Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation

In the paper

“have all been used to monitor kidney function, as their plasma levels increase upon kidney injury71”

What the sources say

• Partly supported

  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)

  cites [71] Du, T. et al. Circulating serum trefoil factor 3 (TFF3) is dramatically increased in chronic kidney disease. PLoS One 8, e80271 (2013). sourceExperimental — accuracy not yet measured

In the paper

“However, several complement subunits also play key roles in microglia-mediated synapse destruction during AD progression74–76”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  cites [76] Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–6 (2016). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [73] Schupf, N. & Sergievsky, G. H. Genetic and host factors for dementia in Down’s syndrome. Br. J. Psychiatry 180, 405–10 (2002). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [68] Ram, G. & Chinen, J. Infections and immunodeficiency in Down syndrome. Clin. Exp. Immunol. 164, 9–16 (2011). source
• Supported

  The Abstract reports that complement-depleted animals cleared less Streptococcus pneumoniae from their lungs after four hours than controls (75% versus 91%). This supports the clearance claim attached to citation 69. The Down syndrome and otitis media context is attached to citation 68, not this source. (LLM, conf=0.93)

  cites [69] Gross, G. N., Rehm, S. R. & Pierce, A. K. The effect of complement depletion on lung clearance of bacteria. J. Clin. Invest. 62, 373–8 (1978). source

In the paper

“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”

What the sources say

• Supported

  The Results sections report transcriptome analyses of four human cell types—fibroblasts, lymphoblastoids, monocytes, and T cells—from people with and without T21. They describe widespread gene-expression changes associated with T21, including differentially expressed genes distributed across the genome rather than confined to chromosome 21. (LLM, conf=0.94)

  cites [17] Sullivan, K. D. et al. Trisomy 21 consistently activates the interferon response. Elife 5, e16220 (2016). source

In the paper

“A third neurotrophin receptor required for normal GABAergic synapse development, SLITRK383, is also downregulated (Fig. 4m).”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Of note, VEGFA induction is a hallmark of inflammatory processes leading to wound healing81.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Of note, altered GABAergic signaling has been linked to the cognitive deficits caused by T21 in myriad studies (reviewed in84).”

What the sources say

• Supported

  The review’s section on pharmacological interventions to rescue cognitive deficits in Down syndrome mouse models reports that blocking GABAB signaling restored cognitive performance in Ts65Dn mice and links that signaling to cognitive impairment. Its discussion of GABA signaling in DS mouse models also describes altered GABAergic activity. This supports the citing sentence’s broad, hedged claim of a link. (LLM, conf=0.92)

  cites [84] Contestabile, A., Magara, S. & Cancedda, L. The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome. Front. Cell. Neurosci. 11, 54 (2017). source

In the paper

“only five proteins in total were differentially detected in females versus males.”

In the paper

“This group consists of 21 proteins, 18 of which are downregulated in the circulating proteome of people with DS”

In the paper

“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”

In the paper

“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)”

In the paper

“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”

In the paper

“Among the 50 proteins encoded on chr21 for which aptamers were available, 9 were significantly upregulated, and none significantly downregulated”

In the paper

“CST3, B2M, and TFF3, which are among the most significantly upregulated proteins in DS”

In the paper

“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”

In the paper

“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”

In the paper

“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).”

In the paper

“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).”

In the paper

“suggesting that chronic activation of interferon signaling could cause complement consumption”

In the paper

“In fact, hypocomplementia is a common feature of type I interferonopathies66,67”

What the sources say

• ?Not checked — no full text of the sourcecites [66] Crow, Y. J. & Manel, N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–40 (2015). source
• ?Not checked — no full text of the sourcecites [67] Pickering, M. C. & Walport, M. J. Links between complement abnormalities and systemic lupus erythematosus. Rheumatology (Oxford). 39, 133–41 (2000). source

In the paper

“In sum, these results reveal a clear pro-inflammatory signature in the circulating proteome of people with DS, with multiple ties to interferon signaling.”

In the paper

“Thus, we posit that hypocomplementia could modulate AD progression in these individuals.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [80] Jackson, C. C., Medeiros, L. J. & Miranda, R. N. 8p11 myeloproliferative syndrome: a review. Hum. Pathol. 41, 461–76 (2010). source

In the paper

“both beta amyloid deposits and soluble B2M are known to activate the classic complement cascade77”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [64] Nydegger, U. E. Immune complex pathophysiology. Ann. N. Y. Acad. Sci. 1109, 66–83 (2007). source
• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Multiple hypothesis correction was performed using the Benjamini-Hochberg method.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Interestingly, loss-of-function mutations in RET cause Hirschsprung’s disease86, which is significantly more prevalent in people with DS87.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [80] Jackson, C. C., Medeiros, L. J. & Miranda, R. N. 8p11 myeloproliferative syndrome: a review. Hum. Pathol. 41, 461–76 (2010). source

In the paper

“Each sample was assayed in duplicate and absolute values determined using linear regression analysis with standard curves.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [80] Jackson, C. C., Medeiros, L. J. & Miranda, R. N. 8p11 myeloproliferative syndrome: a review. Hum. Pathol. 41, 461–76 (2010). source

In the paper

“Multiple hypothesis correction was performed using the Bonferroni method for the larger discovery study or the Benjamini-Hochberg method for the smaller Validation Studies.”

In the paper

“Interestingly, loss-of-function mutations in RET cause Hirschsprung’s disease86, which is significantly more prevalent in people with DS87.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Multiple hypothesis correction was performed using the Bonferroni method for the larger discovery study or the Benjamini-Hochberg method for the smaller Validation Studies.”