Polymorphism in the Innate Immune Receptor SIRPα Controls CD47 Binding and Autoimmunity in the Nonobese Diabetic Mouse

Wong, Andrea S.L.; Mortin-Toth, Steven M.; Sung, Michael T.; Canty, Angelo J.; Gulban, Omid M.; Greaves, David R.; Danska, Jayne S.

doi:10.4049/jimmunol.1401984

Cited by 29 publications

(34 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SIRPα engagement by its ubiquitously expressed monomorphic ligand CD47 delivers an inhibitory signal that represses phagocytosis by macrophages and inhibits multiple aspects of DC activation (18–20). In some contexts, CD47-SIRPα signaling is bidirectional as SIRPα binding to CD47 triggers stimulatory signals in T cells and neurons (12, 21, 22). We therefore took a genetic approach to test whether donor SIRPα polymorphism controls the MHC-independent alloreactions we had observed.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with these functions, CD47 −/− mice were refractory to the induction of autoimmune diseases; for example, experimental allergic encephalomyelitis (38), experimental colitis (39), and murine lupus (40). In addition, Wong et al showed that enhanced binding of SIRPα to CD47 in the NOD mouse is a key determinant of the pathogenesis of autoimmune diabetes, likely due to the costimulatory actions of CD47 on T cells (12). Together, these data support our proposal that engagement of CD47 on recipient monocytes by SIRPα on graft cells provides an activation signal that causes monocyte proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Flow-based mouse CD47-Fc (mCD47-Fc) (R&D Systems) binding assay was performed as previously described with some modifications (12). Briefly, spleen cells from indicated mouse strains were blocked with anti-CD16/32 (BD Biosciences) followed by pre-clustering of SIRPα with unconjugated P84 antibody (eBiosciences).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts

et al. 2017

Self Cite

View full text Add to dashboard Cite

Mice devoid of T, B, and NK cells distinguish between self and allogeneic non-self despite the absence of an adaptive immune system. When challenged with an allograft they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce IL-12 and initiate graft rejection. The molecular mechanisms, however, by which the innate immune system detects allogeneic non-self to generate these DCs are not known. To address this question, we studied the innate response of Rag2−/−γc−/− mice, which lack T, B, NK cells, to grafts from allogeneic donors. We identified by positional cloning that donor polymorphism in the gene encoding signal regulatory protein alpha (SIRPα) is a key modulator of the recipient’s innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic non-self independently of T, B, and NK cells.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…While this model is currently on the BALB/c background, it is likely that this will be developed on a NOD.scid background for T1D studies. SIRPalpha has already been shown to be important for diabetes susceptibility, both in terms of polymorphic variation and the level of protein expression [202]. Therefore developing these MISTRG mice on a NOD background will provide further discoveries into the pathogenesis of autoimmune diabetes.…”

Section: Humanized Nod Micementioning

confidence: 99%

The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes

Pearson

Wong

2016

Journal of Autoimmunity

239

197

View full text Add to dashboard Cite

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mice and the development of humanized NOD mice, providing novel insights into human T1D.

show abstract

“…Interestingly, some of the genes in this N et P oco are previously reported to be associated with T2D [52], while some may have links to T2D although no direct associations are previously reported. More precisely, Wong et al [53] show that SIRPA is a T1D risk gene in the non-obese diabetic mouse. The inclusion of this gene in a N et P oco that is used in risk assessment for T2D suggests that this gene can be a potential novel candidate for association with T2D as well.…”

Section: Resultsmentioning

confidence: 99%

PoCos: Population Covering Locus Sets for Risk Assessment in Complex Diseases

Ayati

Koyutürk

2016

PLoS Comput Biol

View full text Add to dashboard Cite

Susceptibility loci identified by GWAS generally account for a limited fraction of heritability. Predictive models based on identified loci also have modest success in risk assessment and therefore are of limited practical use. Many methods have been developed to overcome these limitations by incorporating prior biological knowledge. However, most of the information utilized by these methods is at the level of genes, limiting analyses to variants that are in or proximate to coding regions. We propose a new method that integrates protein protein interaction (PPI) as well as expression quantitative trait loci (eQTL) data to identify sets of functionally related loci that are collectively associated with a trait of interest. We call such sets of loci “population covering locus sets” (PoCos). The contributions of the proposed approach are three-fold: 1) We consider all possible genotype models for each locus, thereby enabling identification of combinatorial relationships between multiple loci. 2) We develop a framework for the integration of PPI and eQTL into a heterogenous network model, enabling efficient identification of functionally related variants that are associated with the disease. 3) We develop a novel method to integrate the genotypes of multiple loci in a PoCo into a representative genotype to be used in risk assessment. We test the proposed framework in the context of risk assessment for seven complex diseases, type 1 diabetes (T1D), type 2 diabetes (T2D), psoriasis (PS), bipolar disorder (BD), coronary artery disease (CAD), hypertension (HT), and multiple sclerosis (MS). Our results show that the proposed method significantly outperforms individual variant based risk assessment models as well as the state-of-the-art polygenic score. We also show that incorporation of eQTL data improves the performance of identified POCOs in risk assessment. We also assess the biological relevance of PoCos for three diseases that have similar biological mechanisms and identify novel candidate genes. The resulting software is publicly available at http://compbio.case.edu/pocos/.

show abstract

Polymorphism in the Innate Immune Receptor SIRPα Controls CD47 Binding and Autoimmunity in the Nonobese Diabetic Mouse

Cited by 29 publications

References 49 publications

Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts

Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts

The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes

PoCos: Population Covering Locus Sets for Risk Assessment in Complex Diseases

Contact Info

Product

Resources

About