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Alternative complement pathway
Alternative complement pathway
Alternative complement pathway
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The classical and alternative complement pathways.
Alternative pathway. (Some labels are in Polish.)

The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.

The alternative pathway is one of three complement pathways that opsonize and kill pathogens. The pathway is triggered when the C3b protein directly binds a microbe. It can also be triggered by foreign materials and damaged tissues.

Signaling cascade

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This change in shape allows the binding of plasma protein Factor B, which allows Factor D to cleave Factor B into Ba and Bb.

Bb remains bound to C3(H2O) to form C3(H2O)Bb. This complex is also known as a fluid-phase C3-convertase. This convertase, the alternative pathway C3-convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b. The complex is believed to be unstable until it binds properdin, a serum protein. The addition of properdin forms the complex C3bBbP, a stable compound which can bind an additional C3b to form alternative pathway C5-convertase.

The C5-convertase of the alternative pathway consists of (C3b)2BbP (sometimes referred to as C3b2Bb). After the creation of C5 convertase (either as (C3b)2BbP or C4b2a3b from the classical pathway), the complement system follows the same path regardless of the means of activation (alternative, classical, or lectin). C5-convertase cleaves C5 into C5a and C5b. C5b binds sequentially to C6, C7, C8 and then to multiple molecules of C9 to form membrane attack complex.

Regulation

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Since C3b is free and abundant in the plasma, it can bind to either a host cell or a pathogen surface. To prevent complement activation from proceeding on the host cell, there are several different kinds of regulatory proteins that disrupt the complement activation process:

  • Complement Receptor 1 (CR1 or CD35) and DAF (decay accelerating factor also known as CD55) compete with Factor B in binding with C3b on the cell surface and can even remove Bb from an already formed C3bBb complex
  • The formation of a C3 convertase can also be prevented when a plasma protease called complement factor I cleaves C3b into its inactive form, iC3b. Factor I requires a C3b-binding protein cofactor such as complement factor H, CR1, or membrane cofactor of proteolysis (MCP or CD46)
  • Complement factor H can inhibit the formation of the C3 convertase by competing with factor B for binding to C3b;[1] accelerate the decay of the C3 convertase;[2] and act as a cofactor for factor I-mediated cleavage of C3b.[3] Complement factor H preferentially binds to vertebrate cells (because of affinity for sialic acid residues), allowing preferential protection of host (as opposed to bacterial) cells from complement-mediated damage.
  • CFHR5 (Complement factor H-Related protein 5) is able to bind to act as a cofactor for factor I, has decay accelerating activity and is able to bind preferentially to C3b at host surfaces.[4]

Role in disease

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Dysregulation of the complement system has been implicated in several diseases and pathologies, including atypical hemolytic uremic syndrome in which kidney function is compromised. Age related macular degeneration (AMD) is now believed to be caused, at least in part, by complement overactivation in retinal tissues.[5] Alternative pathway activation also plays a significant role in complement-mediated renal disorders such as atypical hemolytic uremic syndrome, C3 glomerulopathy, and C3 glomerulonephritis (Dense Deposit Disease or MPGN Type II).[5]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Alternative complement pathway

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from Grokipedia
The alternative complement pathway (AP) is one of the three principal activation routes of the complement system—a key arm of innate immunity—distinguished by its antibody-independent mechanism that relies on spontaneous hydrolysis of the central protein C3 in plasma, a process termed C3 tickover. This low-level, continuous activation generates C3(H₂O), which functions as a thioester-containing analog of C3b, enabling the pathway to surveil for foreign surfaces and rapidly amplify responses upon detecting pathogens or altered host cells. The AP culminates in the formation of C3 and C5 convertases, driving effector functions including opsonization for phagocytosis, recruitment of inflammatory cells via anaphylatoxins (C3a and C5a), and assembly of the membrane attack complex (MAC) for direct lysis of targets. Initiation of the AP occurs through the binding of Factor B to C3(H₂O) or surface-deposited C3b, followed by cleavage of Factor B by the Factor D to yield the Bb fragment and form the initial , C3(H₂O)Bb, in the fluid phase. On pathogen surfaces lacking host regulators, C3b-Factor B complexes are similarly processed by Factor D into the stable surface-bound C3bBb, which is further stabilized by to extend its half-life and enhance activity. This convertase proteolytically cleaves additional C3 molecules, releasing C3a and depositing more C3b to perpetuate a amplification loop that accounts for the majority—often over 80%—of total C3b generation during complement , including in the classical and pathways. The AP's primary physiological role is to provide constitutive immune surveillance and rapid amplification of complement responses against microbes, damaged cells, and immune complexes, thereby bridging innate and adaptive immunity through enhanced and B-cell activation. It is tightly regulated to avoid host damage, primarily by soluble inhibitors such as (which competes with Factor B for C3b binding and acts as a cofactor for Factor I-mediated degradation) and membrane-bound proteins like (/CD55), membrane cofactor protein (/CD46), and (CR1/CD35), which disassemble convertases or promote C3b inactivation selectively on self-surfaces. Dysregulation of the AP underlies a spectrum of inflammatory and autoimmune disorders, including (aHUS) and C3 glomerulopathy (C3G) due to overactivation leading to endothelial damage and renal pathology, (PNH) from unchecked MAC formation on blood cells, and (AMD) via chronic in the eye. Conversely, genetic deficiencies in AP components like or Factor D heighten vulnerability to infections and other encapsulated bacteria, underscoring its essential protective function. Therapeutic targeting of AP regulators, such as Factor D inhibitors (e.g., danicopan, approved in 2024 for PNH) and Factor B inhibitors (e.g., , approved in 2023 for PNH and expanded in 2025 for C3G and ), has emerged as a strategy to mitigate these conditions while preserving immune defense.[](https://www.fepblue.org/-/media/PDFs/Medical-Policies/2025/January/Pharmacy-Policies/Remove-and-Replace/585060-Voydeya-danico pan.pdf)

Overview

Definition and Significance

The alternative complement pathway is an antibody-independent arm of the that amplifies innate immune responses through the spontaneous hydrolysis of the central protein C3 in plasma, generating a fluid-phase that recognizes and targets foreign surfaces lacking host regulatory proteins. This pathway provides a constitutive surveillance mechanism, enabling rapid opsonization, , and of pathogens without requiring prior exposure or adaptive immunity. Unlike the classical and pathways, which depend on specific recognition molecules, the alternative pathway initiates broadly via low-level C3 activation and surface discrimination, converging with the other pathways at the C3 level to drive downstream effector functions. In immune responses, the alternative pathway accounts for approximately 80-90% of total complement activity, primarily through its amplification loop that enhances C3 and C5 cleavage initiated by other pathways, underscoring its role as a dominant contributor to host defense. It serves as a first-line barrier against , viruses, and other microbes, promoting efficient clearance in serum and on tissues while minimizing self-damage through host-specific regulators. This basal activity ensures continuous monitoring of the extracellular environment, making the pathway essential for innate immunity's speed and versatility. Historically, the alternative pathway was first identified in the as the "properdin system" by Louis Pillemer and colleagues, who described as a novel serum protein mediating non-antibody-dependent bacteriolysis, establishing its distinct role in immune phenomena. This discovery highlighted the pathway's function in serum-based surveillance, independent of the then-dominant classical pathway, and laid the foundation for understanding complement's multifaceted activation. The alternative pathway exhibits strong evolutionary conservation across all s, reflecting its fundamental importance in innate host defense from fish to mammals, where it likely emerged as one of the earliest complement activation routes before the development of antibody-dependent mechanisms. This preservation emphasizes its core contribution to survival against infection throughout vertebrate evolution.

Comparison with Other Pathways

The alternative complement pathway differs fundamentally from the classical and pathways in its initiation mechanism, relying on spontaneous of C3—a process known as "tickover"—to generate a fluid-phase C3b that can bind to nearby surfaces without requiring specific recognition molecules. In contrast, the classical pathway is triggered by antibody-antigen immune complexes binding to C1q, while the activates via mannose-binding lectin (MBL) or ficolins recognizing patterns on pathogens. This spontaneous initiation enables the alternative pathway to provide a constant, low-level surveillance of host tissues and the environment for potential threats. A key distinction lies in amplification efficiency: the alternative pathway features a self-amplifying loop where surface-bound C3b recruits factor B to form more (C3bBb), exponentially depositing additional C3b and enhancing opsonization or on target surfaces. The classical and lectin pathways, however, initiate through distinct C1 or MASP complexes that cleave C4 and C2 to form the (C4b2a) in a more linear, non-amplifying manner, making them less efficient for rapid escalation without prior immune priming. This loop positions the alternative pathway as the primary amplifier across all complement routes, often accounting for over 80-90% of C3 activation during immune responses. Physiologically, the alternative pathway serves as a frontline, non-specific defense mechanism, conducting ongoing patrolling in the absence of adaptive immunity or , which suits its role in innate immunity against novel pathogens or host debris. The classical pathway, tied to , excels in targeted responses to known s, whereas the bridges innate recognition of microbial sugars with downstream complement effects, but both are more antigen- or pattern-driven and less ubiquitous than the alternative's basal activity. Despite these differences, all three pathways converge at the central hub of C3 cleavage, sharing the terminal sequence that assembles the membrane attack complex (MAC) to lyse targets. Notably, the alternative pathway predominates in the fluid phase, where it can initiate and amplify independently before other routes engage.

Components

Central Protein: C3

Complement component C3 serves as the cornerstone molecule of the alternative complement pathway, integrating activation signals and mediating key effector functions through its cleavage products. As the most abundant complement protein in human plasma, C3 ensures rapid responsiveness to immune threats by providing a reservoir for opsonization, , and amplification. Its activation marks the convergence point for all complement pathways, highlighting its pivotal role in innate immunity. C3 is a 185 kDa glycoprotein composed of two disulfide-linked polypeptide chains: an α-chain of approximately 110 kDa and a β-chain of approximately 75 kDa. The chains are derived from a single precursor polypeptide that undergoes post-translational processing, including cleavage by furin-like proteases to separate the chains while maintaining their linkage via an intermolecular disulfide bond. A critical structural feature is the internal thioester bond within the thioester-containing domain (TED) of the α-chain, formed between Cys-1010 and Gln-1013, which remains latent in native C3 but becomes reactive upon activation to enable covalent attachment to target surfaces. C3 is primarily synthesized in the liver by hepatocytes, contributing to its high systemic levels, but it is also produced extrahepatically by various cell types such as monocytes, macrophages, fibroblasts, and epithelial cells, allowing for localized immune responses in tissues. In plasma, C3 circulates at a concentration of approximately 1.2 g/L, representing about 2.5% of total serum globulin and underscoring its readiness for immediate deployment in complement activation. Upon proteolytic cleavage by C3 convertases—formed through interactions with factors B and D in the alternative pathway—C3 generates two multifunctional fragments: C3a and C3b. C3a acts as an anaphylatoxin, binding to C3a receptor (C3aR) on immune cells to promote , , and pro-inflammatory cytokine release. In contrast, C3b functions as an , facilitating by binding complement receptors, and its exposed thioester bond allows irreversible covalent deposition on or host surfaces, marking them for immune clearance. The C3 gene, located on 19p13.3, encodes a 1663-amino-acid pre-pro-protein that is processed into mature C3. Genetic polymorphisms in C3, such as the common C3F (fast) and C3S (slow) allotypes resulting from variants like rs2230199, have been associated with altered susceptibility to autoimmune and infectious diseases, though specific mechanisms are pathway-dependent.

Auxiliary Factors: B, D, Properdin

Factor B is a 93 kDa and that serves as a key component in the alternative complement pathway, where it binds to C3b and is subsequently cleaved by Factor D into the catalytic subunit Bb (approximately 60 kDa) and the regulatory subunit Ba (approximately 33 kDa). The Bb fragment provides the protease activity essential for convertase function, while Ba contributes to regulatory interactions that influence pathway efficiency. Factor B circulates in plasma at concentrations around 200 μg/mL and is structurally characterized by three complement control protein (CCP) domains in Ba and a domain in Bb, enabling its specific recognition and activation within the pathway. Factor D, also known as adipsin, is a 24 kDa that functions as the rate-limiting in the alternative pathway due to its low plasma concentration of approximately 1 μg/mL, the lowest among complement proteins. It exists in a constitutively active form without requiring activation, featuring a single-chain structure with a typical of serine proteases, which allows it to selectively cleave Factor B only when bound to an activating surface. This specificity ensures efficient pathway initiation while minimizing off-target activity in soluble environments. Properdin, or Factor P, is a highly positively charged 53 kDa that exists primarily as multimers, including dimers (P2), trimers (P3), and tetramers (P4), which enhance its for surfaces. It stabilizes the C3bBb convertase complex by binding to C3b, increasing its half-life by 5- to 10-fold and thereby amplifying alternative pathway activity on surfaces. The multimeric forms, particularly higher-order oligomers, provide extended conformations that facilitate clustering and prolonged enzymatic function. Biosynthesis of Factors B and D occurs predominantly in the liver by hepatocytes, with Factor D also produced by adipocytes and myeloid cells, contributing to its systemic distribution. In contrast, is primarily synthesized by immune cells such as monocytes, T lymphocytes, and neutrophils, with additional production from hepatocytes and endothelial cells under specific conditions like . These sites of production allow for localized regulation of pathway components during immune responses.

Activation Process

Spontaneous Initiation

The alternative complement pathway begins with the spontaneous of the internal bond in native complement component C3, a process that occurs continuously in plasma at a low but steady rate. This hydrolysis exposes reactive groups on C3, converting it to a conformationally altered form known as C3(H₂O), which structurally and functionally mimics C3b, the activated fragment of C3. C3(H₂O) can then bind factor B in the fluid phase, setting the stage for further interactions with auxiliary factors. The rate of this spontaneous , often termed "C3 tickover," is approximately 0.2–0.4% of total plasma C3 per hour under physiological conditions, ensuring a basal level of activated C3 derivatives without external stimuli. This low-level activation maintains the pathway in a primed state, generating sufficient C3(H₂O) to support ongoing surveillance. The resulting fluid-phase complex facilitates the cleavage of additional C3 molecules into C3b, which are released and available for deposition. These C3b fragments deposit covalently onto nearby surfaces through their reactive , enabling surface recruitment during the initiation phase. On membranes, which lack host-specific protective elements, this deposition is sustained and progresses, distinguishing foreign entities from self-surfaces where progression is limited due to the absence of such regulators. This mechanism allows the pathway to preferentially amplify on non-host materials while minimizing unintended activation on healthy cells.

Formation of C3 Convertase

The formation of the C3 convertase (C3bBb) in the alternative complement pathway occurs through a stepwise assembly process initiated after C3b deposition. C3b binds Factor B in a magnesium ion (Mg²⁺)-dependent reaction to form the proenzyme complex C3bB. Factor D, a serine protease, then cleaves Factor B within this complex, releasing the Ba fragment and generating the active C3 convertase C3bBb. This assembly is depicted by the following reactions: C3b + Factor B→Mg2+C3bB\text{C3b + Factor B} \xrightarrow{\text{Mg}^{2+}} \text{C3bB}
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