TY - JOUR
T1 - Human IgE+ B cells are derived from T cell-dependent and T cell-independent pathways
AU - Berkowska, Magdalena A.
AU - Heeringa, Jorn J.
AU - Hajdarbegovic, Enes
AU - Van Der Burg, Mirjam
AU - Thio, H. Bing
AU - Van Hagen, P. Martin
AU - Boon, Louis
AU - Orfao, Alberto
AU - Van Dongen, Jacques J M
AU - Van Zelm, Menno C.
PY - 2014
Y1 - 2014
N2 - Background The prevalence of IgE-mediated diseases has been increasing worldwide, yet IgE-expressing B cells are poorly characterized, mainly because of their scarcity and low membrane IgE levels. Objective We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and patients with allergic disease. Methods We used a stepwise approach for flow cytometric detection and purification of human IgE-expressing B cells in control subjects, CD40 ligand-deficient patients, and patients with atopic dermatitis. Molecular analysis of replication histories, somatic hypermutation (SHM), and immunoglobulin class-switching was performed. Results Using multicolor flow cytometry, we reliably detected IgE-expressing plasma cells and 2 IgE-expressing memory B-cell subsets. These IgE-expressing cells showed molecular and phenotypic signs of antigen responses. The replication history and SHM levels of IgE+ plasma cells and CD27+IgE+ memory B cells fitted with a germinal center (GC)-dependent pathway, often through an IgG intermediate, as evidenced from Sγ remnants in Sμ-Sε switch regions. CD27-IgE+ cells showed limited proliferation and SHM and were present in CD40 ligand-deficient patients, indicating a GC-independent origin. Patients with atopic dermatitis had normal numbers of blood IgE+ plasma cells and CD27+IgE+ memory B cells but increased numbers of CD27-IgE+ memory B cells with high SHM loads compared with those seen in healthy control subjects and patients with psoriasis. Conclusions We delineated GC-dependent and GC-independent IgE+ B-cell responses in healthy subjects and indicated involvement of the GC-independent pathway in a human IgE-mediated disease. These findings provide new insights into the pathogenesis of IgE-mediated diseases and might contribute to accurate monitoring of IgE + B cells in patients with severe disease undergoing anti-IgE treatment.
AB - Background The prevalence of IgE-mediated diseases has been increasing worldwide, yet IgE-expressing B cells are poorly characterized, mainly because of their scarcity and low membrane IgE levels. Objective We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and patients with allergic disease. Methods We used a stepwise approach for flow cytometric detection and purification of human IgE-expressing B cells in control subjects, CD40 ligand-deficient patients, and patients with atopic dermatitis. Molecular analysis of replication histories, somatic hypermutation (SHM), and immunoglobulin class-switching was performed. Results Using multicolor flow cytometry, we reliably detected IgE-expressing plasma cells and 2 IgE-expressing memory B-cell subsets. These IgE-expressing cells showed molecular and phenotypic signs of antigen responses. The replication history and SHM levels of IgE+ plasma cells and CD27+IgE+ memory B cells fitted with a germinal center (GC)-dependent pathway, often through an IgG intermediate, as evidenced from Sγ remnants in Sμ-Sε switch regions. CD27-IgE+ cells showed limited proliferation and SHM and were present in CD40 ligand-deficient patients, indicating a GC-independent origin. Patients with atopic dermatitis had normal numbers of blood IgE+ plasma cells and CD27+IgE+ memory B cells but increased numbers of CD27-IgE+ memory B cells with high SHM loads compared with those seen in healthy control subjects and patients with psoriasis. Conclusions We delineated GC-dependent and GC-independent IgE+ B-cell responses in healthy subjects and indicated involvement of the GC-independent pathway in a human IgE-mediated disease. These findings provide new insights into the pathogenesis of IgE-mediated diseases and might contribute to accurate monitoring of IgE + B cells in patients with severe disease undergoing anti-IgE treatment.
KW - atopic dermatitis
KW - B cell
KW - CD40 ligand
KW - IgE
KW - plasma cell
UR - http://www.scopus.com/inward/record.url?scp=84906944558&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2014.03.036
DO - 10.1016/j.jaci.2014.03.036
M3 - Article
C2 - 24835500
AN - SCOPUS:84906944558
SN - 0091-6749
VL - 134
SP - 688-697.e
JO - The Journal of Allergy and Clinical Immunology
JF - The Journal of Allergy and Clinical Immunology
IS - 3
ER -