Hypothesis. Bystanders or bad seeds? Many autoimmune-target cells may be transforming to cancer and signalling "danger" to the immune system.

Autoimmune-target cells in autoimmune disease (AID) are usually construed as constitutionally normal healthy cells. A related assumption is that other cells in the body of AID patients, except for certain immunocytes, are healthy cells. An implication of that view is that any systemic pathology in organ-specific AID is related to metabolic derangements secondary to tissue destruction. However, much data on target and other cells in AID suggest widespread primary cellular defects. In insulin-dependent diabetes mellitus (IDDM), for example, many "complications" such as atherosclerosis, premature arterial stiffening, senescence of fibroblasts in vitro, and exuberant growth of smooth muscle and mesangial cells in vivo are not strictly attributable to glucose elevation. Also unexplained is the similar appearance of IDDM beta-cells and cells from insulinoma and why the prodromal phase of IDDM has many insulinoma-like features. While AID target cells have often been likened to neoplastic cells, investigators have rarely explored the possibility that autoimmunity in AID is fundamentally antineoplastic. This is likely because the dominant ideas in oncology and immunology-somatic mutation and clonal deletion, respectively-have prevented explanations for how normal immunity could detect transforming cells not expressing non-self antigens. New and less conventional theories of cancer and immunity have facilitated such an explanation. I use Rubin's "epigenetic" aging model of carcinogenesis and Matzinger's "danger" model of immunity to integrate the immunological and oncological sides of AID. In particular, I postulate that individuals suffering from AID have inherited many foci of prematurely aging cells. Those inherently damaged cells adapt to in vivo challenges by beginning to transform into cancer cells. However, as long as those stressed cells have not fully transformed, they will continue to signal "danger" to the innate immune system. The clinical outcome of that struggle between incipient neoplasia and immunity will vary depending upon the degree of tumor-proneness and resistance of the individual. Borrowing from cancer geneticist Henry Lynch, I postulate that tumor-resistance is inherited as a quantitative polygenic trait in direct proportion to tumor-proneness. I further contend that tumor-proneness and immunity are linked polygenic traits such that the greater one's tumor-proneness, the more powerful his/her antitumor immunity. I point to the shared DNA repair deficiency of certain cancer-prone syndromes and HLA-linked AID, their occasional co-occurrence, and their demonstrably exceptional immunity against solid tumors. I propose that HLA-linked AID constitute "chronic hypersensitivity syndromes" due to immunity's largely hidden battle to suppress multiple incipient neoplastic microfoci. Much of the physiopathology of AID is explicable as a sustained systemic response to threatened neoplastic transformation.

On the locus of medical discovery.

A search for consensus about the methodology of discovery among physicians and physiologists led the author to identify a crucial anomaly of medical historiography: in general, physicians stress the significance of clinicopathologic method, while physiologists emphasize the experimental. Hence, physicians and bench scientists might be perceived as members of epistemically distinct research traditions. However, analysis of the historical development of discoveries in medicine, exemplified by case studies in physiology, bacteriology, immunology, and therapeutics, reveals that the epistemic dichotomy is illusory. Both physicians and bench scientists discover in the same way: by identifying and explaining clinical anomalies. It is argued that the sociological role of experimentation is to dramatize clinical hypotheses and not test them in a Popperian sense.