TYK2 :p.Pro1104Ala Variant Protects Against Autoimmunity by Modulating Immune Cell Levels

ABSTRACT The TYK2:p.Pro1104Ala (rs34536443) hypomorph variant has been associated with protection against numerous autoimmune disorders. Thus, its mechanism of action becomes of great interest. Here, consistent with the participation of activated immune cells in autoimmunity, we show that the varian...

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Veröffentlicht in:Immunology Jg. 174; H. 4; S. 462 - 469
Hauptverfasser: Steri, Maristella, Orrù, Valeria, Sidore, Carlo, Mulas, Antonella, Pitzalis, Maristella, Busonero, Fabio, Maschio, Andrea, Serra, Valentina, Dei, Mariano, Lai, Sandra, Virdis, Francesca, Lobina, Monia, Loizedda, Annalisa, Marongiu, Michele, Masala, Marco, Floris, Matteo, Curreli, Nicolò, Balaci, Lenuta, Loi, Francesco, Pilia, Maria Grazia, Delitala, Alessandro, Fiorillo, Edoardo, Schlessinger, David, Zoledziewska, Magdalena
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Wiley Subscription Services, Inc 01.04.2025
John Wiley and Sons Inc
Schlagworte:
Autoimmune diseases
Autoimmune Diseases - genetics
Autoimmune Diseases - immunology
Autoimmunity
Autoimmunity - genetics
Autoimmunity - immunology
B-Lymphocytes - immunology
CD4 antigen
Female
Humans
immune cell levels
Immune system
immunophenotyping
Lymphocyte Activation - genetics
Lymphocyte Activation - immunology
Lymphocytes
Lymphocytes B
Lymphocytes T
Male
naïve cells
Original
Therapeutic targets
TYK2
TYK2 Kinase - genetics
TYK2 Kinase - immunology
Tyk2 protein
immune cell levels
TYK2
autoimmunity
immunophenotyping
naïve cells
ISSN:0019-2805, 1365-2567, 1365-2567
Online-Zugang:Volltext
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Zusammenfassung:ABSTRACT The TYK2:p.Pro1104Ala (rs34536443) hypomorph variant has been associated with protection against numerous autoimmune disorders. Thus, its mechanism of action becomes of great interest. Here, consistent with the participation of activated immune cells in autoimmunity, we show that the variant regulates the levels of immune cells at a human, general population level and is associated particularly with higher levels of T and B lymphocytes, especially the naïve (non‐activated) compartment. Also, consistent with a protective function in autoimmunity, the level of regulatory CD4+ T cells was increased. Thus, this variant decreases immune activation thereby protecting from autoimmunity. Our work links the cellular mechanism regulated by the TYK2:p.Pro1104Ala variant to autoimmunity protection and supports TYK2 as a therapeutic target in autoimmunity. TYK2:p.Pro1104Ala variant confers protection from several autoimmune disorders but predisposes to infection and we show that the mechanism of its action includes an increase of the levels of lymphocytes in all compartments (CD4+, CD8+ and B), but these cells are mainly naive. Thus, this variant constrains immune activation thereby protecting from autoimmunity. Our work identifies the cellular mechanisms of regulation by the TYK2:p.Pro1104Ala variant providing novel hypotheses for the general immune mechanisms of protection from autoimmunity.
Bibliographie:This work was supported by Intramural Research Program of the National Institute of Aging (HHSN271201100005C, 75N95021C00012), Italian Foundation for Multiple Sclerosis—FISM—Fondazione Italiana Sclerosi Multipla (Grant cod. 2019/S/03) and financed or co‐financed with the ‘5 per mille’ public funding. Sardinia Autonomous Region and its regional agency for research and development in Sardinia—Sardegna Ricerche and local Lanusei government for continues support.
Funding
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Funding: This work was supported by Intramural Research Program of the National Institute of Aging (HHSN271201100005C, 75N95021C00012), Italian Foundation for Multiple Sclerosis—FISM—Fondazione Italiana Sclerosi Multipla (Grant cod. 2019/S/03) and financed or co‐financed with the ‘5 per mille’ public funding. Sardinia Autonomous Region and its regional agency for research and development in Sardinia—Sardegna Ricerche and local Lanusei government for continues support.
ISSN:0019-2805
1365-2567
1365-2567
DOI:10.1111/imm.13902