Pitfalls in complement analysis: A systematic literature review of assessing complement activation

Ricardo J M G E Brandwijk; Marloes A H M Michels; Mara van Rossum; Aline H de Nooijer; Per H Nilsson; Wieke C C de Bruin; Erik J M Toonen

doi:10.3389/fimmu.2022.1007102

Pitfalls in complement analysis: A systematic literature review of assessing complement activation

Front Immunol. 2022 Oct 18:13:1007102. doi: 10.3389/fimmu.2022.1007102. eCollection 2022.

Authors

Ricardo J M G E Brandwijk¹, Marloes A H M Michels², Mara van Rossum¹, Aline H de Nooijer³, Per H Nilsson^{4

5

6}, Wieke C C de Bruin¹, Erik J M Toonen¹

Affiliations

¹ R&D Department, Hycult Biotechnology b.v., Uden, Netherlands.
² Radboud Institute for Molecular Life Sciences, Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands.
³ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
⁴ Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁵ Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
⁶ Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.

Abstract

Background: The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. Complement analysis requires accurate and standardized sampling and assay procedures, which has proven to be challenging.

Objective: We performed a systematic analysis of the current methods used to assess complement components and reviewed whether the identified studies performed their complement measurements according to the recommended practice regarding pre-analytical sample handling and assay technique. Results are supplemented with own data regarding the assessment of key complement biomarkers to illustrate the importance of accurate sampling and measuring of complement components.

Methods: A literature search using the Pubmed/MEDLINE database was performed focusing on studies measuring the key complement components C3, C5 and/or their split products and/or the soluble variant of the terminal C5b-9 complement complex (sTCC) in human blood samples that were published between February 2017 and February 2022. The identified studies were reviewed whether they had used the correct sample type and techniques for their analyses.

Results: A total of 92 out of 376 studies were selected for full-text analysis. Forty-five studies (49%) were identified as using the correct sample type and techniques for their complement analyses, while 25 studies (27%) did not use the correct sample type or technique. For 22 studies (24%), it was not specified which sample type was used.

Conclusion: A substantial part of the reviewed studies did not use the appropriate sample type for assessing complement activation or did not mention which sample type was used. This deviation from the standardized procedure can lead to misinterpretation of complement biomarker levels and hampers proper comparison of complement measurements between studies. Therefore, this study underlines the necessity of general guidelines for accurate and standardized complement analysis.

Keywords: complement activation; complement diagnostics; complement system; immunoassays; standardization of measurements; systematic review.

Publication types

Systematic Review
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Complement Activation*
Complement C3
Complement C5*
Complement Membrane Attack Complex
Humans

Substances

Complement C5
Complement C3
Complement Membrane Attack Complex
Biomarkers