Early Life Stress in Summer Months Accelerates the Progression of Autoimmunity in Female Lupus‐Prone Mice

Abstract

Systemic lupus erythematosus (SLE) is a classic autoimmune inflammatory disorder in which a loss of tolerance causes over-activation of B and T cells that results in autoantibody production. These “self-attacking” autoantibodies [e.g., double-stranded (ds) DNA autoantibodies] are a hallmark of SLE and correlate with disease severity. Although it is thought that a mix of genetic, environmental, immunoregulatory, hormonal and/or epigenetic factors may initiate the autoimmune process, the exact cause of this aberrant immune activity is unknown. Our lab has worked with an established mouse model of SLE, the female NZBWF1 mouse, for over 10 years. Our SLE mice endure the stressful trek from Jackson Labs in Bar Harbor, ME to our campus in Fort Worth, TX early in life (<6 weeks of age), age in our animal facility, and remain untouched usually until 30-35 weeks of age when renal inflammation, renal injury and hypertension are prevalent. Historically, we have used the NZBWF1 mouse to determine mechanisms involved in hypertension induced by chronic renal inflammation. In doing so, we have observed that different cohorts of female SLE mice have different ranges of urinary albumin (measured via dipstick) and mortality by 34-35 weeks of age. We hypothesize that the difference in disease progression is dependent upon the season in which the mice were subjected to travel stress early in life. We retrospectively analyzed data from our published and unpublished studies and separated naïve female SLE mice from these studies into two groups based on their month of travel and arrival to our campus: winter (October-March; n = 51) and summer (April-September; n = 38). Plasma dsDNA autoantibodies at 34-35 weeks of age was higher in mice that traveled and arrived in Texas in summer months versus winter months (6.0e5 ± 8.6e4 vs. 4.1e5 ± 5.1e4 U/mL; p = 0.049). Urinary albumin (measured via ELISA), an index of renal injury, was higher in SLE mice that arrived in summer months versus winter months (13.5e3 ± 3.0e3 vs. 5.8e3 ± 1.5e3 ug/mL; p = 0.0137). Mean arterial pressure was not significantly different between the groups (144 ± 3 vs. 140 ± 2 mmHg; p =0.410). Our findings indicate that factors associated with long travel during the summer months (e.g., changes in temperature, humidity, and/or water intake) may accentuate the stress of travel during early life and accelerate the progression of autoimmunity in female SLE mice. Our current and future studies are critical in determining causative mechanisms involved in the development and maintenance of SLE autoimmunity. Additionally, these studies may provide insight into why SLE is predominate in certain groups that are more susceptible to early life stressors.