Журнал клинической и клеточной иммунологии
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Sympathetic Nervous System Regulation of Th Cells in Autoimmunity: Beyond Th1 and Th2 Cell Balance

Dianne Lorton and Denise L Bellinger

Mechanisms that cause autoimmune disease are complex and include interactions with genetic, environmental, immunologic, and neural-endocrine factors. These events are often separated by many years, suggesting that disease onset requires a triggering event that if understood, could be targeted therapeutically. How tolerance is broken and disease onset is initiated remain enigmatic. Psychological stressors are implicated in the development and progression of autoimmune diseases. First, severe life stressors are strongly associated with disease onset in up to 80% of patients. Second, the major stress pathways, the sympathetic nervous system (SNS) and hypothalamicpituitary- adrenal (HPA) axis function become pathological in autoimmune diseases. Finally, there is a common “trifecta” of dysregulated immune functions, elevated SNS activity, low parasympathetic and low HPA-axis responsiveness across most autoimmune diseases. Understanding the changes in bidirectional cross-talk between these systems leading to this “trifecta” is key to fully understanding autoimmune diseases. These neuro-endocrine systems normally function to regulate immune responses and restore immune system homeostasis after immune challenges. Here, we focus on our current understanding of the imbalance of the CD4⁺ T cell subtypes thought to drive autoimmunity and how dysregulation of the cross-talk between the SNS and the immune system impacts CD4⁺ Th cell subtype balance in the autoimmune disease, rheumatoid arthritis (RA). Our lab has shown that elevated SNS tone and altered nerve to β2-adrenergic receptor (β2-AR) signaling occurs in lymphocytes in immune organs where arthritogenic CD4⁺ T helper cells develop. In an animal model of RA, these receptors no longer signal via cAMP, the canonical signaling pathway for β2-ARs. Instead, β2-AR signaling is shifted towards signaling pathways expected to promote the generation of arthritogenic CD4⁺ T cells. These findings indicate that dysfunctions in SNS to immune system communication are pathological events that could trigger the onset of RA and, by extension, other autoimmune diseases.