The improved antibody responses of class-switched memory B cells depend on enhanced signaling from their B cell antigen receptors (BCRs). However, BCRs on both naive and antigen-experienced B cells use the canonical immunoglobulin-associated alpha and beta-protein signaling subunits. Here we identified a BCR isotype-specific signal-amplification mechanism. Whereas immunoglobulin M (IgM)-containing BCRs initiated intracellular signals exclusively through immunoglobulin-associated alpha- and beta-proteins, IgG- and IgE-containing BCRs also used a conserved tyrosine residue in the cytoplasmic segments of immunoglobulin heavy chains. When phosphorylated, this tyrosine recruited the adaptor Grb2, resulting in sustained protein kinase activation and prolonged generation of second messengers, which together culminated in enhanced B cell proliferation. Hence, membrane-bound IgG and IgE exert antigen recognition as well as costimulatory functions, thereby rendering memory B cells less dependent on T cell help.

Purpose: Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs. Experimental Design: Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay. Results: Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with P = 0.056]. A protective role of IL-10–1087A, −824T, and −597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different. Conclusions: Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. Clin Cancer Res; 18(13); 3637–47. ©2012 AACR.

<div>Abstract<p><b>Purpose:</b> Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs.</p><p><b>Experimental Design:</b> Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay.</p><p><b>Results:</b> Patients characterized by <i>TNFRI-609GG</i> (rs4149570) showed a trend toward better event free survival [EFS; univariate: <i>P</i> = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with <i>P</i> = 0.056]. A protective role of <i>IL-10–1087A</i>, −<i>824T</i>, and −<i>597A</i> reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: <i>P</i> = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with <i>P</i> = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: <i>P</i> = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with <i>P</i> = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different.</p><p><b>Conclusions:</b> Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. <i>Clin Cancer Res; 18(13); 3637–47. ©2012 AACR</i>.</p></div>

<p>PDF file, 109KB, S1: Genotype and allele frequency of the analyzed IL-10, IL-4R, TNFRI and II gene variations in patients with T-NHL (n = 117); S2: 2. 3-year survival rates for OS and EFS of patients suffering from T-NHL in relation to analyzed gene variation; S3: Real time PCR Taqman� assays used to analyze IL-10, IL-4R, TNFRI and TNFRII gene variations; S4: Primer for SNaPshot Assay used to analyze IL-10 gene variations.</p>

<p>PDF file, 139KB, Overall and Event free survival of patients suffering from T-cell Non-Hodgkin lymphoma in relation to circulating serum levels of sTNFRI, IL-10 and sIL-4R. The survival curves (Kaplan-Meier plots) show a comparison of the OS (A,C,E) and EFS (B,D,F) of T-NHL patients with circulating serum levels of sTNFRI (A,B), IL-10 (C,D) and sIL-4R (E,F). The respective threshold used to define high and low producers is indicated in the figure legend (lower left). For high producers of sTNFRI (B) and sIL-4R (F) an insignificant trend for shorter EFS was observed (p=0.0886 and p=0.333). The other survival curves show no trends for associations of serum levels and survival periods. P refers to the log-rank test. Patients at risk represents the number of patients which still can develop an event (OS or EFS) at defined time points.</p>