C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus

Schaarenburg, Rosanne A. van; Magro-Checa, César; Bakker, J.; Teng, Y K Onno; Bajema, Ingeborg M.; Huizinga, Tom W J; Steup-Beekman, Gerda M; Trouw, Leendert A.

doi:10.3389/fimmu.2016.00647

Cited by 36 publications

(27 citation statements)

References 39 publications

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“…All other time points showed only modest differences (Figure 4 ). The simultaneous elevation of Th1, Th2, and Th17 associated cytokines was also observed in systemic lupus erythematosus patients, which is associated with C1q deficiency ( 49 – 51 ), suggesting C1q plays a role in balancing T cell response in tissue inflammation and damage. As indicated earlier, the significant elevation of cytokines/chemokines were only observed in C1qα −/− mice infected with B. burgdorferi for 28 days, suggesting that the imbalance of T-cell response in C1qα −/− mice involves a cell-mediated response to borrelial infection.…”

Section: Discussionmentioning

confidence: 89%

The Classical Complement Pathway Is Required to Control Borrelia burgdorferi Levels During Experimental Infection

2018

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Activation of the classical complement pathway occurs to varying degrees within strains of the Borrelia burgdorferi sensu lato complex, which contain a group of pathogenic spirochetes that cause tick-borne Lyme borreliosis, including the agent of Lyme disease in the United States, B. burgdorferi. Despite this information, details related to the control of B. burgdorferi by the classical pathway are not clear. To address this question, we infected C1qα−/− mice, which cannot assemble the C1 complex and thus fail to activate the classical pathway, with B. burgdorferi sensu stricto strain B31. Using bioluminescent in vivo imaging, we found that C1qα−/− mice harbored more B. burgdorferi following 10 days of infection relative to their isogenic C57BL/6 parent. Quantitative PCR (qPCR) demonstrated that C1qα−/− mice harbored significantly more B. burgdorferi than parent mice did within lymph nodes, skin, heart, and joints. The increased B. burgdorferi load in C1qα−/− mice was observed at 21 and 28 days of infection, consistent with the classical pathway promoting complement-dependent, antibody-mediated killing following the development of a B. burgdorferi-specific humoral immune response. In addition, circulating borrelial-specific IgM was higher in C1qα−/− mice relative to their parent mouse strain and did not decrease at 21 and 28 days post-infection, indicating that IgG class switching was delayed in C1qα−/− mice. At day 28, both Borrelia-specific IgG1 and IgG3 levels were higher in infected C1qα−/− mice, but that these antibodies were not sufficient to control borrelial infection in the absence of the classical pathway. Furthermore, the lack of C1q also altered the balance of the Th1/Th2 response, as both circulating Th1 (MIP-1α, IL-2, IL-12, and TNFα), Th2 (IL-4, IL-10, and MCP-1), and Th17 (IL-17) cytokines were elevated in infected C1qα−/− mice. These data imply that C1q and the classical pathway play important roles in controlling borrelial infection via antibody and complement-dependent killing, as well as altering both antibody maturation processes and the T cell response following exposure to infectious B. burgdorferi.

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Section: Discussionmentioning

confidence: 89%

The Classical Complement Pathway Is Required to Control Borrelia burgdorferi Levels During Experimental Infection

2018

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“…C1q levels in sera were measured using an in-house developed ELISA. Maxisorp plates (nunc) were coated overnight with mouse anti-human C1q (2204) ( 38 ), Nephrology department, LUMC) in coating buffer (0.1 M Na 2 CO 3 , 0.1 M NaHCO 3 , pH9.6). Plates were washed and blocked with PBS/1%BSA for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis

Lubbers

Sutherland

Goletti³

et al. 2018

Front. Immunol.

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Background: Tuberculosis (TB) remains a major threat to global health. Currently, diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI.Methods: C1q protein levels were determined using ELISA in sera from patients, from geographically distinct populations, with active TB, LTBI as well as disease controls.Results: Serum levels of C1q were increased in active TB compared to LTBI in four independent cohorts with an AUC of 0.77 [0.70; 0.83]. After 6 months of TB treatment, levels of C1q were similar to those of endemic controls, indicating an association with disease rather than individual genetic predisposition. Importantly, C1q levels in sera of TB patients were significantly higher as compared to patients with sarcoidosis or pneumonia, clinically important differential diagnoses. Moreover, exposure to other mycobacteria, such as Mycobacterium leprae (leprosy patients) or BCG (vaccinees) did not result in elevated levels of serum C1q. In agreement with the human data, in non-human primates challenged with Mycobacterium tuberculosis, increased serum C1q levels were detected in animals that developed progressive disease, not in those that controlled the infection.Conclusions: In summary, C1q levels are elevated in patients with active TB compared to LTBI in four independent cohorts. Furthermore, C1q levels from patients with TB were also elevated compared to patients with sarcoidosis, leprosy and pneumonia. Additionally, also in NHP we observed increased C1q levels in animals with active progressive TB, both in serum and in broncho-alveolar lavage. Therefore, we propose that the addition of C1q to current biomarker panels may provide added value in the diagnosis of active TB.

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“…C1q AR SLE, AGS [18][19][20][21][22][23][24] C1r/C1s AD [7,25,26] C2 AR [27] C4 AR [28][29][30][31][32] Type…”

Section: Complement Pathwaymentioning

confidence: 99%

“…The frequency of SLE or SLE-like phenotype is approximately 90% in patients with C1q deficiency, 65% in C1r/C1s deficiency, 75% in C4 deficiency and 10% in C2 deficiency [7,[22][23][24]26,27,[110][111][112][113][114]. Compared to the polygenic form of SLE, more severe disease course, frequent cutaneous manifestations and a high mortality rate are noted [7,12,18,[22][23][24][25][26]114,115]. The association of C1q and C1r deficiency with an upregulation in type I IFN signaling may explain the increased prevalence of SLE in early complement deficient patients [18,112].…”

Section: Complement Pathwaymentioning

confidence: 99%

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Demirkaya

Şahin

Romano

et al. 2020

JCM

107

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Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

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C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus

Cited by 36 publications

References 39 publications

The Classical Complement Pathway Is Required to Control Borrelia burgdorferi Levels During Experimental Infection

The Classical Complement Pathway Is Required to Control Borrelia burgdorferi Levels During Experimental Infection

Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

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