Phagolysosomal resistance hypothesized to be a danger signal.

Antigen presenting cells sometimes require T cell "help" to kill and decompose microbes they capture, especially when those microbes resist effector molecules including nitric oxide and reactive oxygen species. Pathogens are more likely to resist those effectors, shared by the innate and adaptive immune systems, than are commensals. Does such resistance alert the immune system to the danger posed by those pathogens? Several lines of evidence suggest this occurs. Mouse studies showed a surprising exacerbation, not alleviation of experimental autoimmune encephalomyelitis, by suppression of nitric oxide production, but only when the suppression was applied to animals undergoing vaccination with myelin. In contrast, animals receiving T cells activated by vaccination without suppression of nitric oxide benefitted from reduced autoimmune cytotoxicity when nitric oxide production was suppressed after adoptive transfer. Vaccinia and adenovirus suppress nitric oxide production and have been successful vaccine platforms, also consistent with the above phagolysosomal resistance hypothesis. The hypothesis solves a long-standing quandary-how can nitric oxide protect against both infection and autoimmunity, especially autoimmune diseases for which it seems a major effector? The importance of physical linkage between epitopes, first proposed in Bretscher's Two-Step, Two-Signal theory dependent on B cells, is extended to include phagolysosomal resistance in general, plus a corollary proposition that the immune system detects resistance to dissociation of high-affinity pathogenic ligands from host binding sites to make neutralizing antibodies.