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Relative complement deficiency predicts development of islet autoimmunity and type 1 diabetes

ABSTRACT: Complement proteins were measured using selected reaction monitoring (SRM)-based targeted proteomics.

INSTRUMENT(S): TSQ Altis

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Ernesto Nakayasu

PROVIDER: MSV000090848 | MassIVE | Tue Dec 06 11:39:00 GMT 2022

REPOSITORIES: MassIVE

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Publications

Decrease in multiple complement proteins associated with development of islet autoimmunity and type 1 diabetes.

Webb-Robertson Bobbie-Jo M BM Nakayasu Ernesto S ES Dong Fran F Waugh Kathy C KC Flores Javier E JE Bramer Lisa M LM Schepmoes Athena A AA Gao Yuqian Y Fillmore Thomas L TL Onengut-Gumuscu Suna S Frazer-Abel Ashley A Rich Stephen S SS Holers V Michael VM Metz Thomas O TO Rewers Marian J MJ

iScience 20231220 2

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 o ...[more]

PMID: 38303689

Similar Datasets

Decrease in multiple complement proteins associated with development of islet autoimmunity and type 1 diabetes.

Project description: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 time frame. 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.

| S-EPMC10831269 | biostudies-literature

Complement Factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice.

Project description:Purpose: The complement system is closely linked to the pathogenesis of age-related macular degeneration (AMD). Several complement genes are expressed in retinal pigment epithelium (RPE), and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- C57BL/6J mice was analysed by microarrays. Expression of a wide range of complement genes was compared to expression in splenocytes and in liver tissue by qRT-PCR. Results: An age-associated increased expression of complement, particularly C1q, C3 and Factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Both hepatic and splenic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions: While the connection between CFH deficiency and failure to up-regulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh-/- mouse retina that occur with age, and further suggests that deficient neuroretinal regulation of complement could represent an early event in AMD. Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- mice, 4 biological replicates in each group.

2012-10-02 | E-GEOD-38671 | biostudies-arrayexpress

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.

2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress

Complement Factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice.

2012-10-02 | GSE38671 | GEO

Identification of miRNA target genes in C. elegans by RIP-chip-SRM

Project description:RIP-chip-SRM : a New Combinatorial Large Scale Approach Identifies a Set of Translationally Regulated bantam/miR 58 Targets in C. elegans RNA binding protein immunopurification + microarray + targeted protein quantification via Selected Reaction Monitoring This SuperSeries is composed of the SubSeries listed below.

2012-03-01 | GSE32944 | GEO

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

2016-03-31 | GSE75083 | GEO

Multi-omics profiling of human pancreatic islet dysregulation from normoglycemia to type 2 diabetes

Project description:Type-2 diabetes (T2D) mellitus results from a complex interplay of genetic and environmental factors leading to deficient insulin secretion from pancreatic islet beta cells. Here, we provide a the first comprehensive study of the human islet state of metabolically profiled pancreatectomized living human donors in relationship to glycemic control integrating clinical traits with multiple in situ islet and pre-operative blood omics datasets across the glycemia continuum from non diabetic healthy to overt T2D levels. Our transcriptomics and proteomics data suggest that progressive dysregulation of islet gene expression associated with increasing glucose intolerance is a disharmonic process resembling a non-linear trajectory of mature beta cell states towards trans-differentiation. Furthermore, we identify a unique islet gene set altered already in early-onset glucose intolerance and that, which correlates well across HbA1c levels - the gold-standard in clinical monitoring. Our findings reach beyond conventional clinical thresholds and can serve as direct or indirect prognostic markers for beta cell failure.

2021-10-12 | PXD022561 | Pride

Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young.

Project description:Larger childhood body size and rapid growth have been associated with increased type 1 diabetes risk. We analysed height, weight, BMI and velocities of growth in height, weight and BMI, for association with development of islet autoimmunity (IA) and type 1 diabetes.Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased type 1 diabetes risk, based on HLA-DR, -DQ genotype or family history, for the development of IA and type 1 diabetes. IA was defined as the presence of autoantibodies to insulin, GAD or protein tyrosine phosphatase islet antigen 2 twice in succession, or autoantibody-positive on one visit and diabetic at the next consecutive visit within 1 year. Type 1 diabetes was diagnosed by a physician. Height and weight were collected starting at age 2 years. Of 1,714 DAISY children <11.5 years of age, 143 developed IA and 21 progressed to type 1 diabetes. We conducted Cox proportional hazards analysis to explore growth velocities and size measures for association with IA and type 1 diabetes development.Greater height growth velocity was associated with IA development (HR 1.63, 95% CI 1.31-2.05) and type 1 diabetes development (HR 3.34, 95% CI 1.73-6.42) for a 1 SD difference in velocity.Our study suggests that greater height growth velocity may be involved in the progression from genetic susceptibility to autoimmunity and then to type 1 diabetes in pre-pubertal children.

| S-EPMC2813468 | biostudies-literature

Characterization of molecular changes associated with complement factor B deficiency in the mouse auditory nerve

Project description:Overall goal of the study is to investigate the role of the complement system in auditory nerve development and hearing

2022-01-17 | GSE182417 | GEO

Deficiency of the complement regulatory protein CD59 accelerates the development of diabetes-induced atherosclerosis in mice.

Project description:AIMS:Clinical and experimental evidence supports a strong link between the complement system, complement regulatory proteins and the pathogenesis of diabetes vascular complications. We previously reported that the complement regulatory protein CD59 is inactivated by glycation in humans with diabetes. Our objective for this study is to assess experimentally how the deficiency of CD59 impacts the development of diabetic atherosclerosis in vivo. METHODS:We crossed mCD59 sufficient and deficient mice into the ApoE-/- background to generate mCd59ab+/+/ApoE-/- and mCd59ab-/-/ApoE-/- mice, and induced diabetes by multiple low dose injections of streptozotocin. Atherosclerosis was detected by hematoxylin and eosin (H&E) and oil red-O staining. Membrane attack complex (MAC) deposition and macrophage infiltration were detected by immunostaining. RESULTS:Diabetic mCD59 deficient (mCD59ab-/-/ApoE-/-) mice developed nearly 100% larger atherosclerotic lesion areas in the aorta (7.5%±0.6 vs 3.6%±0.7; p<0.005) and in the aortic roots (H&E: 26.2%±1.9 vs. 14.3%±1.1; p<0.005), in both cases associated with increased lipid (Oil red-O: 14.9%±1.1 vs. 7.8%±1.1; p<0.05) and MAC deposition (6.8%±0.8 vs. 3.0%±0.7; p<0.005) and macrophage infiltration (31.5%±3.7 vs. 16.4%±3.0; p<0.05) in the aortic roots as compared to their diabetic mCD59 sufficient (mCD59ab+/+/ApoE-/-) counterpart. CONCLUSIONS:The deficiency of CD59 accelerates the development of diabetic atherosclerosis.

| S-EPMC5460985 | biostudies-literature

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