Btk Supports Autoreactive B Cell Development and Protects against Apoptosis but Is Expendable for Antigen Presentation.

Autor:	Nyhoff LE; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.; Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN., Griffith AS; Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO., Clark ES; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL; and., Thomas JW; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.; Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN., Khan WN; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL; and., Kendall PL; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN; peggy.kendall@wustl.edu.; Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.; Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2021 Dec 15; Vol. 207 (12), pp. 2922-2932. Date of Electronic Publication: 2021 Nov 19.
DOI:	10.4049/jimmunol.2000558
Abstrakt:	Bruton's tyrosine kinase (Btk) propagates B cell signaling, and BTK inhibitors are in clinical trials for autoimmune disease. Although autoreactive B cells fail to develop in the absence of Btk, its role in mature cells is unknown. To address this issue, a model of conditional removal ( Btk flox / Cre-ER T2 ) was used to excise Btk from mature transgenic B cells that recognize the pathophysiologic autoantigen insulin. Anti-insulin B cells escape central tolerance and promote autoimmune diabetes, mimicking human autoreactive cells. Lifelong Btk deficiency was previously shown to eliminate 95% of anti-insulin B cells, but in this model, mature anti-insulin B cells survived for weeks after targeted Btk deletion, even when competing with a polyclonal repertoire. BCR-stimulated cells could still signal via Syk, PLCy2, and CD22, but failed to upregulate the antiapoptotic protein Bcl-xL, and proliferation was impaired. Surprisingly, Btk -depleted anti-insulin B cells could still present Ag and activate T cells, a critical function in promoting T cell-mediated islet cell destruction. Thus, pharmacologic targeting of Btk may be most effective by blocking expansion of established autoreactive cells, and preventing emergence of new ones. (Copyright © 2021 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu