Immunogenetics of autoimmune thyroid diseases: A comprehensive review.

Lupus erythematosus (LE) is a heterogeneous disease ranging from skin-restricted manifestations to a progressive multisystem disease. The specific skin lesions include chronic cutaneous, subacute cutaneous and acute cutaneous LE. Both genetic and environmental factors are involved in the development of LE. However, reports on the genetic background of cutaneous lupus erythematosus (CLE) forms, namely discoid (DLE) and subacute cutaneous lupus erythematosus (SCLE), are sparse. We investigated whether the known systemic LE (SLE) susceptibility genes also predispose to CLE. Altogether, 219 Finnish patients with DLE or SCLE and 356 healthy controls were recruited. Single nucleotide polymorphisms tagging reported risk genes were genotyped. Tyrosine kinase 2 (TYK2) rs2304256 was associated with increased risk of DLE (P = 0.012, OR = 1.47, 95% CI = 1.01-1.98). Expression of TYK2 was demonstrated by immunohistochemistry in macrophage-like cells and neutrophils and interferon regulatory factor 5 (IRF5) in macrophage- and fibroblast-like cells of DLE, SCLE and SLE skin. IRF5 rs10954213 showed association with DLE (P = 0.017, OR = 1.40, 95% CI = 1.06-1.86) and SCLE (P = 0.022, OR = 1.87, 95% CI = 1.09-3.21). A haplotype of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) showed association with DLE (P = 0.0065, OR = 2.51, 95% CI = 1.25-5.04). Our results show that the TYK2, IRF5 and CTLA4 genes previously associated with SLE also confer risk for DLE and SCLE, suggesting that different LE subphenotypes may share pathogenetic pathways.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0625.2009.00982.x

Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus

Immune checkpoint regulators are critical modulators of the immune system, allowing the initiation of a productive immune response and preventing the onset of autoimmunity. Co-inhibitory and co-stimulatory immune checkpoint receptors are required for full T-cell activation and effector functions such as the production of cytokines. In autoimmune rheumatic diseases, impaired tolerance leads to the development of diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome. Targeting the pathways of the inhibitory immune checkpoint molecules CD152 (cytotoxic T lymphocyte antigen-4) and CD279 (programmed death-1) in cancer shows robust anti-tumor responses and tumor regression. This observation suggests that, in autoimmune diseases, the converse strategy of engaging these molecules may alleviate inflammation owing to the success of abatacept (CD152-Ig) in rheumatoid arthritis patients. We review the preclinical and clinical developments in targeting immune checkpoint regulators in rheumatic disease.

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Immune checkpoint receptors in regulating immune reactivity in rheumatic disease.

Gene association studies are less appealing in cancer compared to autoimmune diseases. Complexity, heterogeneity, variation in histological types, age at onset, short survival, and acute versus chronic conditions are cancer related factors which are different from an organ specific autoimmune disease, such as Grave's disease, on which a large body of multicentre data is accumulated. For years the focus of attention was on diversity and polymorphism of major histocompatibility complex in respect to human diseases specially the autoimmune diseases, but in recent years, access to other human gene sequences prompted investigators to focus on genes encoding the immune regulatory proteins such as the co-stimulatory, adhesion molecules, cytokines and chemokines and their receptors. Among them, CTLA4 (CD152) has been in the centre of attention for its pivotal role in autoimmunity and cancer. Although not fully understood, CTLA4 with no doubt plays an important role in the maintenance of the immune response by its expression on activated and regulatory T cells. CTLA4 (Gene ID:1493, MIM number:123890) has many variants and polymorphic forms, some present in regulatory positions, some in 3' UTR and the most important one in the leader sequence (+49 A/G). As a pivotal regulatory element of the immune responses magnitude, CTLA4 could be considered as a two-blade knife, for which only the optimal expression ensures an effective, but at the same time, safe immune response. It can accordingly be speculated that CTLA4 alleles associated with extraordinary expression could make a person more susceptible to tumor growth and/or progression. On the other hand, alleles associated with a compromised CTLA4 expression/function may accelerate the formation and/or manifestation of inflammatory autoimmune disorder. I hypothesized a spectrum of the functional dichotomy of CTLA4 SNPs diverging from autoimmunity to cancer. To examine these hypotheses, results from previously published investigations on CTLA4 polymorphisms together with the work done by our own group are discussed in details. Because the most published data are about the polymorphism at position +49, I concentrated on this position; however the data regarding other SNPs are also included for comparison. To support the significance of CTLA4 gene variation in these two major human diseases evidences from organ transplantation are also included. As will be discussed in the manuscript, our work and reports by others from a normal population perspective support the hypothesis that individuals inheriting a GG genotype at position +49, for which lower CTLA4 expression has been extensively suggested, are more susceptible for developing autoimmune disorders and those with AA genotype, with an existence of a state of self-tolerance, may have a higher chance of developing cancer. CTLA4 SNPs may accordingly be considered as a crucial element, along with other known or yet unknown mechanisms, in keeping the immune balance in predisposed individuals to cancer and autoimmunity. Although an spectrum line can be drawn between autoimmunity and cancer by considering published data regarding CTLA4 +49 polymorphism, the extreme functional dichotomy of this SNP appears to be more complex and difficult to understand, but there is no doubt that the future investigations will resolve most ambiguities.

http://iji.sums.ac.ir/article_17019_790d1af7de566269466cfa593dfb50fd.pdf

CTLA4 gene variants in autoimmunity and cancer: a comparative review.

CTLA-4 is a critical gatekeeper of T-cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA-4 in SLE. Our results reveal increased CTLA-4 expression in FOXP3(-) responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA-4 was unable to regulate T-cell proliferation, lipid microdomain formation and phosphorylation of TCR-zeta following CD3/CD28 co-stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co-stimulation, there was no parallel increase in CTLA-4 expression, which would normally provide a break on T-cell proliferation. These defects were associated with exclusion of CTLA-4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA-4 dysfunction as a potential cause for abnormal T-cell activation in patients with SLE, which could be targeted for therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.200939781

Abnormal CTLA-4 function in T cells from patients with systemic lupus erythematosus.

The aim of this study was to summarize results on the association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism with systemic lupus erythematosus (SLE) susceptibility by using the meta-analysis. We searched all the publications about the association between CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism and SLE from PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang (Chinese). Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta-analysis to better assess the purported associations. A total of 17 independent studies (to June 2012) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at two polymorphic sites found in exon-1 (at +49) and the promoter region (at −1722). The data demonstrate that the exon-1 +49 polymorphism is associated with SLE susceptibility in Asian population. The overall risk, measured by odds ratio (OR), stratification by ethnicity indicates the exon-1 +49 GG+GA genotype is associated with SLE, at least in Asians (OR = 0.85, 95 % CI = 0.73–0.99, P = 0.04 for GG+GA vs. AA; OR = 0.85, 95 % CI = 0.72–1.00, P = 0.05 for AG vs. AA). Similar trends are found in allele-specific risk estimates and disease association. Overall, there was significant association between the 1722T/C polymorphism and overall SLE risks (OR = 0.78, 95 % CI = 0.63–0.97, P = 0.04 for GG+GA vs. AA, OR = 0.87, 95 % CI = 0.76–0.99, P = 0.04 for G vs. A) in Asian population.In summary, this meta-analysis demonstrates that the CTLA-4 promoter +49A/G and promoter −1722C/T polymorphism may confer susceptibility to SLE, especially in Asian-derived population.

CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis

Semantic web (SW) technology has been widely applied to many domains such as medicine, health care, finance, geology. At present, researchers mainly rely on their experience and preferences to develop and evaluate the work of SW technology. Although the general architecture (e.g., Tim Berners-Lee's Semantic Web Layer Cake) of SW technology was proposed many years ago and has been well-known, it still lacks a concrete guideline for standardizing the development of SW technology. In this paper, we propose an SW technology index to standardize the development for ensuring that the work of SW technology is designed well and to quantitatively evaluate the quality of the work in SW technology. This index consists of 10 criteria that quantify the quality as a score of [Formula: see text]. We address each criterion in detail for a clear explanation from three aspects: (1) what is the criterion? (2) why do we consider this criterion and (3) how do the current studies meet this criterion? Finally, we present the validation of this index by providing some examples of how to apply the index to the validation cases. We conclude that the index is a useful standard to guide and evaluate the work in SW technology. 

/pdf/a-semantic-web-technology-index-9crfpg7o.pdf

A semantic web technology index

Objective: Results from published studies on the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and prostate cancer (PCa) risk are inconsistent. To derive a more precise estimate, we performed a meta-analysis. Methods: We searched in the PubMed and Elsevier Science Direct database for studies on the association between the COMT Val158Met polymorphism and PCa. We used the odds ratio with 95% confidence interval for PCa risk, detected potential sources of heterogeneity with the Chi-square-based Q-test, performed sensitivity analysis of studies adapted to the Hardy–Weinberg equilibrium. Results: We found seven case–control studies included 2292 patients and 2158 controls. Fix-effects meta-analysis failed to explore any significant association of PCa with the genetic model and the allelic model of COMT Val158Met. We also did not detect any association in the subgroup analysis by ethnicity in all genetic models. The gene-based analysis suggested that the genetic polymorphism...

No association between COMT Val158Met polymorphism and prostate cancer risk: a meta-analysis.

/pdf/a-semantic-web-technology-index-1uyx9xdr.pdf

Abstract Scientific publications present biological relationships but are structured for human reading, making it difficult to use this resource for semantic integration and querying. Existing databases, on the other hand, are well structured for automated analysis, but do not contain comprehensive biological knowledge. We devised an approach for constructing comprehensive knowledge graphs from these two types of resources and applied it to investigate relationships between pre-/probiotics and microbiota–gut–brain axis diseases. To this end, we created (i) a knowledge base, dubbed ppstatement, containing manually curated detailed annotations, and (ii) a knowledge base, called ppconcept, containing automatically annotated concepts. The resulting Pre-/Probiotics Knowledge Graph (PPKG) combines these two knowledge bases with three other public databases (i.e. MeSH, UMLS and SNOMED CT). To validate the performance of PPKG and to demonstrate the added value of integrating two knowledge bases, we created four biological query cases. The query cases demonstrate that we can retrieve co-occurring concepts of interest, and also that combining the two knowledge bases leads to more comprehensive query results than utilizing them separately. The PPKG enables users to pose research queries such as “ which pre-/probiotics combinations may benefit depression? ”, potentially leading to novel biological insights. 

/pdf/towards-a-knowledge-graph-for-pre-probiotics-and-microbiota-2vetsrgk.pdf

Ting Liu

Papers

CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis

A semantic web technology index

No association between COMT Val158Met polymorphism and prostate cancer risk: a meta-analysis.

A semantic web technology index

Towards a knowledge graph for pre-/probiotics and microbiota–gut–brain axis diseases