TY - JOUR
T1 - Predominantly Antibody-Deficient Patients With Non-infectious Complications Have Reduced Naive B, Treg, Th17, and Tfh17 Cells
AU - Edwards, Emily S.J.
AU - Bosco, Julian J.
AU - Aui, Pei M.
AU - Stirling, Robert G.
AU - Cameron, Paul U.
AU - Chatelier, Josh
AU - Hore-Lacy, Fiona
AU - O'Hehir, Robyn E.
AU - van Zelm, Menno C.
PY - 2019/11/15
Y1 - 2019/11/15
N2 - Background: Patients with predominantly antibody deficiency (PAD) suffer from severe and recurrent infections that require lifelong immunoglobulin replacement and prophylactic antibiotic treatment. Disease incidence is estimated to be 1:25,000 worldwide, and up to 68% of patients develop non-infectious complications (NIC) including autoimmunity, which are difficult to treat, causing high morbidity, and early mortality. Currently, the etiology of NIC is unknown, and there are no diagnostic and prognostic markers to identify patients at risk. Objectives: To identify immune cell markers that associate with NIC in PAD patients. Methods: We developed a standardized 11-color flow cytometry panel that was utilized for in-depth analysis of B and T cells in 62 adult PAD patients and 59 age-matched controls. Results: Nine males had mutations in Bruton's tyrosine kinase (BTK) and were defined as having X-linked agammaglobulinemia. The remaining 53 patients were not genetically defined and were clinically diagnosed with agammaglobulinemia (n = 1), common variable immunodeficiency (CVID) (n = 32), hypogammaglobulinemia (n = 13), IgG subclass deficiency (n = 1), and specific polysaccharide antibody deficiency (n = 6). Of the 53, 30 (57%) had one or more NICs, 24 patients had reduced B-cell numbers, and 17 had reduced T-cell numbers. Both PAD–NIC and PAD+NIC groups had significantly reduced Ig class-switched memory B cells and naive CD4 and CD8 T-cell numbers. Naive and IgM memory B cells, Treg, Th17, and Tfh17 cells were specifically reduced in the PAD+NIC group. CD21lo B cells and Tfh cells were increased in frequencies, but not in absolute numbers in PAD+NIC. Conclusion: The previously reported increased frequencies of CD21lo B cells and Tfh cells are the indirect result of reduced naive B-cell and T-cell numbers. Hence, correct interpretation of immunophenotyping of immunodeficiencies is critically dependent on absolute cell counts. Finally, the defects in naive B- and T-cell numbers suggest a mild combined immunodeficiency in PAD patients with NIC. Together with the reductions in Th17, Treg, and Tfh17 numbers, these key differences could be utilized as biomarkers to support definitive diagnosis and to predict for disease progression.
AB - Background: Patients with predominantly antibody deficiency (PAD) suffer from severe and recurrent infections that require lifelong immunoglobulin replacement and prophylactic antibiotic treatment. Disease incidence is estimated to be 1:25,000 worldwide, and up to 68% of patients develop non-infectious complications (NIC) including autoimmunity, which are difficult to treat, causing high morbidity, and early mortality. Currently, the etiology of NIC is unknown, and there are no diagnostic and prognostic markers to identify patients at risk. Objectives: To identify immune cell markers that associate with NIC in PAD patients. Methods: We developed a standardized 11-color flow cytometry panel that was utilized for in-depth analysis of B and T cells in 62 adult PAD patients and 59 age-matched controls. Results: Nine males had mutations in Bruton's tyrosine kinase (BTK) and were defined as having X-linked agammaglobulinemia. The remaining 53 patients were not genetically defined and were clinically diagnosed with agammaglobulinemia (n = 1), common variable immunodeficiency (CVID) (n = 32), hypogammaglobulinemia (n = 13), IgG subclass deficiency (n = 1), and specific polysaccharide antibody deficiency (n = 6). Of the 53, 30 (57%) had one or more NICs, 24 patients had reduced B-cell numbers, and 17 had reduced T-cell numbers. Both PAD–NIC and PAD+NIC groups had significantly reduced Ig class-switched memory B cells and naive CD4 and CD8 T-cell numbers. Naive and IgM memory B cells, Treg, Th17, and Tfh17 cells were specifically reduced in the PAD+NIC group. CD21lo B cells and Tfh cells were increased in frequencies, but not in absolute numbers in PAD+NIC. Conclusion: The previously reported increased frequencies of CD21lo B cells and Tfh cells are the indirect result of reduced naive B-cell and T-cell numbers. Hence, correct interpretation of immunophenotyping of immunodeficiencies is critically dependent on absolute cell counts. Finally, the defects in naive B- and T-cell numbers suggest a mild combined immunodeficiency in PAD patients with NIC. Together with the reductions in Th17, Treg, and Tfh17 numbers, these key differences could be utilized as biomarkers to support definitive diagnosis and to predict for disease progression.
KW - autoimmunity
KW - CD21 B cells
KW - common variable immunodeficiency
KW - EuroFlow
KW - follicular helper T cells
KW - naive T cells
KW - predominantly antibody deficiency
KW - X-linked agammaglobulinemia
UR - http://www.scopus.com/inward/record.url?scp=85076025039&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2019.02593
DO - 10.3389/fimmu.2019.02593
M3 - Article
C2 - 31803177
AN - SCOPUS:85076025039
VL - 10
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 2593
ER -