B-cell stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B-cell lymphoma

Abstract

Background: The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine whether elevated serum levels of molecules associated with B-cell activation precede the diagnosis of AIDS-associated NHL (AIDS-NHL).

Methods: Serum levels of B-cell activation-associated molecules, interleukin (IL)6, IL10, soluble CD23 (sCD23), sCD27, sCD30, C-reactive protein (CRP), and immunoglobulin E were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to 3 time points per subject, 0 to 5 years prior to AIDS-NHL diagnosis.

Results: Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared with HIV+ controls or with AIDS controls, after adjusting for CD4 T-cell number. Elevated serum levels of B-cell activation-associated molecules were seen to be associated with the development of systemic [non-CNS (central nervous system)] NHL, but not with the development of primary CNS lymphoma.

Conclusions: Levels of certain B-cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B-cell activation contributes to the development of these hematologic malignancies.

Impact: Marked differences in serum levels of several molecules are seen for several years prediagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL.

Figure 1. Mean serum levels of several B cell activation-associated molecules are consistently elevated more than three years preceding AIDS-associated lymphoma diagnosis

Natural log-transformed mean values (± s.e.m.) for HIV-infected subjects who went on to develop AIDS-NHL (filled triangles) and HIV-infected controls without lymphoma (open triangles) for (a) interleukin 6 (IL6), (b) C′-reactive protein (CRP), (c) soluble CD27 (sCD27), and (d) sCD30, in the years prior to NHL diagnosis in the case; p values (univariate t-test) are shown only if <0.05

Figure 2. Mean serum levels of additional B cell activation-associated molecules may be elevated prior to lymphoma

Natural log-transformed mean values (± s.e.m.) for (a) sCD23 and (b) total IgE, and (c) percentage of samples with detectable (≥2 pg/ml) serum IL10, are shown for all AIDS-NHL subjects (filled triangles) and HIV+ controls (open triangles); p values for continuous variables (univariate t-test), and frequency of detectable IL10 (chi square) are shown only if <0.05

Figure 3. Some B cell activation markers are elevated prior to lymphoma in those AIDS- NHL cases that had another AIDS-defining condition prior to NHL

Natural log-transformed mean values (± s.e.m.) for (a) IL6, (b) sCD27, and (c) sCD30, and (d) percentage of subjects with detectable serum IL10, are shown for the subset of AIDS-NHL subjects (n=100) that had a primary AIDS diagnosis other than lymphoma, then went on to develop NHL (filled circles), and controls who had an AIDS diagnosis but did not develop lymphoma (open circles); p values for continuous variables (univariate t-test), and frequency of detectable IL10 (chi square) are shown only if <0.05

Figure 4. Elevated levels of B cell activation markers prior to AIDS-NHL are seen only in those subjects who develop systemic lymphoma

CD4-adjusted odds ratios (OR) ± 95% confidence intervals (CI) for increased serum cytokine levels are shown for AIDS-NHL cases compared to matched HIV+ controls, stratified according to primary tumor location outside of the central nervous system (systemic, filled squares) or within the central nervous system (CNS, open squares). For all markers except IL10, ORs are in terms of one unit increase in natural log-transformed values; for IL10, ORs are in terms of detectable vs. undetectable. ORs are missing for IL10 for CNS tumors at two time-points (>3 years and 0–1 year) due to failure of the logistic regression model to converge on account of sparse data.