Age and Sex-Associated Changes of Complement Activity and Complement Levels in a Healthy Caucasian Population

Costa, Mariana Gaya de; Poppelaars, Felix; Kooten, Cees van; Mollnes, Tom Eirik; Tedesco, Francesco; Würzner, Reinhard; Trouw, Leendert A.; Truedsson, Lennart; Daha, Mohamed R.; Roos, Anja; Seelen, Marc A.

doi:10.3389/fimmu.2018.02664

Cited by 193 publications

(184 citation statements)

References 69 publications

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“…We have found in our study that MBL level correlates negatively with age. This observation was expected, as immune system efficiency decreases naturally with age, and is in agreement with earlier observations showing that the lectin pathway activated by mannan is lower in the elderly [16].…”

Section: Discussionsupporting

confidence: 93%

High normal TSH is associated with lower mannan-binding lectin in women of childbearing age

et al. 2020

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Background: Mannan-binding lectin (MBL) is a main component of the lectin pathway of the complement system. Lower MBL levels are associated with, among other conditions, hypothyroidism and adverse pregnancy outcomes. In turn, adverse pregnancy outcomes and infertility may result from hypothyroidism, even in patients with high normal Thyroid-stimulating hormone (TSH). The aim of this study was to determine if MBL level differs between women of reproductive age with low normal (< 2.5 mIU/l) and high normal (≥2.5 mIU/l) TSH. Associations with other parameters potentially affected by hypothyroidism were also evaluated. Methods: Ninety five (95) patients with normal thyroid tests (TSH 0.27-4.2 mIU/l), aged 18-48 years, were prospectively enrolled. Several laboratory parameters were measured, including MBL level, thyroid tests and lipid profile. Results: Serum MBL level was lower in women with TSH ≥ 2.5 mIU/l than with TSH < 2.5 mIU/l. This association was confirmed by univariate regression analysis. MBL level was significantly lower in patients with abnormally low HDLC/cholesterol ratio and a positive correlation was found between MBL level and HDL/cholesterol ratio. Conclusion: In women of reproductive age with normal thyroid tests, lower MBL is associated with high normal TSH and with less favourable lipid profile. Therefore treatment with L-thyroxine should be considered in women of reproductive age with TSH ≥ 2.5 mIU/l.

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Section: Discussionsupporting

confidence: 93%

High normal TSH is associated with lower mannan-binding lectin in women of childbearing age

et al. 2020

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“…The elevated concentrations of C3 and C4 proteins in CSF of men parallel earlier findings that, in plasma, C3 and C4 are also present at higher levels in men than women [15][16][17] . The large sample size (n > 50,000) of 285 the plasma studies allows sex differences to be further analyzed as a function of developmental age.…”

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confidence: 85%

Complement component 4 genes contribute sex-specific vulnerability in diverse illnesses

Kamitaki

Sekar

Handsaker

et al. 2019

Preprint

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1 Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren's syndrome affect nine times more women than men 1,2 , whereas schizophrenia affects men more frequently and severely 3-5 . All three illnesses have their strongest common-genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren's syndrome has long been thought to arise from HLA alleles 6-13 . Here we show that the complement component 4 (C4) genes in the MHC locus, recently found to increase risk for schizophrenia 14 , generate 7fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10 -117 in total) and 16-fold variation in risk for Sjögren's syndrome (95% CI: 8.59-30.89; p < 10 -23 in total), with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia, greatly reduced risk for lupus and Sjögren's syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjögren's syndrome in men (vs. 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid (p < 10 -5 for both C4 and C3) and plasma among adults ages 20-50 15-17 , corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women's greater risk of SLE and Sjögren's, and men's greater vulnerability in schizophrenia. These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

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“…b). Differences in the normal blood levels of C5–C9 in humans between the sexes has recently been reported for Caucasians and, with the exception of C6, the levels are lower in females . Taken together, this suggests similar kinetics of C3 tickover/regulation and production/turnover of sMAC between the sexes – factors which contribute to the plasma levels of sMAC found in healthy individuals.…”

Section: Discussionmentioning

confidence: 55%

Plasma levels of soluble membrane attack complex are elevated despite viral suppression in HIV patients with poor immune reconstitution

Schein

Blackburn

Heath

et al. 2019

Clinical and Experimental Immunology

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The complement system is now a therapeutic target for the management of serious and life-threatening conditions such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, glomerulonephritis and other diseases caused by complement deficiencies or genetic variants. As complement therapeutics expand into more clinical conditions, monitoring complement activation is increasingly important, as is the baseline levels of complement activation fragments in blood or other body fluid levels. Although baseline complement levels have been reported in the literature, the majority of these data were generated using non-standard assays and with variable sample handling, potentially skewing results. In this study, we examined the plasma and serum levels of the soluble membrane attack complex of complement (sMAC). sMAC is formed in the fluid phase when complement is activated through the terminal pathway. It binds the regulatory proteins vitronectin and/or clusterin and cannot insert into cell membranes, and can serve as a soluble diagnostic marker in infectious disease settings, as previously shown for intraventricular shunt infections. Here we show that in healthy adults, serum sMAC levels were significantly higher than those in plasma, that plasma sMAC levels were similar between in African Americans and Caucasians and that plasma sMAC levels increase with age. Plasma sMAC levels were significantly higher in virally suppressed people living with HIV (PLWH) compared to non-HIV infected healthy donors. More specifically, PLWH with CD4 + T cell counts below 200 had even greater sMAC levels, suggesting diagnostic value in monitoring sMAC levels in this group.

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Age and Sex-Associated Changes of Complement Activity and Complement Levels in a Healthy Caucasian Population

Cited by 193 publications

References 69 publications

High normal TSH is associated with lower mannan-binding lectin in women of childbearing age

High normal TSH is associated with lower mannan-binding lectin in women of childbearing age

Complement component 4 genes contribute sex-specific vulnerability in diverse illnesses

Plasma levels of soluble membrane attack complex are elevated despite viral suppression in HIV patients with poor immune reconstitution

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