Heterogeneity of tissue-destructive mechanisms
Classically, tissue-infiltrating cells in autoimmune inflammation include multiple different cell types. Besides antigen-specific lymphocytes, nonspecific phagocytes, granulocytes, fibroblasts and others are part of the lesion. Expecting a single process of tissue aggression would be oversimplified. Also, the attacked tissue responds to the injury with a series of events counteracting or amplifying tissue destruction. The concerted action of several cell types in destroying intact tissue might give a pathognomonic histomorphology, such as granulomatous inflammation.
Diversity of initiating agents
The paradigm that a disease-inducing antigen breaks tolerance and thus causes an autoimmune disease has dominated our approach to this type of syndrome over the last decades. Despite intense searches, such an antigen has not been identified in any of the human autoimmune entities. The simple reason might be that for most disorders such an antigen does not exist. This paradigm has continued to be appealing due to the simplicity and straightforwardness of postulating an infectious origin of these mysterious diseases. It might be a more productive approach to hypothesise that several agents can initiate an immune response that in the microenvironment of the affected tissue and the genetic background of the patient finally leads to pathology.
The multifactorial pathogenesis of autoimmunity
Emerging data are most compatible with the concept that autoimmune diseases develop in hosts with multiple inherited risk factors combined with environmental contributions. Single components are insufficient to induce the disease state. Rather, complex genotypes, somatic events and random environmental risk determinants interact to reach the threshold for disease. The combinations of disease-relevant components might actually differ from patient to patient, thus adding additional complexity to the pathogenesis. From a clinical point of view such a disease model would much better fit the experience that autoimmune diseases are characterised by heterogeneity in clinical pattern, course, and treatment response.
Unraveling the pathologic events leading to such diverse entities as inflammatory joint disease, insulin-dependent diabetes mellitus, or multiple sclerosis remains a challenge for the next generation of investigators.
Reference
Stites DP, Terr AI, Parslow TG (1997) Medical Immunology, 9th edition. Appleton & Lange, Stamford, CT, USA