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Autoimmune diseases represent chronic disorders that affect a significant proportion of the population in Europe, with a impact on patients’ quality of life and socioeconomic costs for the healthcare system and community. Virtually, all autoimmune diseases are associated with the presence of serum autoantibodies. After the preclinical period, clinical manifestations develop, and a delay in the diagnosis and treatment can account for further organ damage, physical and psychological disability that cause a reduction of the working capacity and finally a high economic impact on society. Based on these findings, we aimed to: 1. Estimate the prevalence of disease specific autoantibodies in the general population of an area of Lombardia region by using the most recently developed methods for the detection of autoantibodies. 2. Analyze the autoantibodies predictive value for the development of autoimmune diseases over 15 years of follow-up. 3. Analyze if there are factors at baseline that can predict the development of autoimmune disease over 15 years of follow-up, in order to identify patients at higher risk of developing an autoimmune disease that need a closer follow-up. 4. Analyze the autoantibodies predictive value for the development of malignancies over 15 years of follow-up. Research design and methodology The present study was conducted on two different cohorts derived from the general population of Lombardia region in Northern Italy: ISOLA (2,828 subjects) and CA.ME.LI.A. (CArdiovascular risk, MEtabolic syndrome, LIver, and Autoimmunity) (1,712 subjects). Serum samples were tested for serum autoantibodies (ANA, anti-ENA, rheumatoid factor, anti-CCP, anti-phospholipid antibodies, AMA, anti-LKM, anti-LC1, anti-SLA, anti-DGP, anti-tTG) using the most innovative techniques. Autoimmune diseases diagnosis were researched analyzing the administrative health databases. Furthermore, we detected hospitalization, cancer diagnosis, and death. In the CA.ME.LI.A. cohort cardiovascular risk factors were analyzed and 1/3 underwent carotid ultrasonographic analysis. In summary, we report that: 1. Serum ANA are detected in up to 18% of the general population, being more frequent in women and in elder ages while being ANA associated with an higher risk of connective tissue disease development 2. Serum rheumatoid factor is detected in 8.1% of the general population, while serum anti-CCP are found in 4.8% of the population, the prevalence of double positivity is 0.6%.Anti-CCP are associated with a significant increased risk of RA development, while rheumatoid factor is associated with both HBV and HCV infection. Anti-CCP are associated with an increased risk of cancer and rheumatoid factor is associated with an increased risk of death. 3. Anti-phospholipid antibodies are detected in 15% of an unselected population, especially newly identified autoantibodies not currently included in the classification criteria. Anti-phospholipid antibodies are associated with an increased cardiovascular risk profile and independently with cardiovascular disease, especially subclinical atherosclerosis. 4. AMA are detected in 3.8%, but at high titer in 1% of an unselected population; we identified only two cases of PBC, of which only one was AMA positive therefore we cannot estimate the risk; anti-LKM, anti-SLA, anti-LC1 antibodies are rarely found. 5. Anti-DPG antibodies are detected in 1.85% of an unselected population, while, anti-tTG were found in 2.2%, with no differences between sexes. We identified 7 cases of coeliac disease, of which only one resulted positive for both anti-DPG and anti-tTG antibodies at high-titer. In conclusion, autoantibodies are frequently found in subjects randomly selected from the general population, while being only seldom associated with an increased risk of developing an overt autoimmune disease. Furthermorre, autoantibodies may be associated with predisposing factors, as viral infections or cancer.