRB1∗03:01 transgenic mice were immunized with hAQP4281-300, or whole-length hAQP4 protein emulsified in complete Freund's adjuvant. Humoral immune responses to both antigens were assessed longitudinally. In vivo T cell frequencies were assessed by tetramer staining. Mice were followed clinically, and the anterior visual pathway was tested by pupillometry. CNS tissue was examined histologically post-mortem. Flow cytometry was utilized for MHC binding assays and to immunophenotype T cells, and T cell frequencies were determined by ELISpot assay. Results Immunization with hAQP4281-300, resulted in an in vivo expansion of antigen-specific CD4+ T cells, and an immunoglobulin isotype switch. HLA-DRB1∗03:01 TG mice actively immunized with hAQP4281-300, or with whole-length hAQP4 protein were resistant to developing a neurological disease that resembles NMO. Experimental mice show no histological evidence of CNS inflammation, nor change in pupillary responses. Subsequent analysis reveals that a single amino acid substitution from aspartic acid in hAQP4 to glutamic acid in murine (m)AQP4 at position 290 prevents the recognition of hAQP4281-300, by the murine T cell receptor (TCR). Conclusion Induction of a CNS inflammatory autoimmune disorder by active immunization of HLADRB1∗ 03:01 TG mice with human hAQP4281-300, will be complex due to a single amino acid substitution. The pathogenic role of T cells in this disorder remains critical despite these observations.",
author = "Benjamine Arellano and Rehana Hussain and Miller-Little, {William A.} and Emily Herndon and Doris Lambracht-Washington and Eagar, {Todd N.} and Robert Lewis and Don Healey and Steven Vernino and Greenberg, {Benjamin M.} and Olaf St{\"u}ve",
year = "2016",
month = "4",
day = "1",
doi = "10.1371/journal.pone.0152720",
language = "English (US)",
volume = "11",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

RIS

TY - JOUR

T1 - A single amino acid substitution prevents recognition of a dominant human aquaporin-4 determinant in the context of HLA-DRB1-03

T2 - PLoS ONE

AU - Arellano, Benjamine

AU - Hussain, Rehana

AU - Miller-Little, William A.

AU - Herndon, Emily

AU - Lambracht-Washington, Doris

AU - Eagar, Todd N.

AU - Lewis, Robert

AU - Healey, Don

AU - Vernino, Steven

AU - Greenberg, Benjamin M.

AU - Stüve, Olaf

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Background Aquaporin 4 (AQP4) is considered a putative autoantigen in patients with Neuromyelitis optica (NMO), an autoinflammatory disorder of the central nervous system (CNS). HLA haplotype analyses of patients with NMO suggest a positive association with HLA-DRB1∗ 03:01.We previously showed that the human (h) AQP4 peptide 281-300 is the dominant immunogenic determinant of hAQP4 in the context of HLA-DRB1∗03:01. This immunogenic peptide stimulates a strong Th1 and Th17 immune response. AQP4281-300-specific encephalitogenic CD4+ T cells should initiate CNS inflammation that results in a clinical phenotype in HLA-DRB1∗03:01 transgenic mice. Methods Controlled study with humanized experimental animals. HLA-DRB1∗03:01 transgenic mice were immunized with hAQP4281-300, or whole-length hAQP4 protein emulsified in complete Freund's adjuvant. Humoral immune responses to both antigens were assessed longitudinally. In vivo T cell frequencies were assessed by tetramer staining. Mice were followed clinically, and the anterior visual pathway was tested by pupillometry. CNS tissue was examined histologically post-mortem. Flow cytometry was utilized for MHC binding assays and to immunophenotype T cells, and T cell frequencies were determined by ELISpot assay. Results Immunization with hAQP4281-300, resulted in an in vivo expansion of antigen-specific CD4+ T cells, and an immunoglobulin isotype switch. HLA-DRB1∗03:01 TG mice actively immunized with hAQP4281-300, or with whole-length hAQP4 protein were resistant to developing a neurological disease that resembles NMO. Experimental mice show no histological evidence of CNS inflammation, nor change in pupillary responses. Subsequent analysis reveals that a single amino acid substitution from aspartic acid in hAQP4 to glutamic acid in murine (m)AQP4 at position 290 prevents the recognition of hAQP4281-300, by the murine T cell receptor (TCR). Conclusion Induction of a CNS inflammatory autoimmune disorder by active immunization of HLADRB1∗ 03:01 TG mice with human hAQP4281-300, will be complex due to a single amino acid substitution. The pathogenic role of T cells in this disorder remains critical despite these observations.

AB - Background Aquaporin 4 (AQP4) is considered a putative autoantigen in patients with Neuromyelitis optica (NMO), an autoinflammatory disorder of the central nervous system (CNS). HLA haplotype analyses of patients with NMO suggest a positive association with HLA-DRB1∗ 03:01.We previously showed that the human (h) AQP4 peptide 281-300 is the dominant immunogenic determinant of hAQP4 in the context of HLA-DRB1∗03:01. This immunogenic peptide stimulates a strong Th1 and Th17 immune response. AQP4281-300-specific encephalitogenic CD4+ T cells should initiate CNS inflammation that results in a clinical phenotype in HLA-DRB1∗03:01 transgenic mice. Methods Controlled study with humanized experimental animals. HLA-DRB1∗03:01 transgenic mice were immunized with hAQP4281-300, or whole-length hAQP4 protein emulsified in complete Freund's adjuvant. Humoral immune responses to both antigens were assessed longitudinally. In vivo T cell frequencies were assessed by tetramer staining. Mice were followed clinically, and the anterior visual pathway was tested by pupillometry. CNS tissue was examined histologically post-mortem. Flow cytometry was utilized for MHC binding assays and to immunophenotype T cells, and T cell frequencies were determined by ELISpot assay. Results Immunization with hAQP4281-300, resulted in an in vivo expansion of antigen-specific CD4+ T cells, and an immunoglobulin isotype switch. HLA-DRB1∗03:01 TG mice actively immunized with hAQP4281-300, or with whole-length hAQP4 protein were resistant to developing a neurological disease that resembles NMO. Experimental mice show no histological evidence of CNS inflammation, nor change in pupillary responses. Subsequent analysis reveals that a single amino acid substitution from aspartic acid in hAQP4 to glutamic acid in murine (m)AQP4 at position 290 prevents the recognition of hAQP4281-300, by the murine T cell receptor (TCR). Conclusion Induction of a CNS inflammatory autoimmune disorder by active immunization of HLADRB1∗ 03:01 TG mice with human hAQP4281-300, will be complex due to a single amino acid substitution. The pathogenic role of T cells in this disorder remains critical despite these observations.

UR - http://www.scopus.com/inward/record.url?scp=84963527467&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84963527467&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0152720

DO - 10.1371/journal.pone.0152720

M3 - Article

VL - 11

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 4

M1 - e0152720

ER -

ID: 20879531