Marylin Desjardins1,2,3, Marianne Béland4, Marieme Dembele4, Duncan Lejtenyi5, Jean-Phillipe Drolet6, Martine Lemire7, Christos Tsoukas7, Moshe Ben-Shoshan5, Francisco J D Noya5, Reza Alizadehfar5, Christine T McCusker5,4, Bruce D Mazer5,4. 1. Division of Allergy and Immunology, Department of Paediatrics, McGill University Health Centre, Montreal, Quebec, Canada. marylin.desjardins@mcgill.ca. 2. Meakins-Christie Laboratories of the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. marylin.desjardins@mcgill.ca. 3. Centre for Translational Biology, Research Institute of the McGill University Health Centre, Block E, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3J1, Canada. marylin.desjardins@mcgill.ca. 4. Meakins-Christie Laboratories of the Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. 5. Division of Allergy and Immunology, Department of Paediatrics, McGill University Health Centre, Montreal, Quebec, Canada. 6. Division of Allergy and Clinical Immunology, Department of Medicine, Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada. 7. Division of Allergy & Clinical Immunology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
Abstract
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.
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.
Entities:
Keywords:
B lymphocytes; Common Variable Immunodeficiency; antibody production; humoral immune response; interleukin-21; interleukin-4
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