The Concept of Environmental Exposures Accelerate Lupus

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Anti-glomerular basement membrane antibodies from urinary of nephritic rats were collected, purified, and then injected into normal inbred WKY/NCrj recipient the day 2 and the day 3 Haematuria and proteinuria respectively appeared. The first histological change, which was observed and was the same as those in the actively-immunized nephritis were Endocapillary hypercellularity of mononuclear cells in glomeruli and extracapillary changes such as, capsular adhesion, fibrin deposition, and crescent formation. This new passively-immunized model of anti-GBM nephritis makes it possible and easier to analyze further the mechanism of renal inflammation and damage that occur from immune complex deposition because only isologous antibodies are used. This study also indicates that the urine of the nephritic rat is a good source of autoantibodies.

Several environmental triggers, such as exposure to silica, trichloroethylene (TCE), heavy metals most commonly mercury, certain drugs, UV, hair dyes, pesticides, cigarette smoking, infection, high fat/low antioxidant diet have all been associated with SLE1,2,3,4 ,some factors have been more studies to understand there associated in the development of SLE. For instance, silica exposure in the NZM 2410 lupus mouse model significantly accelerated the course of the disease. this exacerbation of disease involved increased levels of serum autoantibodies, immune complexes, glomerulonephritis, and proteinuria.1 Experimental studies suggest that the silica may play a role as an adjuvant stimulating T cell responses or as an inducer of apoptosis on the pathogenesis of SLE.

Low-Level mercury (Hg) exposure is one potential factor in the development of autoimmune disease. Two-week exposure to low-dose iHg to donor and host mice ending 1 week before GVHD induction can significantly worsen the subsequent course of disease, resulting in premature mortality. Trichloroethylene (TCE) exposure in MRL +/+ mice results in early autoantibody production but does not impact clinical disease presentation. In MRL lpr/lpr mice, TCE exposure causes suppressed serum levels of total IgG. In NZBWF1 mice, TCE suppresses specific humoral antibody responses to SRBCs and increases autoantibody levels. TCE did not contribute to the progression of autoimmune disease in autoimmune-prone mice during the period of 11–36 weeks of age, but rather lead to increased expression of markers associated with autoimmune disease in a non-genetically prone mouse strain .

In recent years, three general approaches of engrafting human immune systems (Hu-PBL-SCID, Hu-SRC-SCID, and BLT) into widely used today immunodeficient IL2rgnull mice (NSG, NOG, BRG.) were developed to construct a humanized mouse model. This enables researchers to penetrate much deeper into specific human pathologies and to create more detailed models for diseases.153 (1)

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Immunodeficient mouse strains have been used as recipients for human cells or tissues because they lack host immunity and easily accept heterologous cells. Humanized mouse models are now a powerful tool to aid researchers in understanding the human features of lupus disease and to facilitate translational studies and pre-clinical evaluations of human-specifc mechanisms, establish future therapeutics.

Transfer of human PBL from SLE patients or healthy controls intraperitoneally into 8–10-week-old SCID mice or lethally irradiated BALB/c mice radio protected with bone marrow of SCID mice (human/mouse chimera) was successful in most (78.4%) recipient mice as determined by the levels of human IgG measured. In about 50% of either SCID mice or human/mouse chimeras that were successfully engrafted with PBL of SLE patients, significant anti-dsDNA autoantibodies, mostly of the IgG1 and IgG2 isotypes, were determined. Interestingly, in a significant number (84.5%) of recipients of PBL of the healthy controls, anti-dsDNA antibodies were observed as well, suggesting that PBL of at least some of the healthy controls have the potential to develop SLE-associated autoantibodies under the appropriate stimulatory conditions. Glomerular immune deposits (human IgG, mouse C3) were detected in 70-80% of SCID mice with human DNA specific antibodies and in a third of the human/mouse chimeras. Thus, SLE serology and glomerular pathology were reproducibly demonstrated in two models of human SLE. These models should allow the evaluation of potential therapies for the treatment of lupus patients.

A newly generated inbred SCID mouse, the BALB-RAG-2–/–IL-2R–/– double-knockout (BRG) non irradiated 4–5-week-old mouse, which lacks T cells, B cells, and natural killer cells (5,6) were injected half intravenously / half intraperitoneally with human peripheral blood mononuclear cells from systemic lupus erythematosus patients. Within 5-6 weeks, the SLE-DKO mice developed clinical and immunological features of human SLE like anti-DNA,anti-ANA antibodies, anti-cardiolipin antibody (aCL), proteinuria and IgG immune complexes in the kidney. Mice engrafted from one specific donor who had high anti-phospholipid antibodies presented with up to 3 times more anti-cardiolipin antibodies than mice engrafted with other SLE or healthy donors..DKO mice are more permissive hosts for engraftment of human cells than CB17/SCID mice are.

This model may be useful to analyze the contribution of different immune cell types to SLE pathogenesis and for testing therapeutics these previous models were limited by low efficiency of human cells engraftment, requirement of large numbers of PBMCs from SLE patients who are often lymphopenic, or the lack of human anti-nuclear autoantibodies production, which is widely considered as one of the hallmark symptoms of SLE. Previous attempt to model human SLE by engraftment of PBMCs from SLE patients into immunodeficient mice did not induce increased production of human IgG and anti-dsDNA antibodies

Signifcantly increased the total level of human IgG and IgM, and importantly, induced the production of a wide range of human anti-nuclear autoantibodies, including anti-dsDNA, anti-histone, anti-RNP70, anti-SM and anti-SSA antibodies ,and other clinical and immunological features of human SLE,like pulmonary serositis, lupus nephritis, proteinuria, lymphopenia, lymphocytes hyperactivation and aberrant cytokine production .this new Hu-mice SLE model can provide a closest-to-human in vivo platform for studies of human-specifc genes/factors, such as IL-8, in the induction and pathogenesis of SLE and as potential immunotherapy targets.While hu-mice have proven to be instrumental in translational research involving human-specific immune responses, several limitations remain in the current generation of humanised mice. These limitations include the presence of residual mouse myeloid cells; suboptimal myeloid subsets reconstitution and function; and impaired B cells maturation and antibody production.

Besides the achievements gained in the last years, several limitations of the next generation humanized mice still exist. Firstly, the expression of human immune factors in immunodeficient mice has the disadvantage that many human factors cross-react with mouse cells with the possible consequence of unexpected phenotypic changes.Secondly, lymphoid reconstitution in engrafted mice is challenging. Even though the mesenteric lymph nodes develop, the organization and size of the peripheral lymph nodes is less sufficient.

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