Patterns and trajectories of peripheral inflammatory cytokines, immune tolerance, and lymphocyte differentiation predict transition from acute to chronic low back pain in a sex- and age-specific manner

The immune system mediates pain perception in preclinical models. Yet, the role of the immune system in transition to a chronic pain state in humans remains unclear, and biomarkers to inform the clinical management and/or development of therapies to prevent chronic pain are needed. We leveraged peripheral blood from 2 community-based cohorts of adults with an acute low back pain (LBP) episode (n = 108) to define the relationship(s) between the transition to chronic LBP and peripheral inflammation, immune cell phenotypes and functionalities, and their trajectories. Distinct patterns of baseline plasma cytokine profiles associated with transition to chronic LBP in a sex-dependent manner, of which lower IFN-β and TNF and higher IL-18 and BDNF were associated with chronic LBP development. Analysis of peripheral immune cells uncovered relationships between monocyte, T-cell, and B-cell inflammation and transition to chronic LBP that were influenced by both sex and age. It revealed relatively tolerized immune responses in participants who did not transition to chronic LBP. Baseline inflammatory cytokine and immune cell features improved the prediction of the transition to chronic LBP relative to established self-reported pain measures alone. While perceived pain at baseline was more strongly associated with immune cell phenotypes, B-cell maturation trajectories uniquely predicted transition to chronic LBP independent of self-reported pain intensity/frequency, sex, and age. Collectively, these data demonstrate that distinct patterns of peripheral inflammation are associated with the transition to chronic LBP and point towards a unique association between B-cell maturation and the development of a chronic pain state.