Factors that can overcome effective resolution processes are (i) genetic factors that encode for exaggerated immune responses (e.g., HLA-B27 in arthritis, NOD2, and IL-10R mutations in colitis) or modulate the gut microflora, (ii) mechanisms that promote the development of autoimmunity (e.g., citrullinated protein antibodies in arthritis), and (iii) processes leading to impairment of the barrier function of epithelial surfaces leading to prolonged microbial exposure (e.g., defensin and mucin reduction in inflammatory bowel diseases) (Fig. 1). This evidence concerns the gene NOD2 and arthritic joint disease.