Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation

Carole Le Coz, Brian E Nolan, Melissa Trofa, Alicia M Kamsheh, Mustafa K Khokha, Saquib A Lakhani, Antonio Novelli, Elaine H Zackai, Kathleen E Sullivan, Silvana Briuglia, Tricia R Bhatti, Neil Romberg

Research output: Contribution to journalArticle

Abstract

Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects' underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.

Original languageEnglish
Pages (from-to)1715
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 2018

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Haploinsufficiency
Cytotoxic T-Lymphocytes
Inflammation
T-Lymphocytes
Proteins
Autoimmune Lymphoproliferative Syndrome
Chromosomes
Lymphocytes
Cytokines
Interleukin-17
T-Cell Antigen Receptor
Immunoglobulins
Ligands
Phenotype
Biopsy
Genes

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Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation. / Le Coz, Carole; Nolan, Brian E; Trofa, Melissa; Kamsheh, Alicia M; Khokha, Mustafa K; Lakhani, Saquib A; Novelli, Antonio; Zackai, Elaine H; Sullivan, Kathleen E; Briuglia, Silvana; Bhatti, Tricia R; Romberg, Neil.

In: Frontiers in Immunology, Vol. 9, 2018, p. 1715.

Research output: Contribution to journalArticle

Le Coz, C, Nolan, BE, Trofa, M, Kamsheh, AM, Khokha, MK, Lakhani, SA, Novelli, A, Zackai, EH, Sullivan, KE, Briuglia, S, Bhatti, TR & Romberg, N 2018, 'Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation', Frontiers in Immunology, vol. 9, pp. 1715. https://doi.org/10.3389/fimmu.2018.01715
Le Coz, Carole ; Nolan, Brian E ; Trofa, Melissa ; Kamsheh, Alicia M ; Khokha, Mustafa K ; Lakhani, Saquib A ; Novelli, Antonio ; Zackai, Elaine H ; Sullivan, Kathleen E ; Briuglia, Silvana ; Bhatti, Tricia R ; Romberg, Neil. / Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation. In: Frontiers in Immunology. 2018 ; Vol. 9. pp. 1715.
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AU - Trofa, Melissa

AU - Kamsheh, Alicia M

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AU - Bhatti, Tricia R

AU - Romberg, Neil

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AB - Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects' underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.

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