Rashtak, Shadi

Abstract Background/Aim: Dermatitis Herpetiformis is the autoimmune skin manifestation of celiac disease, and similar to celiac disease, is tightly associated with HLA-DQ2 and HLA-DQ8. Previously we have generated a mouse model of DH using DQ8 transgenic mice on an NOD background. Herein, we describe a similar DH-like blistering disease that spontaneously develops in DQ2 transgenic mice. Methods: Transgenic mice that express DQ2 on a background deficient in endogenous MHC II (Aeo) were raised on a gluten containing (GC) chow or a gluten free chow . Results: When raised and maintained on a gluten containing chow, approximately 15% of these Aeo DQ2 mice spontaneously developed blisters on the ears and tails at about six months of age. Control Aeo mice that were also raised on a gluten containing chow did not develop this blistering disease during their lifetime. Hematoxilyn and eosin staining revealed subepidermal blisters. Immunohistochemistry revealed IgA deposits at the dermal/epidermal junction in perilesional ear tissue. However, when these mice were raised and maintained on a gluten free diet, these mice did not develop blisters. Conclusions: This blistering disease is a gluten dependent disease that has many of the elements typically associated with Dermatitis Herpetiformis, most especially the association with the DQ2 gene.

SummaryBackgroundCoeliac disease is managed by life‐long gluten withdrawal from the diet. However, strict adherence to a gluten‐free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.AimTo review recent advances in new therapeutic options for coeliac disease.MethodsA literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrials.gov for English articles and abstracts. The search terms used included, but not limited to, ‘Celiac disease’, ‘new’, ‘novel’, ‘Advances’, ‘alternatives’ and ‘Drug therapy’. The cited articles were selected based on the relevancy to the review objective.ResultsSeveral new therapeutic approaches for coeliac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.ConclusionsGluten‐free diet is still the only practical treatment for patients with coeliac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.

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 0 DQ2). These AE 0 DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE 0 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 0 DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE 0 DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE 0 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 0 DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE 0 DQ2 mice compared with AE 0 DQ6 mice (p < 0.001). In conclusion, AE 0 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 systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815—829.

Abstract Active delivery of recombinant autoantigens or allergens at the intestinal mucosa by genetically modified Lactococcus lactis (LL) provides a novel therapeutic approach for the induction of tolerance. Celiac disease is associated with either HLA-DQ2- or HLA-DQ8-restricted responses to specific antigenic epitopes of gliadin, and may be treated by induction of Ag-specific tolerance. We investigated whether oral administration of LL-delivered DQ8-specific gliadin epitope induces Ag-specific tolerance. LL was engineered to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and the induction of Ag-specific tolerance was studied in NOD AB° DQ8 transgenic mice. Tolerance was assessed by delayed-type hypersensitivity reaction, cytokine measurements, eDQ8d-specific proliferation, and regulatory T cell analysis. Oral administration of LL-eDQ8d induced suppression of local and systemic DQ8-restricted T cell responses in NOD AB° DQ8 transgenic mice. Treatment resulted in an Ag-specific decrease of the proliferative capacity of inguinal lymph node (ILN) cells and lamina propria cells. Production of IL-10 and TGF-β and a significant induction of Foxp3+ regulatory T cells were associated with the eDQ8d-specific suppression induced by LL-eDQ8d. These data provide support for the development of effective therapeutic approaches for gluten-sensitive disorders using orally administered Ag-secreting LL. Such treatments may be effective even in the setting of established hypersensitivity.