Within the more than one hundred disease entities for which autoimmunity causation have been alleged, two subgroups can be identified. The first group is characterized by ability of disruption of the effector arm of the immune response to temporarily reverse the signs and symptoms of disease. The second group is characterized by the presence of antibodies directed against the target organ’s cellular or subcellular components. As long as therapeutic palliation of the signs and symptoms of disease can be achieved, attributing causation to autoimmunity has tended to arrest therapeutics focus on attaining cure. Data relevant to a prime disease entity within each of the two allegedly autoimmune disease, Crohn’s disease and Type 1 diabetes mellitus, refute the claim of autoimmunity. In particular, the events that combine to produce Crohn’s disease have identified a mechanism by which a dysfunctional immune-mediated response against a specific set of antigens/agent can produces disease. Identification of this mechanism opens to rethinking the pathogenesis of other classic autoimmune diseases within that 5 subgroup.