Autoimmune diseases arise from dysregulated innate and adaptive immunity, often driven by persistent inflammation, exposure to self-antigens, and defective immune tolerance. Neutrophil extracellular traps (NETs) play a dual role in host defense and autoimmunity by exposing DNA–protein complexes that activate nucleic acid–sensing receptors. Efficient degradation of extracellular DNA, largely mediated by deoxyribonuclease I (DNase I) encoded by the DNASE1 gene, is essential for preventing chronic inflammation. Impaired DNase I activity contributes to systemic lupus erythematosus, rheumatoid arthritis, and vasculitis by allowing NET accumulation, autoantibody production, and endothelial damage. Parasitic helminths induce eosinophilia and Th2-skewed responses, which modulate neutrophil activity, neutralize inflammatory mediators such as histamine, and interact with extracellular traps. We hypothesize that helminth-induced eosinophil activation protects against autoimmunity by limiting neutrophil-mediated tissue toxicity, enhancing NET clearance via DNase I, and regulating histamine-driven inflammation. In this model, DNASE1 serves as a central integrator of extracellular DNA metabolism, innate immune sensing, and eosinophil–neutrophil cross-talk. Disruption of this axis predisposes to autoimmunity, whereas helminth-driven modulation restores immune tolerance. This framework provides a testable hypothesis linking extracellular DNA clearance, helminth exposure, and autoimmune disease pathogenesis.