Some experimental and clinical evidence supports most theories of autoimmunity
Data generally support more than one theory; need to develop predictions and tests that differentiate between theories
Few theories or models of autoimmune disease explicitly explain how host tolerance is abrogated and those that do rarely describe the epidemiology and incidence of disease
New theories and models need to focus on anomalies (verifiable phenomena that do not fit theories)
AutoAbs, ICs, and autoreactive T cells are not necessarily “defective” but part of a normal healing process to clear and repair damaged self: How do triggers transform normal responses to pathogenic ones?
Damaged self must be presented to antigen presenting cells at the same time (day 0) as an infection, adjuvant or other environmental exposure: Why does timing matter?
Is there a role for recurrent infections in triggering autoimmune disease and if so, how can it be explained?
How can the relative rarity of autoimmune disease be explained in the context of the relative frequency of putative environmental triggers?
Some epidemiological evidence suggests multi-factorial causes of autoimmunity, but theories and models are generally mono-causal: what kind of autoimmune theories can explain multi-causal triggering of disease?
There is general confusion between necessity and sufficiency in use of data to test theories of autoimmunity: theories must be comprehensive
What are the roles of adjuvants in experimental models and how can these roles be explained within autoimmune disease theory?
Why do so-called adjuvant effects appear to be “specific”, individual adjuvants pairing with particular antigens, activating specific TLRs, etc.?
How can specific innate pathways required to initiate autoimmune disease be integrated with adaptive responses in a more comprehensive theory of autoimmune disease?
No theory or model of autoimmune disease defines a role for sex-dependent susceptibility yet all major autoimmune diseases occur predominantly either in men or women.
Innate activation of self-with-adjuvant or by infection occurs in the context of sex: how can this interplay be explained theoretically?
How can the fact that sex hormone receptors on/in immune cells direct the innate and adaptive immune response to the same antigen in different directions (i.e., Th1, Th2 or Th17) be incorporated into autoimmune disease theory and models?
Finally, and most importantly, can a comprehensive theory of autoimmune disease be developed that predicts novel prevention, treatment and therapy options?
