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Comment
. 2021 Feb;22(2):106-108.
doi: 10.1038/s41590-020-00842-9.

Complement inhibitor for therapy of CHAPLE

Chack-Yung Yu  1 , Stacy P Ardoin  2   3
Affiliations
Comment

Complement inhibitor for therapy of CHAPLE

Chack-Yung Yu et al. Nat Immunol. 2021 Feb.
No abstract available

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Figures

Figure 1.
Figure 1.
Activation and regulation of complement pathways. The complement system is designed to be a key defensive armament against infections for both innate and adaptive immune responses. It is a set of highly sophisticated tools that lyses microbial cells through the formation of membrane attack complexes (MACs) that detrimentally pierce through target membrane to form multiple pores. However, they exert minimum damage to the self or autologous host cells under normal conditions. Activation products of the complement system summon inflammatory cells to migrate to the site of microbial invasion to assist performing the defense task, a process known as anaphylaxis. Covalent depositions of activated complement proteins on microbes help solubilizing immune aggregates, facilitate the clearance immune complexes (IC) in the circulation by red blood cells by complement receptor CR1, and opsonize IC for phagocytosis through binding to complement receptors expressed on myeloid cell membranes. Complement activation starts by recognition of foreign objects through three different pathways or strategies to generate an initiation complex. The initiation complex produces active subunits for C3 convertase, which are C4b2a (i.e., C4bC2a) for the classical pathway (CP) and the lectin pathway (LP), and C3bBb for the alternative pathway (AP). The C3 convertase cleaves C3 to C3a and C3b. An association of C3b with either of the convertases changes the enzyme specificity from C3 to C5. The C5 convertase cleaves C5 to C5a and C5b. Both C3 convertase and C5 convertase are serine proteinases. The enzymatic subunits are present in C2a for the lectin and classical pathways, and Bb for the alternative pathway. The smaller moieties of activation products for the convertases, C3a and C5a, are potent anaphylatoxins that attract inflammatory cells to the sites of complement activation and stimulate inflammatory cell to release secretary granules. Anaphylatoxins also increase the permeability of endothelial linings for blood and lymphatic vessels to facilitate infiltrations of inflammatory cells into tissues. The larger moieties, C3b and C5b, stay close to the target surface. C5b is a seeding molecule for the bindings of C6 and C7. The resultant trimolecular structure, C5b-C6-C7 (i.e., C5b-7), penetrates into the target membrane, attracts the association of C8 and promotes the polymerization of C9 to form a tunnel-like structure (C5b-9n) across the target membrane to destroy the invading microbe. The progression of activation and terminal pathways are shown in red arrows. Regulations by dissociations and blockage are shown by unfilled green arrows; proteolytic degradations of C4b and C3b are shown by solid green arrows. A positive feedback mechanism to generate C3b is shown by blue dotted lines. The location of inhibition by Eculizumab in the terminal pathway is shown by purple diamond arrows.
See this image and copyright information in PMC

Comment on

  • Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.
    Ozen A, Kasap N, Vujkovic-Cvijin I, Apps R, Cheung F, Karakoc-Aydiner E, Akkelle B, Sari S, Tutar E, Ozcay F, Uygun DK, Islek A, Akgun G, Selcuk M, Sezer OB, Zhang Y, Kutluk G, Topal E, Sayar E, Celikel C, Houwen RHJ, Bingol A, Ogulur I, Eltan SB, Snow AL, Lake C, Fantoni G, Alba C, Sellers B, Chauvin SD, Dalgard CL, Harari O, Ni YG, Wang MD, Devalaraja-Narashimha K, Subramanian P, Ergelen R, Artan R, Guner SN, Dalgic B, Tsang J, Belkaid Y, Ertem D, Baris S, Lenardo MJ. Ozen A, et al. Nat Immunol. 2021 Feb;22(2):128-139. doi: 10.1038/s41590-020-00830-z. Epub 2021 Jan 4. Nat Immunol. 2021. PMID: 33398182 Free PMC article.

References

    1. Ozen A, Comrie WA, Ardy RC, et al. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 2017;377:52–61. - PMC - PubMed
    1. Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy. N Engl J Med 2017;377:87–9. - PubMed
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    1. Medof ME, Walter EI, Roberts WL, Haas R, Rosenberry TL. Decay accelerating factor of complement is anchored to cells by a C-terminal glycolipid. Biochemistry 1986;25:6740–7. - PubMed
    1. Barnum S, Schein T. The Complement Facts Book. second ed: AP; 2018.

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