Complement factor H contributes to mortality in humans and mice with bacterial meningitis.

BACKGROUND: The complement system is a vital component of the inflammatory response occurring during bacterial meningitis. Blocking the complement system was shown to improve the outcome of experimental pneumococcal meningitis. Complement factor H (FH) is a complement regulatory protein inhibiting alternative pathway activation but is also exploited by the pneumococcus to prevent complement activation on its surface conferring serum resistance. METHODS: In a nationwide prospective cohort study of 1009 episodes with community-acquired bacterial meningitis, we analyzed whether genetic variations in CFH influenced FH cerebrospinal fluid levels and/or disease severity. Subsequently, we analyzed the role of FH in our pneumococcal meningitis mouse model using FH knock-out (Cfh-/-) mice and wild-type (wt) mice. Finally, we tested whether adjuvant treatment with human FH (hFH) improved outcome in a randomized investigator blinded trial in a pneumococcal meningitis mouse model. RESULTS: We found the major allele (G) of single nucleotide polymorphism in CFH (rs6677604) to be associated with low FH cerebrospinal fluid concentration and increased mortality. In patients and mice with bacterial meningitis, FH concentrations were elevated during disease and Cfh-/- mice with pneumococcal meningitis had increased mortality compared to wild-type mice due to C3 depletion. Adjuvant treatment of wild-type mice with purified human FH led to complement inhibition but also increased bacterial outgrowth which resulted in similar disease outcomes. CONCLUSION: Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial.

Complement 3 and factor h in human cerebrospinal fluid in Parkinson's disease, Alzheimer's disease, and multiple-system atrophy.

Complement activation, a key component of neuroinflammation, has been reported in both Parkinson's disease (PD) and Alzheimer's disease (AD). However, it is unclear whether complement activation and neuroinflammation in general are distinctly different from each another in major neurodegenerative disorders. In the present study, cerebrospinal fluid complement 3 (C3) and factor H (FH) were measured and evaluated together with amyloid-ß(42) (Aß(42)), which in recent investigations was decreased in patients with PD, in particular those with cognitive impairment. The study included 345 participants: 126 patients with PD at various stages with or without cognitive impairment, 50 with AD, and 32 with multiple-system atrophy, and 137 healthy control individuals. In addition to changes in Aß(42) concentrations, there were clear differences in the patterns of complement profiles among neurodegenerative disorders. The C3/FH ratio demonstrated high sensitivity and specificity in differentiating patients with multiple-system atrophy from those with AD or PD and control individuals. In addition, the C3/Aß(42) and FH/Aß(42) ratios not only correlated with PD severity approximated using the Unified Parkinson's Disease Rating Scale but also with the presence of cognitive impairment or dementia in PD. Both C3 and FH correlated with the severity of impairment in AD as indicated using Mini-Mental State Examination scores.

Complement regulator factor H in multiple sclerosis.

A recent proteomic study published in this journal demonstrated lower cerebrospinal fluid (CSF) expression of factor H (fH), an important complement regulator, along with two other complement proteins, in active multiple sclerosis (MS) patients. We have previously demonstrated raised serum fH levels in MS and here, an extended analysis, quantifying fH in CSF, demonstrates no change in fH levels in active disease, but significantly raised levels in progressive disease. These findings support our previous work showing raised serum fH in patients with progressive MS, and our results predict that CSF fH levels will be raised rather than reduced in active disease.

Complement regulator factor H as a serum biomarker of multiple sclerosis disease state.

Multiple sclerosis has a variable phenotypic presentation and subsequent disease course that, although unpredictable at disease onset, is of crucial importance in guiding interventions. Effective and accessible biomarkers are required in order to stratify patients and inform treatment. We examined whether the complement regulator factor H and its Tyr402His polymorphism, recently implicated as biomarkers in other chronic inflammatory central nervous system conditions, might identify or predict specific pathological processes and outcomes in multiple sclerosis. Employing novel assays, we measured factor H and its His402 variant in serum from 350 patients with multiple sclerosis classified according to disease course and relapse status. Serum factor H levels were significantly higher in progressive disease (P < 0.001) compared to controls and relapsing patients, after controlling for variables including disease duration, age, gender, disability and treatment. Serum factor H levels were capable of distinguishing secondary progressive from relapsing remitting disease (excluding patients in clinical relapse) with a sensitivity of 89.41%, specificity of 69.47% and a positive predictive value of 72.38%. Acute relapse was also associated with transiently increased factor H levels (P = 0.009) compared to stable relapsing disease. In clinically stable patients, factor H levels remained constant over 1 year (coefficient of variation percentage = 6.8), however, in patients in transition from relapsing to progressive disease, factor H levels significantly increased over a period of 2 years (P = 0.007). Concentration of the His402 variant in heterozytgotes was significantly higher in secondary progressive (P < 0.01) and primary progressive (P < 0.05) disease, suggesting altered expression or consumption of variants when factor H is upregulated. Serum factor H may be an effective indicator of progression and a practical and accessible biomarker and stratifying tool in determining disease course, providing objective evidence to help guide therapeutic decisions.

CSF complement 3 and factor H are staging biomarkers in Alzheimer's disease.

INTRODUCTION: CSF levels of established Alzheimer's disease (AD) biomarkers remain stable despite disease progression, and non-amyloid non-tau biomarkers have the potential of informing disease stage and progression. We previously identified complement 3 (C3) to be decreased in AD dementia, but this change was not found by others in earlier AD stages. We hypothesized that levels of C3 and associated factor H (FH) can potentially distinguish between mild cognitive impairment (MCI) and dementia stages of AD, but we also found their levels to be influenced by age and disease status. RESULTS: We developed a biochemical/bioinformatics pipeline to optimize the handling of complex interactions between variables in validating biochemical markers of disease. We used data from the Alzheimer's Disease Neuro-imaging Initiative (ADNI, n = 230) to build parallel machine learning models, and objectively tested the models in a test cohort (n = 73) of MCI and mild AD patients independently recruited from Emory University. Whereas models incorporating age, gender, APOE ε4 status, and CSF amyloid and tau levels failed to reliably distinguish between MCI and mild AD in ADNI, introduction of CSF C3 and FH levels reproducibly improved the distinction between the two AD stages in ADNI (p < 0.05) and the Emory cohort (p = 0.014). Within each AD stage, the final model also distinguished between fast vs. slower decliners (p < 0.001 for MCI, p = 0.007 for mild AD), with lower C3 and FH levels associated with more advanced disease and faster progression. CONCLUSIONS: We propose that CSF C3 and FH alterations may reflect stage-associated biomarker changes in AD, and can complement clinician diagnosis in diagnosing and staging AD using the publically available ADNI database as reference.

Complement protein isoforms in CSF as possible biomarkers for neurodegenerative disease.

It has been suggested that the activation of the complement system is involved in the pathogenesis of several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Here, the CSF expression levels of complement proteins C3b, C4b, factor B, and factor H were compared between normal subjects and patients diagnosed with AD, PD, MS, and neurosyphilis. The CSF proteins were initially separated using two-dimensional gel electrophoresis, which allowed the comparison of some of the individual complement isoforms. Patients with AD, PD, and MS all showed more than one complement isoform with a significant change (p < 0.05) in CSF expression level compared to normal subjects. PD patients were found to have the greatest number of significantly changed isoforms, all showing a decreased expression level in PD CSF. The complement isoforms examined were able to distinguish between some, but not all, of the diseases studied. The data suggest that when investigating a protein as a possible biomarker, it may be useful to compare individual protein isoform expression levels in addition to the more commonly measured total protein expression level.