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In: Anatomy and Physiology

Describe the effect of a mutation in the gene that encodes for the C3 protein of...

  1. Describe the effect of a mutation in the gene that encodes for the C3 protein of the complement pathway.

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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.

The classical pathway is especially important for control of infections with pyogenic encapsulated bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae, although it has also been implicated in control of viral infections, such as influenza. The pathway is initiated when the recognition protein C1q binds to antibodies bound to microbes or in immune complexes. Preexisting “natural IgM” produced by naive B cells5 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 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.. 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.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.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 (. 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 The cascade then proceeds as described above for the classical pathway.


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