Classical Pathway

The classical pathway is one of three activation pathways of the complement system, which is a major contributor to the defense of infections, clearance of pathogens, removal of apoptotic/necrotic cells, and maintenance of homeostasis. There are at least 21 different serum proteins have been confirmed as components of the classical pathway, in which 11 major protein play the most critical role, including C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, C9. In immune responses, the antibody isotypes IgG or IgM specifically recognizes invasive antigens to form the antigen-antibody complexes, which is the initiation factor of the classical complement pathway. C1q, as part of C1 complex (C1q C1r2C1s2), has affinity for the Fc regions of IgG/ IgM. It is the first enzyme in this pathway to trigger a series of enzymatic events. The classical pathway can also be activated by apoptotic/necrotic cells and acute phase proteins.

Illustration of the classical and alternative pathway. （https://commons.wikimedia.org/wiki/File:Complement_pathway.svg)

Fig 1. Illustration of the classical and alternative pathway.1

Activation of the Classical Pathway

The enzyme cascade can be divided into three phases:

  1. Initiation

The recognition of C1q and IgM or hexameric IgG immune complexes, surface proteins of bacteria/viruses, apoptotic cells, is a signal to start the complement classical pathway. Three steps are showed in this stage:
1) Zymogen C1 binds directly to the triggers via the globular heads of C1q.
2) Ligand binding induces conformational changes in C1q, resulting in subsequent repositioning and autocatalysis of the C1r zymogen dimer to be active form.
3) C1r cleaves C1s forming fully activated C1s with catalytic capabilities.

  1. Formation of C3 convertase

Activated C1s binds C4 and enzymatically liberates C4a and C4b, which in turn promotes the cleavage of C2 into C2a and C2b. Surface-attached C4b serves as a platform for the formation of C3 convertase (C4bC2a). C3 convertase can cleave C3 into C3a and C3b, which is essential for the next enzymic reaction.

  1. Formation of C5 convertase and MAC

C3b binds to the C4b2a complex to form C5 convertase (C4b2a3b), while C3a plays role in the recruitment of inflammatory cells (anaphylatoxin). C5 convertase then cleaves C5 into C5a and C5b. C5b combines with other terminal components C6, C7, C8, and C9 to form the Membrane Attack Complex (MAC), which leads to lysis of invasive bacteria through insertion into the target cell membranes to create functional pores.

Inhibitors of the Classical Pathway

Because the classical pathway mediates a lot of autoimmune and inflammatory disorders, the regulation is very strict to prevent unwanted complement activation. The complement inhibitors which can antagonize excessive activation of complement have potential clinical application. Scientists have identified a series of inhibitors targeting the proteins in this pathway, including C1q, C1r, C3 etc.

Creative Biolabs provides a full range of therapeutic antibodies, inhibitors, soluble complement regulators, as well as customized services based on the classical pathway targets, including:

  1. C1 Complex
  2. C1 Inhibitor
  3. Complement Therapeutic Target-C2
  4. Complement Therapeutic Target-C3
  5. Complement Therapeutic Target-C4
  6. Complement Therapeutic Target-C5
  7. C5aR

Our comprehensive complement platform offers a great number of complement-related products in a rapid and cost-effective manner. If you are interested, please feel free to contact us for more details.

References
1. From Wikipedia: https://commons.wikimedia.org/wiki/File:Complement_pathway.svg

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Questions & Answer

Q: What is the primary role of the classical pathway in the complement system?

A: The primary role of the classical pathway in the complement system is to deal with pathogens and damaged cells. This pathway becomes active when it recognizes and binds to antibodies that are attached to the surfaces of such cells or pathogens.

Q: What is the focus of Creative Biolabs in relation to complement classical pathway? And what are the advantages of complement therapies provided by Creative Biolabs?

A: Creative Biolabs focuses on providing comprehensive complement therapeutic services targeted the classical pathway, with particular interest in drug discovery and development. We offer tailor-made solutions to its clients to meet their specific research needs relating to the classical pathway.The advantages include, but are not limited to, a comprehensive collection of complement therapeutic services, a team of experienced scientists, state-of-the-art techniques and several years of research experience.

Q: What potential advantages does complement therapy offer compared to traditional treatments for conditions involving the classical pathway?

A: Complement therapy provides a targeted approach to modulating immune responses by specifically addressing the classical pathway. This can potentially lead to fewer systemic side effects compared to broad immunosuppression. Researchers design complement inhibitors or activators to specifically interact with certain complement proteins in the classical pathway, minimizing off-target effects and enhancing therapeutic specificity.

For Research Use Only.
Related Sections:
Complement System

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