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).
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.
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.
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.
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.
"B-cell activation is characterized by lymphocyte proliferation, class switch recombination (CSR), and somatic hypermutation, all of which are prone to resultant errors in DNA that may lead to lymphomagenesis. B-cell activation leads to the expression of activation induced cytidine deaminase (AICDA), a DNA modifying enzyme that mediates immunoglobulin gene CSR and somatic hypermutation.99 "
[Show abstract][Hide abstract] ABSTRACT: Cancer biomarkers have provided great opportunities for improving the management of cancer patients by enhancing the efficiency of early detection, diagnosis, and efficacy of treatment. Every cell type has a unique molecular signature, referred to as biomarkers, which are identifiable characteristics such as levels or activities of a myriad of genes, proteins, or other molecular features. Biomarkers can facilitate the molecular definition of cancer, provide information about the course of cancer, and predict response to chemotherapy. They offer the hope of early detection as well as tracking disease progression and recurrence. Current progress in the characterization of molecular genetics of HIV-associated cancers may form the basis for improved patient stratification and future targeted or individualized therapies. Biomarker use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. This review focuses on the relevance of biomarkers in the most common HIV-associated malignancies, namely, Kaposi sarcoma, non-Hodgkin's lymphoma, and invasive cervical cancer.
"Notably, besides immunosuppression and lack of immune surveillance against tumor viruses, chronic immune activation, a hallmark of HIV pathogenesis, may play a role in the onset of malignancies. Manifestations of chronic immune activation include increased levels of pro-inflammatory cytokines and chemokines, polyclonal B-cell activation, increased cell turnover and accelerated immune senescence, all features which may increase the risk of cancer   . "
[Show abstract][Hide abstract] ABSTRACT: Highly Active Antiretroviral Therapy (HAART) changed the natural history of pediatric HIV infection. This review focuses on trends of HIV-associated cancers in childhood in the HAART era and analyses potential pathogenetic mechanisms. HAART reduced AIDS-defined malignancies (ADM), but incidence of several non-ADM is increasing. HIV-associated immune activation and inflammation, promoting tumorigenesis, can only partially be reduced by HAART. In addition, HIV-infected children may undergo accelerated immune senescence that favors cancer development. How HAART affects this condition is an open question. Lastly, there is no evidence that prenatal exposure to HAART increases the risk of cancer in childhood, but long-term studies are needed.
Cancer letters 02/2014; 347(1). DOI:10.1016/j.canlet.2014.02.002 · 5.62 Impact Factor
"Chronic B cell hyperactivation is driven by overproduction of B cell stimulatory cytokines, such as IL-6, IL-10, interferon-α (IFN-α), and tumor necrosis factor (TNF; Rieckmann et al., 1991; Takeshita et al., 1995; Mandl et al., 2008). The serum levels of these B cell stimulatory cytokines and other molecules, such as soluble sCD27 and sCD30 generated from the corresponding B cell receptors during the process of immune activation, were significantly high 1–5 years prior to diagnosis of systemic AIDS-NHL (Ambinder et al., 2010; Breen et al., 2011). Elevated serum levels of IL-6 have also been observed 1–3 years prior to the onset of AIDS-NHL, thus supporting the role of IL-6-driven B cell stimulation in the development of these lymphomas (Breen et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous human γ-herpes virus which establishes a life-long asymptomatic infection in immunocompetent hosts. In human immunodeficiency virus type 1 (HIV-1) infected patients, the impaired immunosurveillance against EBV may favor the development of EBV-related diseases, ranging from lymphoproliferative disorders to B cell non-Hodgkin's lymphomas (NHL). Antiretroviral therapy (ART) has significantly modified the natural course of HIV-1 infection, resulting in decreased HIV-1 plasmaviremia, increased CD4 lymphocytes, and decreased opportunistic infections, indicating a restoration of immune functions. However, the impact of ART appears to be less favorable on EBV-related malignancies than on other AIDS-defining tumors, such as Kaposi's sarcoma, and NHL remains the most common cancer during the ART era. EBV-driven tumors are associated with selective expression of latent oncogenic proteins, but uncontrolled lytic cycle with virus replication and/or reactivation may favor cell transformation, at least in the early phases. Several host's factors may promote EBV reactivation and replication; besides immunodepression, inflammation/chronic immune stimulation may play an important role. Microbial pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, through Toll-like receptors, activate the immune system and may promote EBV reactivation and/or polyclonal expansion of EBV-infected cells. A body of evidence suggests that chronic immune stimulation is a hallmark of HIV-1 pathogenesis and may persist even in ART-treated patients. This review focuses on lymphomagenesis driven by EBV both in the context of the natural history of HIV-1 infection and in ART-treated patients. Understanding the mechanisms involved in the expansion of EBV-infected cells is a premise for the identification of prognostic markers of EBV-associated malignancies.
Frontiers in Microbiology 10/2013; 4:311. DOI:10.3389/fmicb.2013.00311 · 3.99 Impact Factor
Colm Keane, Frank Vari, Mark Hertzberg, Kim-Anh Lê Cao, Michael R Green, Erica Han, John F Seymour, Rodney J Hicks, Devinder Gill, Pauline Crooks, Clare Gould, Kimberley Jones, Lyn R Griffiths, Dipti Talaulikar, Sanjiv Jain, Josh Tobin, Maher K Gandhi
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