scholarly journals Blocking I Ag7 class II major histocompatibility complex by drug-like small molecules alleviated Sjögren's syndrome in NOD mice

Life Sciences ◽  
2021 ◽  
pp. 120182
Author(s):  
Shivai Gupta ◽  
Danmeng Li ◽  
David A. Ostrov ◽  
Cuong Q. Nguyen
Keyword(s):  
Major Histocompatibility Complex ◽  
Small Molecules ◽  
Sjögren's Syndrome ◽  
Nod Mice ◽  
Sjogren’S Syndrome ◽  
Class Ii ◽  
Sjogren's Syndrome ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Sjögren‘S Syndrome

scholarly journals Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren’s syndrome

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248429
Author(s):  
Calvin Chi ◽  
Kimberly E. Taylor ◽  
Hong Quach ◽  
Diana Quach ◽  
Lindsey A. Criswell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Major Histocompatibility Complex ◽  
Genetic Association ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Major Histocompatibility ◽  
Causal Mediation ◽  
Histocompatibility Complex ◽  
Sjögren‘S Syndrome

Differential methylation of immune genes has been a consistent theme observed in Sjögren’s syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren’s International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.

AB0062 Alteration of Tibial Metaphysis Area in NOD Mice Whit Sjögren's Syndrome

2016 ◽  
Vol 75 (Suppl 2) ◽  
pp. 918.1-918
Author(s):  
C.A. Gobbi ◽  
B. Busamia ◽  
M.B. Guglielmotti ◽  
S. Fontana ◽  
M.C. Mariani ◽  
...  
Keyword(s):  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Nod Mice ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Tibial Metaphysis ◽  
Sjögren‘S Syndrome

scholarly journals Mesenchymal Stem Cells Extract (MSCsE)-Based Therapy Alleviates Xerostomia and Keratoconjunctivitis Sicca in Sjogren’s Syndrome-Like Disease

2019 ◽  
Vol 20 (19) ◽  
pp. 4750 ◽  
Author(s):  
Ghada Abughanam ◽  
Osama A. Elkashty ◽  
Younan Liu ◽  
Mohammed O. Bakkar ◽  
Simon D. Tran
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Nod Mice ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Peripheral Tolerance ◽  
Lacrimal Glands ◽  
Sjögren‘S Syndrome

Sjogren’s syndrome (SS) is an autoimmune disease that manifests primarily in salivary and lacrimal glands leading to dry mouth and eyes. Unfortunately, there is no cure for SS due to its complex etiopathogenesis. Mesenchymal stem cells (MSCs) were successfully tested for SS, but some risks and limitations remained for their clinical use. This study combined cell- and biologic-based therapies by utilizing the MSCs extract (MSCsE) to treat SS-like disease in NOD mice. We found that MSCsE and MSCs therapies were successful and comparable in preserving salivary and lacrimal glands function in NOD mice when compared to control group. Cells positive for AQP5, AQP4, α-SMA, CK5, and c-Kit were preserved. Gene expression of AQP5, EGF, FGF2, BMP7, LYZ1 and IL-10 were upregulated, and downregulated for TNF-α, TGF-β1, MMP2, CASP3, and IL-1β. The proliferation rate of the glands and serum levels of EGF were also higher. Cornea integrity and epithelial thickness were maintained due to tear flow rate preservation. Peripheral tolerance was re-established, as indicated by lower lymphocytic infiltration and anti-SS-A antibodies, less BAFF secretion, higher serum IL-10 levels and FoxP3+ Treg cells, and selective inhibition of B220+ B cells. These promising results opened new venues for a safer and more convenient combined biologic- and cell-based therapy.

scholarly journals Reduction of T Cell Receptor Diversity in NOD Mice Prevents Development of Type 1 Diabetes but Not Sjögren’s Syndrome

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e112467 ◽  
Author(s):  
Joanna Kern ◽  
Robert Drutel ◽  
Silvia Leanhart ◽  
Marek Bogacz ◽  
Rafal Pacholczyk
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Receptor ◽  
Sjögren's Syndrome ◽  
Nod Mice ◽  
Cell Receptor ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

scholarly journals Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

1993 ◽  
Vol 178 (5) ◽  
pp. 1675-1680 ◽  
Author(s):  
H Deng ◽  
R Apple ◽  
M Clare-Salzler ◽  
S Trembleau ◽  
D Mathis ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Protective Effects ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

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