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Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

Cell-surface HLA-I molecules consisting of β2-microglobulin (β2m) associated heavy chains (HCs), referred to as Face-1, primarily present peptides to CD8+ T-cells. HCs consist of three α-domains, with selected amino acid sequences shared by all alleles of all six isoforms. The cell-surface HLA under...

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Autores principales: Ravindranath, Mepur H., El Hilali, Fatiha, Amato-Menker, Carly J., El Hilali, Hajar, Selvan, Senthamil R., Filippone, Edward J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495617/
https://www.ncbi.nlm.nih.gov/pubmed/36134954
http://dx.doi.org/10.3390/antib11030058
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author Ravindranath, Mepur H.
El Hilali, Fatiha
Amato-Menker, Carly J.
El Hilali, Hajar
Selvan, Senthamil R.
Filippone, Edward J.
author_facet Ravindranath, Mepur H.
El Hilali, Fatiha
Amato-Menker, Carly J.
El Hilali, Hajar
Selvan, Senthamil R.
Filippone, Edward J.
author_sort Ravindranath, Mepur H.
collection PubMed
description Cell-surface HLA-I molecules consisting of β2-microglobulin (β2m) associated heavy chains (HCs), referred to as Face-1, primarily present peptides to CD8+ T-cells. HCs consist of three α-domains, with selected amino acid sequences shared by all alleles of all six isoforms. The cell-surface HLA undergoes changes upon activation by pathological conditions with the expression of β2m-free HCs (Face-2) resulting in exposure of β2m-masked sequences shared by almost all alleles and the generation of HLA-polyreactive antibodies (Abs) against them. Face-2 may homodimerize or heterodimerize with the same (Face-3) or different alleles (Face-4) preventing exposure of shared epitopes. Non-allo immunized males naturally carry HLA-polyreactive Abs. The therapeutic intravenous immunoglobulin (IVIg) purified from plasma of thousands of donors contains HLA-polyreactive Abs, admixed with non-HLA Abs. Purified HLA-polyreactive monoclonal Abs (TFL-006/007) generated in mice after immunizing with Face-2 are documented to be immunoregulatory by suppressing or activating different human lymphocytes, much better than IVIg. Our objectives are (a) to elucidate the complexity of the HLA-I structural variants, and their Abs that bind to both shared and uncommon epitopes on different variants, and (b) to examine the roles of those Abs against HLA-variants in maintaining immune homeostasis. These may enable the development of personalized therapeutic strategies for various pathological conditions.
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spelling pubmed-94956172022-09-23 Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis Ravindranath, Mepur H. El Hilali, Fatiha Amato-Menker, Carly J. El Hilali, Hajar Selvan, Senthamil R. Filippone, Edward J. Antibodies (Basel) Review Cell-surface HLA-I molecules consisting of β2-microglobulin (β2m) associated heavy chains (HCs), referred to as Face-1, primarily present peptides to CD8+ T-cells. HCs consist of three α-domains, with selected amino acid sequences shared by all alleles of all six isoforms. The cell-surface HLA undergoes changes upon activation by pathological conditions with the expression of β2m-free HCs (Face-2) resulting in exposure of β2m-masked sequences shared by almost all alleles and the generation of HLA-polyreactive antibodies (Abs) against them. Face-2 may homodimerize or heterodimerize with the same (Face-3) or different alleles (Face-4) preventing exposure of shared epitopes. Non-allo immunized males naturally carry HLA-polyreactive Abs. The therapeutic intravenous immunoglobulin (IVIg) purified from plasma of thousands of donors contains HLA-polyreactive Abs, admixed with non-HLA Abs. Purified HLA-polyreactive monoclonal Abs (TFL-006/007) generated in mice after immunizing with Face-2 are documented to be immunoregulatory by suppressing or activating different human lymphocytes, much better than IVIg. Our objectives are (a) to elucidate the complexity of the HLA-I structural variants, and their Abs that bind to both shared and uncommon epitopes on different variants, and (b) to examine the roles of those Abs against HLA-variants in maintaining immune homeostasis. These may enable the development of personalized therapeutic strategies for various pathological conditions. MDPI 2022-09-08 /pmc/articles/PMC9495617/ /pubmed/36134954 http://dx.doi.org/10.3390/antib11030058 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Ravindranath, Mepur H.
El Hilali, Fatiha
Amato-Menker, Carly J.
El Hilali, Hajar
Selvan, Senthamil R.
Filippone, Edward J.
Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis
title Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis
title_full Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis
title_fullStr Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis
title_full_unstemmed Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis
title_short Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis
title_sort role of hla-i structural variants and the polyreactive antibodies they generate in immune homeostasis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495617/
https://www.ncbi.nlm.nih.gov/pubmed/36134954
http://dx.doi.org/10.3390/antib11030058
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