Swiprosin‐1/EFhd2 limits germinal center responses and humoral type 2 immunity

Abstract

Activated B cells are selected for in germinal centers by regulation of their apoptosis.The Ca 2+ -binding cytoskeletal adaptor protein Swiprosin-1/EFhd2 (EFhd2) can promote apoptosis in activated B cells. We therefore hypothesized that EFhd2 might limit humoral immunity by repressing both the germinal center reaction and the expected enhancement of immune responses in the absence of EFhd2. Here, we established EFhd2 −/− mice on a C57BL/6 background, which revealed normal B-and T-cell development, basal Ab levels, and T-cell independent type 1, and T-cell independent type 2 responses. However, T cell-dependent immunization with sheep red blood cells and infection with the helminth Nippostrongylus brasiliensis (N.b) increased production of antibodies of multiple isotypes, as well as germinal center formation in EFhd2 −/− mice. In addition, serum IgE levels and numbers of IgE + plasma cells were strongly increased in EFhd2 −/− mice, both after primary as well as after secondary N.b infection. Finally, mixed bone marrow chimeras unraveled an EFhd2-dependent B cell-intrinsic contribution to increased IgE plasma cell numbers in N.b-infected mice. Hence, we established a role for EFhd2 as a negative regulator of germinal center-dependent humoral type 2 immunity, with implications for the generation of IgE. Keywords:Germinal center r IgE r Nippostrongylus brasiliensis r Plasma cell r Swiprosin-1/ EFhd2Additional supporting information may be found in the online version of this article at the publisher's web-site [11]. These short-lived plasma cells provide an initial wave of mostly non class-switched low affinity antibodies. Second, the early activated B cells can form GC where Ab affinity maturation takes place [12,13]. GC B cells upregulate activation induced deaminase (AID), and start to hypermutate the V exons of their Ig genes in the dark zone of the GC [10]. Later, these B cells migrate to the light zone of the GC, where they differentiate into centrocytes. There, they become negatively selected by default through apoptosis but can be rescued by antigen presentation to follicular T helper cells (T FH ) to receive essential survival signals [14]. Those survival signals are usually reserved for high affine, non autoreactive B cells. Centrocytes can leave the GC to develop into long-lived, class-switched and affinity-matured plasma cells that home back to the BM, resulting in sustained production of high-affinity antibodies [15], but to what extent IgE-expressing plasma cells participate in this step is being controversially discussed [16][17][18][19][20].The mechanism of the maturation of IgE-positive B cells is of considerable interest with respect to type I hypersensitivity reactions that can have life-threatening anaphylactic outcomes. Maturation of IgE-positive B cells involves a GC-dependent CSR pathway [16,17] but there is also evidence for indirect CSR to IgE by switching to IgG1 through an initial GC reaction, followed by an extrafollicular maturation phase and switching to IgE [19,20]. It is agreed upon t...

T follicular regulatory cells and IL-10 promote food antigen–specific IgE

“…Specifically, IgE + switched GCB cells have altered Ag receptor signaling, differentiate more readily into plasmablasts, display increased apoptosis, and are less efficiently selected than are GCB cells expressing other Ig isotypes (25,27,28,(49)(50)(51). Furthermore, inhibition of apoptosis in the GC helps to promote IgE responses (52). We hypothesize that Tfr-derived IL-10 is essential to maintain the survival and clonal expansion of IgE + GCB cells by promoting entry into the GC dark zone, where they can proliferate rather than differentiate or undergo apoptosis.…”

Swiprosin‐1: Its Expression and Diverse Biological Functions

“…EFhd2 ‐/‐ (swiprosin‐1) mice does not affect B‐cell responses to T‐cell independent immunization with TI1 (Nitrophenol‐Ficoll) and TI2 (Trinitrophenol‐LPS) antigens but it strongly elicits a T‐cell dependent Th2 cell mediated IgE and IgM production in response to the mice infected with helminth Nippostrongylus brasiliensis as compared to the EFhd2 +/+ mice. After 7 days of immunization with sheep red blood cells and Nippostrongylus brasiliensis, the germinal center area, B‐cell numbers, and antibodies production of multiple isotopes were significantly increased in EFhd2 −/− mice, suggesting that swiprosin‐1 acts as a negative regulator of germinal center dependent humoral type 2 immunity [Brachs et al, ].…”

Swiprosin-1 Promotes Mitochondria-Dependent Apoptosis of Glomerular Podocytes via P38 MAPK Pathway in Early-Stage Diabetic Nephropathy

“…Swiprosin-1 knockout mice were generated as described previously [16]. Recombineering was used to generate a gene targeting construct from a bacterial artificial chromosome (BAC) containing the swiprosin-1 gene (C57Bl/6J inbred strain).…”

“…In murine B cells, ectopic expression of swiprosin-1 was found to enhance spontaneous and B-cell receptor induced apoptosis [16, 22]. In addition, swiprosin-1 was found to be involved by signaling cascades involving Ca 2+ [19, 20], protein kinase C, and nuclear factor-κB [23].…”