Disease-Causing Mutations in Genes of the Complement System
2011; Elsevier BV; Volume: 88; Issue: 6 Linguagem: Inglês
10.1016/j.ajhg.2011.05.011
ISSN1537-6605
AutoresSøren E. Degn, Jens Christian Jensenius, Steffen Thiel,
Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoRecent studies have revealed profound developmental consequences of mutations in genes encoding proteins of the lectin pathway of complement activation, a central component of the innate immune system. Apart from impairment of immunity against microorganisms, it is known that hereditary deficiencies of this system predispose one to autoimmune conditions. Polymorphisms in complement genes are linked to, for example, atypical hemolytic uremia and age-dependent macular degeneration. The complement system comprises three convergent pathways of activation: the classical, the alternative, and the lectin pathway. The recently discovered lectin pathway is less studied, but polymorphisms in the plasma pattern-recognition molecule mannan-binding lectin (MBL) are known to impact its level, and polymorphisms in the MBL-associated serine protease-2 (MASP-2) result in defects of complement activation. Recent studies have described roles outside complement and immunity of another MBL-associated serine protease, MASP-3, in the etiology of 3MC syndrome, an autosomal-recessive disorder involving a spectrum of developmental features, including characteristic facial dysmorphism. Syndrome-causing mutations were identified in MASP1, encoding MASP-3 and two additional proteins, MASP-1 and MAp44. Furthermore, an association was discovered between 3MC syndrome and mutations in COLEC11, encoding CL-K1, another molecule of the lectin pathway. The findings were confirmed in zebrafish, indicating that MASP-3 and CL-K1 underlie an evolutionarily conserved pathway of embryonic development. Along with the discovery of a role of C1q in pruning synapses in mice, these recent advances point toward a broader role of complement in development. Here, we compare the functional immunologic consequences of "conventional" complement deficiencies with these newly described developmental roles. Recent studies have revealed profound developmental consequences of mutations in genes encoding proteins of the lectin pathway of complement activation, a central component of the innate immune system. Apart from impairment of immunity against microorganisms, it is known that hereditary deficiencies of this system predispose one to autoimmune conditions. Polymorphisms in complement genes are linked to, for example, atypical hemolytic uremia and age-dependent macular degeneration. The complement system comprises three convergent pathways of activation: the classical, the alternative, and the lectin pathway. The recently discovered lectin pathway is less studied, but polymorphisms in the plasma pattern-recognition molecule mannan-binding lectin (MBL) are known to impact its level, and polymorphisms in the MBL-associated serine protease-2 (MASP-2) result in defects of complement activation. Recent studies have described roles outside complement and immunity of another MBL-associated serine protease, MASP-3, in the etiology of 3MC syndrome, an autosomal-recessive disorder involving a spectrum of developmental features, including characteristic facial dysmorphism. Syndrome-causing mutations were identified in MASP1, encoding MASP-3 and two additional proteins, MASP-1 and MAp44. Furthermore, an association was discovered between 3MC syndrome and mutations in COLEC11, encoding CL-K1, another molecule of the lectin pathway. The findings were confirmed in zebrafish, indicating that MASP-3 and CL-K1 underlie an evolutionarily conserved pathway of embryonic development. Along with the discovery of a role of C1q in pruning synapses in mice, these recent advances point toward a broader role of complement in development. Here, we compare the functional immunologic consequences of "conventional" complement deficiencies with these newly described developmental roles. As a prelude to discussing the polymorphisms and genetics of the complement system, we wish to set the stage with a brief introduction to the complement pathways and the proteins involved. The complement system is the humoral backbone of the innate immune defense. It is thus involved in a number of diverse processes involving antimicrobial defense, clearance of immune complexes, and tissue regeneration. The system comprises more than 35 humoral and cell-associated proteins forming three converging enzymatic cascades: the classical pathway, the alternative pathway, and the lectin pathway.1Ricklin D. Hajishengallis G. Yang K. Lambris J.D. Complement: a key system for immune surveillance and homeostasis.Nat. Immunol. 2010; 11: 785-797Crossref PubMed Scopus (1136) Google Scholar An overview is shown in Figure 1, where some of the proteins mentioned in the following are placed in their context. The classical pathway is especially important for control of infections with pyogenic encapsulated bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae,2Walport M.J. Complement. First of two parts.N. Engl. J. Med. 2001; 344: 1058-1066Crossref PubMed Scopus (1713) Google Scholar although it has also been implicated in control of viral infections, such as influenza.3Jayasekera J.P. Moseman E.A. Carroll M.C. Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity.J. Virol. 2007; 81: 3487-3494Crossref PubMed Scopus (122) Google Scholar The pathway is initiated when the recognition protein C1q binds to antibodies bound to microbes or in immune complexes.2Walport M.J. Complement. First of two parts.N. Engl. J. Med. 2001; 344: 1058-1066Crossref PubMed Scopus (1713) Google Scholar, 4Walport M.J. Complement. Second of two parts.N. Engl. J. Med. 2001; 344: 1140-1144Crossref PubMed Scopus (968) Google Scholar Preexisting "natural IgM" produced by naive B cells5Alugupalli K.R. Gerstein R.M. Divide and conquer: division of labor by B-1 B cells.Immunity. 2005; 23: 1-2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and IgM or IgG generated through an adaptive response (primary or secondary) will bind to, for example, determinants on the capsule of pathogenic bacteria, leading to agglutination. Binding of IgM exposes cryptic binding sites on IgM, allowing C1q to bind, and binding of arrays of IgG similarly allows high-avidity binding of C1q. C1q is in complex with two serine proteases, C1r and C1s. Upon binding of C1q, conformational changes lead to autoactivation of C1r, which in turn activates C1s. Activated C1s is capable of cleaving C4 and C2. A fragment of C4, C4b, is deposited on the activating surface, where it is covalently attached through a reactive thioester, while a small fragment, C4a, is released. The proenzyme C2 is likewise cleaved by C1s into two fragments, and C2a joins C4b on the surface. C2a is a serine protease, capable of cleaving C3. Cleaved C3 in the form of C3b is covalently bound to the surface-attached C4bC2a complex, while the concomitantly generated small fragment C3a is released to mediate inflammation. C2a in the newly formed complex, C4bC2aC3b, is now able to cleave C5, and two fragments are again generated: C5a is a potent inflammatory mediator, while C5b initiates the formation of a membrane attack complex (MAC), which is expanded through deposition of C6, C7, C8 and C9 (Figure 1), leading to the formation of a hole in the target cell membrane. More importantly, the deposited components C4b and C3b function as molecular tags (opsonins) interacting with complement receptors, hereby facilitating engulfment by phagocytes and activation of B cells. The lectin pathway is quite similar to the classical pathway.6Degn S.E. Jensenius J.C. Bjerre M. The lectin pathway and its implications in coagulation, infections and auto-immunity.Current Opin. Organ Transplant. 2010; (Published online December 9, 2010)Google Scholar An overview of the components of this pathway and the structure of some of the proteins is presented in Figure 2. The lectin pathway is also involved mainly in the control of bacterial infections, as has been observed in the case of children suffering from recurrent pyogenic infections.2Walport M.J. Complement. First of two parts.N. Engl. J. Med. 2001; 344: 1058-1066Crossref PubMed Scopus (1713) Google Scholar, 7Super M. Thiel S. Lu J. Levinsky R.J. Turner M.W. Association of low levels of mannan-binding protein with a common defect of opsonisation.Lancet. 1989; 2: 1236-1239Abstract PubMed Scopus (424) Google Scholar It would appear that the lectin pathway is especially important during the interval between the loss of passively acquired maternal antibody and the acquisition of a mature immunologic repertoire, as well as in individuals with immunosuppression. The pathway is initiated when one or more recognition molecules bind to patterns of carbohydrates or patterns of acetyl groups on the surface of, for example, bacteria or viruses. Four such recognition molecules are capable of activating the lectin pathway: mannan-binding lectin (MBL), H-ficolin, L-ficolin, and M-ficolin.8Thiel S. Complement activating soluble pattern recognition molecules with collagen-like regions, mannan-binding lectin, ficolins and associated proteins.Mol. Immunol. 2007; 44: 3875-3888Crossref PubMed Scopus (153) Google Scholar These pattern-recognition molecules (PRMs) are found in complexes with three serine proteases (termed MBL-associated serine proteases [MASPs]), MASP-1, MASP-2, and MASP-3, as well as two nonenzymatic fragments hereof (termed MBL-associated proteins), MAp19 and MAp44 (Figure 2A). When one of the recognition molecules binds to an adequate pattern, the MASPs are activated. MASP-1 and MASP-2 are responsible for complement activation through cleavage of C2 and C4 (Figure 2B).9Møller-Kristensen M. Thiel S. Sjöholm A. Matsushita M. Jensenius J.C. Cooperation between MASP-1 and MASP-2 in the generation of C3 convertase through the MBL pathway.Int. Immunol. 2007; 19: 141-149Crossref PubMed Scopus (0) Google Scholar The cascade then proceeds as described above for the classical pathway. Recently, a fifth PRM, CL-K1,10Keshi H. Sakamoto T. Kawai T. Ohtani K. Katoh T. Jang S.J. Motomura W. Yoshizaki T. Fukuda M. Koyama S. et al.Identification and characterization of a novel human collectin CL-K1.Microbiol. Immunol. 2006; 50: 1001-1013Crossref PubMed Google Scholar was reported to associate with MASPs.11Hansen S. Selman L. Palaniyar N. Ziegler K. Brandt J. Kliem A. Jonasson M. Skjoedt M.-O. Nielsen O. Hartshorn K. et al.Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding activity.J. Immunol. 2010; 185: 6096-6104Crossref PubMed Scopus (0) Google Scholar Although it reportedly binds to various pathogen-associated molecular patterns (PAMPs), it remains to be determined whether CL-K1 can activate complement. Whereas MASP-1 and MASP-2 have been described to be true enzymes with defined substrates, MASP-3, MAp19, and MAp44 have been suggested to act as regulators of complement activation,12Dahl M.R. Thiel S. Matsushita M. Fujita T. Willis A.C. Christensen T. Vorup-Jensen T. Jensenius J.C. MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway.Immunity. 2001; 15: 127-135Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13Degn S.E. Hansen A.G. Steffensen R. Jacobsen C. Jensenius J.C. Thiel S. MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation.J. Immunol. 2009; 183: 7371-7378Crossref PubMed Scopus (0) Google Scholar, 14Iwaki D. Kanno K. Takahashi M. Endo Y. Lynch N.J. Schwaeble W.J. Matsushita M. Okabe M. Fujita T. Small mannose-binding lectin-associated protein plays a regulatory role in the lectin complement pathway.J. Immunol. 2006; 177: 8626-8632Crossref PubMed Google Scholar but the relevance of these in vitro observations remains unknown. The surprising new findings of potential functions of MASP-3 and CL-K1 are described in detail below. The third way of activating complement, the alternative pathway, is also presented in Figure 1. In many regards, this pathway can be described as an amplification mechanism, because it is always activated after activation by the classical and the lectin pathways. Thus, the alternative pathway is important for the activity of the classical and lectin pathways. When the C3b fragment is bound to a surface (see above) it forms a complex with factor B. This leads to the cleavage of factor B by factor D, giving rise to an active enzyme complex with the fragment Bb as the enzyme. The substrate for Bb is C3, and efficient deposition of more C3b fragments occurs onto nearby surfaces, again giving rise to even more complex formations. In analogy with C2a, the active Bb enzyme may now also cleave C5 and thus generate all of the functions described above. In addition to its function as an amplification mechanism of the classical and the lectin pathway, the alternative pathway may be initiated when C3 in plasma is spontaneously activated through hydrolysis of an internal thioester (so-called "tick-over"). This spontaneous event occurs at a constant low rate wherever in the body C3 is present (blood and interstitial fluids) and is an effect of small perturbations of a somewhat unstable structure of C3, exposing the internal thioester to the solvent.15Carroll M. Immunology: exposure of an executioner.Nature. 2006; 444: 159-160Crossref PubMed Scopus (0) Google Scholar, 16Janssen B.J.C. Christodoulidou A. McCarthy A. Lambris J.D. Gros P. Structure of C3b reveals conformational changes that underlie complement activity.Nature. 2006; 444: 213-216Crossref PubMed Scopus (0) Google Scholar Thus, generated C3(H2O) can form a complex with factor B, leading to cleavage of factor B by factor D and thus the formation of a C3-activating complex, C3(H2O)Bb, which upon further cleavage and addition of C3 forms a C5-activating complex, C3(H2O)BbC3b. The alternative pathway and the terminal lytic pathway are especially important for control of Neisserial infections, particularly Neisseria meningitidis.2Walport M.J. Complement. First of two parts.N. Engl. J. Med. 2001; 344: 1058-1066Crossref PubMed Scopus (1713) Google Scholar Plasma and cell surfaces harbor regulators of complement activation (e.g., factor H and CD59, respectively), immediately causing a local shutdown of the cascade, thus leaving host cells unharmed. On a foreign surface, which does not contain such regulators, the cascade continues undisturbed, ending with opsonization of the target and the formation of membrane-spanning MAC complexes. The regulators of complement activation thus add an extra layer of control to the already specific activation events of the classical and lectin pathways. Notably, in the case of the spontaneous activation of the alternative pathway, the regulators entirely determine the specificity on the basis of the recognition of so-called host-associated molecular patterns (HAMPs), a phenomenon termed "reverse recognition."17Pangburn M.K. Ferreira V.P. Cortes C. Discrimination between host and pathogens by the complement system.Vaccine. 2008; 26: I15-I21Crossref PubMed Scopus (0) Google Scholar Importantly, activation of complement is also tightly regulated in time and space by a very short half-life of activated C3 and C4; i.e., these activated components have a limited diffusion range because of quenching by water, ensuring that only surfaces nearby the site of activation are targeted.18Dodds A.W. Ren X.D. Willis A.C. Law S.K. The reaction mechanism of the internal thioester in the human complement component C4.Nature. 1996; 379: 177-179Crossref PubMed Scopus (0) Google Scholar Experiments with genetically engineered complement-deficient mice have been useful in research on the complement system. However, in general, inbred mouse strains display poor complement activity,19Lachmann P.J. Preparing serum for functional complement assays.J. Immunol. Methods. 2010; 352: 195-197Crossref PubMed Scopus (0) Google Scholar and numerous susceptibility differences exist between mouse and man. The study of individuals with increased susceptibility to a variety of clinical symptoms, including suspect immunodeficiency, has proven to be a most important source of information about defects of (and thus function of) the human complement system. In the following, we focus on recessive complement deficiencies based on complete absence of components or functionally defective components. The significance of partial deficiencies is less clear but may be of relevance in some situations. With regards to genetic association studies based on polymorphisms, we refer to recent reviews. As a primer to such studies, strong associations between SNPs in the gene encoding factor H (CFH [MIM 134370, 609814]) and age-related macular degeneration (AMD [MIM 610698]) have been identified.20de Córdoba S.R. de Jorge E.G. Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H.Clin. Exp. Immunol. 2008; 151: 1-13Crossref PubMed Scopus (147) Google Scholar, 21Zipfel P.F. Lauer N. Skerka C. The role of complement in AMD.Adv. Exp. Med. Biol. 2010; 703: 9-24Crossref PubMed Scopus (0) Google Scholar, 22Ryu E. Fridley B.L. Tosakulwong N. Bailey K.R. Edwards A.O. Genome-wide association analyses of genetic, phenotypic, and environmental risks in the age-related eye disease study.Mol. Vis. 2010; 16: 2811-2821PubMed Google Scholar Polymorphisms in genes encoding other members of the complement system, e.g., factor B (CFB [MIM 138470]) and C3 (C3 [MIM 120700, 613779]), have also been associated with AMD.23Gold B. Merriam J.E. Zernant J. Hancox L.S. Taiber A.J. Gehrs K. Cramer K. Neel J. Bergeron J. Barile G.R. et al.AMD Genetics Clinical Study GroupVariation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.Nat. Genet. 2006; 38: 458-462Crossref PubMed Scopus (0) Google Scholar, 24Yates J.R. Sepp T. Matharu B.K. Khan J.C. Thurlby D.A. Shahid H. Clayton D.G. Hayward C. Morgan J. Wright A.F. et al.Genetic Factors in AMD Study GroupComplement C3 variant and the risk of age-related macular degeneration.N. Engl. J. Med. 2007; 357: 553-561Crossref PubMed Scopus (0) Google Scholar Studies are underway with regards to treatment regimens involving restoration of control mechanisms in this condition. Another example is the finding in atypical hemolytic uremic syndrome (aHUS [MIM 235400]) of a number of "loss-of function" polymorphisms in CFH and CD46 (encoding membrane cofactor protein, MCP or CD46 [MIM 120920]) and "gain-of-function" polymorphisms in CFB.25Hirt-Minkowski P. Dickenmann M. Schifferli J.A. Atypical hemolytic uremic syndrome: update on the complement system and what is new.Nephron Clin. Pract. 2010; 114: c219-c235Crossref PubMed Scopus (0) Google Scholar The prevalence of inherited complement deficiencies is difficult to estimate because most deficiencies may be caused by numerous different mutations in the relevant gene. Furthermore, deficiency is only revealed when by chance the physician or clinician decides that the symptoms of the patient warrant examination of the possible involvement of the complement system. As an example, the prevalence of C2 deficiency is fairly well known in southern Sweden because researchers at Lund University have an interest in the complement system. The clinical conditions most frequently associated with complement defects are cases of hereditary angioedema (HAE [MIM 106100]), systemic lupus erythematosus (SLE [MIM 152700]), and recurrent meningococcal infection.1Ricklin D. Hajishengallis G. Yang K. Lambris J.D. Complement: a key system for immune surveillance and homeostasis.Nat. Immunol. 2010; 11: 785-797Crossref PubMed Scopus (1136) Google Scholar, 26Botto M. Kirschfink M. Macor P. Pickering M.C. Würzner R. Tedesco F. Complement in human diseases: Lessons from complement deficiencies.Mol. Immunol. 2009; 46: 2774-2783Crossref PubMed Scopus (122) Google Scholar, 27Frank M.M. Complement disorders and hereditary angioedema.J. Allergy Clin. Immunol. 2010; 125: S262-S271Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 28Ram S. Lewis L.A. Rice P.A. Infections of people with complement deficiencies and patients who have undergone splenectomy.Clin. Microbiol. Rev. 2010; 23: 740-780Crossref PubMed Scopus (129) Google Scholar But because it is a multifunctional system and due to redundancies in immune defense mechanisms, the frequency of complement deficiencies in other patient groups is likely underestimated. Many inherited complement deficiencies have been revealed through association with invasive bacterial infections. This susceptibility appears to be restricted to a limited spectrum of bacteria, mainly encapsulated bacteria. The reason is not clear, but many bacteria (e.g., Streptococcus pyogenes, Staphylococcus aureus, Helicobacter pylori, and Pseudomonas aeruginosa) and several other microorganisms29Lambris J.D. Ricklin D. Geisbrecht B.V. Complement evasion by human pathogens.Nat. Rev. Microbiol. 2008; 6: 132-142Crossref PubMed Scopus (0) Google Scholar have evolved mechanisms to counteract the activities of the complement system and are thus less likely to be associated with complement deficiency. It is interesting that the strongest disease-susceptibility gene candidates for the development of SLE are found within members of the classical pathway of complement activation. This is speculated to be due to impaired immune complex handling and inefficient clearance of apoptotic cells in such patients.30Pickering M.C. Botto M. Taylor P.R. Lachmann P.J. Walport M.J. Systemic lupus erythematosus, complement deficiency, and apoptosis.Adv. Immunol. 2000; 76: 227-324Crossref PubMed Google Scholar An alternative model has been presented in which complement—together with other components of the innate immune system—participates in the "presentation" of SLE-inducing self-antigens to developing B cells. In this model, the complement system and innate immunity protect against responses to SLE (self) antigens by enhancing the elimination of self-reactive lymphocytes.31Carroll M.C. A protective role for innate immunity in systemic lupus erythematosus.Nat. Rev. Immunol. 2004; 4: 825-831Crossref PubMed Scopus (0) Google Scholar Homozygous deficiency of C1q is very strongly associated with a lupus-like disease with rash and glomerulonephritis. 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