Arthritis and rheumatism · 2002
Mice lacking endogenous major histocompatibility complex class II develop arthritis resembling psoriatic arthritis at an advanced age.
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Bárdos Tamás, Zhang Jian, Mikecz Katalin, David Chella S, Glant Tibor T
Аннотация
OBJECTIVE: To describe and characterize a novel inflammatory toe disease with severe bone destruction that developed spontaneously in "humanized" (HLA transgenic) mice lacking their own major histocompatibility complex (MHC).
METHODS: We studied 5 different HLA transgenic mouse lines (HLA-DR2.Ab(0), DR3.Ab(0), DR4.Ab(0), DQ6.Ab(0), and DQ8.Ab(0)) in similar genetic background for an extended period of time (>14 months). Clinical, radiologic, and histologic abnormalities were monitored, and the MHC-related major immunologic parameters in affected and resistant mice were compared.
RESULTS: Animals of 4 transgenic lines (HLA-DR2.Ab(0), DR4.Ab(0), DQ6.Ab(0), and DQ8.Ab(0)) developed severe toe inflammation accompanied by progressive bone resorption, hyperkeratosis, alopecia, loss of nails, and shortening and thickening of the distal phalanges. HLA-DR3.Ab(0) transgenic mice were resistant to inflammation. The disease manifested only at advanced ages (6 months or older) and affected 70-100% of the mice, with a female preponderance. The clinical signs and the radiographic and histopathologic features of the affected toes were not similar to those of any disease previously described in mice but did resemble those described for human psoriatic arthritis (PsA). Mice from the 4 susceptible lines expressed lower levels of the HLA transgene and exhibited significantly fewer CD4+ cells in the peripheral blood and reduced natural killer cell activity compared with mice from the resistant HLA-DR3.Ab(0) line.
CONCLUSION: This novel, spontaneously developing PsA-like toe disease in MHC-manipulated mice seems to be related to the absence of endogenous MHC class II. Replacement with HLA transgene expression that is insufficient (or no replacement at all) may result in imbalanced MHC class I and class II functions and lead to development of the disease.
METHODS: We studied 5 different HLA transgenic mouse lines (HLA-DR2.Ab(0), DR3.Ab(0), DR4.Ab(0), DQ6.Ab(0), and DQ8.Ab(0)) in similar genetic background for an extended period of time (>14 months). Clinical, radiologic, and histologic abnormalities were monitored, and the MHC-related major immunologic parameters in affected and resistant mice were compared.
RESULTS: Animals of 4 transgenic lines (HLA-DR2.Ab(0), DR4.Ab(0), DQ6.Ab(0), and DQ8.Ab(0)) developed severe toe inflammation accompanied by progressive bone resorption, hyperkeratosis, alopecia, loss of nails, and shortening and thickening of the distal phalanges. HLA-DR3.Ab(0) transgenic mice were resistant to inflammation. The disease manifested only at advanced ages (6 months or older) and affected 70-100% of the mice, with a female preponderance. The clinical signs and the radiographic and histopathologic features of the affected toes were not similar to those of any disease previously described in mice but did resemble those described for human psoriatic arthritis (PsA). Mice from the 4 susceptible lines expressed lower levels of the HLA transgene and exhibited significantly fewer CD4+ cells in the peripheral blood and reduced natural killer cell activity compared with mice from the resistant HLA-DR3.Ab(0) line.
CONCLUSION: This novel, spontaneously developing PsA-like toe disease in MHC-manipulated mice seems to be related to the absence of endogenous MHC class II. Replacement with HLA transgene expression that is insufficient (or no replacement at all) may result in imbalanced MHC class I and class II functions and lead to development of the disease.