Complement activation-related pseudoallergy: A stress reaction in blood triggered by nanomedicines and biologicals
Abstract
Intravenous injection of a variety of nanotechnology enhanced (liposomal, micellar, polymer-conjugated) and protein-based (antibodies, enzymes) drugs can lead to hypersensitivity reactions (HSRs), also known as infusion, or anaphylactoid reactions. The molecular mechanism of mild to severe allergy symptoms may differ from case to case and is mostly not known, however, in many cases a major cause, or contributing factor is activation of the complement (C) system. The clinical relevance of C activation-related HSRs, a non-IgE-mediated pseudoallergy (CARPA), lies in its unpredictability and occasional lethal outcome. Accordingly, there is an unmet medical need to develop laboratory assays and animal models that quantitate CARPA. This review provides basic information on CARPA; a short history, issues of nomenclature, incidence, classification of reactogenic drugs and symptoms, and the mechanisms of C activation via different pathways. It is pointed out that anaphylatoxin-induced mast cell release may not entirely explain the severe reactions; a "second hit" on allergy mediating cells may also contribute. In addressing the increasing requirements for CARPA testing, the review evaluates the available assays and animal models, and proposes a possible algorithm for the screening of reactogenic drugs and hypersensitive patients. Finally, an analogy is proposed between CARPA and the classic stress reaction, suggesting that CARPA represents a "blood stress" reaction, a systemic fight of the body against harmful biological and chemical agents via the anaphylatoxin/mast-cell/circulatory system axis, in analogy to the body's fight of physical and emotional stress via the hypothalamo/pituitary/adrenal axis. In both cases the response to a broad variety of noxious effects are funneled into a uniform pattern of physiological changes.
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The complement system and Toll-like receptors may participate in innate immune activation by immunogenic lipids.
“Although the immunogenicity of these lipids has not yet been fully understood, complement system and Toll-like receptors may participate in innate immune activation170,173–175.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [174]
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- Authors
- Szebeni, J.
- Venue
- Molecular Immunology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 61
- Issue
- 2
- Pages
- 163-173
- ISSN
- 0161-5890 (ISSN-L)
- OpenAlex
- W1968376422
- Cited by
- 457
- References
- 77
- Citations by year
- 2026: 65 · 2025: 39 · 2024: 42 · 2023: 46 · 2022: 55 · 2021: 46 · 2020: 35 · 2019: 33 · 2018: 35 · 2017: 20 · 2016: 20 · 2015: 17
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Development Agency of Hungary (TECH-08-D1-2008-0030)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Health Sciences › Medicine › Immunology and Allergy › Food Allergy and Anaphylaxis Research
- Keywords
- complement system, hypersensitivity, infusion reactions, anaphylactoid reactions, nanomedicine, liposomes, micelles, protein-based drugs, anaphylatoxins, mast cell degranulation, stress reactions, hypersensitivity testing, animal models, drug screening
- MeSH terms
- Animals, Complement System Proteins, Complement Activation, Humans, Hypersensitivity, Stress, Physiological, Nanomedicine, Drug-Related Side Effects and Adverse Reactions
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