Background:  HIV-infected persons have highly elevated risk of developing non-Hodgkin’s lymphoma, and risk remains increased in the HAART era. Although immunosuppression plays an important role in AIDS lymphomagenesis, non-Hodgkin’s lymphoma precursor states are poorly defined. We evaluated serum/plasma immunoglobulin proteins as markers of dysregulated B cell function and predictors of subsequent AIDS/non-Hodgkin’s lymphoma risk.

Methods:  We conducted a case-control study of non-Hodgkin’s lymphoma nested in 3 cohorts of HIV-infected persons (1985 to 2004). Non-Hodgkin’s lymphoma cases (n = 66, median CD4 79 cells/mm³) were matched to 1 to 4 HIV-infected controls (n = 225) according to cohort, sex, race, age, and CD4 count. Serum/plasma samples obtained 0 to 2 years and 2 to 5 years prior to diagnosis/selection were assayed for immunoglobulin (Ig) G, IgM, and IgA levels (protein electrophoresis); monoclonal immunoglobulins (M-spikes, using protein electrophoresis confirmed with immunofixation); and k and l antibody free light chain levels. We compared cases and matched controls using conditional logistic regression.

Results: Non-Hodgkin’s lymphoma risk was not associated with IgG, IgM, or IgA levels (e.g., median IgG = 1815 vs 1815 mg/dL in cases vs controls in 2- to 5-year window). Free light chain k and l levels were elevated in HIV-infected controls compared to the general population (e.g., median k = 3.25, l = 3.58 mg/dL in 0- to 2-year window vs upper reference value = 1.94 and 2.63 mg/dL, respectively). Both k and l free light chains were higher in cases than in controls (e.g., in 2- to 5-year window median k = 4.24 vs 3.43 mg/dL, median l = 4.04 vs 3.09 mg/dL). Of note, free light chains predicted non-Hodgkin’s lymphoma risk in a dose-response manner 2 to 5 years prior to diagnosis/selection (OR [95%CI] per quartile increase in free light chain: k, 1.81 (1.23 to 2.66), p = 0.001; l, 2.15 (1.35 to 3.41), p = 0.0003) and 0 to 2 years prior to diagnosis/selection (k, 1.36 (1.03 to 1.80), p = 0.03; l, 1.65 (1.19 to 2.27), p = 0.002). The k/l free light chain ratio did not differ between cases and controls, nor did change in free light chains over time predict non-Hodgkin’s lymphoma development. M-spikes were detected in only 2 non-Hodgkin’s lymphoma cases (3%) vs 9 controls (4%), and were not significantly associated with non-Hodgkin’s lymphoma risk.

Conclusions:  Among HIV-infected individuals, circulating free light chain levels were elevated and strongly predicted non-Hodgkin’s lymphoma risk independent of CD4 count. In contrast, markers of monoclonal B cell proliferation (distorted free light chain ratio, M-spikes) were not statistically associated with non-Hodgkin’s lymphoma development. Free light chains may be a sensitive marker of polyclonal B cell activation/dysfunction and could identify HIV-infected persons at increased non-Hodgkin’s lymphoma risk.