Spontaneous lupus-like syndrome in HLA-DQ2 transgenic mice with a mixed genetic background

Abstract

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE°DQ2). These AE°DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE°DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE°DQ2 mice also developed significant and progressive hematuria and proteinuria as compared to the AE°DQ6 mice (P<0.05). Histopathology showed immune complex deposits in the glomeruli of AE°DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a “fingerprint” substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE°DQ6 mice. Serum anti-dsDNA IgM and IgG levels were also significantly elevated among AE°DQ2 mice compared to AE°DQ6 mice (P<0.001). In conclusion, AE°DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this SLE-like syndrome in HLA-DQ2 transgenic mice.

Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease

“…The expression of DQ2 and DQ8 was checked by PCR. Expression levels of DQ2 in AEoDQ2 mice and DQ8 in AEoDQ8 have been described (44,52). Both AEo DQ2DQ8 and NOD Abo DQ8 mice were weaned and maintained on a GFD (33).…”

Chella David: A lifetime contribution in translational immunology

“…Using these transgenic mice, they have generated mouse models of disease for Auricular Chondritis [34], Asthma [35], Myasthenia Gravis [36], Multiple Sclerosis [37], Diabetes [38], and dermatitis herpetiformis [39]. They have provided these transgenic mice to other laboratories to generate models in thyroiditis [40], uveitis [41], Toxoplasma Infection [42], Sepsis [43,44], Lupus [45,46], Myocarditis [47], Celiac Disease [48,49], Multiple Sclerosis [50,51], Influenza Pathogenesis [52], and Allergy [53]. To date Chella has published over 500 research articles.…”

Generation of an HLA-DQ2.5 Knock-In Mouse

“…Many mouse strains transgenic (tg) for various human HLA class II allotypes have been made over the years, including for HLA-DQ2.5 (5)(6)(7)(8)(9), but most of these mice have been made by untargeted insertion of either cDNA or fragments of genomic human DNA. Untargeted insertion is an effective method of introducing transgenes in mice, but it carries the risk of unintended consequences that can affect the disease model (10).…”