Reference Intervals of Factor H and Factor H-Related Proteins in Healthy Children

Abstract

Complement is activated as part of the innate immune defense against invading pathogens. Also, it helps to remove apoptotic debris and immune complexes from the circulation. Impaired complement function due to aberrant plasma levels of complement proteins may be indicative for complement-mediated diseases or can be involved in susceptibility for infections. To determine whether plasma levels are abnormal, reference intervals (RIs) are used from adult healthy donors. Since many complement-mediated diseases have an onset during childhood, it is important to know whether these RIs can be extrapolated to children. RIs of Factor H (FH), the crucial fluid-phase regulator, and the FH-related proteins (FHRs), its homologous counterparts, are unknown in healthy children. While FH is measured to diagnose and monitor therapy of patients with atypical hemolytic uremic syndrome, recent studies also implicated increased plasma levels of FHRs in disease. Here, we investigated the levels of FH and FHRs in healthy children using recently developed specific ELISAs. We found that levels of FH, FHR-2, and FHR-3 were equal to those found in healthy adults. Levels of FHR-4A and FHR-5 were lower in children than in adults. However, only the FHR-5 levels associated with age. The RIs of these FH family proteins now serve to support the interpretation of plasma levels in prospective and retrospective studies that can be used for routine diagnostic and monitoring purposes including pediatric patient samples.

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

“…Previous studies did not find significant differences between sexes in factor H levels in adults ( 57 ). In addition, very recent work did not observe an effect of sex or age in factor H levels in children ( 54 ). However, since we observed a lower AP functional activity in females, a possible explanation for this difference could be higher levels of factor H and/or factor I.…”

“…Troldborg et al studied complement proteins restricted to the lectin pathway and showed comparable results to ours, showing that female have lower complement levels than males ( 53 ). Previously, an animal study demonstrated the influence of sex hormones on the complement system by injecting estrogen and testosterone in healthy and castrated mice from both sexes ( 54 ). Mice treated with testosterone showed increased late acting complement activity while mice treated with estrogen showed diminished activity ( 48 ).…”

Factor H‐related protein 1: a complement regulatory protein and guardian of necrotic‐type surfaces

“…(Irmscher et al, 2019, Zhang et al, 2017. A FHR-1 concentration of 11.2 µg/ml was measured in children with two copies of CFHR1; this level was independent of age and gender (Van Beek et al, 2018).…”

Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

“…Early studies investigating FHRs focused on the most abundant FHR, i.e., FHR-1, which was reported to circulate at approximately 40–100 µg/ml in human plasma ( 15 , 17 ). A recent study utilizing a panel of tailor-made detection antibodies reported a lower FHR-1 plasma concentration of approximately 10–15 µg/ml (351 nM) ( 18 ). Two FHR-1 molecular weight variants exist, which both comprise five CCP domains but differ in their number of N-linked carbohydrates (one versus two sites, yielding a 37 or 42 kDa plasma protein, respectively) [reviewed in ( 19 )].…”