scholarly journals Permutational immune analysis reveals architectural similarities between inflammaging, Down syndrome and autoimmunity

2021 ◽  
Author(s):  
Katharina Lambert ◽  
Keagan G. Moo ◽  
Azlann Arnett ◽  
Gautam Goel ◽  
Kaitlin J. Flynn ◽  
...  

AbstractPeople with Down syndrome show cellular and clinical features of dysregulated aging of the immune system, including naïve-memory shift in the T cell compartment and increased incidence of autoimmunity. However, a quantitative understanding of how various immune compartments change with age in Down syndrome remains lacking. Here we performed deep immunophenotyping of a cohort of individuals with Down syndrome across the lifespan, selecting for individuals not affected by autoimmunity. We simultaneously interrogated age- and sex-matched healthy neurotypical controls and people with type 1 diabetes, as a representative autoimmune disease. We built a new analytical software, IMPACD, that enabled us to rapidly identify many features of immune dysregulation in Down syndrome that are recapitulated in other autoimmune diseases. We found significant quantitative and qualitative dysregulation of naïve CD4+ and CD8+ T cells in Down syndrome and identified IL-6 as a candidate driver of some of these changes, thus extending the consideration of immunopathologic cytokines in Down syndrome beyond interferons. Notably, we successfully used immune cellular composition to generate three quantitative models of aging (i.e. immune clocks) trained on control subjects. All three immune clocks demonstrated significantly advanced immune aging in people with Down syndrome. Notably, one of these clocks, informed by Down syndrome-relevant biology, also showed advanced immune aging in people with type 1 diabetes. Together, our findings demonstrate a novel approach to studying immune aging in Down syndrome which may have implications in the context of other autoimmune diseases.One Sentence SummaryPermutational analysis of immune landscape reveals advanced immune aging in people with Down syndrome and in people with type 1 diabetes.

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 268
Author(s):  
Marta Ferrari ◽  
Stefano Stagi

Within immune system-related diseases, autoimmunity has always represented a field of great interest, although many aspects remain poorly understood even today. Genetic syndromes associated with immunity disorders are common and represent an interesting model for a better understanding of the underlying mechanism of autoimmunity predisposition. Among these conditions, Down syndrome (DS) certainly deserves special attention as it represents the most common genetic syndrome associated with immune dysregulation, involving both innate and adaptive immunity. Autoimmunity represents a well-known complication of DS: it is estimated that people affected by this disease present a risk four to six times higher than the normal population to develop autoimmune diseases such as celiac disease, type 1 diabetes mellitus, and hypo- or hyperthyroidism. Several factors have been considered as possible etiology, including genetic and epigenetic modifications and immune dysregulation. In times in which the life expectancy of people with DS has been extremely prolonged, thanks to improvements in the diagnosis and treatment of congenital heart disease and infectious complications, knowledge of the mechanisms and proper management of autoimmune diseases within this syndrome has become essential. In this short review, we aim to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes.


GYNECOLOGY ◽  
2020 ◽  
Vol 22 (5) ◽  
pp. 27-30
Author(s):  
Elena N. Andreeva ◽  
Olga R. Grigoryan ◽  
Yulia S. Absatarova ◽  
Irina S. Yarovaya ◽  
Robert K. Mikheev

The reproductive potential of a woman depends on indicators of the ovarian reserve, such as the anti-Muller hormone (AMH) and the number of antral follicles (NAF). Autoimmune diseases have a significant effect on fertility and contribute to the development of premature ovarian failure. Aim.To evaluate the parameters of the ovarian reserve in patients with type 1 diabetes mellitus, carriers of antibodies to the thyroid gland in a state of euthyroidism and compare them with similar parameters in healthy women. Materials and methods.In the first block of the study, the level of AMH, follicle-stimulating hormone, luteinizing hormone, NAF was studied among 224 women with diabetes and 230 healthy women in the control group. In block II, the level of the above hormonal indices was studied in 35 carriers of antithyroid antibodies in the state of euthyroidism and 35 healthy women. Results.In patients with type 1 diabetes, the level of AMH, NAF was statistically significantly lower when compared with the control group. Among carriers of antithyroid antibodies and healthy women, no difference in AMH and NAF was found. Conclusion.The autoimmune processes accompanying diabetes are more influenced by the ovarian reserve indices than autoimmune aggression to the tissues of the thyroid gland.


2013 ◽  
Vol 5 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Gökşen Şimşek Damla ◽  
Aycan Zehra ◽  
Özen Samim ◽  
Çetinkaya Semra ◽  
Kara Cengiz ◽  
...  

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257265
Author(s):  
Seung-Soo Kim ◽  
Adam D. Hudgins ◽  
Jiping Yang ◽  
Yizhou Zhu ◽  
Zhidong Tu ◽  
...  

Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.


Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 68-OR
Author(s):  
DIANA FERRO ◽  
DAVID D. WILLIAMS ◽  
SUSANA R. PATTON ◽  
RYAN MCDONOUGH ◽  
MARK A. CLEMENTS

Author(s):  
Nicole Prinz ◽  
Sascha R Tittel ◽  
Rainer Bachran ◽  
Robert Birnbacher ◽  
Joachim Brückel ◽  
...  

Abstract Context Autoimmune diseases affect ~8% of the population. Type 1 diabetes mellitus (T1DM) is linked to other autoimmune diseases (AID) like autoimmune thyroid disease, or Addison’s disease (AD) that may impact diabetes therapy and outcome. Objective To analyze demographic and clinical characteristics of other AID in T1DM from a large standardized registry, the prospective diabetes follow-up (DPV). Methods We searched the registry for T1DM with the additional diagnosis of Hashimoto’s thyroiditis (HT), Graves’ disease (GD), and/or AD. T1DM with other AID (n=6,166, 5.4%) were compared to isolated T1DM (n=107,457). For group comparisons, we used multivariable regression models with age, sex, diabetes duration, migration background, and type of insulin regimen as basic adjustments (microvascular endpoints: additionally adjusted for HbA1c). Results Patients with additional AID were more often female (54.7 vs. 32.0%, p<0.001) and had a longer diabetes duration (7.9 [4.2-12.5] vs. 6.7 [2.7-12.9] years, p<0.001). After adjustment, daily insulin dosage was higher in AD and HT compared to isolated T1DM (0.858±0.032 and 0.813±0.005 vs. 0.793±0.001 IU/kg*d). Retinopathy was less common in HT (1.5%), whereas it was more frequent in GD (3.1%) if compared to isolated T1DM (1.8%). In both GD and HT, microalbuminuria occurred less often (10.6% and 14.3% vs. 15.5%) and neuropathy (2.1% and 1.8% vs. 0.8%) was more common compared to isolated T1DM. Conclusions T1DM with additional AID show heterogeneous differences compared to isolated T1DM. T1DM plus AD or HT requires more insulin. Further, the rate of neuropathy is higher in HD or GD, whereas the rate of microalbuminuria is lower.


Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Amena Keshawarz ◽  
Martin Cech ◽  
Teresa Witten ◽  
Young-Min Park ◽  
Jason Richards ◽  
...  

Cardiovascular risk is increased in adults with type 1 diabetes (T1D), although the mechanism is poorly understood. Endothelial dysfunction may contribute to increased coronary artery calcium (CAC) in T1D, and CAC severity may be associated with reduced nitric oxide (NO) synthesis and/or increased inflammation. We tested the hypotheses that high CAC and T1D are associated with expression of endothelial NO synthase (eNOS, enzyme that produces NO), phosphorylated eNOS (p-eNOS), and NFκB (pro-inflammatory transcription factor). Participants were categorized as having high (>80 Agatston units [AU]) or low CAC (<15 AU), measured by CT scan. Protein expression was measured using quantitative immunofluorescence in endothelial cells harvested from 14 women with T1D (mean age 52±8 years; 7 high CAC); 13 men with T1D (mean age 58±7 years; 5 high CAC); 10 women without diabetes (mean age 61±4 years; 3 high CAC); and 10 men without diabetes (mean age 59±6 years; 4 high CAC). All analyses used ratios of endothelial cell protein expression to control human umbilical vein endothelial cell protein expression. Independent t-tests compared protein expression by sex and T1D. Linear regression tested the associations of high vs. low CAC and T1D with the 3 proteins of interest after adjustment for age and sex. In men, eNOS expression differed by T1D: men with T1D had reduced cytoplasmic (0.34 vs.0.52, p=0.03) and nuclear (0.44 vs. 0.60, p=0.02) eNOS expression compared with men without T1D, suggesting reduced NO synthesis. There were no differences in p-eNOS expression, indicating that eNOS levels were likely not due to differential activation. In women, NFκB expression similarly differed by T1D: women with T1D had higher cytoplasmic (0.81 vs. 0.63, p=0.01) and nuclear (0.99 vs. 0.75, p=0.01) NFκB expression compared with women without T1D, suggesting greater inflammation. After adjustment for age and sex, there was no significant association between high vs. low CAC in endothelial expression of any proteins. The data trend suggested that high vs. low CAC is associated with reduced cytoplasmic (0.36 vs. 0.47, p=0.06) and nuclear (0.48 vs. 0.55, p=0.12) eNOS expression. T1D trended in the same direction for both cytoplasmic (0.36 vs. 0.47, p=0.06) and nuclear (0.47 vs. 0.55, p=0.13) eNOS expression. High vs. low CAC also trended towards an association with greater cytoplasmic (0.72 vs. 0.66, p=0.21) and nuclear (0.85 vs. 0.80, p=0.40) NFκB expression, while T1D was significantly associated with greater cytoplasmic (0.76 vs. 0.63, p=0.006) and nuclear (0.92 vs. 0.73, p=0.003) NFκB expression. Neither CAC nor T1D was associated with p-eNOS expression in linear regression. In conclusion, eNOS and NFκB expression are potential mechanisms for increased CAC given their roles in reduced NO synthesis and increased inflammation, and may differ by sex in people with T1D. Regardless of high CAC, inflammation in T1D is increased.


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