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Moieties of Complement iC3b Recognized by the I-domain of Integrin ?X?2.

ABSTRACT: Complement fragment iC3b serves as a major opsonin for facilitating phagocytosis via its interaction with complement receptors CR3 and CR4, also known by their leukocyte integrin family names, ?M?2 and ?X?2, respectively. Although there is general agreement that iC3b binds to the ?M and ?X I-domains of the respective ?2-integrins, much less is known regarding the regions of iC3b contributing to the ?X I-domain binding. In this study, using recombinant ?X I-domain, as well as recombinant fragments of iC3b as candidate binding partners, we have identified two distinct binding moieties of iC3b for the ?X I-domain. They are the C3 convertase-generated N-terminal segment of the C3b ?'- chain (?'NT) and the factor I cleavage-generated N-terminal segment in the CUBf region of ?-chain. Additionally, we have found that the CUBf segment is a novel binding moiety of iC3b for the ?M I-domain. The CUBf segment shows about a 2-fold higher binding activity than the ?'NT for ?X I-domain. We also have shown the involvement of crucial acidic residues on the iC3b side of the interface and basic residues on the I-domain side.

SUBMITTER: Choi J

PROVIDER: S-EPMC7772510 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Moieties of Complement iC3b Recognized by the I-domain of Integrin αXβ2.

Choi Jeongsuk J Buyannemekh Dolgorsuren D Nham Sang-Uk SU

Molecules and cells 20201201 12

Complement fragment iC3b serves as a major opsonin for facilitating phagocytosis via its interaction with complement receptors CR3 and CR4, also known by their leukocyte integrin family names, αMβ2 and αXβ2, respectively. Although there is general agreement that iC3b binds to the αM and αX I-domains of the respective β2-integrins, much less is known regarding the regions of iC3b contributing to the αX I-domain binding. In this study, using recombinant αX I-domain, as well as recombinant fragment ...[more]

PMID: 33372665

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Project description:ObjectiveTo examine correlations between blood levels of complement split product iC3b and serum component C3 with clinically meaningful changes in disease activity in patients with systemic lupus erythematosus (SLE).MethodsA total of 159 consecutive patients with SLE, diagnosed according to the American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria, were enrolled in CASTLE (Complement Activation Signatures in Systemic Lupus Erythematosus), a prospective observational study. Patients with 1-7 study visits were included in this longitudinal analysis. In addition, 48 healthy volunteers were enrolled to establish a normal reference value for the ratio of blood iC3b to serum C3 concentrations. Serum C3 and C4 levels were measured by nephelometry, and blood iC3b levels were measured by a lateral flow assay. SLE disease activity was monitored with the Responder Index 50 instrument of the SLE Disease Activity Index 2000.ResultsRelative changes in the iC3b:C3 ratio, levels of anti-double-stranded DNA (anti-dsDNA) antibodies, and use of a supraphysiologic dose of prednisone (>7.5 mg/day) each independently correlated with SLE disease activity, as determined in multilevel multiple logistic regression analyses. Only the iC3b:C3 ratio was significantly associated with clinically meaningful improvements in disease activity among patients with SLE who were receiving a supraphysiologic dose of prednisone. The iC3b:C3 ratio outperformed C3 and C4 levels with regard to discriminating active SLE from inactive SLE, and major flares from no disease activity. The iC3:C3 ratio, anti-dsDNA antibody levels, erythrocyte sedimentation rate, and use of a supraphysiologic prednisone dose were each independently associated with the presence of lupus nephritis, whereas none of these measures was associated with SLE rash. The association of the iC3b:C3 ratio with lupus nephritis was independent of other observed clinical manifestations.ConclusionThe ratio of blood iC3b to serum C3 concentrations correlates with the extent of SLE disease activity and with clinically meaningful changes in disease activity in patients with SLE. Furthermore, the iC3b:C3 ratio may discriminate between active and inactive SLE, and between major flares and no active disease.

Dataset Information

Moieties of Complement iC3b Recognized by the I-domain of Integrin ?X?2.

Publications

Moieties of Complement iC3b Recognized by the I-domain of Integrin αXβ2.

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