The ZAP-70W163C mutation alone is not sufficient, however, for triggering arthritis in SKG mice. In the presence of the genetic abnormality of ZAP-70, environmental factors are needed for triggering arthritis, as illustrated by the following findings. First, in contrast with a high incidence of severe arthritis in our conventional environment, SKG mice raised in a microbially clean environment fail to develop arthritis . When the latter are transferred after weaning to a conventional environment, they start to develop the disease at a high incidence . Second, under the arthritis-resistant clean condition, a single injection of zymosan, a crude yeast cell wall extract, or glucose polymer ß-1, 3-D-glucans (ß-glucans), which are the main constituents of zymosan, can provoke chronically progressing severe arthritis in SKG mice . Polyinosinic-polycytidylic acid (Poly [I:C]), a double-stranded RNA characteristic of some viruses, also shows a mild arthritogenic effect in SKG mice. Third, in the linkage analysis of the genes determining the susceptibility to arthritis in SKG mice, there is a significant linkage with the H-2 locus on chromosome 17, besides the skg locus on chromosome 1 . The mice that developed arthritis even in an arthritis-resistant microbially clean environment showed much more frequent homozygosity of the H-2d haplotype than heterozygosity.
Taken together, in the presence of the SKG mutation, certain microbes, such as fungi, bacteria, and viruses, can activate arthritogenic T-cells through stimulating innate immunity, thereby evoking chronic autoimmune arthritis. Furthermore, the MHC gene polymorphism plays a significant role in determining the susceptibility to SKG arthritis and this genetic susceptibility exerts its effects depending on environmental conditions.
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