Immunoglobulins form the core of the body’s adaptive immune system, a name that reflects its ability to generate antibodies against novel infectious agents. The innate immune system derives its name from the fact that the number, function, and specificity of its components are fixed and remain constant throughout life. The complement system forms the humoral arm of the innate immune system. Since it can be activated by exposure to antibody-antigen complexes, it can be considered to function as a support for or “complement” of the adaptive immune system.

The complement system displays features reminiscent of the clot-inducing coagulation cascade. Both consist of sets of circulating zymogens (proproteins) that remain catalytically dormant until activated by proteolytic cleavage. These proproteins, called complement factors, are synthesized by a variety of cell types that include hepatocytes, macrophages, monocytes, and intestinal endothelial cells. As is the case for clotting factors, most complement factors are proproteases that, on activation, target other components of the system, thereby generating a series or cascade of proteolytic activation events that produce one or more protective end products (eg, fibrin).

The classical pathway for activating the complex system is triggered when an antibody-antigen complex binds to and stimulates the protease activity of factor C1. Activated C1 then cleaves complement factor C2 to form two smaller proteins, C2a and C2b, as well as cleaving complement factor C4 to form C4a and C4b (Figure 1). Two of the proteolytic fragments, C2a and C4b, then associate together to form a new protease, the C3 convertase, which cleaves complement factor C3 into C3a and C3b. C3a now binds with the C2a:C4b heterodimer to form a heterotrimeric complex, the C5 convertase, that cleaves complement factor C5 into C5a and C5b. The C5b protein then combines with complement factors C6, C7, C8, and C9 to form the membrane attack complex (MAC). MAC kills bacterial invaders by binding to and opening a pore in their plasma membrane. Following lysis, the bacterial remains are destroyed by phagocytic macrophages. Meanwhile, the C3a and C5a proteins serve as chemoattractants that recruit leukocytes to the site of infection and stimulate an inflammatory response.

Fig1. The complement cascade. Activation of the complement system can occur via three different mechanisms, referred to as the classical, lectin, and alternative pathways. Shown are the major components involved in each pathway, the products formed by proteolytic cleavage of the inactive proproteins, and the major complexes formed. Colons are used to indicate association in a complex.

Targeting of the MAC to invading bacteria is facilitated by the presence of thioester bonds in C3 and C4. Like the thioester bond in the plasma protease inhibitor α2-macroglobulin, these highly reactive bonds becomes exposed as a result of the con formational change that accompanies proteolytic activation. In the case of C3 and C4, the thioester reacts with the hydroxyl groups of the bacteria’s surface polysaccharides, covalently anchoring the C5 convertase complex of which they are a part to the targeted pathogen. This enables the remaining components of the MAC to be formed in close proximity to the bacterial membrane, facilitating assembly.

Activation can also be triggered via the lectin pathway. Bacterial polysaccharides bind to a complement factor called mannose-binding lectin (MBL) or mannan-binding protein (MBP). The lectin-polysaccharide complex then recruits and activates C4 (see Figure 1). The term lectin refers to any protein that binds polysaccharides. Most lectins are highly selective. MBL is specific for the mannose-containing carbohydrate moieties (mannans) of glycoproteins and lipopolysaccharides present on the surface of gram-positive bacteria, some viruses, and several fungi. On binding to the polysaccharide-MBL com plex, C4 undergoes autoproteolysis, releasing C4a and C4b. In addition, C4 cleaves C2 into C2a and C2b. The remainder of cascade mirrors that for the classical pathway.

MBL circulates as large, ≈ 400 to 700 kDa, multivalent complexes consisting of four or more copies of a homotrimeric core unit, each of which contains three identical ≈ 30-kDa subunits. The polypeptides in this core are linked by the intertwining of their collagen-like domains. The carbohydrate binding-domain reside in their globular heads. To form MBL, four or more homotrimers become covalently linked by disulfide bonds between their amino-terminal tail regions. These form a “stalk” from which the C-terminal carbohydrate binding heads project in a branched arrangement resembling that of an immunoglobulin (Figure 2).

Fig2. Schematic representation of mannose binding lectin (MBL). Shown is a schematic diagram of a MBL comprised of four sets of MBL homotrimers. The carbohydrate-binding domains are colored. The intertwined collagen-like binding domains for each trimer are shown in blue. The stalk region, where the amino terminal portions of the homotrimers of collagen-like domains associate together, is colored orange and yellow, with yellow marking the region where the S—S cross-links that stabilize the tetramer of homotrimers located.

The complement system also can be activated by the alternative pathway, in which C3 is activated by direct chemical hydrolysis, a process sometimes referred to as “ticking over.” In the alternative pathway, C3b binds complement factor B, forming a C3b:B complex that is then cleaved by complex factor D. The resulting C3b:Bb complex possesses C5 convertase activity.

اخر الاخبار

اخبار العتبة العباسية المقدسة

خدمات صحية متكاملة قدَّمها قسم الشؤون الطبية لزائري ليلة النصف من شعبان في مجمَّع الشيخ الكليني

خدمات صحية متكاملة قدَّمها قسم الشؤون الطبية لزائري ليلة النصف من شعبان في مجمَّع الشيخ الكليني

في ذكرى ولادة الإمام المهدي (عجّل الله فرجه).. قسم الشؤون الفكرية يصدر عددًا خاصًّا من مجلة العقيدة

للاطّلاع على خدماته المقدمة للزائرين مركز السيد جعفر الحلي يستقبل المدير العام لمديرية العمليات والخدمات الطبية في وزارة الصحة

المزيد

الآخبار الصحية

دراسة تكشف "سر الوسادة".. ودورها في حماية البصر

بالأشعة تحت الحمراء.. "ثورة علمية" في علاج اللاعبين

مشروب أحمر يخفض ضغط الدم "بشكل ملحوظ"

الصحة العالمية تكشف حقيقة انتشار فيروس نيباه خارج الهند

المزيد

الآخبار التكنلوجية

دراسة تدفعك لشراء ساعة ذكية "فورا".. هذا ما تقوله عن قلبك

علماء حاصلون على "نوبل": الذكاء الاصطناعي لن يستبدل الإنسان

وانغ هو: القمة العالمية للعلماء تجسد تقدير الإمارات للعلم

رئيس رابطة كبار العلماء يعلن تأسيس مقر في الإمارات

المزيد

مواضيع ذات صلة

Monocytopoiesis

Eosinophil Production

Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Cytokine Regulation of Myeloid Proliferation and Differentiation

Neutrophil Granules and Their Content Proteins

Stages of Neutrophil Differentiation

T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity

Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion

Allogeneic Banked Cells

Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies

Types of Cellular Immunotherapy

Adoptive Immunotherapy of Cancer