Circulating C1q levels in health and disease, more than just a biomarker

Bovenkamp, Fleur S. van de; Dijkstra, Douwe J.; Kooten, Cees van; Gelderman, Kyra A.; Trouw, Leendert A.

doi:10.1016/j.molimm.2021.10.010

Cited by 29 publications

(16 citation statements)

References 152 publications

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“…an activity which is not shared by native low density lipoproteins. In addition to KCs as a source of circulating C1q and ApoE, activated immune cells and particularly macrophages and other cells of myeloid origin are known to produce both C1q and ApoE upon activation ( 21 , 22 ) at sites of acute or chronic tissue inflammation ( 23 ). While the source of the large majority of circulating ApoE is derived from liver hepatocytes ( 22 , 24 ), myeloid cells may also be a major source of both C1q and ApoE locally as shown by bone marrow transplantation studies in mice ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease

Habenicht

Wang²,

Zhang³

et al. 2022

Front. Immunol.

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We recently identified a high-affinity C1q-ApoE complex in human artery atherosclerotic intima lesions and in human amyloid plaques of Alzheimer’s Disease brains defining a common pathogenetic pathway of two diverse diseases, i.e. atherosclerosis and dementia. C1q is the initiating and controlling protein of the classical complement cascade (CCC), which occupies a key role in multiple acute and chronic inflammatory tissue responses. C1q is largely produced by myeloid cells including Kupffer cells (KCs) and subsequently secreted into the circulation as an inactive preprotein. Its binding partner, Apolipoprotein E (ApoE), is produced by KCs and hepatocytes and it is also secreted into the circulation, where it regulates essential steps of lipid transport. In addition to its major source, ApoE can be produced by non-liver cells including immune cells and multiple other cells depending on local tissue contexts. To initiate the CCC cascade, C1q must be activated by molecules as varied as oxidized lipids, amyloid fibrils, and immune complexes. However, ApoE is mute towards inactive C1q but binds at high-affinity to its activated form. Specifically, our studies revealed that ApoE is a CCC-specific checkpoint inhibitor via the formation of the C1q-ApoE complex. We proposed that it may arise in multiple if not all CCC-associated diseases and that its presence indicates ongoing CCC activity. Here, we turned to the liver to examine C1q-ApoE complexes in human B- and C-viral hepatitis and nonalcoholic fatty liver disease (NAFLD). In addition, we used multidrug-resistance-2 gene-knockout (Mdr2-KO) mice as a model for inflammatory liver disease and hepatocellular carcinoma (HCC) pathogenesis. In normal murine and human livers, KCs were the major C1q-producing cell type while hepatocytes were the primary ApoE-forming cell type though the C1q-ApoE complex was rare or nonexistent. However, significant numbers of C1q-ApoE complexes formed in both Mdr2-KO, human viral hepatitis, and NAFLD around portal triads where immune cells had infiltrated the liver. Additionally, high numbers of C1q-ApoE complexes emerged in human livers in areas of extracellular lipid droplets across the entire liver parenchyma in NAFLD-affected patients. Thus, the C1q-ApoE complex is a new pathological hallmark of viral hepatitis B and C and NAFLD.

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Section: Introductionmentioning

confidence: 99%

The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease

Habenicht

Wang²,

Zhang³

et al. 2022

Front. Immunol.

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“…Anti-C1q autoantibodies are typically present in diseases like SLE, Hypocomplementemic Urticarial Vasculitis Syndrome and Rheumatoid Vasculitis, but are also present in a fraction of healthy individuals ( 15 ). Importantly, anti-C1q autoantibodies do not deplete circulating C1q, but may amplify classical pathway driven complement activation ( 16 ) and dysregulate other processes driven by C1q ( 17 ). Autoantibodies to FH have been described in atypical Hemolytic Uremic Syndrome and C3-glomerulopathy as well as in antiphospholipid syndrome and other autoimmune diseases ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

Circulating Levels of Anti-C1q and Anti-Factor H Autoantibodies and Their Targets in Normal Pregnancy and Preeclampsia

et al. 2022

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Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE.

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“…C1q is the recognition molecule key which contributes to the innate immune defense and regulates the adaptive immune response for the neuroprotection of the CNS and mediation of the formation of central synapses. Although linked to PD, it is still very difficult to elucidate the total role of the expression of C1q in the development of this disease [ 17 , 64 ].…”

Section: Resultsmentioning

confidence: 99%

The Potential Roles of Extracellular Vesicles as Biomarkers for Parkinson’s Disease: A Systematic Review

Valencia

Феррейра

Merino-Torres

et al. 2022

IJMS

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Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder, characterized by the misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The urge for an early diagnosis biomarker comes from the fact that clinical manifestations of PD are estimated to appear once the substantia nigra has deteriorated and there has been a reduction of the dopamine levels from the striatum. Nowadays, extracellular vesicles (EVs) play an important role in the pathogenesis of neuro-degenerative diseases as PD. A systematic review dated August 2022 was carried out with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses with the aim to analyze the potential role of EVs as biomarkers for PD. From a total of 610 articles retrieved, 29 were eligible. This review discusses the role of EVs biochemistry and their cargo proteins, such as α-syn and DJ-1 among others, detected by a proteomic analysis as well as miRNAs and lncRNAs, as potential biomarkers that can be used to create standardized protocols for early PD diagnosis as well as to evaluate disease severity and progression.

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Circulating C1q levels in health and disease, more than just a biomarker

Cited by 29 publications

References 152 publications

The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease

The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease

Circulating Levels of Anti-C1q and Anti-Factor H Autoantibodies and Their Targets in Normal Pregnancy and Preeclampsia

The Potential Roles of Extracellular Vesicles as Biomarkers for Parkinson’s Disease: A Systematic Review

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