The classical pathway (CP), so called because it was the earliest studied arm of the complement system, directly links the innate and acquired immune systems. There are nine proteins in the CP. As a matter of terminology, each CP component protein is designated with an uppercase C followed by a number. Fragments of these proteins generated by cleavage during the complement cascade are designated with a lower-case letter suffix (e.g., C3a, C3b). In general, the smaller product arising from a proteolytic activation step is given the fragment designation “a,” and the larger product is designated “b.” The sole exception to this rule is for the naming of the C2 proteolytic activation fragments, where, for historical reasons, the larger fragment is C2a and the smaller one is C2b.

C1, the first component of the CP, binds and is activated by the Fc portion of the antibody molecule. C1q is a macromolecule com plex composed of three individual protein subunits: C1q, C1r, and C1s. The largest of these subunits, C1q, is an 18-chain molecule with six copies each of three chains: A, B, and C. Structurally, C1q consists of a central core with six radiating arms. Each arm possesses a triple helical structure similar to collagen that is capped at the end with a head region consisting of a quaternary assembly of the globular domains from each of chains A, B, and C. C1q, largely through ionic interactions, links the C1 complex to the antibody molecule. In addition to its capacity for binding to antibody molecules, C1q possesses the capability to bind directly to the surfaces of some microorganisms and apoptotic cells, not unlike mannan-binding lectin (MBL; see Lectin Pathway discussion, later).

Associated with C1q are two molecules each of C1r and C1s. In unactivated C1, C1r and C1s are proenzyme serine esterases. Upon binding of C1q with an array of target-associated immunoglobulin G (IgG) Fc regions, which themselves have a propensity to form hexamers on the target surface, or directly to surface molecules of the pathogen, a conformational distortion of the C1q arms occurs that leads to reciprocal autoactivation of the associated C1r molecules. The active form of C1r then cleaves its associated C1s to generate an active serine protease.

Activated C1s is responsible for cleaving C4 and C2, the next two proteins in the complement pathway. Cleavage of C4 yields two fragments: C4a and C4b. C4b possesses a highly reactive thioester group within its C4d/TED region (structurally analogous to the C3d/TED region of C3 discussed further below) that allows it to bind covalently to molecules in the immediate vicinity of its active site. Only a small proportion of the C4b produced binds to proteins or carbohydrates on the targeted surface; the rest is inactivated by reaction with water in the surrounding milieu. This helps to prevent inadvertent C4b binding to surrounding host cells.

C2, the next substrate in the CP cascade, is susceptible to cleavage by C1s. Upon association with C4b, C2 is cleaved by activated C1s into two fragments: C2a and C2b. C2a, which is now an active serine protease, remains bound to C4b, thereby confining it to the targeted surface. C4b2a is termed the C3 convertase, an enzymatic complex that is responsible for binding and cleaving C3, the next component in the cascade. The function of the C3 convertase is to cleave large numbers of C3 molecules to produce C3b and C3a. Nascently activated C3b, similar to C4b, also possesses a highly reactive thioester bond, allowing a portion of the nascent C3b to covalently bind to the targeted surface (opsonization of the target) and thereby mark it for phagocytosis. The activated thioester in the bulk of the nascent C3b becomes water hydrolyzed and can no longer bind to a target. By contrast, all of the C3a fragment remains in solution, where it initiates a local inflammatory response.

An Ig-independent mechanism for activation of C1q has been identified.  The lectin protein Sign R1, which is expressed on a sub set of macrophages within the outer marginal zone sinus of the spleen, is capable of capturing to the surface of the marginal zone macrophage both C-polysaccharide–containing bacteria and C1q. The recruited C1 becomes activated and propagates the CP to deposit C3b on the captured bacterium. Sign R1 was also identified on the surface of resident dendritic cells (DC) in draining lymph nodes (LN) and shown to be important in capture and transport of inactivated influenza virus. This novel pathway provides an alternative innate recognition of pathogens leading to activation of the CP of complement.

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قسم التطوير يقيم دورة عن أخلاقيات المهنة للمنتسبين الجدد

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المجمع العلمي يحتفي بذكرى ولادة الإمامين الباقر والهادي (عليهما السلام)

قسم الشؤون الفكرية يطلق فعاليات الأسبوع الثالث من برنامج البذرة الصالحة

المزيد

الآخبار الصحية

ثورة طبية.. الذكاء الاصطناعي يكشف سرطان الكلى في وقت قياسي

لتعزيز الطاقة والتغلب على التعب.. عليك بـ7 طرق بسيطة

لتحسين الهضم والتحكم في الشهية.. ما أفضل وقت لتناول التمر؟

خبراء يكشفون تأثير الاستحمام في الظلام على جودة النوم !

المزيد

الآخبار التكنلوجية

إزالة ثاني أكسيد الكربون من الغلاف الجوي.. ما دور المحيطات والبحار؟

نظائر الهيليوم مقياس لاكتشاف رواسب الذهب.. كيف ذلك؟

الصين تطلق أول ناقلة نفط خام ذكية في العالم تعمل بالميثانول

الزمن على المريخ أسرع من الأرض.. دراسة علمية تكشف الفوارق

المزيد

مواضيع ذات صلة

B-Lymphocyte Coreceptors

The Complement System : Alternative Pathway

The Complement System : Lectin Pathway

Secondary Lymphoid Tissue

The Hematopoietic Microenvironment

The Pro-B- and Pre-B-Cell Checkpoints

Immunoglobulin Gene Rearrangement : Heavy Chain Gene Rearrangement

Transcriptional Regulation of B-Cell Development

Stages of B-Cell development

Genetic Engineering of Natural Killer Cells

The role of Natural Killer Cells in Human Disease

Natural Killer Cells and Hematopoietic Cell Transplantation