Dysregulated B-cell TLR2 expression and elevated regulatory B-cell frequency precede the diagnosis of AIDS-related non-Hodgkin lymphoma

Objectives: In antiretroviral therapy (ART)-treated patients, to determine if AIDSrelated non-Hodgkin lymphoma (AIDS-NHL) is preceded by: elevated frequency of potentially malignant abnormal activated/germinal center-like B cells, elevated serum prevalence of B-cell stimulatory Toll-like receptor (TLR) ligands resulting from HIV infection-associated microbial translocation, dysregulated B-cell TLR expression/signaling, and perturbations in the frequency of immunoregulatory cells. Design: A case-control study nested with a cohort study of HIV-infected women. Methods: Prediagnostic AIDS-NHL cases (n=12, collected 1-12 months before diagnosis) and controls (n=42) from the Women's Interagency HIV Study cohort, were matched for HIV and ART status, age, race, and CD4⁺ lymphocyte count. Serum levels of TLR ligands, the prevalence of malignancy-associated abnormal activated/germinal center-like (CD19⁺CD10⁺CD71⁺CD86⁺AID⁺) B cells, TLR2 expression on B cells, expression of TLR2-modulating micro-RNA, and the frequency of regulatory T and B cells were assessed. Results: Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/germinal center-like CD19⁺CD10⁺CD71⁺CD86⁺AID⁺ B cells (P=0.0072), elevated serum prevalence of the TLR2 ligand, and significantly elevated B-cell TLR2 expression (P=0.0015), positively correlating with the frequency of activated/germinal center-like B cells (rho=0.7273, P=0.0144). In cases, a purified subset of activated/germinal center-like B cells exhibited decreased expression of microRNAs that modulate TLR2 signaling, including miR-21, 146a, 146b, and 155. Finally, cases also exhibited significantly elevated frequencies of antitumor immunity inhibitory regulatory B cells (P=0.0024), but not regulatory T cells. Conclusions: Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of regulatory B cells, precede the diagnosis of AIDS-NHL in HIV-infected ART-treated patients.