Decrease in multiple complement protein levels is associated with the development of islet autoimmunity and type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a chronic condition caused by autoimmune destruction of the insulin-producing pancreatic β-cells. While it is known that gene-environment interactions play a key role in triggering the autoimmune process leading to T1D, the pathogenic mechanism leading to the appearance of islet autoantibodies - biomarkers of autoimmunity - is poorly understood. Here we show that disruption of the complement system precedes the detection of islet autoantibodies and persists through disease onset. Our results suggest that children who exhibit islet autoimmunity and progress to clinical T1D have lower complement protein levels relative to those who do not progress within a similar timeframe. Thus, the complement pathway, an understudied mechanistic and therapeutic target in T1D, merits increased attention for use as protein biomarkers of prediction and potentially prevention of T1D.

Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response

“…Upon closer inspection (Additional file 1 : Table S2), C4 (combining C4A and C4B observations) was the most identified protein, followed by C3 in this systematic review, which was reported to be primarily downregulated in post-seroconversion and post-diagnosis compared to controls [ 11 , 14 , 16 , 19 ]. This was further corroborated by Webb-Robertson et al, where C3 and C4 levels were consistently low in pre- and post-seroconverted subjects [ 10 ]. Interestingly, further breakdown of the disease progression by Nakayasu et.…”

“…Our literature search identified 6 papers that investigated the temporal protein abundance changes in individuals with T1D. Studies by Moulder et al [ 7 ], Fronhert et al [ 8 ], Nakayasu et al [ 9 ], and Webb-Robertson et al [ 10 ] looked at protein abundance changes at both pre-and post-seroconversion stages. In contrast, von Toerne et al and Lui et al examined the protein profile only after seroconversion [ 11 , 12 ].…”

A Composite Biomarker Signature of Type 1 Diabetes Risk Identified via Augmentation of Parallel Multi-Omics Data from a Small Cohort

“…Proteomics analyses were performed in the TEDDY/DAISY cohorts and in the small cohort of samples noted above, as previously described in detail in [74, 98] and [31], respectively. In brief, LC-MS/MS analysis in the small cohort was done on a Waters NanoAquity UPLC system with a custom packed C18 column (70 cm × 75 μm i.d., Phenomenex Jupiter, 3 μm particle size, 300 Å pore size) coupled to a Q-Exactive mass spectrometer (Thermo Fisher Scientific).…”

Protection of β cells against pro-inflammatory cytokine stress by the GDF15-ERBB2 signaling

“…GDF15 measurement was conducted on samples from the Diabetes Autoimmunity Study in the Young (DAISY) study in parallel with the analysis of complement proteins [17]. DAISY has monitored 2,547 children at increased risk for T1D, consisting of first-degree relatives of individuals with T1D and children with T1D susceptibility HLA DR-DQ genotypes [18].…”

“…Protocols approved by the Colorado Multiple Institutional Review Board and written informed consent was obtained from donors or their parents. Proteins were digested with trypsin in an Eppendorf epMotion 5075 Liquid Handler, and peptides were analyzed on an Acquity M-Class Nano UHPLC system (Waters) connected to a triple quadrupole mass spectrometry (TSQ Altis, Thermo Fisher) as previously described [17]. Data were extracted with Skyline software [19] with peak boundaries and alignment manually inspected, and submitted to quality control [16], followed by statistical analysis using a linear mixed model comparing the control group to cases prior to or after seroconversion.…”