Fact-checked by Grok 2 weeks ago

Alternative complement pathway

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.^[1] 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.^[2] 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.^[3] 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 serine protease Factor D to yield the Bb fragment and form the initial C3 convertase, C3(H₂O)Bb, in the fluid phase.^[1] On pathogen surfaces lacking host regulators, C3b-Factor B complexes are similarly processed by Factor D into the stable surface-bound C3 convertase C3bBb, which is further stabilized by properdin to extend its half-life and enhance activity.^[2] This convertase proteolytically cleaves additional C3 molecules, releasing C3a and depositing more C3b to perpetuate a positive feedback amplification loop that accounts for the majority—often over 80%—of total C3b generation during complement activation, including in the classical and lectin pathways.^[3] 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 antigen presentation and B-cell activation.^[1] It is tightly regulated to avoid host damage, primarily by soluble inhibitors such as Factor H (which competes with Factor B for C3b binding and acts as a cofactor for Factor I-mediated degradation) and membrane-bound proteins like decay-accelerating factor (DAF/CD55), membrane cofactor protein (MCP/CD46), and complement receptor 1 (CR1/CD35), which disassemble convertases or promote C3b inactivation selectively on self-surfaces.^[2] Dysregulation of the AP underlies a spectrum of inflammatory and autoimmune disorders, including atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) due to overactivation leading to endothelial damage and renal pathology, paroxysmal nocturnal hemoglobinuria (PNH) from unchecked MAC formation on blood cells, and age-related macular degeneration (AMD) via chronic inflammation in the eye.^[3] Conversely, genetic deficiencies in AP components like properdin or Factor D heighten vulnerability to Neisseria infections and other encapsulated bacteria, underscoring its essential protective function.^[2] Therapeutic targeting of AP regulators, such as Factor D inhibitors (e.g., danicopan, approved in 2024 for PNH) and Factor B inhibitors (e.g., iptacopan, approved in 2023 for PNH and expanded in 2025 for C3G and IgA nephropathy), has emerged as a strategy to mitigate these conditions while preserving immune defense.^[3]^[4]^[5][](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 complement system that amplifies innate immune responses through the spontaneous hydrolysis of the central protein C3 in plasma, generating a fluid-phase C3 convertase that recognizes and targets foreign surfaces lacking host regulatory proteins.^[1] This pathway provides a constitutive surveillance mechanism, enabling rapid opsonization, inflammation, and lysis of pathogens without requiring prior antigen exposure or adaptive immunity.^[6] Unlike the classical and lectin 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.^[1] 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.^[6] It serves as a first-line barrier against bacteria, viruses, and other microbes, promoting efficient pathogen clearance in serum and on tissues while minimizing self-damage through host-specific regulators.^[7] This basal activity ensures continuous monitoring of the extracellular environment, making the pathway essential for innate immunity's speed and versatility.^[6] Historically, the alternative pathway was first identified in the 1950s as the "properdin system" by Louis Pillemer and colleagues, who described properdin as a novel serum protein mediating non-antibody-dependent bacteriolysis, establishing its distinct role in immune phenomena.^[8] 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.^[9] The alternative pathway exhibits strong evolutionary conservation across all vertebrates, 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.^[10] This preservation emphasizes its core contribution to survival against infection throughout vertebrate evolution.^[11]

Comparison with Other Pathways

The alternative complement pathway differs fundamentally from the classical and lectin pathways in its initiation mechanism, relying on spontaneous hydrolysis 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 lectin pathway activates via mannose-binding lectin (MBL) or ficolins recognizing carbohydrate 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 positive feedback loop where surface-bound C3b recruits factor B to form more C3 convertase (C3bBb), exponentially depositing additional C3b and enhancing opsonization or lysis on target surfaces. The classical and lectin pathways, however, initiate through distinct C1 or MASP complexes that cleave C4 and C2 to form the C3 convertase (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 pattern recognition, which suits its role in innate immunity against novel pathogens or host debris. The classical pathway, tied to humoral immunity, excels in targeted responses to known antigens, whereas the lectin pathway 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, inflammation, and amplification. Its activation marks the convergence point for all complement pathways, highlighting its pivotal role in innate immunity.^[12] 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.^[13] 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 human 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.^[12]^[14] 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 chemotaxis, mast cell degranulation, and pro-inflammatory cytokine release. In contrast, C3b functions as an opsonin, facilitating phagocytosis by binding complement receptors, and its exposed thioester bond allows irreversible covalent deposition on pathogen or host surfaces, marking them for immune clearance.^[13]^[12] The C3 gene, located on chromosome 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.^[15]^[16]

Auxiliary Factors: B, D, Properdin

Factor B is a 93 kDa glycoprotein and serine protease zymogen 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).^[17] The Bb fragment provides the protease activity essential for convertase function, while Ba contributes to regulatory interactions that influence pathway efficiency.^[18] 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 serine protease domain in Bb, enabling its specific recognition and activation within the pathway.^[19] Factor D, also known as adipsin, is a 24 kDa serine protease that functions as the rate-limiting enzyme in the alternative pathway due to its low plasma concentration of approximately 1 μg/mL, the lowest among complement proteins.^[3] It exists in a constitutively active form without requiring zymogen activation, featuring a single-chain structure with a catalytic triad typical of serine proteases, which allows it to selectively cleave Factor B only when bound to an activating surface.^[20] This specificity ensures efficient pathway initiation while minimizing off-target activity in soluble environments.^[21] Properdin, or Factor P, is a highly positively charged 53 kDa glycoprotein that exists primarily as multimers, including dimers (P2), trimers (P3), and tetramers (P4), which enhance its avidity for surfaces.^[22] 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 pathogen surfaces.^[23] The multimeric forms, particularly higher-order oligomers, provide extended conformations that facilitate clustering and prolonged enzymatic function.^[24] 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.^[25] In contrast, properdin 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 shear stress.^[26] These sites of production allow for localized regulation of pathway components during immune responses.^[27]

Activation Process

Spontaneous Initiation

The alternative complement pathway begins with the spontaneous hydrolysis of the internal thioester 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.^[28] The rate of this spontaneous hydrolysis, 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.^[29] 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.^[28] These C3b fragments deposit covalently onto nearby surfaces through their reactive thioester, enabling surface recruitment during the initiation phase. On pathogen 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.^[30] This mechanism allows the pathway to preferentially amplify on non-host materials while minimizing unintended activation on healthy cells.^[30]

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.^[28] Factor D, a serine protease, then cleaves Factor B within this complex, releasing the Ba fragment and generating the active C3 convertase C3bBb.^[28] This assembly is depicted by the following reactions:

\text{C3b + Factor B} \xrightarrow{\text{Mg}^{2+}} \text{C3bB}

\text{C3bB + Factor D} \rightarrow \text{C3bBb + Ba}

The C3bBb complex exhibits limited stability in the fluid phase, with a half-life of approximately 90 seconds due to spontaneous dissociation of the Bb subunit.^[31] Properdin enhances the stability of surface-bound C3bBb by binding to both C3b and Bb domains, extending the half-life to about 30 minutes and thereby promoting sustained enzymatic activity on pathogen or host surfaces.^[32] As the core enzyme of the pathway, C3bBb proteolytically cleaves additional C3 molecules into C3a and C3b at a rate approximately 1,000-fold higher than the spontaneous thioester hydrolysis of native C3, enabling rapid generation of more C3b for pathway amplification.^[28] This efficient cleavage underscores the convertase's role in escalating the response while maintaining focus on activated surfaces.

Amplification and C5 Convertase

The amplification loop of the alternative complement pathway represents a key positive feedback mechanism that enhances the deposition of C3b on activator surfaces. Once the initial C3 convertase (C3bBb) is formed, it cleaves additional C3 molecules into C3a and C3b, with the nascent C3b fragments covalently attaching to nearby surfaces or the convertase itself. This binding of a second C3b molecule to the C3bBb complex generates the C5 convertase, denoted as (C3b)₂Bb, which possesses greater stability and proteolytic efficiency compared to the C3 convertase.^[1] Properdin (factor P) further stabilizes this C5 convertase by associating with it to form (C3b)₂BbP, extending its half-life on pathogen surfaces and promoting sustained amplification. The core reactions of this loop can be summarized as follows:

\text{C3bBb} + \text{C3} \to (\text{C3b})_2\text{Bb}

(\text{C3b})_2\text{Bb} + \text{C5} \to \text{C5b} + \text{C5a}

The C5 convertase then specifically cleaves C5 into C5a, a potent anaphylatoxin that recruits inflammatory cells, and C5b, which nucleates the terminal complement components to form the membrane attack complex (MAC).^[33] This feedback process drives exponential growth in complement activation, with each cycle of the amplification loop capable of depositing up to 1000 C3b molecules per initial convertase on target surfaces, thereby rapidly scaling the immune response while confining it to non-host cells. This amplification culminates in terminal pathway activation, converging with the classical and lectin pathways at the MAC formation step.^[1]

Regulation

Soluble Regulators: Factor H and I

Factor H is a soluble glycoprotein regulator of the alternative complement pathway, with a molecular weight of approximately 155 kDa.^[34] It consists of 20 short consensus repeat (SCR) domains, also known as complement control protein (CCP) modules, which enable its flexible structure and specific interactions.^[34] Factor H circulates in human plasma at a concentration of about 500 μg/mL.^[34] Its primary functions include binding to C3b, which competes with Factor B for binding sites and thereby inhibits the formation of the C3 convertase (C3bBb).^[34] Additionally, Factor H accelerates the decay of preformed C3bBb by displacing the Bb component.^[34] The C-terminal SCR domains 19-20 are crucial for recognizing host cell surfaces, such as those bearing sialic acid or other polyanions, allowing Factor H to preferentially protect self-surfaces from complement activation.^[34] Factor I is a serine protease that serves as another key soluble inhibitor in the alternative pathway, with a molecular weight of 88 kDa as a heterodimer composed of heavy and light chains linked by disulfide bonds.^[35] It is present in plasma at a concentration of approximately 35 μg/mL.^[36] Factor I alone exhibits minimal proteolytic activity toward C3b, but it cleaves the α-chain of C3b to generate the inactivated form iC3b, which serves as a less active opsonin and prevents further convertase assembly.^[35] The concerted action of Factor H and Factor I is essential for efficient regulation, as Factor H acts as a cofactor that dramatically enhances the rate of Factor I-mediated C3b cleavage compared to spontaneous inactivation.^[34] This complex formation allows for rapid degradation of C3b in the fluid phase, preventing uncontrolled amplification of the pathway on non-target surfaces.^[34] Together, these regulators maintain homeostasis by limiting alternative pathway activity in plasma while permitting targeted responses on pathogens.^[34]

Membrane Regulators: DAF, MCP, CR1

Membrane regulators of the alternative complement pathway are cell-surface proteins that protect host tissues from unintended complement activation and amplification, primarily by targeting the C3 convertase (C3bBb) and its downstream effects. These proteins, including decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), and complement receptor 1 (CR1, CD35), are expressed ubiquitously on mammalian cells but are often absent on microbial surfaces, enabling selective complement attack on pathogens.^[37]^[38] DAF (CD55) is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein consisting of four short consensus repeats (SCRs) that accelerate the dissociation of the Bb component from the alternative pathway C3 convertase (C3bBb), thereby inhibiting its assembly and activity; it also disrupts the C5 convertase (C3bBbC3b) to prevent downstream activation. This decay-accelerating mechanism provides rapid, transient protection against complement amplification on host cell surfaces. DAF is broadly expressed on hematopoietic and non-hematopoietic cells, including endothelial cells, podocytes, and erythrocytes.^[37]^[38]^[39] MCP (CD46), a type I transmembrane protein with four SCRs and a serine-threonine-rich region, functions as a cofactor for factor I-mediated proteolytic cleavage of C3b to its inactivated form iC3b, permanently inactivating the molecule and halting alternative pathway progression; this process requires the soluble regulator factor I. MCP exists in multiple isoforms (51–68 kDa) and is expressed on nearly all nucleated human cells, providing essential protection against autologous complement damage.^[37]^[38]^[39] CR1 (CD35), a large transmembrane glycoprotein (~220 kDa) with 30 SCRs organized into long homologous repeats, exhibits both decay-accelerating activity by dissociating Bb from C3bBb and cofactor activity for factor I to cleave C3b and C4b, while also binding iC3b and C3d with lower affinity to facilitate immune complex clearance. As a complement receptor, CR1 is predominantly expressed on erythrocytes, B cells, neutrophils, monocytes, and glomerular podocytes, where it concentrates complement fragments for regulated processing.^[37]^[38]^[39] These membrane regulators cooperate with soluble factors, such as factor H and factor I, to enhance overall control of alternative pathway activation on host surfaces.^[38]

Functions

Microbial Lysis and Opsonization

The alternative complement pathway contributes to microbial defense primarily through two mechanisms: opsonization, which tags pathogens for phagocytosis, and direct lysis via formation of the membrane attack complex (MAC). In opsonization, C3 convertase (C3bBb) cleaves C3 into C3a and C3b, with C3b covalently binding to microbial surfaces such as carbohydrates or lipids on bacteria and fungi. This C3b coating, along with its degradation product iC3b, serves as an opsonin by interacting with complement receptors CR1 (CD35) on erythrocytes, macrophages, and neutrophils, and CR3 (CD11b/CD18) on myeloid cells, thereby facilitating enhanced uptake and destruction by phagocytes.^[1] Direct microbial lysis occurs through assembly of the MAC, initiated when C5 convertase (C3bBbC3b) cleaves C5 into C5a and C5b. C5b sequentially binds C6, C7, and C8, anchoring the complex to the target membrane, followed by polymerization of 12-18 C9 molecules to form a transmembrane pore approximately 100 Å in diameter. These pores disrupt the integrity of the microbial lipid bilayer, particularly in Gram-negative bacteria like Neisseria meningitidis, by causing colloid-osmotic lysis and loss of membrane potential. The alternative pathway's amplification loop ensures robust MAC formation on pathogen surfaces, independent of antibodies.^[1] The efficacy of these processes is evident in the pathway's role against Neisseria species, where normal alternative pathway activity mediates efficient killing of serum-sensitive strains in bactericidal assays, whereas deficiencies in components like properdin or terminal complement proteins (C5-C9) result in markedly reduced lysis and heightened infection risk. Additionally, the anaphylatoxins C3a and C5a generated during activation amplify the response by binding G protein-coupled receptors (C3aR and C5aR) on neutrophils, eosinophils, and mast cells, promoting chemotaxis, degranulation, and local inflammation to recruit further phagocytic cells to the site of infection.^[40]

Clearance of Apoptotic Cells

The alternative complement pathway plays a crucial role in the non-inflammatory clearance of apoptotic cells by initiating low-level activation on their surface, particularly on apoptotic blebs. This process begins with the spontaneous hydrolysis of C3, leading to the formation of a fluid-phase C3 convertase (C3(H2O)Bb) that deposits small amounts of C3b onto the exposed surfaces of dying cells, which often lack sufficient membrane regulators to inhibit this "tick-over" activity. Unlike robust activation against pathogens, this controlled deposition of C3b serves as an opsonin without progressing to the formation of the membrane attack complex (MAC), thereby facilitating phagocytosis while preventing the release of pro-inflammatory signals.^[41] The opsonized apoptotic cells are recognized through the cleavage product iC3b, which binds to complement receptor 3 (CR3, also known as CD11b/CD18) on the surface of macrophages and other phagocytes. This interaction promotes silent phagocytosis, where the apoptotic cells are engulfed without triggering an inflammatory response, ensuring efficient removal in tissues such as the spleen and liver. Regulation by factors like Factor H and I limits amplification, preventing excessive complement activation that could lead to tissue damage.^[42]^[43] Physiologically, this mechanism is essential for clearing approximately 10^11 apoptotic cells generated daily in the human body, a process that maintains immune homeostasis and prevents the accumulation of autoantigens that could trigger autoimmunity. By promoting tolerance to self-antigens during clearance, the pathway supports long-term immune regulation and reduces the risk of autoimmune diseases.^[44]^[45] The alternative pathway integrates with phosphatidylserine (PS) exposure on apoptotic cells, where PS serves as an initial "eat-me" signal that enhances targeted C3b tagging, combining direct recognition by phagocyte receptors with complement-mediated opsonization for more effective clearance.^[46]

Clinical Aspects

Dysregulation in Diseases

Dysregulation of the alternative complement pathway contributes to several immune-mediated disorders, primarily through genetic mutations or acquired defects that impair regulatory mechanisms, leading to uncontrolled activation and tissue damage. In atypical hemolytic uremic syndrome (aHUS), mutations in the factor H gene (CFH) are a major cause, resulting in deficient regulation of C3 convertase and excessive complement activation on endothelial cells, which triggers thrombosis and hemolytic anemia. These mutations, often loss-of-function variants, reduce factor H's ability to bind and inhibit C3b on host surfaces, promoting microvascular injury. Recent data indicate that aHUS recurrence rates after kidney transplantation range from 50-60% in patients with complement gene mutations, highlighting the persistent risk despite supportive care.^[47] C3 glomerulopathy represents another key pathology linked to alternative pathway overactivity, characterized by persistent C3 convertase formation due to genetic alterations in complement regulators like factor H, factor I, or C3 itself, or autoantibodies stabilizing the convertase. This leads to glomerular deposition of C3 fragments and complement-mediated kidney injury, manifesting as proteinuria and renal failure. The condition encompasses subtypes such as dense deposit disease, where electron-dense intramitochondrial deposits in the glomerular basement membrane reflect chronic alternative pathway dysregulation. Overactive C3 convertase activity results in uncontrolled amplification, driving inflammation and fibrosis in the renal tissue.^[48]^[49] Variants in the complement factor H (CFH) gene also significantly elevate the risk of age-related macular degeneration (AMD), a leading cause of vision loss, by impairing complement inhibition in the retina and promoting chronic inflammation. The Y402H polymorphism in CFH, for instance, reduces binding affinity to C-reactive protein and other ligands, leading to heightened alternative pathway activation and accumulation of drusen—lipid-rich deposits under the retinal pigment epithelium. Homozygosity for this variant confers a 3- to 7-fold increased risk of AMD development. Recent 2024 studies further elucidate how CFH dysregulation facilitates drusen formation through unchecked C3b deposition and bystander damage to retinal cells.^[50]^[51] Emerging associations highlight the alternative pathway's role in infectious and chronic conditions. During the COVID-19 pandemic (2020-2022), hyperactivation of the alternative pathway contributed to coagulopathy in severe cases, with elevated C3a and C5a levels correlating with thrombosis and endothelial dysfunction via neutrophil extracellular trap formation. In chronic kidney disease, recent 2025 findings demonstrate enhanced alternative pathway activity due to altered plasma levels of regulators like factor H and properdin, exacerbating systemic inflammation and vascular injury. Additionally, properdin deficiency, an X-linked disorder, markedly increases susceptibility to meningococcal infections, with affected individuals facing a 250-fold higher risk of severe Neisseria meningitidis disease due to impaired C3 convertase stabilization and opsonization. Therapeutic strategies targeting complement dysregulation, such as inhibitors, are under evaluation for these conditions.^[52]^[53]^[54]

Therapeutic Interventions

Therapeutic interventions targeting the alternative complement pathway primarily involve small-molecule inhibitors and monoclonal antibodies that modulate key components such as Factors B and D, C3, and C5 to treat complement-mediated diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), immunoglobulin A nephropathy (IgAN), and geographic atrophy (GA) in age-related macular degeneration (AMD).^[55] These therapies aim to prevent excessive pathway activation while minimizing off-target effects on immune surveillance.^[56] A prominent example is iptacopan, an oral Factor B inhibitor that blocks the formation of the C3 convertase in the alternative pathway. The U.S. Food and Drug Administration (FDA) approved iptacopan (Fabhalta) in December 2023 for adults with PNH to reduce hemolysis, and granted accelerated approval in August 2024 for reducing proteinuria in adults with primary IgAN at risk of rapid progression. In March 2025, the FDA approved iptacopan for adults with C3 glomerulopathy (C3G) to reduce proteinuria and slow kidney function decline.^[57] In Phase III trials for IgAN, iptacopan achieved a 38.3% reduction in proteinuria compared to placebo after 9 months, alongside slowing estimated glomerular filtration rate decline.^[58]^[59]^[60] Monoclonal antibodies targeting C5, such as eculizumab and its successor ravulizumab, inhibit the terminal complement complex formation downstream of the alternative pathway. Eculizumab, a humanized anti-C5 antibody, was approved by the FDA in 2011 for treating aHUS by preventing complement-mediated thrombotic microangiopathy.^[61] Ravulizumab, engineered for an extended half-life (approximately 50 days versus 12 days for eculizumab), received FDA approval in October 2019 for aHUS in adults and pediatric patients one month or older, allowing less frequent dosing every 8 weeks.^[62] Clinical studies demonstrated comparable efficacy to eculizumab in resolving thrombotic microangiopathy, with 53.6% of treatment-naïve aHUS patients achieving complete response.^[63] Emerging therapies expand the therapeutic landscape, with over 50 complement inhibitors in clinical development as of 2024, targeting various pathway nodes for conditions like chronic kidney disease (CKD) and complement factor H (FH) deficiencies.^[64] Gene therapies using adeno-associated virus (AAV) vectors to deliver truncated or mini-FH constructs have shown promise in preclinical models of FH deficiency, restoring alternative pathway regulation and reversing renal damage without eliciting immune rejection.^[65] For instance, AAV-mediated human FH Y402 variant therapy in CFH-knockout mice reduced C3 deposition and glomerular injury long-term.^[66] Danicopan, an oral Factor D inhibitor, received FDA approval in 2024 as add-on therapy for PNH patients with extravascular hemolysis.^[67] Challenges in these interventions include heightened infection risk, particularly meningococcal infections from broad C5 or proximal inhibition, necessitating vaccination protocols.^[55] To address this, bispecific antibodies are under development for selective targeting, confining inhibition to disease-relevant surfaces like microbial pathogens or apoptotic cells while sparing systemic immunity.^[56] A key success metric is pegcetacoplan, a pegylated C3 inhibitor approved by the FDA in 2023 for GA secondary to AMD, which reduced the progression of GA lesion growth by 22% (monthly dosing) and 16% (every other month) in Phase III trials (OAKS and DERBY) over 24 months compared to sham treatment.^[68] Long-term data through 36 months confirmed sustained efficacy, with reduced photoreceptor degeneration beyond GA borders.^[68]

References

[1]
The complement system and innate immunity - Immunobiology - NCBI
The alternative pathway of complement activation can amplify the classical or the MB-lectin pathway by forming an alternative C3 convertase and depositing more ...
[2]
The complement alternative pathway in health and disease ...
Nov 24, 2022 · This article introduces a series of reviews covering The Alternative Pathway or Amplification Loop of Complement appearing in Volume 313 of Immunological ...ALTERNATIVE PATHWAY... · COMPONENTS AND BASIC... · COMPLEMENT...
[3]
Complement Factor D as a Strategic Target for Regulating ... - Frontiers
Sep 8, 2021 · One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation ...Abstract · The Alternative Complement... · Dysregulation of Complement...
[4]
The alternative complement pathway revisited - PMC
The alternative pathway should be regarded as a dual system, namely a recognition pathway principally similar to the classical and lectin pathways, and an ...
[5]
Dengue virus and the complement alternative pathway - FEBS Press
Jan 14, 2020 · The AP amplification loop drives ~ 80–90% of total C5 cleavage ... activity of the complement alternative pathway in infected cells. J ...Dengue Virus And The... · Abbreviations · Dengue: A Complement...
[6]
Looking back on the alternative complement pathway - ScienceDirect
The alternative pathway of complement originated from the Properdin pathway originally described by the Pillemer laboratory in the 1950s. ... properdin system and ...
[7]
Complement in the Initiation and Evolution of Rheumatoid Arthritis
The original properdin-dependent pathway, now called the AP of the complement system, was discovered in the 1950s (61). ... The properdin system and immunity. IV.
[8]
Phylogeny of the C3/C4/C5 complement-component gene family ...
This phylogeny is most consistent with the hypothesis that the alternative complement pathway was the first to evolve, followed by the terminal pathway and then ...
[9]
Specific Evolution and Gene Family Expansion of Complement 3 ...
The results of the global analysis of the genes of the complement system in vertebrates indicate it was well conserved during evolution.
[10]
Complement component C3 - The “Swiss Army Knife” of innate ...
Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation ...
[11]
Complement Component C3: a Structural Perspective and Potential ...
This Review provides a concise classification, summary, and interpretation of the more than 50 unique crystal structure determinations for human C3.Missing: paper | Show results with:paper
[12]
[PDF] C3 Protein Concentrated Catalog Number: A113c Sizes Available
Serum concentration is 1.0 to 1.5 mg/mL with the average of 1.2 mg/mL which makes C3 the most abundant complement protein in blood. It represents approx. 2.5% ...
[13]
Entry - *120700 - COMPLEMENT COMPONENT 3; C3 - (OMIM.ORG)
(1982) assigned the gene for fibroblast-derived C3 to chromosome 19. It was at first unclear whether fibroblast and serum C3 were identical; it was known ...
[14]
Molecular basis of polymorphisms of human complement ...
Oct 1, 1990 · C3 exhibits two common allotypic variants that may be separated by gel electrophoresis and are called C3 fast (C3 F) and C3 slow (C3 S).Missing: chromosome | Show results with:chromosome
[15]
Local Production of the Alternative Pathway Component Factor B Is ...
Complement factor B is a glycosylated, single-chain polypeptide with a molecular weight of 93 kDa and approximate plasma concentration of 200 μg/mL. In the ...
[16]
Factor B as a therapeutic target for the treatment of complement ...
Feb 14, 2025 · In this review, we outline the role of Factor B (FB), a key protease of the alternative pathway (AP) of the complement system in health and disease, as an ...
[17]
Complement | New England Journal of Medicine
Apr 5, 2001 · Complement is part of the innate immune system and underlies one of the main effector mechanisms of antibody-mediated immunity.Complement · Activation Of C3 · C3 Nephritic Factor
[18]
Complement Factor D as a Strategic Target for Regulating the ...
Sep 9, 2021 · One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation ...<|separator|>
[19]
Complement activation, regulation, and molecular basis for ...
Complement is activated through the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). The recognition of invading ...
[20]
Functional and structural insight into properdin control of ...
Mar 6, 2017 · Properdin (FP) is an essential positive regulator of the complement alternative pathway (AP) providing stabilization of the C3 and C5 convertases.
[21]
Soluble collectin-12 mediates C3-independent docking of properdin ...
Sep 10, 2020 · Properdin binds to and stabilizes the alternative C3 convertase C3bBb, thereby extending its half-life 5- to 10-fold and inhibit its ...
[22]
Structural basis for the stabilization of the complement alternative ...
Jul 30, 2013 · Properdin is the only known complement regulator that enhances the stability of the C3bBb convertase and the activity of the AP. Properdin binds ...
[23]
Synthesis of Factor D by Normal Human Hepatocytes - PubMed
Background: Unlike most complement proteins, complement factor D is believed to be synthesized not by the liver but exclusively by adipose tissue.
[24]
Properdin and Factor H: Opposing Players on the ... - Frontiers
The HEP G2 cells derived from human liver has been found to produce functional properdin. Endothelial cells also produce properdin when induced by shear stress, ...Abstract · Properdin Biosynthesis by... · Types of Properdin Deficiencies
[25]
Properdin and Factor H: Opposing Players on the Alternative ...
Apr 23, 2013 · The HEP G2 cells derived from human liver has been found to produce functional properdin. Endothelial cells also produce properdin when induced ...
[26]
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2013.00093/full
[27]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3632793/
[28]
Discrimination between Host and Pathogens by the Complement ...
All three pathways of complement activation deposit C3b on their respective targets. If that surface lacks host markers or membrane-bound complement regulatory ...
[29]
https://doi.org/10.3389/fimmu.2020.00530
[30]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2673523/
[31]
https://doi.org/10.1016/j.imbio.2012.07.016
[32]
Complement control protein factor H - PubMed Central - NIH
Factor H accelerates the decay of the alternative pathway C3 convertase (C3b,Bb) and is also a cofactor for factor I-mediated cleavage and inactivation of C3b ( ...
[33]
Functional evaluation of complement factor I variants by ...
Oct 26, 2023 · FI is a heterodimer with a molecular weight of 88 kDa (9). The non-catalytic heavy chain consists of a FI membrane attack complex (FIMAC) ...
[34]
Complement factor I: Regulatory nexus, driver of immunopathology ...
In humans, FI is broadly considered to circulate at a concentration of around 30 µg/mL in serum and plasma, but with a range of up to ∼ 100 µg/mL that may be ...
[35]
Overview of Complement Activation and Regulation - PMC
C3 convertase enzymes cleave many molecules of C3, resulting in a positive feedback amplification loop. C3b also binds to the C3 convertase, forming the C5 ...The Three Complement... · Complement Regulators · Complement In Kidney...
[36]
Complement Dysregulation and Disease - PubMed Central - NIH
The cell membrane-associated proteins are membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55), complement receptor 1 (CR1; CD35), and ...
[37]
Therapeutic potential of complement modulation - Nature
Dec 4, 2009 · Cell membrane-bound regulators: complement receptor 1 (CR1; also known as CD35), expressed on erythrocytes, phagocytes, B cells and subsets of T ...Key Points · Abstract · Main
[38]
https://pmc.ncbi.nlm.nih.gov/articles/PMC6020056/
[39]
https://www.nature.com/articles/nrd3011
[40]
Complement System Part I – Molecular Mechanisms of Activation ...
Alternative pathway C3 convertase. (A) Structure and domain organization of ... 1000-fold increased enzymatic activity toward C5 cleavage (213) ...
[41]
Complement-dependent Clearance of Apoptotic Cells by Human ...
In the presence of serum, the macrophage receptors for C3bi, CR3 (CD11b/CD18) ... Enhancement of macrophage phagocytosis upon C3b deposition on apoptotic cells.
[42]
iC3b‐opsonized apoptotic cells mediate a distinct anti‐inflammatory ...
Mar 3, 2010 · Taken together, we suggest that iC3b-opsonized apoptotic cells, by binding or phagocytosis, via CD11b/CD18 or additional unknown complement ...
[43]
Role of transcription factors in apoptotic cells clearance - PubMed
Jan 19, 2023 · The human body generates 10-100 billion cells every day, and the same number of cells die to maintain homeostasis.
[44]
Apoptotic cell clearance: basic biology and therapeutic potential - PMC
Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could ...
[45]
Complement System Part II: Role in Immunity - Frontiers
Opsonization of apoptotic cells by autologous iC3b facilitates clearance by immature dendritic cells, down-regulates DR and CD86, and up-regulates CC ...
[46]
Atypical hemolytic uremic syndrome - ScienceDirect.com
May 26, 2025 · Historically, recurrence after transplantation was 58-68%, and 5-year death-censored graft survival was 51%., The exception to this is those ...
[47]
C3 glomerulopathy: a kidney disease mediated by alternative ...
Oct 28, 2024 · C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease caused by to the deregulation of the alternative pathway (AP) of proximal ...
[48]
C3 glomerulopathies: dense deposit disease and C3 ... - NIH
Nov 24, 2023 · The underlying cause of both DDD and C3Gn is an abnormal activation of the alternative complement pathway, which can result from acquired or ...Missing: overactive | Show results with:overactive
[49]
Development and Progression of AMD | amdbook.org
This CFHY402H polymorphism increases AMD risk 2 to 4-fold in heterozygotes and 3 to 7-fold in homozygotes. It causes a significant loss of binding of factor H ...
[50]
Genetic Insights into Age-Related Macular Degeneration - PMC
Jul 4, 2024 · Variants lead to the misregulation of the complement pathway, leading to choroidal neovascularization and drusen formation in wet and dry AMD, ...
[51]
Severe COVID-19 is associated with hyperactivation of the ...
In summary, we have shown that severe COVID-19 is characterized by increased activation of the complement alternative pathway, which was correlated with ...
[52]
Chronic kidney disease enhances alternative pathway activity - JCI
May 1, 2025 · We propose that reduced kidney function contributes to alternative pathway lability in CKD and further fuels systemic and vascular inflammation.Abstract · Reduced kidney function alters... · Systemic consequences of...
[53]
Properdin deficiency and meningococcal disease—identifying ... - NIH
The specific individual risk of meningococcal infection in properdin deficiency has been calculated at around 50%, a 250-fold increase over the baseline ...
[54]
Complement in human disease: approved and up-and-coming ...
Feb 16, 2024 · Below, we have broadly categorised the currently approved complement treatment options (and some of those that are further progressed through ...
[55]
[PDF] The future of complement therapeutics - Open Exploration Publishing
Oct 18, 2024 · Recent FDA approvals and next-generation therapies are at a crucial juncture for complement-targeting therapies, with a competitive landscape ...
[56]
[PDF] FABHALTA® (iptacopan) capsules, for oral use - accessdata.fda.gov
FABHALTA is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine ...
[57]
New Novartis Fabhalta® (iptacopan) data show clinically meaningful ...
Apr 15, 2024 · Fabhalta was approved by the FDA in December 2023 for the treatment of adults with the rare blood disorder paroxysmal nocturnal hemoglobinuria ( ...
[58]
Novartis Fabhalta® (iptacopan) meets Phase III primary endpoint ...
Oct 16, 2025 · Fabhalta also received accelerated approval in the US in August 2024, and in China in September 2025, for the reduction of proteinuria in adults ...
[59]
Comparative Efficacy of Ravulizumab and Eculizumab in the...
Eculizumab (ECU), a C5 inhibitor, was approved to treat aHUS in 2011. Ravulizumab (RAV), approved in 2019, was engineered from ECU to reduce dosing ...
[60]
Ultomiris | European Medicines Agency (EMA)
In aHUS, Ultomiris is used in patients who either have not received complement inhibitors (such as eculizumab) before or who have received eculizumab for at ...
[61]
The long-acting C5 inhibitor, Ravulizumab, is effective and safe in ...
The study showed that ravulizumab rapidly resolved TMA caused by aHUS with 53.6% of patients reaching the primary end point of complete TMA response.<|separator|>
[62]
Complement Inhibitors Clinical Trial Pipeline Analysis: 40+
Oct 28, 2024 · DelveInsight's complement inhibitors pipeline report depicts a robust space with 40+ active players working to develop 50+ pipeline complement ...
[63]
Truncated complement factor H Y402 gene therapy rescues C3 ...
Aug 6, 2025 · Our findings demonstrate restored inhibition of complement's alternative pathway and long-term reversal of disease without immune rejection.
[64]
Truncated complement factor H Y402 gene therapy rescues C3 ...
In this study, we tested the hypothesis that AAV-mediated human CFH Y402 replacement therapy can be used as a treatment to cure C3G in the Cfh−/− mouse model.
[65]
Danicopan – Application in Therapy and Current Clinical Research
C3 Glomerulopathy (C3G) and related kidney diseases: These are rare kidney disorders that can lead to kidney failure. They include conditions such as C3 ...
[66]
FDA Approves Add-on Danicopan In Patients With PNH, EVH
Apr 2, 2024 · Chronic Kidney Disease · COVID-19 and Kidney Disease · Diabetes and ... Danicopan is a first-in-class Factor D inhibitor developed to ...
[67]
Pegcetacoplan Treatment for Geographic Atrophy in Age-Related ...
Over 36 months, pegcetacoplan continued to reduce GA growth with increasing efficacy over time and reduced formation of new scotomatous points.