动物模型,自发性SLE z-bo 2020-08-03 832

　　[Modeling mechanism] ZB/BINJ mice suffer from hemolytic anemia, increased immunoglobulin content, and autoimmune abnormalities, such as anti-nuclear antibodies, anti-DNA antibodies and anti-thymus antibodies. Immune complex glomerulonephritis; ZW/LacJ mice are usually normal, but aging mice will develop anti-DNA antibodies and nephritis. When the female NZB/BINJ is crossed with the male NZW/LacJ, the F1 generation produced has obvious autoimmune diseases, similar to human SLE.

　　[Modeling method] ZBWF1/J mouse is F1 generation, which is a hybrid between female NZB/BINJ and male NZW/LacJ. [Model Features] The autoimmune disease of ZBWF1/J mice is similar to human systemic lupus erythematosus, which is characterized by high titers of antinuclear antibodies, hemolytic anemia, proteinuria and progressive immune complex nephropathy. Glomerulonephritis is increasing. The incidence and severity of female symptoms are more obvious. 26% of F1 generation mice have typical lupus cells, and their morphology is basically the same as that of humans. Lupus cells appear for the first time within 5 months after birth, and most appear within 6-9 months after birth. Women (48%) have more lupus cells than men (2%). In addition, 44% of mice have a typical round hematoxylin, which can be observed from 2 months of age. Hemolytic anemia was found in aging mice over 8 months old. 39% of men and 57% of women have low hematocrit levels below 40% and 21%, which are related to severe kidney disease. 80% of hybrid mice have proteinuria, 40% of them have four or more proteinuria, and most of them are females. Most men suffer from moderate proteinuria, and the urine is clear and dense under a microscope. Lupus nephropathy manifests as thickening of glomerular basement membrane, hematoxylin, focal necrosis, and PAS positive reaction. Fluorescence immunoassay showed that there are many mouse gamma globulin deposits in the glomerular basement membrane. Electron microscopic observation revealed a typical human lupus nephropathy, epithelial podocyte fusion, fibrous endothelial deposits on both sides of capillary basement membrane and endothelial cells were obviously swollen. Fifty percent of lupus nephropathy is serious, and most of them are women. The serum albumin of mice with lupus nephropathy decreased, the α1 globulin increased significantly, and the blood urea nitrogen and cholesterol of mice with end-stage renal disease increased. 46% of the F1 generation have antinuclear antibodies.

　　Other lesions are: 24% of mice suffer from acute and chronic hepatitis, similar to early human lupus-like hepatitis. Single hepatocyte necrosis, polymorphic nuclei and lymphocyte infiltration, ascites; 26% of mice have unique splenic fibrosis from the edge of the white pulp. In severe cases, fibrosis can replace the entire splenic parenchyma.

　　The difference between ZBWF1 and human SLE is that it has no pathological changes in the skin or joints. Exposure of shaved skin to ultraviolet radiation from hot quartz does not cause lupus-like lesions.

　　[Model Evaluation and Application] The most natural SLE model is the mouse. Among them, the NZBWF1/J mouse is a very classic SLE model. Most scholars believe that the NZBWF1/J mouse is the closest to human SLE and is the most classic mouse for studying SLE animal models. Since the early 1960s, it has been widely used to study autoimmune diseases, not only elucidating the complex immunobiological reactions and mechanisms, but also elucidating the etiology, etiology and multifactorial diseases of SLE that can be used in autoimmune diseases. This model uses only F1 generation, including immunomodulation, immune complex nephritis and pharmacodynamic studies of SLE drugs to clarify its complex genetic basis.

　　ZBWF1/J mice have high titers of anti-dsDNA antibodies, and there are obvious gender differences in onset. Women developed earlier and died of glomerulonephritis within 12 months. Male rats usually die of chronic progressive nephritis when they are 15 to 20 months old. In addition, estrogen can make the condition worse, while androgens can make the condition worse. II. BXSB/MpJ mice [Modeling mechanism] BXSB is pathologically similar to human systemic lupus erythematosus. It is a cross between C57BL/6 female mice and SB/Le male mice. Recombinant inbred lines that bring changes. , The tough SLE model. The genetic characteristic of BXSB mice is that the Y-linked autoimmune acceleration site (Y-linked autoimmune acceleration, Yaa) on the Y chromosome is a 4Mbp telomere fragment near the pseudo-autosomal region on the X chromosome, which is copied to the Y chromosome. Is to be done. result. The replicated fragment contains 19 genes, including Toll-like receptor 7 (Toll-like receptor 7, Tlr7) and phosphoribosyl pyrophosphate synthase 2 (phosphoribosyl pyrophosphate synthase 2). [Modeling method] BXSB is a recombinant inbred line, and the male offspring of siblings spontaneously produce severe SLE.

　　[Model Features] Male mice are faster and more severe than female mice. The progression of the disease is characterized by lymph node and splenomegaly. Lymph nodes are enlarged and blurred in structure, accompanied by infiltration of various lymphocytes, plasma cells, histiocytes, hemolytic anemia, hyperimmune globulinemia, antinuclear antibodies, immune complex glomerulonephritis. Monocytes lacking T and B cell markers and plasma cells with Ig in the peripheral blood of 2-month-old male mice increased, and this situation became more serious with age. IgG immune complexes are deposited in the kidney, and there are no B cells in the marginal area of the spleen. T cells and germinal centers are produced in large numbers, while peripheral blood mononuclear cells are abundantly enriched. The 24-hour urine protein content of 3-month-old mice increases with the age of the mice. The antinuclear antibody titer (ANA) can be detected in the serum of 4-month-old mice. The ANA titer is as the moon increases. gradually increase. , Men will produce anti-red blood cell antibodies within 16-25 weeks.

　　BXSB women have shown that autoimmune diseases are weakened, and their promotion is attributed to the presence of Yaa mutations on the Y chromosome.

　　[Evaluation and application of the model] This model can be used to study the etiology, etiology, immunomodulation of autoimmune diseases, gene localization and pharmacodynamics of SLE therapeutics. Female mice in the same litter can be used as sexual controls. The negative control can be BXSB.B6-Yaa +/MobJDcrJ. The Y chromosome of this strain is derived from C57BL/6, which replaces the mutant Y chromosome containing Yaa. BXSB was discovered in the late 1970s, and its genetic etiology is very clear. The incidence is higher in men and relatively low in women, although this situation is very serious because the telomere fragments near the pseudoautosomal region of the X chromosome are copied to the Y chromosome to form a Yaa mutation. Several genes at Yaa locus are related to autoimmunity. For example, the copy of the Tlr7 gene mainly causes an autoimmune phenotype. Therefore, BXSB-Yaa mice provide a model for studying the effect of different Tlr7 copy numbers on autoimmune diseases. In addition, Yaa sites are also involved in signal transduction pathways. Treatment with anti-type 1 interferon receptor antibodies can alleviate the autoimmune disease in BXSB-Yaa mice, indicating that the disease involves type 1 interferon signaling. IL21 receptor (BXSB)-Yaa/Il21-(-/-) is lacking, and BXSB males are highly resistant to the disease, so it is a model for studying the role of IL21 in the pathogenesis of the disease. The regulatory CD8+ population and potential NK cells in this model can also actively delay the development of the disease, thereby helping to study the role of such regulatory cells in the study of autoimmune diseases.

　　BXSB males mate with other inbred females to study the relationship between genetics and SLE. For example, backcross BXSB males to C57BL/6 and replace the C57BL/6 Y chromosomes with the Yaa mutant Y chromosome. This is a negative control for the BXSB mouse SLE model. Without causing autoimmune diseases, BXSB males mate with NZB females, and males accelerate the development of similar autoimmune diseases, but the offspring do not promote interaction. The same effect of Yaa can also be seen when the offspring are mated with sJL, C57BL/6 and AKR lines. (3) MRL/MpJ-FasIpr/J mice [Modeling mechanism] MRL/MpJ mice are several different strains of LG, AKR, C3H, and C57BL/6, which have been mated for up to 12 generations. Consists of hours. By the thirteenth generation, the positive and negative sublines of lymphoid hyperplasia were selected, and their genomes were 89% identical. The mutant gene Faslpr is located on chromosome 19. The mutant gene Faslpr was introduced into other strains to show different clinical manifestations of autoimmune diseases, such as MRL/MpJ-Faslpr/J, B6.MRL-Faslpr/J, C3.MRL-Faslpr/J, NOD.MRL. Create the strain shown as Faslpr/Dvs and other strains. Here, we will mainly introduce the MRI/MpJ-Faslpr/J strain. [Modeling method] The mutant gene Faslpr was introduced into MRL/MpJ mice.

　　[Model Features] Homozygous MRL/MpJ-Faslpr/J can spontaneously cause systemic autoimmune diseases, lymphadenopathy, abnormal T cell proliferation, arthritis, and immune complex glomerulonephritis may be possible. In MRL-1pr/lpr homozygous mice, circulating immune complexes increased significantly at 3 months of age. The severity of diseases associated with the Faslpr mutant gene is related to the strain. For example, compared with the weight of normal control lymph nodes, lymphatic hyperplasia and severe kidney damage increased 75 times at 4-7 months of age. The binding rate of self-anti-dsDNA antibody was detected by radionuclide-labeled dsDNA, and it was 49% in MRL/Mp-Faslpr/Faslpr strain. The average life span of female MRL/Mp-Faslpr mice is 17 weeks, males are 22 weeks, C57BL/6J-Faslpr/Faslpr female strains are 42 weeks, and C3H/HeJ-Faslpr/Faslpr female strains are 52 weeks. It is shorter than blood.

　　[Model Evaluation and Application] This strain is a good model for SLE and Sjorgren syndrome. MRL/MpJ mice were used as MRL/MpJ-Faslpr/J controls. MRL/MpJ strains also show autoimmune diseases, but the time of symptom onset is much later than MRL/MpJ-Faslpr/J. will

　　The introduction of

　　Faslpr/Faslpr mutant genes into other strains revealed the clinical manifestations of various autoimmune diseases and revealed the phenotypes of the mutant genes in different genetic backgrounds. Among them, MRL/MpJ-Faslpr/J is an excellent SLE model. These models fully prove that SLE is polygenic and affected by surrounding genes, so it shows various clinical manifestations.