Secreted proteins may become damaged, misfolded, and self-aggregated because they are subject to increased chemical stress such as oxidation, or to physical stress such as shear forces in the vasculature.1 Specific abnormal plasma proteins, such as monoclonal immunoglobulin light chains in amyloid light-chain (AL) amyloidosis or various proteins in hereditary amyloidoses, may have an increased tendency to misfold and aggregate.2 Damaged plasma proteins may be deposited pathologically in extracellular spaces in various tissues. Clinical manifestations of these depositions include the systemic amyloidoses, glomerulonephropathies, neurodegenerative disorders including Alzheimer’s disease, and complications of diabetes mellitus.1,2 Extracellular chaperone proteins can bind denatured misfolded proteins and, thereby, prevent their aggregation while promoting their clearance from the circulation via interactions with specific cellular receptors.1 Extracellular chaperones like clusterin and α2-microglobulin, which bind amyloidogenic proteins, often have other functions. An extracellular chaperone familiar to hematologists is haptoglobin, the acute-phase reactant that binds hemoglobin, but which uses a different site to bind misfolded proteins. In their report, Dr. Mahalakshmi Ramadass and colleagues at Stony Brook University demonstrate a new function for C3b as an extracellular chaperone for denatured plasma proteins and a potential new function for erythrocytes in the clearance of damaged/denatured plasma proteins.
Dr. Ramadass and colleagues, who previously showed that C3b bound covalently to various native plasma proteins,3 used chemically denatured purified human vitamin D-binding protein, serum albumin, and α1-proteinase inhibitor to demonstrate that C3b reacted more avidly with the denatured as opposed to native forms of these plasma proteins. They subsequently showed that incubation of human erythrocytes with human serum, in which C3b was generated by cobra venom factor, resulted in C3bi/plasma protein complexes bound to the erythrocyte membranes. These complexes lead to clearance of denatured plasma proteins by a series of events: 1) human erythrocytes, which express high affinity receptors for C3b in the form of clustered CD35 (complement receptor 1), bind the C3b/protein complex; 2) CD35 is a cofactor for factor I, which converts Cb3 to its inactive degradation products, including C3bi4 ; 3) C3bi/protein complexes on the surface of erythrocytes are delivered to splenic and hepatic macrophages where receptors for C3bi (CD11b/CD18 and CD11c/CD18) mediate phagocytosis of C3bi/protein complexes with release of the erythrocytes back into the circulation.4,5 Lastly, the authors showed that denatured proteins in heat-treated human serum activate complement via the alternative pathway in a limited manner, such that C3b is formed without generating the pro-inflammatory C5a product.
In Brief
The results of the study by Dr. Ramadass and colleagues show that denatured plasma proteins induce production of C3b, and C3b covalently binds the denatured proteins. Complexes of C3b and denatured plasma proteins bind to CD35 on erythrocytes where factor I converts C3b to C3bi, which facilitates delivery of the C3bi/denatured protein complexes to macrophages for phagocytosis. Further studies are needed to confirm that CD35 is the specific erythrocyte receptor for the C3b/denatured protein complexes, and that the C3bi/denatured protein clearance mechanism occurs in vivo. However, the findings are consistent with interactions of C3 with β-amyloid peptide, a major component of fibrillary deposits in Alzheimer’s disease brain lesions, and prior observations that 1) β-amyloid peptide activates alternative and classic complement pathways with formation of complexes of C3b and β amyloid peptide,6 and 2) C3b-dependent binding of β-amyloid peptide to RBCs occurs via CD35.7 Therapeutic modalities that can harness C3b-mediated erythrocyte clearance of damaged and misfolded plasma proteins has the potential to improve treatment of diseases characterized by tissue accumulation of misfolded or denatured proteins such as AL amyloidosis, diabetes mellitus, glomerulonephritis, and neurodegenerative disorders.
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Competing Interests
Dr. Koury has no relevant conflicts of interest.
