Study of the association between the CAPSL-IL7R locus and type 1 diabetes

Santiago, Julia; Alizadeh, Behrooz Z.; Martínez, Alfonso; Espino, Laura; Calle, Hermenegildo de la; Fernández‐Arquero, Miguel; Figueredo, M. Á.; Concha, Emilio G. de la; Roep, Bart O.; Koeleman, Bobby P. C.; Urcelay, Elena

doi:10.1007/s00125-008-1070-4

Cited by 40 publications

(31 citation statements)

References 20 publications

(22 reference statements)

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“…A genetic association with T1DM susceptibility was found for polymorphisms within the CAPSL gene [27]. Although the function of this gene is unknown, it is located adjacent to and in the same linkage disequilibrium block of the IL-7Rα gene.…”

Section: Expansion Of Autoreactive T Cellsmentioning

confidence: 98%

Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus

Monti¹,

Heninger²,

Bonifacio³

2009

Curr Diab Rep

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Autoreactive T cells play a major role in the pathogenesis of type 1 diabetes mellitus (T1DM) and are considered a major target of immunomodulatory strategies aimed at preventing or delaying the disease onset. However, the T-cell response against insulin-producing beta cells is still poorly understood. T cells potentially able to recognize and destroy beta cells are present in most individuals, but only in a few do they differentiate into pathogenic effectors. Recent and novel findings in T-cell biology on the dynamics of T-cell activation and memory maintenance are shedding new light on the general mechanisms of the T-cell response. In this article, we discuss how new discoveries about T-cell differentiation, expansion, and homeostasis could help to clarify mechanisms of autoimmunity that lead to T1DM.

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Section: Expansion Of Autoreactive T Cellsmentioning

confidence: 98%

Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus

Monti¹,

Heninger²,

Bonifacio³

2009

Curr Diab Rep

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“…Since SPARC is a widely expressed profibrotic protein that modulates tissue physiology by altering cell-extracellular matrix interactions, it has the potential to mediate microglia cell proliferation and migration. IL-7r was studied in a Spanish cohort of patients with type 1 diabetes and the homozygous IL-7r allele rs1445898 showed a trend towards a protective effect based on the genotype and an association to early onset diabetes [133]. The adenosine A3 receptor (Adora3) binds adenosine, a phosphohydrolytic derivate of ATP, and mediates microglial migration [134, 135].…”

Section: Molecular Mechanisms Linking Hyperglycemia and Microglialmentioning

confidence: 99%

The Role of Microglia in Diabetic Retinopathy

Grigsby¹,

Cardona

Pouw

et al. 2014

Journal of Ophthalmology

152

157

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There is growing evidence that chronic inflammation plays a role in both the development and progression of diabetic retinopathy. There is also evidence that molecules produced as a result of hyperglycemia can activate microglia. However the exact contribution of microglia, the resident immune cells of the central nervous system, to retinal tissue damage during diabetes remains unclear. Current data suggest that dysregulated microglial responses are linked to their deleterious effects in several neurological diseases associated with chronic inflammation. As inflammatory cytokines and hyperglycemia disseminate through the diabetic retina, microglia can change to an activated state, increase in number, translocate through the retina, and themselves become the producers of inflammatory and apoptotic molecules or alternatively exert anti-inflammatory effects. In addition, microglial genetic variations may account for some of the individual differences commonly seen in patient's susceptibility to diabetic retinopathy.

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“…The SNP is presumed to cause a splice variant, which leads to increased levels of the soluble form of the receptor (8). Interestingly, this SNP is also significantly associated with type I diabetes mellitus (12) and rheumatoid arthritis (13), other autoimmune-mediated diseases where autoreactive lymphocytes play an important role. Additionally, these diseases have a considerable overlap in genetic associations with MS (14).…”

Section: Ultiple Sclerosis (Ms) Is a Complex Disease Presumed Tomentioning

confidence: 99%

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Kreft

Verbraak

Wierenga‐Wolf

et al. 2012

The Journal of Immunology

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The IL-7Rα single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7Rα+ CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7Rα+CD8+ and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8+IL-7Rα+ in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα+ lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7–induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.

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Study of the association between the CAPSL-IL7R locus and type 1 diabetes

Cited by 40 publications

References 20 publications

Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus

Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus

The Role of Microglia in Diabetic Retinopathy

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

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