Systemic Lupus Erythematosus (SLE) is an autoimmune disease affecting 20 to 250 individuals per 100,000 worldwide. Symptomology includes dermatological manifestations such as discoid lesions, acute cutaneous rashes, and oral and nasal ulcers, along with musculoskeletal, pulmonary, and renal complications. Abnormal T and B lymphocyte function and apoptosis, immune complex clearance, complement function, and nucleosome processing are typical of disease pathophysiology. SLE is the result of both environmental and genetic factors, which together create the conditions leading to disease onset and progression. Of these environmental factors, Epstein-Barr virus (EBV) infection is known to cause the genesis of cross-reactive antibodies in SLE prone individuals that can initiate disease activity. Viral infection and modulation of cellular genes is important in understanding the microenvironment that could lead to immune mis-regulation and the inception of lupus in those individuals at risk. During disease development, a variety of variables assist and detract from disease progression and the quality of life experienced by SLE patients. Research into EBV-infected naïve B lymphocytes revealed that EBV modulates the chemotactic receptor EBI2 during viral infection via the BRRF1 viral gene product Na. This likely changes B lymphocyte chemotaxis in secondary tissue in virally infected B cells. Current literature suggests this results in sequestration of cells to peripheral areas of the tissue and mis-regulation of the immune response. It is not uncommon for SLE patients to have neuropsychiatric disorders due to lupus disease activity. With SLE patients being up to 6 times more at risk for depression, recognition and treatment of depression and anxiety have been shown to improve quality of life, pain, and treatment outcomes. Two studies investigate both clinical laboratory and psychosocial assessment variables that we suspect to be correlated with depression in patients with SLE. Univariate and multivariate analysis from our first study identified an array of variables that show strong associations with depression, including: Body Mass Index, Pain, Total Complement, fatigue assessments, and SF-36 scores. The second study found similar associations, but further found that serum IL-10 levels demonstrated a strong correlation with depression in SLE patients. In this final study SLE patients are compared alongside healthy, clinically depressed, and rheumatoid arthritis patients to provide evidence that increased depression in SLE patients is due more to disease pathology than a result of chronic inflammation.