Immunology · Complement System

C3b, Factor H & the Cascade

Complement is a chain reaction sitting in your blood, primed to coat and punch holes in anything foreign. The whole thing pivots on one molecule, C3b, and one bouncer, Factor H, that decides whether the reaction runs on a bug or on you. Let's make it clickable.

Medically reviewed by Fatima Ali, DO & Kaitlyn Cocuzzo, MD

A 4-year-old girl is brought in after a week of pallor and dark urine. She has no bloody diarrhea. Labs show a hemolytic anemia with schistocytes, low platelets, and a rising creatinine (a thrombotic microangiopathy). Complement testing shows a low C3 with a normal C4, and genetics finds a loss-of-function mutation in a plasma regulatory protein. Which protein, when lost, lets complement turn on her own kidney cells?

C1 inhibitor
Factor H
C1q
Factor B
The giveaway is low C3 with a normal C4. That pattern means the alternative pathway is being chewed through while the classical pathway (which uses C4) is untouched. Factor H is the brake that normally shuts the alternative loop off on host cells. Lose it and the loop runs unchecked on her own kidney, which is atypical hemolytic uremic syndrome. C1 inhibitor and C1q sit in the classical pathway (C4 would drop), and Factor B is part of the loop you are trying to stop, not the brake. Low C3 + normal C4 = alternative pathway = think Factor H.
Begin
The Big Picture

One Job, Three Front Doors

Complement is about 30 plasma proteins, mostly made by the liver, that wait in an inactive form until something trips them. Three pathways start the chain; all three meet at the same place.

Overview of the complement system: classical, lectin, and alternative pathways converging on C3, leading to opsonization, inflammation, and the membrane attack complex
The whole system on one page: three pathways feed into C3, and C3 splits into the jobs (tag, inflame, lyse). Tap to enlarge.

Complement does three things for the immune system. It tags microbes for eating (opsonization), it calls in inflammation and white cells (anaphylatoxins and chemotaxis), and it drills holes in membranes (the membrane attack complex). Every one of those jobs is downstream of cleaving C3.

The one sentence that organizes everything All three pathways exist for a single purpose: to assemble a C3 convertase, the enzyme that splits C3 into C3a and C3b. Once you have C3b, the rest of complement falls out of it. Learn the three doors, then learn what happens after C3.

The Three Pathways, Side by Side

Same destination (C3 convertase), three different triggers. Tap each tab. The one fact that separates them is what trips the trigger.

Classical
Lectin
Alternative

Classical · needs antibody

Trigger: C1A three-part starter (C1q, C1r, C1s). C1q is the part that physically grabs the antibody tail. binds to the tail of IgG or IgM that is already stuck to an antigen. No bound antibody, no classical pathway.

C3 convertase: C4b2b (C4 and C2 are cleaved and snap together).

🧠Classical = C1 + antiCbody. The C path needs C1. The classical pathway is the bridge from the adaptive system (antibody) back to the innate one.

Lectin · no antibody needed

Trigger: mannose-binding lectinMBL, a liver protein that recognizes mannose sugars found on microbe surfaces but not on normal human cells. (MBL) binds mannose on a microbe surface, then activates MBL-associated proteases.

C3 convertase: same as classical, C4b2b. The trigger differs; the machinery is identical.

Think of lectin as the classical pathway that skips the antibody and recognizes the sugar coat of the bug directly.

Alternative · always running, no antibody

Trigger: spontaneous C3 tickoverA small amount of C3 is always hydrolyzing on its own in plasma, so a trickle of C3b is constantly being made and tossed onto nearby surfaces.. C3b lands on a surface; on a pathogen it sticks and amplifies.

C3 convertase: C3bBb (built from C3b, Factor B, and Factor D). No C1, no C4.

🧠Alternative = Always on, Antibody-free. Uses B, D, properdin, not C1. This is the loop the whole page is built around.

The classic separation trap The board hides which pathway is running in the lab values. Low C4 means the classical (or lectin) pathway is being consumed. Low C3 with a normal C4 means the alternative pathway is the one burning, because the alternative pathway never touches C4. Memorize this split; it tells you Factor H disease from immune-complex disease.
The Signature Interactive

The Cascade, Made Clickable

Three triggers feed into the C3 convertase. C3 splits into the C3b hub. C3b builds the C5 convertase, and C5 finishes the job at the membrane attack complex. Tap any node for its function and the clinical hook. The dashed pieces at the bottom are the brakes.

Regulators (the brakes)
Tap a node

Start at the top with a trigger, or jump straight to C3b, the hub everything runs through. The green dashed pieces are the regulators that stop the chain on your own cells.

Formation of the membrane attack complex from C5b through C9 forming a pore in the cell membrane
C5b recruits C6, C7, C8, then many C9 to drill a ring-shaped pore. Water rushes in, the cell bursts. Tap to enlarge.
Why the MAC matters most for one bug The membrane attack complex is the only way to lyse Neisseria, because Neisseria species have a thin cell wall and a poor capsule defense against pore drilling. That is why losing the terminal components (C5 through C9) shows up as recurrent Neisseria infections, classically meningococcus.
Gram stain of cerebrospinal fluid showing gram-negative diplococci of Neisseria meningitidis inside neutrophils
Neisseria meningitidis in spinal fluid: gram-negative diplococci. The bug the membrane attack complex is built to kill.
The Center of Everything

C3b and the Amplification Loop

C3b is the molecule the whole system is built to make. It does three jobs at once, and one of them feeds back on itself to flood a surface with more C3b. Run the loop and watch it multiply.

Ribbon structure of complement protein C3 fragment
C3, the most abundant complement protein in blood. Cleave it and you get C3a plus the workhorse C3b. Tap to enlarge.
Job 1: Opsonize

The main tag for eating

C3b coats a microbe and is recognized by CR1Complement receptor 1 on phagocytes. It grabs C3b-coated targets so the phagocyte can swallow them. on phagocytes. C3b is the body's most important opsonin.

🧠C3b = the badge that says eat me. CR1 reads the badge.

Job 2: Build C5 convertase

The bridge to the MAC

Add one more C3b to the C3 convertase and it becomes the C5 convertase, which kicks off the terminal pathway and the membrane attack complex.

No C3b, no C5 convertase, no MAC. The terminal pathway is C3b's child.

Job 3: Amplify

It makes more of itself

C3b binds Factor B; Factor D cleaves it to form C3bBb, a fresh convertase that cleaves more C3 into more C3b. A trickle becomes a flood.

ProperdinAlso called Factor P. It is the only complement protein that stabilizes (rather than inhibits) a convertase, holding C3bBb together so it lasts longer. stabilizes the loop.

Schematic of a phagocyte engulfing a particle by phagocytosis
Opsonization in action: a C3b-tagged target is recognized and swallowed by a phagocyte. Tap to enlarge.

Run the Amplification Loop

This is the alternative-pathway loop that the board tests as a feedback cycle. Press the button and watch one C3b turn into a surface flood.

1
C3b lands on a surface (from tickover or a convertase).
2
C3b binds Factor B, forming C3bB.
3
Factor D cleaves Factor B (properdin stabilizes it).
4
The C3bBb convertase is now built.
5
It cleaves more C3, making more C3b.
each new C3b restarts the loop ↻
C3b on the surface:1
One stray C3b, sitting on a surface. Hit the button and watch it recruit Factor B and Factor D, build a convertase, and copy itself.

Lock It In

Three quick memory cards. The answer is blurred. Decide first, then tap to clear it.

What single molecule do all three pathways exist to make?
tap to reveal
C3b. Every pathway builds a C3 convertase, and the convertase makes C3b.
Which two factors plus C3b build the alternative convertase?
tap to reveal
Factor B and Factor D, giving C3bBb. Properdin holds it together.
How does the C5 convertase differ from the C3 convertase?
tap to reveal
It is just the C3 convertase with one extra C3b stuck on. C3b builds its own boss.
The Brake

Factor H: Self vs Non-Self

The loop you just ran is dangerous, because tickover sprays C3b onto everything nearby, including your own cells. Factor H is the protein that reads the surface and decides whether the loop keeps running. Flip the switch.

On your own cell
Factor H in one chain Factor H recognizes host sialic acid → binds C3b on your cells → acts as a cofactor for Factor I → Factor I cleaves C3b into inactive iC3b → the loop dies. Pathogens lack that sialic acid tag, so Factor H ignores them and the loop amplifies. 🧠Factor H = Host protector. It scissors C3b on YOUR cells with Factor I.

When the Brakes Fail

Each regulator stops the chain at a different step. Knowing the step tells you the disease when it breaks.

Factor H & Factor I

Brake on the C3b loop

Factor H (with Factor I) chops C3b to iC3b on host surfaces. MCP / CD46Membrane cofactor protein, a membrane-bound cofactor for Factor I, like Factor H but anchored to the cell. does the same job on the membrane.

Lost: atypical HUS and dense deposit disease (C3 glomerulopathy, a type of membranoproliferative glomerulonephritis).

DAF (CD55) & CD59

GPI-anchored brakes

DAF / CD55Decay-accelerating factor. It speeds the breakup of the C3 and C5 convertases sitting on your own cells. decays the convertases. CD59 blocks the final MAC from forming.

Lost: both are anchored by GPIGlycosylphosphatidylinositol, a lipid anchor. A PIGA mutation in a stem cell stops it being made, so the anchored proteins fall off., so a PIGA defect strips both off red cells, causing PNH (complement-mediated hemolysis).

C1 inhibitor

Brake on the classical start

C1 inhibitor blocks activated C1 (and also kallikrein in the bradykinin system).

Lost: hereditary angioedema, with low C4 and bradykinin-driven swelling. ACE inhibitors make it worse and are the classic trap.

Light micrograph of membranoproliferative glomerulonephritis showing thickened capillary walls and increased mesangial cells
Membranoproliferative pattern: dense deposit disease lives here when Factor H fails. Tap to enlarge.
Swollen hand during a hereditary angioedema attack
Hereditary angioedema: nonpitting, nonpruritic swelling when C1 inhibitor is missing. Tap to enlarge.
Diagram of paroxysmal nocturnal hemoglobinuria mechanism with complement-mediated red cell lysis
PNH: without GPI-anchored CD55 and CD59, complement chews up red cells, giving dark morning urine and thrombosis. Tap to enlarge.
High-yield traps to keep separate Eculizumab is an antibody that blocks C5, used for PNH and atypical HUS. By blocking the terminal pathway it raises Neisseria risk, so patients must be vaccinated against meningococcus first. C3 nephritic factor is an autoantibody that stabilizes the alternative convertase C3bBb, keeping it on and driving dense deposit disease. And remember: the classical pathway uses C1; the alternative pathway does not.

Decide Before You Peek

Two challenges. Commit to an answer, then read why. These are how the board hides the diagnosis in a complement panel.

A young man has had three separate episodes of Neisseria meningitis. His total complement screen (CH50) is undetectable. Which part of complement is most likely deficient?
C3 alone
Terminal components C5 to C9 (the MAC)
C1 inhibitor
A child has a thrombotic microangiopathy with low C3 and a normal C4. Which problem fits?
Overactive classical pathway from immune complexes
Loss of Factor H letting the alternative loop run on host cells
C1 inhibitor deficiency
Quick Check

Five Fast Ones

Five questions pulled from a bigger pool and shuffled, so every visit is a fresh set. No score counter shaming you, just the explanation when you pick.

Prove It

Clinical Walkthrough

Original full clinical vignettes, one at a time. Shuffled, never-repeat. Answer first, then every choice gets explained and the reasoning chain unlocks. Six patients walked in. Read the complement panel.

Keep Going

Go deeper
Complement Deficiencies
The full deficiency map: which missing piece gives Neisseria, lupus, pyogenic infections, angioedema, or PNH, with the board traps.
Up one level
Immunology
T cells, B cells, the lymphatic system, hypersensitivities, and the immunodeficiencies in clinical practice.
Related
Hypersensitivities
Where C3a and C5a anaphylatoxins fit into the inflammation story.
Home
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References: standard immunology and pathology board texts. Images: Wikimedia Commons (see each lightbox for attribution).

Medically reviewed by Fatima Ali, DO and Kaitlyn Cocuzzo, MD. Vignettes are original clinical teaching cases; demographics, values, and answer order are written for practice. Confirm management against current references at the point of care.

Bone Wizardry is an independent educational resource for visual learning in the medical sciences. It is not affiliated with, endorsed by, or sponsored by any licensing or examination board, contains no real or recalled examination questions, and does not guarantee any educational or examination outcome.

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