Unravelling the Roles of Susceptibility Loci for Autoimmune Diseases in the Post-GWAS Era

Ye, Jody; Gillespie, Kathleen M.; Rodriguez, Santiago

doi:10.3390/genes9080377

Cited by 30 publications

(12 citation statements)

References 118 publications

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“…There are numerous polymorphisms that affect the immune system. These have been linked to autoimmune diseases such as multiple sclerosis and type I diabetes (193) but not to ALS (194). However, it would seem likely that genetic variation in immune genes could influence the immune abnormalities described above, For example, polymorphisms in cytokine genes can influence the levels of cytokines such as IL-6, (195) and TNFα (196) and the IL33/ST2 pathway (197).…”

Section: Immunogenetics Of Alsmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

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Section: Immunogenetics Of Alsmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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“…However, autoimmune disease in humans is relatively common, and the genetics of predisposition is complex, polygenic, and heavily influenced by environmental factors. Hundreds of genetic loci influencing susceptibility to various autoimmune and inflammatory disorders have been discovered by genome-wide association studies (GWAS) in humans, and in many cases have confirmed mouse models and yielded novel insights into mechanisms underpinning disease (2). Despite this, the identity of causal variants and their target genes remain largely unknown because variants rarely alter protein coding sequences.…”

Section: Introductionmentioning

confidence: 99%

Variant to Gene Mapping to Discover New Targets for Immune Tolerance

Mehra

Wells

2021

Front. Immunol.

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The breakdown of immunological tolerance leads to autoimmune disease, and the mechanisms that maintain self-tolerance, especially in humans, are not fully understood. Genome-wide association studies (GWAS) have identified hundreds of human genetic loci statistically linked to autoimmune disease risk, and epigenetic modifications of DNA and chromatin at these loci have been associated with autoimmune disease risk. Because the vast majority of these signals are located far from genes, identifying causal variants, and their functional consequences on the correct effector genes, has been challenging. These limitations have hampered the translation of GWAS findings into novel drug targets and clinical interventions, but recent advances in understanding the spatial organization of the genome in the nucleus have offered mechanistic insights into gene regulation and answers to questions left open by GWAS. Here we discuss the potential for ‘variant-to-gene mapping’ approaches that integrate GWAS with 3D functional genomic data to identify human genes involved in the maintenance of tolerance.

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“…Women mount a more vigorous immune response and are more susceptible to most autoimmune diseases 1,2 . These diseases have a strong but complex genetic component, and it has been di cult to identify the underlying polymorphisms [3][4][5] . The female preponderance in autoimmunity is sex hormone related 6 but could also be genetically dependent 7 .…”

Section: Introductionmentioning

confidence: 99%

Polymorphic estrogen receptor binding site causes CD2-dependent sex bias in the susceptibility to autoimmune diseases

Lahore

Förster

Johannesson

et al. 2021

Preprint

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Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors likely determines the sex discrepancy in the immune response, but conclusive evidence is lacking regarding the underlying molecular mechanisms. Using forward genetics, we positionally identified a polymorphic estrogen receptor binding site that regulates CD2 expression, leading to female-specific differences in mouse models of T cell-dependent autoimmunity. Female mice with reduced CD2 levels displayed diminished expansion of autoreactive T cells. Mechanistically, CD2 affected T cell activation by inhibiting LAG-3 expression. Our findings explain the sexual dimorphism in human autoimmunity, as CD2 associated with rheumatoid arthritis and its regulation through 17-β-estradiol was conserved in human T cells. Hormonal regulation of CD2 has implications for CD2-targeted therapy. Indeed, anti-CD2 treatment was more potent in female mice. In conclusion, our results demonstrate the relevance of sex-genotype interactions and provide strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.

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Unravelling the Roles of Susceptibility Loci for Autoimmune Diseases in the Post-GWAS Era

Cited by 30 publications

References 118 publications

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

Variant to Gene Mapping to Discover New Targets for Immune Tolerance

Polymorphic estrogen receptor binding site causes CD2-dependent sex bias in the susceptibility to autoimmune diseases

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