Modulation of the Interleukin-21 Pathway with Interleukin-4 Distinguishes Common Variable Immunodeficiency Patients with More Non-infectious Clinical Complications

作者：Desjardins Marylin; Beland Marianne; Dembele Marieme; Lejtenyi Duncan; Drolet Jean-Phillipe; Lemire Martine; Tsoukas Christos; Ben-Shoshan Moshe; Noya Francisco J. D.; Alizadehfar Reza; McCusker Christine T.; Mazer Bruce D.

来源：Journal of Clinical Immunology, 2018, 38(1): 45-55.

DOI：10.1007/s10875-017-0452-0

• Common Variable Immunodeficiency
• interleukin-4
• interleukin-21
• B lymphocytes
• humoral immune response
• antibody production

Purpose Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and clinical manifestations such as infections, autoimmunity, and malignancy. We sought to determine if responsiveness to interleukin-21 (IL-21), a key cytokine for B cell differentiation, correlates with distinct clinical phenotypes in CVID.
Methods CVID subjects were recruited through the Canadian Primary Immunodeficiency Evaluative Survey registry. Peripheral blood mononuclear cells were cultured with anti-CD40 +/- interferon-gamma, interleukin-4 (IL-4), IL-21, and/or IL-4+IL-21. B cell subpopulations and IgG production were determined at baseline and day 7 by flow cytometry and ELISA. Clinical complications were compared using contingency tables.
Results CVID subjects exhibited decreased CD27(+) B cells and IgG production after 7 days of stimulation with anti-CD40+IL-21 (p < 0.05). In a subset of subjects [CVID responders (R)], the addition of IL-4 led to significant increases in CD27(+) B cells and IgG (p < 0.05). In CVID non-responders (NR), CD27(+) B cells and IgG remained lower despite the addition of IL-4. CVID NR experienced significantly more non-infectious clinical complications of CVID than R [OR 8.8, 95% confidence interval (CI) 1.6 to 48.13]. Previous studies reported that CVID subjects with <= 2% class-switched memory B cells were more at risk of these complications, but no significant association was found among this cohort of subjects [OR 3.5, CI 0.9 to 13.3]. In fact, 34.6% of CVID NR had > 2% class-switched memory B cells at baseline.
Conclusions The IL-4 and IL-21 in vitro assays distinguish two groups of CVID subjects and can be used with baseline B cell subpopulation phenotyping to better identify patients experiencing more vs. fewer clinical non-infectious complications and potentially to modulate therapy.

• 出版日期2018-1
• 单位McGill