Background/Purpose: Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) is a severe complication of SLE, including a variety of neurological and psychiatric features. Previous studies have demonstrated the close relationship between NPSLE and inflammation. High mobility group protein B1 (HMGB1), a highly conserved protein secreted by innate immune cells in response to pathogenic products and released by injured or dying cells, occupies a central role in the pathogenesis of both sterile and infectious inflammation. Recent studies have shown an association between HMGB1 and chronic inflammation and autoimmunity. Toll-like receptor 4 (TLR4) is the primary receptor of endogenous extracellular HMGB1 in mediating macrophage activation, cytokine release, and tissue injury. HMGB1-TLR4 signaling pathway is the up-stream pathway of NF-ΚB, which could upregulate the expression of various cytokines and other inflammatory mediators. The objective of the study was to explore the potential mechanism of HMGB1-TLR4 axis in NPSLE.

Methods: The study population consisted of 107 SLE patients and 43 age- and sex-matched healthy controls. 73 SLE patients had active disease. 36 of these had NPSLE. Clinical and serological parameters were assessed according to routine procedures. HMGB1 and TLR4 levels were measured by ELISA. Statistical analyses were performed by using the chi-square test and the t-test.

Results: Central nervous system (CNS) manifestations accounted for 94% (34/36 patients), while involvement of the peripheral nervous system (PNS) was 6% (2/36patients). The majority of the manifestations were Seizure disorders (n=17; 47.2%), Headache (n=12; 33.3%), Cognitive dysfunction (n=10; 27.8%), Psychoses (n=8; 22.2%). Within the group of active patients those with NP manifestations had higher HMGB1 levels (0.451 (0.292 to 0.583)) compared to active patients with non-NP manifestations (0.356 (0.098 to 0.436)). In patients with NP (0.429 (0.313 to 0.526)) and non-NP (0.375 (0.196 to 0.478)) manifestations during active periods of the disease, TLR4 levels significant increased in comparison to the controls. TLR4 levels were significantly higher in active patients (0.401 (0.196 to 0.526)) compared to quiescent patients. There was a significant positive correlation between levels of HMGB1 and TLR4 in the total patients group (P<0.0001, r=0.939). We observed a correlation between HMGB1 levels and SLEDAI (P<0.0001, r=0.804). Also, TLR4 levels showed a significant correlation with SLEDAI (P<0.0001, r=0.809). HMGB1 levels correlated with anti-dsDNA levels (P<0.0001, r=0.558). Similarly, TLR4 showed a correlation with anti-dsDNA levels (P<0.0001, r=0.522). We observed a negative correlation in the total SLE group between C3, C4 and HMGB1 levels (P<0.0001, r=-0.545 and P<0.0001, r=-0.270 respectively). Also, TLR4 showed a significant negative correlation with C3 and C4 (P<0.0001, r=-0.559 and P<0.0001, r=-0.285 respectively).

Conclusion: Our data suggest that HMGB1-TLR4 axis plays an important role in the pathogenesis of SLE as well as NPSLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hmgb1-tlr4-axis-in-patients-with-neuropsychiatric-systemic-lupus-erythematosus/