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      Complement Dysregulation and Disease: Insights from Contemporary Genetics

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      Journal: Annual Review of Pathology: Mechanisms of Disease
      Publisher: Annual Reviews

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          Abstract

          <p class="first" id="P1">The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system’s components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age-related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system’s alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases. </p>

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          Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.

          Jessica Caprioli, Marina Noris, Simona Brioschi … (2006)
          Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non-Shiga toxin-associated HUS (non-Stx-HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx-HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.
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            Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration

            Johanna M. Seddon, Yi Yu, Mary-Elizabeth C Miller … (2013)
            To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within AMD-associated loci and pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2×10−8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association to disease. We observed significant association with rare missense alleles outside CFI. Genotyping in 5,115 independent samples confirmed associations to AMD with a K155Q allele in C3 (replication p=3.5×10−5, OR=2.8; joint p=5.2×10−9, OR=3.8) and a P167S allele in C9 (replication p=2.4×10−5, OR=2.2; joint p=6.5×10−7, OR=2.2). Finally, we show that the 155Q allele in C3 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
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              Structures of complement component C3 provide insights into the function and evolution of immunity.

              Bert J C Janssen, Eric G. Huizinga, Hans C A Raaijmakers … (2005)
              The mammalian complement system is a phylogenetically ancient cascade system that has a major role in innate and adaptive immunity. Activation of component C3 (1,641 residues) is central to the three complement pathways and results in inflammation and elimination of self and non-self targets. Here we present crystal structures of native C3 and its final major proteolytic fragment C3c. The structures reveal thirteen domains, nine of which were unpredicted, and suggest that the proteins of the alpha2-macroglobulin family evolved from a core of eight homologous domains. A double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces. Marked conformational changes in the alpha-chain, including movement of a critical interaction site through a ring formed by the domains of the beta-chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.
              Article 0 comments Cited 138 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Title: Annual Review of Pathology: Mechanisms of Disease
                Abbreviated Title: Annu. Rev. Pathol. Mech. Dis.
                Publisher: Annual Reviews
                ISSN (Print): 1553-4006
                ISSN (Electronic): 1553-4014
                Publication date Created: January 24 2017
                Publication date (Print): January 24 2017
                Volume: 12
                Issue: 1
                Pages: 25-52
                Article
                DOI: 10.1146/annurev-pathol-012615-044145
                PMC ID: 6020056
                PubMed ID: 27959629
                SO-VID: c441743b-5f61-40df-b382-3cdbefee340a
                Copyright © © 2017
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