Lymphocyte Activation as a Possible Measure of Atherosclerotic Risk in Patients with Sleep Apnea

Abstract

Obstructive sleep apnea (OSA), a breathing disorder in sleep characterized by intermittent hypoxia and sleep fragmentation, constitutes an independent risk factor for cardiovascular morbidity. Investigating how this breathing disorder modulates immune responses may facilitate understanding one of the risk factors for atherosclerosis. T cells play a significant role in atherogenesis and plaque development via cytokine production and by directly contributing to vascular injury. Using flow cytometry and chromium release assays, we found that CD4 and CD8 T cells of OSA patients undergo phenotypic and functional changes and acquire cytotoxic capabilities. Thus, a shift in CD4 and CD8 T cells toward type 2 cytokine dominance with increased IL-4 expression was noted. IL-10 expression in T cells was negatively correlated with the severity of OSA, as determined by the apnea-hypopnea index (AHI), whereas TNF-alpha was positively correlated. CD8 T cells of OSA patients expressed a fourfold increase in TNF-alpha and CD40 ligand (CD40L), and exhibited an increased OSA severity-dependent cytotoxicity against endothelial cells. The percentage of CD4(+)CD28(null) and cytotoxicity of CD4 T lymphocytes were also significantly higher in OSA patients than in controls. Nasal continuous positive airway pressure (nCPAP) treatment, which ameliorated the severity of OSA, significantly lowered TNF-alpha and CD40L expression, and decreased cytotoxicity in CD8 T cells. In conclusion, increased cytotoxicity and cytokine imbalance in CD4 and CD8 T cells may be involved in atherogenesis in OSA. Nasal CPAP treatment ameliorates some lymphocyte dysfunctions and thus may moderate some atherogenic pathways.

A critical role for DAP10 and DAP12 in CD8+ T cell–mediated tissue damage in large granular lymphocyte leukemia

“…One of the major changes that occurs after chronic T-cell activation and cancerous conditions is the down-regulation of CD28 and expansion of CD8 ϩ CD28 null T cells. 26,[32][33][34][35][36] Consistent with previous findings, CD8 ϩ CD28 null T cells were dramatically overrepresented in the peripheral blood of LGLL patients compared with healthy donors, as shown in Figure 4A,B. The absolute number of CD8 ϩ CD28 null T cells present in the blood was greater in LGLL patients compared with healthy donors and nearly all of the patients' CD8 ϩ T cells lacked CD28 expression.…”

Sleep Apnea and Cardiovascular Disease

“…93 There also is evidence for enhanced leukocyte activation in OSA. 94,95 Monocytes from OSA patients bind more actively to cultured endothelial cells than do monocytes from control subjects, and treatment by CPAP attenuates this monocyte binding. 94 Ryan et al 96 reported that in vitro, intermittent hypoxia and reoxygenation selectively activated the proinflammatory transcription factor nuclear factor-B, whereas the adaptive regulator hypoxia-inducible factor-1␣ was not activated.…”

Sleep Apnea and Metabolic Dysfunction: Cause or Co-Relation?

“…Compared to normal subjects, sleep apnea patients have higher levels of circulating adhesion molecules (123)(124)(125)(126)(127)(128)(129) and inflammatory cytokines including IL-6 and TNF-α which decrease with effective CPAP therapy (34;112;130-135). In addition, studies examining specific leukocyte populations reveal that patients with sleep apnea also exhibit monocyte and lymphocyte activation which improves with CPAP therapy (136)(137)(138)(139). While the mechanisms through which sleep apnea disrupts normal immune function are poorly understood, intermittent hypoxemia is likely to play a leading role.…”