Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation
Open accessAbstract
Trisomy 21 (T21) causes Down syndrome (DS), but the mechanisms by which T21 produces the different disease spectrum observed in people with DS are unknown. We recently identified an activated interferon response associated with T21 in human cells of different origins, consistent with overexpression of the four interferon receptors encoded on chromosome 21, and proposed that DS could be understood partially as an interferonopathy. However, the impact of T21 on systemic signaling cascades in living individuals with DS is undefined. To address this knowledge gap, we employed proteomics approaches to analyze blood samples from 263 individuals, 165 of them with DS, leading to the identification of dozens of proteins that are consistently deregulated by T21. Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling. Importantly, people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-α) and pronounced complement consumption, resembling changes seen in type I interferonopathies and other autoinflammatory conditions. Therefore, these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation, and justify investigations to define the therapeutic value of immune-modulatory strategies in DS.
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Written from the paper’s full text.
TL;DR
Trisomy 21 is associated with widespread changes in the circulating proteome, including immune-control, complement/coagulation, growth-factor, and neurogenesis-related proteins. The pattern includes elevated pro-inflammatory cytokines and complement consumption, resembling type I interferonopathies and supporting chronic autoinflammation in Down syndrome.
Key findings
- In the Discovery Study (120 T21, 52 D21; 3,585 epitopes), 299 proteins were differentially detected at Bonferroni-adjusted p < 0.1: 178 downregulated and 121 upregulated in T21. Among 50 chr21-encoded proteins with aptamers, 9 were significantly upregulated and none significantly downregulated.
- Validation was reproducible: ~72% of Discovery differential proteins measured in all three studies validated in at least one Validation Study (FDR < 10%). B2M was consistently elevated and IGHE consistently downregulated; lower IgE was confirmed by ELISA.
- In a separate MSD assay of 40 adults (20 T21, 20 D21), individuals with DS had significantly increased IL-6, IL-22, MCP-1/CCL2, TNF-α, and VEGF-A. CCL17 was elevated in all three SOMAscan studies but fell below the MSD significance cutoff.
- Complement/coagulation proteins showed a consumption pattern: 21 proteins in the category, 18 downregulated in DS, including C1R, C1QA, C3, and C6; C1S was consistently depleted in all three studies. Interferome mining found significant enrichment of interferon-related proteins among differential proteins (p = 1.91E-03, hypergeometric test).
Methods
- SOMAscan aptamer proteomics was performed on plasma/serum: Discovery Study (172 individuals: 120 T21, 52 D21; 3,585 epitopes), Validation Study #1 (53: 38 T21, 15 D21; plasma; 1,047 epitopes), and Validation Study #2 (33: 22 T21, 11 D21; serum; 1,047 epitopes). The abstract reports 263 individuals total, 165 with DS.
- A Mesoscale Discovery assay measured 38 cytokines in plasma from 40 adults (20 T21, 20 D21; ages 20–65), and IgE ELISA was used for confirmation.
- Differential detection used the non-parametric Kolmogorov-Smirnov test with Bonferroni correction for the Discovery Study and Benjamini-Hochberg correction for smaller Validation/MSD studies; functional analyses used Metascape, STRING, and Interferome.
Limitations
- The paper does not state a formal limitations section; it describes the proteomics datasets as “hypothesis-generating” and calls for future mechanistic investigations.
- Evident from the text: the SOMAscan cohorts are largely pediatric (Discovery ages six months to 21 years), while the MSD cohort is only 40 adults (20–65), so age coverage is limited and the design is cross-sectional.
- Evident from the text: no direct measurement of interferon signaling or functional validation is reported, and the findings are associations in the circulating proteome; causality and therapeutic benefit of immune modulation are not tested.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
13 of 41 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Trisomy 21 causes consistent activation of the interferon transcriptional response in human cells.
“including, most prominently, consistent activation of the interferon transcriptional response17”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Sullivan, K. D. et al. Trisomy 21 consistently activates the interferon response. Elife 5, e16220 (2016). source
- Findingown data
STRING analysis revealed numerous groups of physically interacting proteins within the Immune Control functional category.
“We next queried the STRING database of protein-protein interactions27, which revealed numerous groups of physically interacting proteins within this functional category”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] Szklarczyk, D. et al. STRINGv10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, D447–D452 (2015). source
- Interpretationown data
Many of the changes in the circulating proteome in people with Down syndrome are highly reminiscent of those observed in type I interferonopathies and other autoinflammatory conditions.
“Our study of the circulating proteome in people with DS, the largest and most comprehensive study of this kind reported to date, reveals that T21 causes profound immune dysregulation, with many of the changes being highly reminiscent of those observed in type I interferonopathies and other autoinflammatory conditions54,58–60,88 (Table 1).”
Quote in the paperSubstantial claim3 of 5 sources checked- cites [54] Obermoser, G. & Pascual, V. The interferon-alpha signature of systemic lupus erythematosus. Lupus 19, 1012–9 (2010). source
The section “The IFN-α signature of SLE” reports elevated interferon and upregulated interferon-regulated transcripts in the blood of people with lupus, supporting an analogy to interferon-associated immune changes. It does not examine the circulating proteome in Down syndrome or establish that its protein changes resemble those in lupus or other conditions. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [58] Szodoray, P., Alex, P., Brun, J. G., Centola, M. & Jonsson, R. Circulating Cytokines in Primary Sjogren’s Syndrome Determined by a Multiplex Cytokine Array System. Scand. J. Immunol. 59, 592–599 (2004). source
- cites [59] Meyer, P. W. A. et al. Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Mediators Inflamm. 2010, 158514 (2010). source
The Results (§3.2; page unavailable) report broadly elevated circulating cytokines, chemokines, and growth factors in patients with rheumatoid arthritis, supporting an inflammatory-condition example. The paper does not study Down syndrome or type I interferonopathies, or establish that many of their proteomic changes resemble those in rheumatoid arthritis. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [60] Takanohashi, A. et al. Elevation of proinflammatory cytokines in patients with Aicardi-Goutieres syndrome. Neurology 80, 997–1002 (2013). source
- cites [88] Antonelli, A. et al. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun. Rev. 13, 272–80 (2014). source
- Findingown data
Changes associated with trisomy 21 are more profound in number of proteins affected and fold changes than those associated with sex-specific karyotypes.
“changes associated with T21 are far more profound, both in number of proteins affected and fold changes, than those associated with the sex-specific karyotypes”
Quote in the paperNot a substantial claim - Findingown data
People with Down syndrome display higher levels of many pro-inflammatory cytokines, including IL-6, MCP-1, IL-22, and TNF-α.
“people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-α)”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Findingown data
ERAP2 is downregulated in people with Down syndrome.
“ERAP2, also downregulated in people with DS”
Quote in the paperSubstantial claim - Findingown data
Trisomy 21 consistently deregulates dozens of proteins in the circulating proteome.
“leading to the identification of dozens of proteins that are consistently deregulated by T21”
- Also stated in: § Introduction · plain
“Collectively, these efforts identified dozens of proteins consistently deregulated in the circulating proteome of people with T21.”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Also stated in: § Introduction · plain
- Findingown data
FGF1 is downregulated in individuals with T21.
“For example, FGFR1 is upregulated in individuals with T21, while its ligand FGF1, is down (Fig. 4c,d).”
Quote in the paperNot a substantial claim - Findingown data
Immune Control constituted the largest functional category, consisting of 150 differential proteins.
“Immune Control constituted the largest functional category, consisting of 150 differential proteins”
Quote in the paperNot a substantial claim - Findingown data
FGFR1 is upregulated in individuals with T21.
“For example, FGFR1 is upregulated in individuals with T21, while its ligand FGF1, is down (Fig. 4c,d).”
Quote in the paperNot a substantial claim - Findingown data
FCRL3 is significantly downregulated in people with Down syndrome.
“FCRL3, which is significantly downregulated in people with DS”
Quote in the paperSubstantial claim - Findingown data
ZAP70 is downregulated in people with trisomy 21.
“ZAP70 (Src-related kinase, SRK), which is also downregulated in people with T21”
Quote in the paperSubstantial claim - Findingown data
C1S is consistently depleted in all three studies.
“The reproducibility of this result is further illustrated by the consistent depletion of C1S observed in all three studies”
Quote in the paperNot a substantial claim - Findingown data
Approximately 72% of the differentially abundant proteins from the Discovery Study that were measured in all three studies validated in at least one Validation Study.
“we found that ~72% of the differentially abundant proteins from the Discovery Study that were measured in all three studies validated in at least one Validation Study”
Quote in the paperSubstantial claim - Findingown data
Immunoglobulin E (IGHE) is consistently downregulated in the circulating proteome of people with trisomy 21.
“Immunoglobulin E (IGHE), which is consistently downregulated”
Quote in the paperNot a substantial claim - Findingown data
Protein C (PROC) is upregulated in T21 samples.
“while another inhibitor of numerous coagulation factors, protein C (PROC), is upregulated (Fig. 3j).”
Quote in the paperNot a substantial claim - Findingown data
Components of the FGF, VEGF, and EGF pathways are significantly deregulated within the group of Growth Factor Signaling proteins in T21.
“Significantly deregulated within the group of Growth Factor Signaling proteins are components of the FGF, VEGF, and EGF pathways (Fig. 4b).”
Quote in the paperNot a substantial claim - Findingown data
Multiple proteins within the coagulation cascade are downregulated in T21 samples, including Factor II (F2), fibrinogen (FGA), and SERPINC1.
“Finally, multiple proteins within the coagulation cascade were also identified as downregulated in T21 samples, including Factor II (F2), fibrinogen (FGA) and the inhibitor SERPINC1 (Fig. 3g–i)”
Quote in the paperNot a substantial claim - Findingown data
LILRB1 and LILRB2 are downregulated in individuals with trisomy 21.
“LILRB1 and LILRB2 (leukocyte immunoglobulin-like receptors B1 and 2), which are downregulated in individuals with T21”
Quote in the paperSubstantial claim - Findingown data
Metascape results were dominated by functional categories related to control of the immune system, including humoral immune response, inflammatory response, complement activation, regulation of coagulation, regulation of proteolysis, and leukocyte mediated immunity.
“These Metascape results were dominated by functional categories related to control of the immune system, including humoral immune response, inflammatory response, complement activation, regulation of coagulation, regulation of proteolysis, and leukocyte mediated immunity, among others.”
Quote in the paperSubstantial claim - Findingown data
C1R, C1QA, C3, and C6 are downregulated in individuals with trisomy 21.
“Examples of subunits of the complement pathway that are downregulated in individuals with T21 include C1R, C1QA, C3, and C6”
Quote in the paperSubstantial claim - Findingown data
Higher levels of circulating TNFRSF1A were confirmed in both validation studies.
“Higher levels of circulating TNFRSF1A were confirmed in both validation studies”
Quote in the paperSubstantial claim - Findingown data
There is a statistically significant enrichment of interferon-related proteins among proteins differentially detected in people with trisomy 21 relative to all proteins detected by SOMAscan (p = 1.91E-03, hypergeometric test).
“we mined the Interferome database (www.interferome.org), and found a statistically significant enrichment of interferon-related proteins among those that are differentially detected in people with T21 relative to all proteins detected by the SOMAscan® platform (p = 1.91E-03, hypergeometric test”
Quote in the paperSubstantial claim - Findingown data
Beta-2-microglobulin (B2M) is consistently elevated in the circulating proteome of people with trisomy 21.
“β-2-microglobulin (B2M, a subunit of the Major Histocompatibility Complex I (MHC I)), which is consistently elevated in the circulating proteome of people with T21”
Quote in the paperSubstantial claim - Findingown data
CST3 is clearly elevated in people with Down syndrome.
“cystatin 3 (CST3), which is clearly elevated in people with DS”
Quote in the paperNot a substantial claim - Findingown data
The most prominent differentially abundant proteins in Down syndrome are involved in immune control, the complement cascade, and growth factor signaling.
“Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling.”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Findingown data
Most proteome changes observed in people with Down syndrome correspond to proteins encoded elsewhere in the genome.
“Thus, most of the proteome changes observed in people with DS correspond to proteins encoded elsewhere in the genome”
Quote in the paperSubstantial claim - Findingown data
Four broad categories encompassing 215 proteins were identified: Immune Control, Complement and Coagulation, Growth Factor Signaling, and Regulation of Neurogenesis.
“Further examination revealed four broad categories encompassing 215 proteins, with some overlapping proteins among groups: Immune Control, Complement and Coagulation, Growth Factor Signaling, and Regulation of Neurogenesis”
Quote in the paperNot a substantial claim - Findingown data
Growth Factor Signaling is a prominent functional category highly deregulated in people with T21.
“Another prominent functional category that Metascape identified as highly deregulated in people with T21 is Growth Factor Signaling (Figs 1e and 4a).”
Quote in the paperNot a substantial claim - Findingcitation
B2M is upregulated in individuals with trisomy 21.
“B2M is a subunit of the MHC class I complex required for peptide loading and is upregulated in individuals with T21”
Quote in the paperSubstantial claim - Findingown data
VEGFA is upregulated in T21.
“VEGF signaling shows the opposite pattern, with downregulation of the receptor (KDR, VEGFR) and upregulation of the ligand VEGFA (Fig. 4e,f).”
Quote in the paperNot a substantial claim - Findingown data
RET displays lower circulating levels in people with Down syndrome.
“Finally, RET, a receptor tyrosine kinase of the cadherin superfamily with key roles in neural crest development85, also displays lower circulating levels in people with DS (Fig. 4n).”
Quote in the paperNot a substantial claim - Findingown data
NTRK3 is downregulated in the plasma of people with Down syndrome.
“For example, NTRK2 and NTRK3, the transmembrane receptors for the Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin 3, respectively82, are clearly downregulated in the plasma of people with DS (Fig. 4k,l).”
Quote in the paperNot a substantial claim - Findingown data
KDR (VEGFR) is downregulated in T21.
“VEGF signaling shows the opposite pattern, with downregulation of the receptor (KDR, VEGFR) and upregulation of the ligand VEGFA (Fig. 4e,f).”
Quote in the paperNot a substantial claim - Findingown data
NTRK2 is downregulated in the plasma of people with Down syndrome.
“For example, NTRK2 and NTRK3, the transmembrane receptors for the Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin 3, respectively82, are clearly downregulated in the plasma of people with DS (Fig. 4k,l).”
Quote in the paperNot a substantial claim - Findingown data
17 of the 75 proteins linked to Growth Factor Signaling by Metascape were also linked to Regulation of Neurogenesis, including EGFR, ERBB4, NTRK2, NTRK3, and RET.
“Notably, 17 of the 75 proteins linked to Growth Factor Signaling by Metascape were also linked to Regulation of Neurogenesis, including EGFR, ERBB4, NTRK2, NTRK3, and RET (Fig. 1 S4).”
Quote in the paperNot a substantial claim - Findingown data
SLITRK3 is downregulated in people with Down syndrome.
“A third neurotrophin receptor required for normal GABAergic synapse development, SLITRK383, is also downregulated (Fig. 4m).”
Quote in the paperNot a substantial claim - Interpretationown data
Individuals with Down syndrome display obvious signs of autoinflammation across their lifespan.
“individuals with DS display obvious signs of autoinflammation across their lifespan”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Interpretationown data
The downregulation of complement proteins suggests a complement consumption phenotype.
“suggesting a complement consumption phenotype”
Quote in the paperSubstantial claim - Interpretationreasoning
The proteome changes reveal signaling pathways consistently dysregulated downstream of trisomy 21.
“revealing the existence of signaling pathways consistently dysregulated downstream of T21”
Quote in the paperSubstantial claim - Interpretationcitation
The changes in both B2M and IGHE can be explained by increased interferon signaling.
“the changes in both B2M and IGHE can be explained by increased interferon signaling21–24.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [21] Calvo, F. et al. Quantitative modifications of major histocompatibility complex (MHC) antigens induced by recombinant gamma interferon in two human breast cancer lines. Int. J. Immunopharmacol. 9, 459–68 (1987). source
- cites [22] Wedgwood, J. F., Hatam, L. & Bonagura, V. R. Effect of interferon-gamma and tumor necrosis factor on the expression of class I and class II major histocompatibility molecules by cultured human umbilical vein endothelial cells. Cell. Immunol. 111, 1–9 (1988). source
- cites [23] Remes, K., Tienhaara, A. & Pelliniemi, T.-T. Effects of Alpha-Interferon on Serum Beta-2-Microglobulin. Leuk. Lymphoma 21, 233–238 (1996). source
- cites [24] Gonzales-van Horn, S. R. & Farrar, J. D. Interferon at the crossroads of allergy and viral infections. J. Leukoc. Biol. 98, 185–194 (2015). source
- Study design and conductown data
The functional categories identified by Metascape are not due to an underlying bias in the list of SOMAmer reagents.
“which revealed that the functional categories identified are not due to an underlying bias in the list of SOMAmer® reagents”
Quote in the paperSubstantial claim - Interpretationown data
Down syndrome could be understood in good measure as an immune disorder.
“reinforcing the notion that DS could be understood in good measure as an immune disorder.”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Study design and conductown data
The lower levels of IgE in people with Down syndrome were confirmed by ELISA.
“The lower levels of IgE in people with DS were confirmed by ELISA (Fig. 1 S2).”
Quote in the paperNot a substantial claim - Study design and conductown data
Replicate variability was minimal both for samples run in replicate within the same assay or a year apart.
“replicate variability was minimal both for samples run in replicate within the same assay or a year apart”
Quote in the paperSubstantial claim - Interpretationown data
Down syndrome could be understood partially as an interferonopathy.
“proposed that DS could be understood partially as an interferonopathy”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Interpretationreasoning
Increased interferon signaling caused by trisomy 21 leads to chronic immune dysregulation.
“these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Interpretationown data
The changes in people with Down syndrome resemble those seen in type I interferonopathies and other autoinflammatory conditions.
“resembling changes seen in type I interferonopathies and other autoinflammatory conditions”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Interpretationown data
People with Down syndrome display pronounced complement consumption.
“and pronounced complement consumption”
Quote in the paperSubstantial claim- Rests on an assumption: Trisomy 21 causes Down syndrome.
- Interpretationown data
People with Down syndrome show obvious signs of increased TNF-α signaling.
“people with DS show obvious signs of increased TNF-α signaling”
Quote in the paperSubstantial claim - Interpretationown data
Trisomy 21 causes profound immune dysregulation.
“Our study of the circulating proteome in people with DS, the largest and most comprehensive study of this kind reported to date, reveals that T21 causes profound immune dysregulation, with many of the changes being highly reminiscent of those observed in type I interferonopathies and other autoinflammatory conditions54,58–60,88 (Table 1).”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 25
- May combine two claims. 18
Classified as probably not a substantial claim. May combine two claims.
PremisecitationCST3, B2M, and TFF3 have all been used to monitor kidney function, as their plasma levels increase upon kidney injury.
“have all been used to monitor kidney function, as their plasma levels increase upon kidney injury71”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [71] Du, T. et al. Circulating serum trefoil factor 3 (TFF3) is dramatically increased in chronic kidney disease. PLoS One 8, e80271 (2013). source
The Discussion reports that serum TFF3 is higher in patients with chronic kidney disease and rises with CKD severity. It does not establish that TFF3 has been used to monitor kidney function; it describes clinical diagnostic development as a future possibility. The passages also provide no support for the claims about CST3 or B2M. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationSeveral complement subunits play key roles in microglia-mediated synapse destruction during Alzheimer's disease progression.
“However, several complement subunits also play key roles in microglia-mediated synapse destruction during AD progression74–76”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [74] Jiang, H., Burdick, D., Glabe, C. G., Cotman, C. W. & Tenner, A. J. beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J. Immunol. 152, 5050–9 (1994). source
- cites [75] Veerhuis, R., Janssen, I., Hack, C. E. & Eikelenboom, P. Early complement components in Alzheimer’s disease brains. Acta Neuropathol. 91, 53–60 (1996). source
- cites [76] Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–6 (2016). source
The paper reports that inhibiting C1q, C3, or the microglial complement receptor CR3 reduces early synapse loss in Alzheimer mouse models. The claim’s broader wording about AD progression is not established: the discussion says the findings concern pre-plaque models and leaves a role in plaque-associated synapse loss for future study. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPeople with Down syndrome are the largest human population with a genetic predisposition to early-onset Alzheimer's disease, largely explained by the presence of the APP gene on chromosome 21.
“People with DS are the largest human population with a genetic predisposition to early-onset AD, which is largely explained by the presence of the APP gene on chr2173.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [73] Schupf, N. & Sergievsky, G. H. Genetic and host factors for dementia in Down’s syndrome. Br. J. Psychiatry 180, 405–10 (2002). source
The paper’s Background and Amyloid Cascade Hypothesis sections link the high risk of Alzheimer’s-related dementia in Down syndrome to triplication and overexpression of APP on chromosome 21, while noting that other factors affect the age of onset. Our copy does not establish that people with Down syndrome are the largest human population with this genetic predisposition. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationHypocomplementia could contribute to the increased risk of bacterial lung pneumonia and otitis media in Down syndrome, as complement depletion prevents proper clearance of Streptococcus pneumoniae.
“Hypocomplementia could clearly contribute to the observed increased risk of bacterial lung pneumonia and otitis media in the population with DS68, as complement depletion prevents proper clearance of Streptococcus pneumoniae 69.”
Quote in the paperSubstantial claim1 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationTrisomy 21 causes widespread alterations in gene expression across the genome in multiple human cell types.
“we reported the results of transcriptome analyses of four different cell types obtained from people with and without T21, which demonstrated that T21 causes widespread alterations in gene expression across the genome”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Sullivan, K. D. et al. Trisomy 21 consistently activates the interferon response. Elife 5, e16220 (2016). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSLITRK3 is a neurotrophin receptor required for normal GABAergic synapse development.
“A third neurotrophin receptor required for normal GABAergic synapse development, SLITRK383, is also downregulated (Fig. 4m).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [83] Takahashi, H. et al. Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction. Nat. Neurosci. 15, 389–98, S1-2 (2012). source
The Abstract and Discussion identify Slitrk3 as required for normal functional GABAergic synapse development. They describe it as a postsynaptic adhesion molecule, however, not a neurotrophin receptor; the receptor identified for its trans-synaptic interaction is PTPδ. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVEGFA induction is a hallmark of inflammatory processes leading to wound healing.
“Of note, VEGFA induction is a hallmark of inflammatory processes leading to wound healing81.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [81] Roth, D. et al. Plasmin modulates vascular endothelial growth factor-A-mediated angiogenesis during wound repair. Am. J. Pathol. 168, 670–84 (2006). source
The wound-healing results report increased cellular infiltration and vascularized granulation tissue after VEGF165 treatment, and the Discussion links VEGF165 treatment to improved re-epithelialization (pages unavailable). These passages support a role for VEGF-A in wound repair, but they do not establish that endogenous VEGF-A induction is a hallmark of inflammatory processes leading to healing. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAltered GABAergic signaling has been linked to the cognitive deficits caused by trisomy 21.
“Of note, altered GABAergic signaling has been linked to the cognitive deficits caused by T21 in myriad studies (reviewed in84).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [84] Contestabile, A., Magara, S. & Cancedda, L. The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome. Front. Cell. Neurosci. 11, 54 (2017). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataOnly five proteins in total were differentially detected in females versus males in the Discovery Study.
“only five proteins in total were differentially detected in females versus males.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe Complement and Coagulation group consists of 21 proteins, 18 of which are downregulated in the circulating proteome of people with Down syndrome.
“This group consists of 21 proteins, 18 of which are downregulated in the circulating proteome of people with DS”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe largest group of physically interacting proteins included B2M, LILRB1, LILRB2, FCRL3, ZAP70, and ERAP2, many of which have been linked to autoimmune disorders.
“The largest group of physically interacting proteins included factors with key roles in antigen presentation, autoimmunity, and T cell regulation, including B2M, LILRB1, LILRB2, FCRL3, ZAP70, and ERAP2, many of which have been linked to autoimmune disorders”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCCL17 was significantly elevated in people with Down syndrome in each of the three SOMAscan studies but fell below the statistical significance cut-off in the MSD assay.
“Another inflammatory cytokine that was also significantly elevated in people with DS in each of the three SOMAscan® studies, but which fell below the statistical significance cut-off in the MSD assay was CCL17 (TARC)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIndividuals with Down syndrome have significantly increased levels of IL-6, IL-22, MCP-1, TNF-α, and VEGF-A in the Mesoscale Discovery assay.
“individuals with DS have significantly increased levels of potent inflammatory cytokines and chemokines known to act downstream of IFN signaling, including IL-6, IL-22, MCP-1 (CCL2), TNF-α, and VEGF-A”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong the 50 chromosome 21-encoded proteins for which aptamers were available, 9 were significantly upregulated and none significantly downregulated in people with trisomy 21.
“Among the 50 proteins encoded on chr21 for which aptamers were available, 9 were significantly upregulated, and none significantly downregulated”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCST3, B2M, and TFF3 are among the most significantly upregulated proteins in Down syndrome.
“CST3, B2M, and TFF3, which are among the most significantly upregulated proteins in DS”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExamination of individual chromosomes did not reveal obvious spatial relationships among deregulated proteins, except that proteins encoded on chromosome 21 display a consistent trend toward upregulation.
“Examination of individual chromosomes did not reveal any obvious spatial relationships among deregulated proteins, with the notable exception of proteins encoded on chr21, which display a consistent trend toward upregulation”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSOMAscan revealed elevated circulating levels of TNFRSF1A, TNFRSF1B, and RFK in people with Down syndrome.
“The SOMAscan® proteomics platform revealed elevated circulating levels of the two TNF-α receptors, TNFRSF1A and TNFRSF1B, as well as the protein kinase RFK which is required for ROS production downstream of TNF-α receptor engagement”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the Discovery Study, 299 proteins were differentially detected between plasma of individuals with trisomy 21 and euploid controls using the Kolmogorov-Smirnov test with Bonferroni-adjusted p(a) < 0.1; 178 were downregulated and 121 upregulated.
“Overall, 299 proteins were differentially detected between the plasma of individuals with T21 versus euploid controls, as defined by the Kolmogorov-Smirnov (KS) test with Bonferroni-adjusted p-values [p(a)] < 0.1 (Fig. 1a, 178 proteins downregulated in individuals with T21, 121 upregulated, Supplementary File 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNumerous components of the EGF signaling cascade are downregulated in Down syndrome, including the receptors EGFR, ERBB3, and ERBB4, and the ligand HBEGF.
“Interestingly, numerous components of the EGF signaling cascade are downregulated in DS, including the receptors EGFR, ERBB3, and ERBB4, and the ligand itself (HBEGF) (Fig. 4g–j).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningChronic activation of interferon signaling could cause complement consumption.
“suggesting that chronic activation of interferon signaling could cause complement consumption”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationHypocomplementia is a common feature of type I interferonopathies.
“In fact, hypocomplementia is a common feature of type I interferonopathies66,67”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [66] Crow, Y. J. & Manel, N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–40 (2015). source
- cites [67] Pickering, M. C. & Walport, M. J. Links between complement abnormalities and systemic lupus erythematosus. Rheumatology (Oxford). 39, 133–41 (2000). source
May combine two claims.
Interpretationown dataThe results reveal a clear pro-inflammatory signature in the circulating proteome of people with Down syndrome, with multiple ties to interferon signaling.
“In sum, these results reveal a clear pro-inflammatory signature in the circulating proteome of people with DS, with multiple ties to interferon signaling.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningHypocomplementia could modulate Alzheimer's disease progression in individuals with trisomy 21.
“Thus, we posit that hypocomplementia could modulate AD progression in these individuals.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGain-of-function mutations in FGFR1 are associated with myeloproliferative disorders leading to leukemia.
“Gain-of-function mutations in FGFR1 are associated with myeloproliferative disorders leading to leukemia, as well as hereditary conditions leading to skeletal and craniofacial abnormalities, both of which are common in DS78–80.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [78] Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Linhardt, R. J. & Mohammadi, M. Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. Hum. Mol. Genet. 13, 69–78 (2004). source
- cites [79] Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat. Genet. 8, 269–274 (1994). source
- cites [80] Jackson, C. C., Medeiros, L. J. & Miranda, R. N. 8p11 myeloproliferative syndrome: a review. Hum. Pathol. 41, 461–76 (2010). source
May combine two claims.
PremisecitationBeta amyloid deposits and soluble B2M activate the classic complement cascade.
“both beta amyloid deposits and soluble B2M are known to activate the classic complement cascade77”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [77] Nybo, M., Nielsen, E. H. & Svehag, S. E. Complement activation by the amyloid proteins A beta peptide and beta 2-microglobulin. Amyloid 6, 265–72 (1999). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataB2M and CST3 were confirmed by Western blot using samples from the low and high SOMAmer detection range.
“Select proteins of interest, such as B2M and CST3 (cystatin C) were confirmed by Western blot using samples from the low and high SOMAmer® detection range (Fig. 1 S2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHypocomplementia is a hallmark of immune complex diseases, including interferon-driven conditions such as systemic lupus erythematosus.
“Hypocomplementia is a hallmark of immune complex diseases, a diverse group of inflammatory conditions characterized by antigen–antibody deposition and consequent complement activation64, including interferon-driven conditions such as SLE65.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [64] Nydegger, U. E. Immune complex pathophysiology. Ann. N. Y. Acad. Sci. 1109, 66–83 (2007). source
- cites [65] Ramos-Casals, M. et al. Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence and clinical significance in 667 patients. Lupus 13, 777–83 (2004). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNTRK2 is a transmembrane receptor for Brain Derived Neurotrophic Factor (BDNF).
“For example, NTRK2 and NTRK3, the transmembrane receptors for the Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin 3, respectively82, are clearly downregulated in the plasma of people with DS (Fig. 4k,l).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [82] Meldolesi, J. Neurotrophin Receptors in the Pathogenesis, Diagnosis and Therapy of Neurodegenerative Diseases. Pharmacol. Res. https://doi.org/10.1016/j.phrs.2017.04.024 (2017). source
Classified as probably not a substantial claim.
Study design and conductnone givenMultiple hypothesis correction was performed using the Benjamini-Hochberg method for the MSD assay.
“Multiple hypothesis correction was performed using the Benjamini-Hochberg method.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRET is a receptor tyrosine kinase of the cadherin superfamily with key roles in neural crest development.
“Finally, RET, a receptor tyrosine kinase of the cadherin superfamily with key roles in neural crest development85, also displays lower circulating levels in people with DS (Fig. 4n).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [85] Delalande, J.-M. et al. The receptor tyrosine kinase RET regulates hindgut colonization by sacral neural crest cells. Dev. Biol. 313, 279–92 (2008). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHirschsprung's disease is significantly more prevalent in people with Down syndrome.
“Interestingly, loss-of-function mutations in RET cause Hirschsprung’s disease86, which is significantly more prevalent in people with DS87.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [87] Friedmacher, F. & Puri, P. Hirschsprung’s disease associated with Down syndrome: a meta-analysis of incidence, functional outcomes and mortality. Pediatr. Surg. Int. 29, 937–46 (2013). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMyeloproliferative disorders leading to leukemia and hereditary skeletal/craniofacial abnormalities are common in Down syndrome.
“Gain-of-function mutations in FGFR1 are associated with myeloproliferative disorders leading to leukemia, as well as hereditary conditions leading to skeletal and craniofacial abnormalities, both of which are common in DS78–80.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [78] Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Linhardt, R. J. & Mohammadi, M. Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. Hum. Mol. Genet. 13, 69–78 (2004). source
- cites [79] Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat. Genet. 8, 269–274 (1994). source
- cites [80] Jackson, C. C., Medeiros, L. J. & Miranda, R. N. 8p11 myeloproliferative syndrome: a review. Hum. Pathol. 41, 461–76 (2010). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataEach sample in the IgE ELISA was assayed in duplicate.
“Each sample was assayed in duplicate and absolute values determined using linear regression analysis with standard curves.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNTRK3 is a transmembrane receptor for Neurotrophin 3.
“For example, NTRK2 and NTRK3, the transmembrane receptors for the Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin 3, respectively82, are clearly downregulated in the plasma of people with DS (Fig. 4k,l).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [82] Meldolesi, J. Neurotrophin Receptors in the Pathogenesis, Diagnosis and Therapy of Neurodegenerative Diseases. Pharmacol. Res. https://doi.org/10.1016/j.phrs.2017.04.024 (2017). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGain-of-function mutations in FGFR1 are associated with hereditary conditions leading to skeletal and craniofacial abnormalities.
“Gain-of-function mutations in FGFR1 are associated with myeloproliferative disorders leading to leukemia, as well as hereditary conditions leading to skeletal and craniofacial abnormalities, both of which are common in DS78–80.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [78] Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Linhardt, R. J. & Mohammadi, M. Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. Hum. Mol. Genet. 13, 69–78 (2004). source
- cites [79] Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat. Genet. 8, 269–274 (1994). source
- cites [80] Jackson, C. C., Medeiros, L. J. & Miranda, R. N. 8p11 myeloproliferative syndrome: a review. Hum. Pathol. 41, 461–76 (2010). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMultiple hypothesis correction was performed using the Benjamini-Hochberg method for the smaller Validation Studies.
“Multiple hypothesis correction was performed using the Bonferroni method for the larger discovery study or the Benjamini-Hochberg method for the smaller Validation Studies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLoss-of-function mutations in RET cause Hirschsprung's disease.
“Interestingly, loss-of-function mutations in RET cause Hirschsprung’s disease86, which is significantly more prevalent in people with DS87.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [86] Tomuschat, C. & Puri, P. RET gene is a major risk factor for Hirschsprung’s disease: a meta-analysis. Pediatr. Surg. Int. 31, 701–10 (2015). source
Classified as probably not a substantial claim.
Study design and conductnone givenMultiple hypothesis correction was performed using the Bonferroni method for the larger discovery study.
“Multiple hypothesis correction was performed using the Bonferroni method for the larger discovery study or the Benjamini-Hochberg method for the smaller Validation Studies.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Trisomy 21 causes Down syndrome.
“Trisomy 21 (T21) causes Down syndrome (DS)”
The paper relies on this without support.
The mechanisms by which trisomy 21 produces the different disease spectrum observed in people with Down syndrome are unknown.
“the mechanisms by which T21 produces the different disease spectrum observed in people with DS are unknown”
The paper relies on this without support.
The impact of trisomy 21 on systemic signaling cascades in living individuals with Down syndrome is undefined.
“the impact of T21 on systemic signaling cascades in living individuals with DS is undefined”
The paper relies on this without support.
The four interferon receptors encoded on chromosome 21 are overexpressed in trisomy 21.
“consistent with overexpression of the four interferon receptors encoded on chromosome 21”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation, which could exacerbate the neuroinflammatory response.
“Notably, both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation,30,31,32,33,34,35,36,37,38,39,40 that could exacerbate the neuroinflammatory response.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [31]
The Results and Discussion report a pro-inflammatory circulating proteome in people with Down syndrome, with multiple ties to interferon signaling; the Final Remarks describe profound immune dysregulation. The paper does not establish constitutive interferon hyperactivation or chronic inflammation in Down syndrome mouse models. The clause about a possible exacerbation of neuroinflammation follows the citation cluster and is not attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPeople with DS present increased IFN signaling likely driven by triplication of four of the six IFN receptors encoded on HSA21, rather than by massive elevation of IFN ligands, and this has been associated with chronic immune dysregulation.
“people with DS present an increased IFN signaling likely driven by triplication of four of the six IFN receptors encoded on HSA21,36 rather than by massive elevation of the IFN ligands themselves as seen in interferonopathies,80 and this has been associated with chronic immune dysregulation.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [31]
The Results and Discussion report a pro-inflammatory proteome in people with DS with ties to interferon signaling, and the Final Remarks describe profound immune dysregulation. The paper also discusses overexpression of four chromosome-21 interferon receptors, but our copy does not establish the claimed contrast with a massive elevation of interferon ligands. That ligand comparison is not supported by this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA study of the circulating proteome did not test for differences in DYRK1A protein expression specifically but did find differences in protein expression in general between males and females.
“A study of the circulating proteome did not test for differences in DYRK1A protein expression specifically but did find differences in protein expression in general between males and females (Sullivan et al., 2017).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Sullivan et al., 2017
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Down Syndrome Is Associated with Elevated Risk of Celiac Disease: A Nationwide Case-Control Study
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A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70
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Validation of a blood protein signature for non-small cell lung cancer
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An Updated Survey on Skin Conditions in Down Syndrome
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Early complement components in Alzheimer's disease brains
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Genetic progress towards the molecular basis of autoimmunity
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Is FCRL3 a New General Autoimmunity Gene?
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Altered serum pro-inflammatory cytokines in children with Down's syndrome
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RET gene is a major risk factor for Hirschsprung’s disease: a meta-analysis
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Circulating Serum Trefoil Factor 3 (TFF3) Is Dramatically Increased in Chronic Kidney Disease
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Phenotypic and dermatological manifestations in Down Syndrome
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The receptor tyrosine kinase RET regulates hindgut colonization by sacral neural crest cells
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Neurotrophin receptors in the pathogenesis, diagnosis and therapy of neurodegenerative diseases
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Targeting the complement cascade: novel treatments coming down the pike
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Revisiting Down syndrome from the ENT perspective: review of literature and recommendations
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SPAP2, an Ig family receptor containing both ITIMs and ITAMs
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Immune Complex Pathophysiology
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Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency
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Elevation of proinflammatory cytokines in patients with Aicardi-Goutières syndrome
Takanohashi, A., Prust, M., Wang, J., Gordish-Dressman, H., Bloom, M., Rice, G. I., Schmidt, J. L., Crow, Y. J., Lebon, P., Kuijpers, T. W., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e3182872694 · Cited by 25 · see citing works
High positivity of anti-CCP antibodies in patients with Down syndrome
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Chronic kidney disease in older people with intellectual disability: Results of the HA-ID study
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Is arthritis more common in children with Down syndrome?
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AnaLysis of Expression on human chromosome 21, ALE-HSA21: a pilot integrated web resource
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Atorvastatin reduced soluble receptors of TNF-alpha in systemic lupus erythematosus.
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Effects of Alpha-Interferon on Serum Beta-2-Microglobulin
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Complement activation by the amyloid proteins Aβ peptide and β<sub>2</sub>-microglobulin
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“Discovery Study - Plasma samples from children with DS (120) and healthy controls (52), in some cases siblings of T21-affected individuals, were provided by the Sie Center for Down Syndrome, a coordinated care clinic at the Children’s Hospital Colorado that focuses specifically Figure 4.”
MethodCalvo, F., Jabrane, N., Faille, A., Gauville, C., Cremoux, P. D., Lagier, G., Abita, J. P., & Lechat, P. (1987) · International Journal of Immunopharmacology · doi:10.1016/0192-0561(87)90020-8 · Cited by 3 · see citing works
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Undulating changes in human plasma proteome profiles across the lifespan
Lehallier, B., Gate, D., Schaum, N., Nanasi, T., Lee, S. E., Yousef, H., Moran Losada, P., Berdnik, D., Keller, A., Verghese, J., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0673-2 · Cited by 981 · see citing works
Alzheimer's disease associated with Down syndrome: a genetic form of dementia
Fortea, J., Zaman, S. H., Hartley, S., Rafii, M. S., Head, E., & Carmona-Iragui, M. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00245-3 · Cited by 357 · see citing works
Bradley, K. C., Finsterbusch, K., Schnepf, D., Crotta, S., Llorian, M., Davidson, S., Fuchs, S. Y., Staeheli, P., & Wack, A. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.105 · Cited by 313 · see citing works
“Changes in blood proteomics of Down syndrome individuals resemble those found in type I interferonopathies and other autoinflammatory conditions (Sullivan et al., 2017).”
BackgroundEmergent high fatality lung disease in systemic juvenile arthritis
Saper, V. E., Chen, G., Deutsch, G. H., Guillerman, R. P., Birgmeier, J. A., Jagadeesh, K. A., Canna, S., Schulert, G. S., Deterding, R. R., Xu, J., et al. (2019) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2019-216040 · Cited by 224 · see citing works
“64 An association of T21 and PAP in the context of haematological malignancy also has been reported.”
Non-IgE-Mediated Gastrointestinal Food Allergies in Children: An Update
Labrosse, R., Graham, F. J., & Caubet, J. (2020) · Nutrients · doi:10.3390/nu12072086 · Cited by 179 · see citing works
“Conversely, regulatory T cells (Tregs) and IL-10 secretion may play a role in the acquisition of tolerance [37,49,51].”
BackgroundAraya, P., Waugh, K. A., Sullivan, K. D., Núñez, N. G., Roselli, E., Smith, K. P., Granrath, R. E., Rachubinski, A. L., Enriquez Estrada, B., Butcher, E. T., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908129116 · Cited by 179 · see citing works
“1073/pnas.1908129116/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1908129116 PNAS Latest Articles | 1 of 11 IM M U N O LO G Y A N D IN FL A M M A TI O N D ow nl oa de d by g ue st o n M ar ch 1 0, 2 02 0 cytokines, such as IL-6, TNF-α, MCP-1, and IL-22 (10).”
BackgroundMethodInfluentialSelf-citationTang, J., Fu, J., Wang, Y., Li, B., Li, Y., Yang, Q., Cui, X., Hong, J., Li, X., Chen, Y., et al. (2018) · Briefings in Bioinformatics · doi:10.1093/bib/bby127 · Cited by 168 · see citing works
“These benchmark data sets included PXD001064 [123] (72 monozygotic & 44 dizygotic twins blood samples), PXD003972 [124] (20 wild-type & 20 GRB2 knock-in mice), PXD004880 [125] (18 ‘Down syndrome’ patients & 18 healthy individuals plasma samples), PXD000672 [126] (18 tumorous & 18 non-tumorous kidney tissue biopsies),…”
Blood and immune development in human fetal bone marrow and Down syndrome
Jardine, L., Webb, S., Goh, I., Londoño, M. Q., Reynolds, G., Mather, M. W., Olabi, B., Stephenson, E., Botting, R. A., Horsfall, D., et al. (2021) · Nature · doi:10.1038/s41586-021-03929-x · Cited by 163 · see citing works
Waugh, K. A., Araya, P., Pandey, A., Jordan, K. R., Smith, K. P., Granrath, R. E., Khanal, S., Butcher, E. T., Estrada, B. E., Rachubinski, A. L., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.038 · Cited by 150 · see citing works
“For example, our plasma proteomics analysis found many cytokines commonly elevated in DS (Sullivan et al., 2017) and SLE (Idborg et al., 2018), such as IL-10, CXCL10, IL-6, TNF-a , MCP-1, CRP, VEGFA, IL-15, IL-8, and eotaxin.”
BackgroundInfluentialSelf-citationImmune Dysregulation in Children With Down Syndrome
Huggard, D., Doherty, D. G., & Molloy, E. J. (2020) · Frontiers in Pediatrics · doi:10.3389/fped.2020.00073 · Cited by 144 · see citing works
“(74) examined proteomics of blood samples from 263 people, 165 of whom had DS, and pointed toward an overall deficiency of complement factors or hypocomplementia as C1QA, C1R, C3 and C6 were downregulated.”
BackgroundTrisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
Powers, R. K., Culp‐Hill, R., Ludwig, M. P., Smith, K. P., Waugh, K. A., Minter, R., Tuttle, K. D., Lewis, H. C., Rachubinski, A. L., Granrath, R. E., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12739-9 · Cited by 139 · see citing works
Self-citationEvolution of neuroinflammation across the lifespan of individuals with Down syndrome
Flores-Aguilar, L., Iulita, M. F., Kovecses, O., Torres, M. D., Levi, S. M., Zhang, Y., Askenazi, M., Wisniewski, T., Busciglio, J., & Cuello, A. C. (2020) · Brain · doi:10.1093/brain/awaa326 · Cited by 138 · see citing works
“heightened inflammatory systemic profile (Licastro et al., 2005; Iulita et al., 2016; Sullivan et al., 2017; Waugh et al., 2019; Huggard et al., 2020; Weber et al., 2020), makes this”
BackgroundDown Syndrome and COVID-19: A Perfect Storm?
Espinosa, J. M. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100019 · Cited by 130 · see citing works
“This overexpression is obvious not 2 Cell Reports Medicine 1, May 19, 2020 only at themRNA level inmultiple immune and non-immune cell types (Figure 1)46 but also at the cell surface level, as demonstrated by a recent mass cytometry analysis of 100 different immune cell types.21 Second, immune and non-immune cell type…”
BackgroundSelf-citationAziz, N. M., Guedj, F., Pennings, J. L. A., Olmos-Serrano, J. L., Siegel, A., Haydar, T. F., & Bianchi, D. W. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.031013 · Cited by 118 · see citing works
“This finding, which is confirmed by both GSEA and DAVID analyses, correlates well with recent work assessing proteomic changes in blood samples from people with DS (Sullivan et al., 2017) and another study analyzing interferon-related gene networks in postnatal Ts1Cje brains (Ling et al., 2014).”
ResultWaugh, K. A., Minter, R., Baxter, J., Chi, C., Galbraith, M. D., Tuttle, K. D., Eduthan, N. P., Kinning, K. T., Andrysik, Z., Araya, P., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01399-7 · Cited by 117 · see citing works
Self-citationLi, F., Zhou, Y., Zhang, Y., Yin, J., Qiu, Y., Gao, J., & Zhu, F. (2022) · Briefings in Bioinformatics · doi:10.1093/bib/bbac040 · Cited by 106 · see citing works
Individuals with Down syndrome hospitalized with COVID-19 have more severe disease
Malle, L., Gao, C., Hur, C., Truong, H., Bouvier, N. M., Percha, B., Kong, X., & Bogunovic, D. (2020) · Genetics in Medicine · doi:10.1038/s41436-020-01004-w · Cited by 99 · see citing works
“Interestingly, the variance of IL-6 concentrations was greater in the DS group, which may indicate that a subset of patients with DS had higher levels of soluble inflammatory markers, as previously reported for patients with DS in the basal state.(8,9) Further studies are required to determine whether these cytokines…”
Opportunities, barriers, and recommendations in Down syndrome research
Hendrix, J. A., Amon, A., Abbeduto, L., Agiovlasitis, S., Alsaied, T., Anderson, H. A., Bain, L. J., Baumer, N., Bhattacharyya, A., Bogunovic, D., et al. (2021) · Translational Science of Rare Diseases · doi:10.3233/trd-200090 · Cited by 100 · see citing works
“Underlying the diverse spectrum of phenotypes seen in people with DS is an extra copy of chromosome 21 (Chr21), or trisomy 21 (T21), which results in overexpression of many genes and changes in the proteome [2].”
Down syndrome: Neurobiological alterations and therapeutic targets
Vacca, R. A., Bawari, S., Valenti, D., Tewari, D., Nabavi, S. F., Shirooie, S., Sah, A. N., Volpicella, M., Braidy, N., & Nabavi, S. M. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.01.001 · Cited by 90 · see citing works
Galbraith, M. D., Rachubinski, A. L., Smith, K. P., Araya, P., Waugh, K. A., Enriquez-Estrada, B., Worek, K., Granrath, R. E., Kinning, K. T., Paul Eduthan, N., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg6218 · Cited by 88 · see citing works
“…response across multiple cell types ( 9 , 10 ), concurrent with changes in the circulating proteome indicative of chronic autoinflammation ( 11 ), global immune remodeling associated with hypersensitivity to type I IFN stimulation and elevated Janus kinase/signal transducer and activator…”
Self-citationLaurent, A. P., Kotecha, R. S., & Malinge, S. (2020) · Leukemia · doi:10.1038/s41375-020-0854-5 · Cited by 82 · see citing works
“During adulthood, individuals with DS display a perturbed immune system, consistent with a state of chronic inflammation [111, 112].”
BackgroundDown syndrome, accelerated aging and immunosenescence
Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020) · Seminars in Immunopathology · doi:10.1007/s00281-020-00804-1 · Cited by 80 · see citing works
β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function
Gao, Y., Hong, Y., Huang, L., Zheng, S., Zhang, H., Wang, S., Yao, Y., Zhao, Y., Zhu, L., Xu, Q., et al. (2023) · Cell · doi:10.1016/j.cell.2023.01.021 · Cited by 75 · see citing works
Fu, J., Tang, J., Wang, Y., Cui, X., Yang, Q., Hong, J., Li, X., Li, S., Chen, Y., Xue, W., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00681 · Cited by 76 · see citing works
Yim, A., Koti, P. S., Bonnard, A., Marchianò, F., Dürrbaum, M., Garcı́a-Pérez, C., Villaveces, J. M., Gamal, S., Cardone, G., Perocchi, F., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1128 · Cited by 75 · see citing works
JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome
Tuttle, K. D., Waugh, K. A., Araya, P., Minter, R., Orlicky, D. J., Ludwig, M., Andrysik, Z., Burchill, M. A., Tamburini, B. A. J., Sempeck, C., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108407 · Cited by 72 · see citing works
“Expansion of this study to characterize the proteome, metabolome, and immune cell repertoire of people with DS demonstrated that T21 causes (1) changes in the circulating proteome, indicative of chronic autoinflammation with clear upregulation of IFN-inducible cytokines (Sullivan et al., 2017); (2) activation of the I…”
BackgroundSelf-citationHaas, O. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03136 · Cited by 70 · see citing works
“Interferons are normally produced by cells in response to viral or bacterial infections, regulate genes in neighboring cells and shut down the production of proteins, which activate the immune system and thereby prevent the spread of the infection (250, 251).”
BackgroundBinstadt, B. A., & Nigrovic, P. A. (2022) · Arthritis & Rheumatology · doi:10.1002/art.42137 · Cited by 69 · see citing works
“For example, trisomy 21 is associated with up-regulation of IFNγ and its receptor (61), expansion of Th1 and Th1/Th17 T cells (62), and higher levels of other proinflammatory cytokines including TNF and IL-6 (63).”
BackgroundDown Syndrome Disintegrative Disorder: A Clinical Regression Syndrome of Increasing Importance
Rosso, M., Fremion, E., Santoro, S. L., et al. (2020) · PEDIATRICS · doi:10.1542/peds.2019-2939 · Cited by 69 · see citing works
“These findings may be understood as a consequence of DS, which is generally associated with high serum levels of proinflammatory cytokines, high rates of complement protein consumption, and various other forms of immune dysregulation.(16) As”
BackgroundDeep immune phenotyping reveals similarities between aging, Down syndrome, and autoimmunity
Lambert, K., Moo, K. G., Arnett, A., Goel, G., Hu, A., Flynn, K. J., Speake, C., Wiedeman, A. E., Gersuk, V. H., Linsley, P. S., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abi4888 · Cited by 64 · see citing works
“First, our findings suggest that naïve CD4+ T cells in DS are hyperactivated, in part because of elevated IL-6 (7).”
InfluentialIllouz, T., Biragyn, A., Iulita, M. F., Aguilar, L. F., Dierssen, M., Toma, I. D., Antonarakis, S. E., Yu, E. Y., Hérault, Y., Potier, M., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.621440 · Cited by 65 · see citing works
“Indeed, Sullivan and coworkers reported that the levels of IgE antibodies, which mediate allergic responses (150), are reduced in individuals with DS (110).”
InfluentialChiang, J.-C., Jiang, J., Newburger, P. E., & Lawrence, J. B. (2018) · Nature Communications · doi:10.1038/s41467-018-07630-y · Cited by 55 · see citing works
Seroconversion stages COVID19 into distinct pathophysiological states
Galbraith, M. D., Kinning, K. T., Sullivan, K. D., Baxter, R. M., Araya, P., Jordan, K. R., Russell, S., Smith, K. P., Granrath, R. E., Shaw, J. R., et al. (2021) · eLife · doi:10.7554/elife.65508 · Cited by 54 · see citing works
Self-citationAicardi goutières syndrome is associated with pulmonary hypertension
Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A. R., Cross, Z., Galambos, C., Helman, G., Kanaan, U. B., et al. (2018) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2018.09.004 · Cited by 53 · see citing works
Ebstein, F., Küry, S., Papendorf, J. J., & Krüger, E. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.733012 · Cited by 51 · see citing works
Janus kinase inhibition in Down syndrome: 2 cases of therapeutic benefit for alopecia areata
Rachubinski, A. L., Estrada, B. E., Norris, D., Dunnick, C. A., Boldrick, J. C., & Espinosa, J. M. (2019) · JAAD Case Reports · doi:10.1016/j.jdcr.2019.02.007 · Cited by 51 · see citing works
“Trisomy 21 (T21), the genetic cause of DS, consistently activates the interferon (IFN) response in multiple cell types, causing hypersensitivity to IFN ligands, hyperactivation of downstream Janus kinase/signal transducer activator of transcription (JAK/STAT) signaling, significant overexpression of IFN-stimulated gen…”
BackgroundSelf-citationPulmonary hypertension in children with Down syndrome
Bush, D. S., Galambos, C., & Ivy, D. D. (2020) · Pediatric Pulmonology · doi:10.1002/ppul.24687 · Cited by 51 · see citing works
“5 times as high as disomic controls.(17,48) Upregulated interferon activity can negatively regulate the NO production through inhibition of NO synthase and contributes to the upregulation of ET‐1.”
BackgroundIGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome
Araya, P., Kinning, K. T., Coughlan, C., Smith, K. P., Granrath, R. E., Enriquez-Estrada, B. A., Worek, K., Sullivan, K. D., Rachubinski, A. L., Wolter-Warmerdam, K., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111883 · Cited by 50 · see citing works
Self-citationImmunotherapy in selected patients with Down syndrome disintegrative disorder
Cardinale, K., Bocharnikov, A., Hart, S. J., et al. (2018) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.14127 · Cited by 50 · see citing works
“Down syndrome is associated with increased rates of autoimmune disease and a recent proteomics study found that people with Down syndrome have elevated levels of several proinflammatory cytokines and increased complement consumption.(4) In our experience, medications aimed toward symptomatic management of patients wit…”
BackgroundLung disease manifestations in Down syndrome
Danopoulos, S., Deutsch, G. H., Dumortier, C., Mariani, T. J., & Alam, D. A. (2021) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00434.2020 · Cited by 49 · see citing works
Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome
Ferrari, M., & Stagi, S. (2021) · Genes · doi:10.3390/genes12020268 · Cited by 46 · see citing works
Khosroshahi, L. M., Parhizkar, F., Kachalaki, S., Aghebati‐Maleki, A., & Maleki, L. A. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107935 · Cited by 43 · see citing works
Accelerated epigenetic aging in newborns with Down syndrome
Xu, K., Li, S., Muskens, I. S., Elliott, N., Myint, S. S., Pandey, P., Hansen, H. M., Morimoto, L. M., Kang, A. Y., Ma, X., et al. (2022) · Aging Cell · doi:10.1111/acel.13652 · Cited by 42 · see citing works
“…et al., 2014; Muskens et al., 2021) and are potentially linked to the upregulation of inflammatory processes in individuals with DS (Huggard et al., 2020; Sullivan et al., 2017), which is further supported by the differences in hematopoiesis revealed by our cell- type deconvolution analyses.”
ResultBreaking down the cellular responses to type I interferon neurotoxicity in the brain
Viengkhou, B., & Hofer, M. J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1110593 · Cited by 40 · see citing works
Ahmed, M. M., Johnson, N. R., Boyd, T. D., Coughlan, C. M., Chial, H. J., & Potter, H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.718426 · Cited by 41 · see citing works
The immune system in Down Syndrome: Autoimmunity and severe infections
Ramba, M., & Bogunovic, D. (2023) · Immunological Reviews · doi:10.1111/imr.13296 · Cited by 42 · see citing works
“…downregulation of multiple complement proteins, including C1R, C1QA, C3, and C6, in the circulating proteome of children and young adults with DS. 25 However, a recent study reported significantly higher levels of complement proteins (C1q, C3, and C9), regulators (clusterin, factor H, C1…”
BackgroundDown syndrome and type I interferon: not so simple
Malle, L., & Bogunovic, D. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.06.006 · Cited by 38 · see citing works
Consequences of chromosome gain: A new view on trisomy syndromes
Krivega, M., Stiefel, C. M., & Štorchová, Z. (2022) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2022.10.014 · Cited by 40 · see citing works
Ebstein, F., Küry, S., Most, V., Rosenfelt, C., Scott-Boyer, M.-P., van Woerden, G. M., Besnard, T., Papendorf, J. J., Studencka-Turski, M., Wang, T., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abo3189 · Cited by 36 · see citing works
“This is particularly well exemplified in patients with Down syndrome who, similar to patients with NDD/ID and PSMC3 dominant variants, exhibit a constitutive activation of type I IFN signaling (79, 80).”
BackgroundVillani, E. R., Carfì, A., Paola, A. D., Palmieri, L., Donfrancesco, C., Noce, C. L., Taruscio, D., Meli, P., Salerno, P., Kodra, Y., et al. (2020) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61867 · Cited by 37 · see citing works
“Moreover, DS is also characterized by high levels of chronic inflammation markers (Sullivan et al., 2017) and this condition too was shown to play a role in the prognosis of CoVID-19 (Tay, Poh, Rénia, MacAry, & Ng, 2020).”
BackgroundJAK inhibition decreases the autoimmune burden in Down syndrome
Rachubinski, A. L., Wallace, E., Gurnee, E., Enriquez-Estrada, B. A., Worek, K. R., Smith, K. P., Araya, P., Waugh, K. A., Granrath, R. E., Britton, E., et al. (2024) · eLife · doi:10.7554/elife.99323 · Cited by 32 · see citing works
Self-citationDown Syndrome patients with COVID-19 pneumonia: A high-risk category for unfavourable outcome
Vita, S., Bari, V. D., Corpolongo, A., Goletti, D., Espinosa, J. M., Petracca, S., Palmieri, F., Nicastri, E., Abbonizio, Agrati, C., et al. (2020) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2020.11.188 · Cited by 31 · see citing works
Self-citationChi, C., Knight, W. E., Riching, A. S., Zhang, Z., Tatavosian, R., Zhuang, Y., Moldovan, R., Rachubinski, A. L., Gao, D., Xu, H., et al. (2023) · iScience · doi:10.1016/j.isci.2023.107012 · Cited by 30 · see citing works
“The development of cardiovascular, neurological, and musculoskeletal systems is particularly affected in individuals with DS.1–3 TheWnt pathway was dramatically downregulated in the entire Dp16 embryo at E9.”
BackgroundInfluentialSelf-citationFood protein‐induced enterocolitis syndrome
Caubet, J., Cianferoni, A., Groetch, M., et al. (2019) · Clinical & Experimental Allergy · doi:10.1111/cea.13415 · Cited by 31 · see citing works
Dumortier, L., & Bricout, V. (2019) · Neuroscience and Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.018 · Cited by 27 · see citing works
The Underlying Relationship between Keratoconus and Down Syndrome
Akoto, T., Li, J. J., Estes, A. J., Karamichos, D., & Liu, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810796 · Cited by 31 · see citing works
Dysregulated systemic metabolism in a Down syndrome mouse model
Sarver, D. C., Xu, C., Vélez, L. M., Aja, S. M., Jaffe, A. E., Seldin, M. M., Reeves, R. H., & Wong, G. W. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101666 · Cited by 31 · see citing works
“At the tissue level, MCP-1 protein levels trended higher (P ¼ 0.051) in iWAT, but IL-1b, IL-6, and TNF-a levels in gWAT and iWAT were not different between genotypes (Figure S11).”
BackgroundInfluentialPanagaki, T., Pecze, L., Randi, E. B., Nieminen, A. I., & Szabó, C. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102416 · Cited by 30 · see citing works
“However, a significant number of the affected proteins were located on other chromosomes, in line with prior observations [40,41].”
ResultComplement dysregulation and Alzheimer's disease in Down syndrome
Veteleanu, A., Pape, S. E., Davies, K., Kodosaki, E., Hye, A., Zelek, W. M., Strydom, A., & Morgan, B. P. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12799 · Cited by 29 · see citing works
Papendorf, J. J., Krüger, E., & Ebstein, F. (2022) · Cells · doi:10.3390/cells11091422 · Cited by 32 · see citing works
Lung Involvement in Systemic Juvenile Idiopathic Arthritis: A Narrative Review
Petrongari, D., Filippo, P. D., Misticoni, F., Basile, G., Pillo, S. D., Chiarelli, F., & Attanasi, M. (2022) · Diagnostics · doi:10.3390/diagnostics12123095 · Cited by 28 · see citing works
Donovan, M. G., Eduthan, N. P., Smith, K. P., Britton, E. C., Lyford, H. R., Araya, P., Granrath, R. E., Waugh, K. A., Estrada, B. A. E., Rachubinski, A. L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49781-1 · Cited by 28 · see citing works
“2”
Self-citationProteomics: Clinical and research applications in respiratory diseases
Norman, K. C., Moore, B. B., Arnold, K. B., & O’Dwyer, D. N. (2018) · Respirology · doi:10.1111/resp.13383 · Cited by 29 · see citing works
Ahmed, M. M., Wang, A. C., Elos, M. T., Chial, H. J., Sillau, S., Solano, D. A., Coughlan, C. M., Aghili, L., Anton, P. E., Markham, N. E., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105694 · Cited by 30 · see citing works
“For example, analyses of a selected proteome in both plasma and brain tissue samples from people with DS have revealed dysregulation of inflammatory protein expression, such as striking increases in several pro-inflammatory cytokines and decreases in numerous complement cascade components (24-26).”
BackgroundSelf-citationMartini, A. C., Gross, T. J., Head, E., & Mapstone, M. E. (2022) · Neuron · doi:10.1016/j.neuron.2022.04.001 · Cited by 26 · see citing works
Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype
Isidor, B., Ebstein, F., Hurst, A., Vincent, M., Bader, I., Rudy, N. L., Cogne, B., Mayr, J., Brehm, A., Bupp, C., et al. (2022) · Genetics in Medicine · doi:10.1016/j.gim.2021.09.005 · Cited by 24 · see citing works
Weber, G. E., Koenig, K. A., Khrestian, M., Shao, Y. Y., Tuason, E. D., Gramm, M., Lal, D., Leverenz, J. B., & Bekris, L. M. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901166 · Cited by 26 · see citing works
“another report describes increased IL-6, VEGF-A, MCP-1, IL-22, and TNF-a in adults aged 20–65 with DS (56).”
BackgroundHart, S. J., Worley, G., Kishnani, P. S., & Mater, H. V. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.621637 · Cited by 25 · see citing works
Petersen, M. E., Zhang, F., Schupf, N., Krinsky‐McHale, S. J., Hall, J. R., Mapstone, M. E., Cheema, A. K., Silverman, W. P., Lott, I. T., Rafii, M. S., et al. (2020) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12039 · Cited by 23 · see citing works
Jones, J. T., Smith, C. A., Becker, M. L., Lovell, D. J., & for the CARRA Registry Investigators (2020) · Arthritis Care & Research · doi:10.1002/acr.24418 · Cited by 21 · see citing works
Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder
Santoro, J. D., Spinazzi, N. A., Filipink, R. A., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02579-z · Cited by 21 · see citing works
Detection of iron deficiency in children with Down syndrome
Hart, S. J., Zimmerman, K. O., Linardic, C. M., Cannon, S., Pastore, A., Patsiogiannis, V., Rossi, P., Santoro, S. L., Skotko, B. G., Torres, A., et al. (2019) · Genetics in Medicine · doi:10.1038/s41436-019-0637-4 · Cited by 21 · see citing works
Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome
Chen, X., Xing, Z., Chen, Q.-D., Salvi, R., Zhang, X., Tycko, B., Mobley, W. C., & Yu, Y. E. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.700280 · Cited by 22 · see citing works
Down syndrome: insights into autoimmune mechanisms
Khor, B., & Buckner, J. H. (2023) · Nature Reviews Rheumatology · doi:10.1038/s41584-023-00970-0 · Cited by 19 · see citing works
Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study
Fernández, M., de Coo, A., Quintela, I., García, E. V., Freitas, M. D., Posse, J. L., Dios, P. D., Blanco, J., Carracedo, Á., & Cruz, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126274 · Cited by 18 · see citing works
“Based on the overexpression of IFN receptors encoded in chromosome 21, it has been suggested that DS could be understood as an interferonopathy that causes chronic immune dysregulation [49].”
BackgroundPorras, A. R., Bramble, M. S., Mosema, K., et al. (2021) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2021.104267 · Cited by 17 · see citing works
Down Syndrome-Associated Arthritis (DA): Diagnostic and Management Challenges
Jones, J. T., Kitchen, J., & Talib, N. (2022) · Pediatric Health Medicine and Therapeutics · doi:10.2147/phmt.s282646 · Cited by 17 · see citing works
Hemophagocytic lymphohistocytosis in trisomy 21: successful treatment with interferon inhibition
Guild, A., Fritch, J., Patel, S. A., Reinhardt, A., & Acquazzino, M. A. (2022) · Pediatric Rheumatology · doi:10.1186/s12969-022-00764-w · Cited by 17 · see citing works
“Given trisomy 21 has elevated IFN levels [4–6], its proteome has multiple ties to IFN signaling [7], and many of the changes are similar to those observed in type I interferonopathies [10], it is reasonable to think of trisomy 21 similarly to an interferonopathy [8, 9, 11].”
BackgroundMortimer, G., & Gillespie, K. M. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01318-8 · Cited by 17 · see citing works
JAK inhibition in Down Syndrome Regression Disorder
Rachubinski, A. L., Patel, L., Sannar, E. M., Kammeyer, R., Sanders, J. S., Estrada, B. A. E., Worek, K. R., Fidler, D. J., Santoro, J. D., & Espinosa, J. M. (2024) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2024.578442 · Cited by 16 · see citing works
“Within the general DS population, hyperactivation of the IFN pathway and downstream JAK/STAT signaling has been involved as a driver of many of the clinical, developmental, and cognitive impacts of DS (Sullivan et al., 2016; Sullivan et al., 2017; Galbraith et al., 2023; Waugh et al., 2023).”
Self-citationTherapeutics for mitochondrial dysfunction-linked diseases in Down syndrome
Ganguly, B. B., & Kadam, N. N. (2022) · Mitochondrion · doi:10.1016/j.mito.2022.11.003 · Cited by 18 · see citing works
Food protein-induced enterocolitis syndrome: epidemiology and comorbidities
Baker, M. G., & Nowak-Wegrzyn, A. H. (2020) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000615 · Cited by 16 · see citing works
Buonaguro, E. F., & Bertelli, M. O. (2020) · Advances in Mental Health and Intellectual Disabilities · doi:10.1108/amhid-07-2020-0016 · Cited by 16 · see citing works
Increased risk of leukaemia in children with Down syndrome: a somatic evolutionary view
Hasaart, K., Bertrums, E. J. M., Manders, F., Goemans, B. F., & van Boxtel, R. (2021) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2021.6 · Cited by 16 · see citing works
“Indeed, inflammatory factors related to chronic inflammation are upregulated in blood cells and plasma of children and adults with DS (Refs 115 – 118).”
Schneider, D. J., Lynch, S. A., Gelinas, A. D., Ostroff, R. M., Rohloff, J. C., Williams, P., Janjić, N., & Drolet, D. W. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-821595-1.00007-5 · Cited by 14 · see citing works
Resistance and resilience to Alzheimer's disease in Down syndrome
Boyle, R. T., Koops, E. A., Ances, B. M., Andrews, E. J., Arenaza‐Urquijo, E. M., Bejanin, A., Brickman, A. M., Buckley, R. F., Clas, G. S., Costello, E., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70151 · Cited by 15 · see citing works
“Although an exacerbated inflammatory response has been partially attributed to the triplication of a range of immune-related genes located on chr21, 93 synergism between inflammatory processes and the brain’s vasculature may contribute to the inflammatory profile in DS. 94 Magnetic resonance…”
Sukreet, S., Rafii, M. S., & Rissman, R. A. (2024) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12580 · Cited by 13 · see citing works
“212,214,215 Futurebiomarkerstudiesshouldfocusonassessingtheroleandtrajec-tory of neuroinflammatory markers throughout the lifespan of those with DS. Irrespectiveofthenatureandrobustnessofabiomarker,itisrecom-mended to develop a combination of biomarkers to predict the onset and AD prognosis in DS.”
BackgroundDonovan, M. G., Rachubinski, A. L., Smith, K. P., Araya, P., Waugh, K. A., Estrada, B. A. E., Britton, E. C., Lyford, H. R., Granrath, R. E., Schade, K. A., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114599 · Cited by 14 · see citing works
“…of potential driver genes and indicate that these phenomena are largely independent of the well-documented elevation in IFN signaling in DS. 27,30,41,44–49 Limitations of the study First, results from our cross-omics correlation analyses should be interpreted with caution and without…”
BackgroundMethodSelf-citationAtypical Inflammatory Syndrome Triggered by SARS-CoV-2 in Infants with Down Syndrome
Malle, L., Bastard, P., Martín‐Nalda, A., Carpenter, T., Bush, D. S., Patel, R. S., Colobrán, R., Soler‐Palacín, P., Casanova, J., Gans, M. D., et al. (2021) · Journal of Clinical Immunology · doi:10.1007/s10875-021-01078-4 · Cited by 14 · see citing works
DNA Methylation Analysis of Ribosomal DNA in Adults With Down Syndrome
Ravaioli, F., Zampieri, M., Morandi, L., Pirazzini, C., Pellegrini, C., Fanti, S. D., Gensous, N., Pirazzoli, G. L., Sambati, L., Ghezzo, A., et al. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.792165 · Cited by 14 · see citing works
Santoro, J. D., Jafarpour, S., Keehan, L. A., Khoshnood, M. M., Kazerooni, L., Boyd, N. K., Vogel, B. N., Nguyen, L., Manning, M. A., Nagesh, D., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-81819-8 · Cited by 13 · see citing works
“…heterogeneous cohorts 6 and has the potential to create a basis for biomarkers of disease activity in persons with DSRD. Inflammation in individuals with DS is well-established and has been linked to the triplication of genes on chromosome 21—particularly several interferon receptor genes 14–18 .”
Rubio, A. D., Hamilton, L. L., Bausch, M., Jin, M., Papetti, A. V., Jiang, P., & Yelamanchili, S. V. (2025) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-025-10181-x · Cited by 16 · see citing works
“…that proteomic analysis of plasma and brain tissue from individuals with DS revealed abnormalities in inflammatory protein expression, including increased levels of various pro-inflammatory cytokines and reduced levels of complement cascade components (Sullivan et al. 2016; Sullivan et al. 2017).”
Nucleotide metabolism, leukodystrophies, and CNS pathology
Gavazzi, F., Gonzalez, C. D., Arnold, K., Swantkowski, M., Charlton, L., Modesti, N. B., Dar, A. A., Vanderver, A. L., Bennett, M. L., & Adang, L. A. (2024) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12721 · Cited by 14 · see citing works
Nicek, A., Talib, N. J., Lovell, D. J., et al. (2020) · Pediatric Rheumatology · doi:10.1186/s12969-020-00445-6 · Cited by 13 · see citing works
Hasselbalch, H. C., Skov, V., Kjær, L., Sørensen, T. L., Ellervik, C., & Wienecke, T. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01877-3 · Cited by 13 · see citing works
“Highly intriguing, a recent study has demonstrated that trisomy 21 causes consistent global changes in the circulating proteome compatible with chronic autoinflammation [61].”
BackgroundAneuploidy, inflammation and diseases
Kirsch‐Volders, M., & Fenech, M. F. (2022) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2022.111777 · Cited by 12 · see citing works
Moni, F., Petersen, M. E., Zhang, F., Lao, P. J., Zimmerman, M. E., Gu, Y., Gutierrez, J., Rizvi, B. M., Laing, K. K., Igwe, K. C., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12627 · Cited by 12 · see citing works
Altered hepatic metabolism in Down syndrome
Dunn, L. N., Niemeyer, B. F., Eduthan, N. P., Schade, K. A., Waugh, K. A., Brown, C., Rachubinski, A. L., Timkovich, A. E., Orlicky, D. J., Galbraith, M. D., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116835 · Cited by 11 · see citing works
Self-citationShimizu, E., Goto‐Hirano, K., Motoi, Y., Arai, M., & Hattori, N. (2024) · Neurological Sciences · doi:10.1007/s10072-023-07292-9 · Cited by 11 · see citing works
“…of ADAD have indicated that overexpression of the DYRKK1A gene causes suppression of neprilysin (NEP) activity, an Aβ-degrading enzyme [6], that the DYRK1A gene increases astrocyte numbers [15] and that interferon receptors on chromosome 21 also affect the chronic immune dysregulation [16].”
Food protein-induced enteropathy: a revision for the clinician
Barni, S., Mori, F., Pecoraro, L., et al. (2024) · Frontiers in Pediatrics · doi:10.3389/fped.2024.1417391 · Cited by 11 · see citing works
- Authors
- Sullivan, K. D., Evans, D., Pandey, A., Hraha, T. H., Smith, K. P., Markham, N., Rachubinski, A. L., Wolter-Warmerdam, K., Hickey, F., Espinosa, J. M., & Blumenthal, T.
- Affiliations
- University of Colorado Anschutz (US)
- SomaLogic (United States) (US)
- Children's Hospital Colorado (US)
- University of Colorado Boulder (US)
- Corresponding author
- Espinosa, Joaquin M.
- Blumenthal, Thomas
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-11-01
- Volume
- 7
- Issue
- 1
- Pages
- 14818-14818
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5665944
- OpenAlex
- W2766826848
- Cited by
- 228
- References
- 95
- Citations by year
- 2026: 23 · 2025: 21 · 2024: 33 · 2023: 29 · 2022: 34 · 2021: 29 · 2020: 31 · 2019: 19 · 2018: 9
- FWCI
- 13.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Global Down Syndrome Foundation
- Anna and John J. Sie Foundation
- Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Anschutz Medical Campus
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- Down syndrome, circulating proteome, interferonopathies, type I interferon signaling, interferon receptor, complement system, inflammatory cytokines, immune dysregulation, growth factor signaling, immunomodulatory therapy
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Chronic Disease, Complement System Proteins, Down Syndrome, Female, Humans, Infant, Inflammation, Male, Trisomy, Cytokines, Receptors, Growth Factor, Proteome, Young Adult
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