AA appears about 2 weeks after immunization of rats to MT. The severity, duration and consequences of the arthritis seem to be influenced by various factors:
1. Genes; major histocompatibility complex (MHC) and other genes contribute to susceptibility. AA is most readily induced in rats and has been studied almost exclusively in this species. Mice, however, were reported to develop AA 2 months after administration of MT.
2. Gender; male rats are more susceptible than are female rats.
3. Microbial environment; germ-free rats and rats maintained in very clean surroundings are much more susceptible to severe AA than are rats raised in contaminated quarters.
4. Amount of MT; the maximum clinical score of the arthritis is directly related to the amount of MT administered to the rats. About 0.2 mg of MT produces mild AA. Increasing the dose of MT causes more severe arthritis; a maximum clinical score is usually elicited by 1 mg of MT.
5. State of MT inoculum; finely pulverized MT is much more arthritogenic than is whole MT. Merely mixing the MT in oil is more arthritogenic than is emulsifying the MT in oil.
6. Site of immunization; intradermal inoculation is most arthritogenic, intramuscular is least and intraperitoneal is intermediate.
The severity of acute AA in rats peaks about 2 weeks after the disease first appears. The arthritis then slowly regresses and may disappear totally (for example in dirty female rats); but it may also persist for a year or more (for example in clean male rats). Protracted AA can lead to irreversible damage (ankylosis) to the joints of the extremities.
The rats that recover from AA acquire resistance to further attempts to induce AA. Resistance to AA can also be obtained by first administering MT under conditions that are not arthritogenic; for example, MT administered intramuscularly or without oil. Thus, the clinical expression of arthritis appears to result from many seemingly trivial factors impinging on the process of immunization to MT; the particulars of the immunization determine the nature of the response, which in turn determines the patho-
genie consequences. Such complexity implies regulation.
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