Complement System Immunology for USMLE Step 1: Pathways, Deficiencies and Lab Patterns

A 23 year old man is admitted with his second episode of meningococcal meningitis in three years. The question stem gives you a normal CBC, normal immunoglobulins and a normal CD4 count, then asks for the most likely underlying defect. If your first thought was the terminal complement pathway, you already have the reflex this guide is built to sharpen. If it was not, stay with us.

The complement system is one of those Step 1 topics that punishes students who study it the way a textbook presents it. The exam does not care about the crystal structure of C1q or the kinetics of C3 tickover. It cares about a small set of patterns: which pathway a trigger activates, what C3a, C3b and C5a each do, which deficiency produces which infection, and what the complement levels look like in six or seven named diseases. This guide covers exactly that and nothing else.

What This Guide Covers and What We Deliberately Left Out

Our earlier pillar guide on this topic ran to more than thirty pages. It was thorough and, frankly, exhausting. We have rebuilt it around a single question: would this line change an answer on the exam? If not, it is gone. What stayed is the activation pathways, the split products, the regulators, the deficiencies, the lab patterns, the drugs that target complement, and the cross system links to rheumatology, nephrology, hematology and microbiology that NBME writers love.

If you are still deciding how deep to go on immunology generally, our breakdown of the Step 1 content outline shows which immunology topics carry real question weight and which do not.

Complement in 60 Seconds

Complement is a cascade of roughly thirty plasma proteins, made mostly by the liver, that circulate as inactive precursors. Once triggered, each protein cleaves the next, amplifying the signal. Everything the system does can be filed under five jobs, and we teach them with the word OCEAN.

• Opsonization: C3b coats pathogens so phagocytes with CR1 receptors can grab them. This is the single most important function for encapsulated bacteria. Opsonization defects also appear in acquired immunodeficiency. We cover how falling CD4 counts change which organisms appear, which is the same logic running through a different arm.
• Chemotaxis: C5a is the strongest chemoattractant in the cascade and pulls neutrophils to the site.
• Enhanced inflammation: C3a, C4a and C5a are anaphylatoxins that degranulate mast cells and increase vascular permeability.
• Attack: C5b through C9 assemble into the membrane attack complex (MAC), a pore that lyses Gram negative bacteria and, critically, Neisseria.
• Neutralization and clearance: C3b tags immune complexes so red cells (via CR1) ferry them to the spleen and liver for removal. Lose this and you get lupus like disease.

Two anchoring facts before the pathways. First, all three activation routes exist to build a C3 convertase, so C3 is the hub. Second, everything downstream of C3 is shared, which is why a C3 deficiency is worse than any single pathway deficiency.

The Three Activation Pathways

The exam tests three things about the pathways: the trigger, the early components, and the C3 convertase each one builds. Figure 1 shows all three converging on C3.

Figure 1. Classical, lectin and alternative pathways converge on the cleavage of C3.

Classical Pathway

Triggered by antibody bound to antigen. C1q must bind the Fc region of at least two IgG molecules or one pentameric IgM, which is why IgM is the strongest complement activator and why free antibody in serum does not set the cascade off. C1q activation turns on C1r and C1s, which cleave C4 and C2. The fragments C4b and C2b join to form C4b2b, the classical C3 convertase. This is the pathway of type II and type III hypersensitivity, of SLE, and of the hemolytic transfusion reaction.

This is the pathway of type II and type III hypersensitivity, of SLE, and of the hemolytic transfusion reaction.

Lectin Pathway

Mannose binding lectin (MBL) recognizes mannose residues on microbial surfaces that human cells do not display. MBL is paired with MBL associated serine proteases (MASP 1 and MASP 2) that behave exactly like C1s, cleaving C4 and C2 to build the same C4b2b convertase. No antibody is needed, so this is innate. The exam trap is that students assume lectin and alternative share a convertase. They do not: lectin uses the classical C4b2b.

Alternative Pathway

Always ticking over at a low level because C3 spontaneously hydrolyzes in plasma. When C3b lands on a surface that lacks host regulators, Factor B binds it, Factor D cleaves Factor B, and the result is C3bBb, the alternative C3 convertase. Properdin stabilizes it. Because C3bBb makes more C3b, this pathway is also the amplification loop for the other two. Classic triggers on the exam are bacterial endotoxin (LPS), yeast cell walls, and aggregated IgA, which is why IgA nephropathy shows alternative pathway activation.

Table 1 puts the three pathways side by side. If you memorize one table from this guide, make it this one.

Feature	Classical	Lectin	Alternative
Trigger	Antigen bound IgG or IgM	Mannose on microbes	Spontaneous C3 tickover, LPS, IgA aggregates
Recognition molecule	C1q	Mannose binding lectin	C3b itself
Early proteases	C1r, C1s	MASP 1, MASP 2	Factor B, Factor D
C3 convertase	C4b2b	C4b2b	C3bBb (stabilized by properdin)
C5 convertase	C4b2b3b	C4b2b3b	C3bBb3b
Innate or adaptive	Adaptive	Innate	Innate
C4 consumed	Yes	Yes	No
Screening test	CH50	Not routinely tested	AH50

UIT Exam Trap: C4b2b or C4b2a? Older texts and some question banks call the classical convertase C4b2a. Newer nomenclature, adopted by First Aid and most current sources, names the larger active fragment C2b, giving C4b2b. Both refer to the same enzyme. If an answer choice uses either form, treat them as identical and do not let it distract you.

C3, C5 and the Membrane Attack Complex

Every C3 convertase does one job: it cleaves C3 into a small fragment, C3a, and a large fragment, C3b. C3b then binds the convertase to make it a C5 convertase, which cleaves C5 into C5a and C5b. C5b recruits C6, C7, C8 and multiple copies of C9 to form the MAC. That is the whole terminal pathway.

The fragments are where the questions live. A useful rule: the small a fragments float away and cause inflammation, the large b fragments stay on the surface and build things.

Table 2 lists the split products you must know and the single phrase the exam will use to hint at each one.

Fragment	Main job	How the vignette hints at it
C3a	Anaphylatoxin, mast cell degranulation	Flushing, hypotension and bronchospasm after a transfusion or dialysis
C3b	Opsonin, binds CR1 on phagocytes, clears immune complexes	Recurrent infections with encapsulated bacteria, or immune complex disease
C4a	Weak anaphylatoxin	Rarely tested on its own
C5a	Strongest chemoattractant, also an anaphylatoxin	Neutrophil recruitment, acute inflammation, ARDS models
C5b through C9	Membrane attack complex, lyses Gram negative organisms	Recurrent Neisseria infections

One clinical detail that earns its place: the MAC matters most for Neisseria because these organisms have a thin outer membrane and few alternative defenses. Most other bacteria are killed mainly by C3b opsonization and phagocytosis, so losing the MAC alone barely affects them. This is the entire logic behind the terminal deficiency vignette.

Regulation: Why Your Own Cells Survive

Complement is indiscriminate. C3b will attach to any nearby surface, including your red cells, so the system depends on a small set of brakes. The exam tests four of them, and each one has a named disease when it fails. Figure 2 shows where each regulator acts.

Figure 2. The four regulators worth knowing, where they act, and what happens when they are absent.

Table 3 summarizes the regulators. Notice that two of them are attached to cell membranes by a GPI anchor, which is the link to PNH.

Regulator	Where it acts	Mechanism	Disease when deficient
C1 esterase inhibitor (C1 INH)	C1r, C1s, and kallikrein	Serine protease inhibitor, prevents classical activation and bradykinin generation	Hereditary angioedema
Decay accelerating factor (DAF, CD55)	C3 convertases on host cell membranes	GPI anchored, dissociates C4b2b and C3bBb	Paroxysmal nocturnal hemoglobinuria
CD59 (MIRL)	MAC on host cell membranes	GPI anchored, blocks C9 polymerization	Paroxysmal nocturnal hemoglobinuria
Factor H	C3b in plasma and on host surfaces	Displaces Factor B, cofactor for Factor I	Atypical HUS, C3 glomerulopathy
Factor I	C3b and C4b	Cleaves C3b to inactive iC3b, needs Factor H or CD46 as cofactor	Secondary C3 deficiency with pyogenic infections

Complement Deficiencies: The Core of What Gets Tested

If you only have twenty minutes for complement, spend them here. Every deficiency maps to a predictable clinical picture, and the vignettes are written to make you recognize the map. Figure 3 lays it out.

Figure 3. Missing component, mechanism of failure, and the clinical picture the exam describes.

Table 4 expands the map with the inheritance pattern, the lab pattern and the confirmatory test for each deficiency.

Deficiency	Inheritance	Presentation	Lab clue	Confirm with
C1, C2, C4 (early classical)	Autosomal recessive	SLE like disease, immune complex glomerulonephritis. C2 deficiency is the most common inherited complement defect	Low CH50, normal AH50	Individual component levels
C3	Autosomal recessive	Severe recurrent pyogenic infections with encapsulated bacteria from infancy, also immune complex disease	Low CH50 and low AH50	C3 level
C5 through C9 (terminal)	Autosomal recessive	Recurrent disseminated Neisseria infections, often in adolescents or young adults	Low CH50 and low AH50	Individual terminal component levels
C1 esterase inhibitor	Autosomal dominant	Recurrent nonpruritic swelling of face, airway, gut wall. No urticaria	Low C4, normal C3	C1 INH level and function
DAF and CD59 (acquired PIGA mutation)	Acquired, somatic, in a hematopoietic stem cell	Intravascular hemolysis, venous thrombosis, pancytopenia, dark morning urine	Low haptoglobin, high LDH	Flow cytometry for CD55 and CD59
Properdin	X linked	Recurrent Neisseria, same picture as terminal deficiency	Normal CH50, low AH50	Properdin level

Complement defects are one branch of a larger tree. Our guide to primary immunodeficiency disorders places these alongside the B cell, T cell and phagocyte defects, with the discriminating test for each.

Hereditary Angioedema in Two Paragraphs

C1 esterase inhibitor does two jobs. It restrains C1, and it restrains kallikrein in the contact system. When it is deficient, kallikrein overproduces bradykinin, and bradykinin is what drives the swelling. This is why the edema is nonpruritic and does not respond to antihistamines or steroids, and why urticaria is absent. Attacks involve the face, extremities, bowel wall (mimicking an acute abdomen) and larynx.

The pharmacology link is what the exam wants. ACE degrades bradykinin, so ACE inhibitors are contraindicated in hereditary angioedema. Acute attacks are treated with C1 INH concentrate, icatibant (a bradykinin B2 receptor antagonist) or ecallantide (a kallikrein inhibitor). Fresh frozen plasma is a fallback. Danazol can be used for prophylaxis because it increases hepatic C1 INH synthesis.

Paroxysmal Nocturnal Hemoglobinuria in Two Paragraphs

PNH is an acquired clonal disorder. A somatic mutation in PIGA in a hematopoietic stem cell removes the ability to make the GPI anchor. DAF (CD55) and CD59 are both GPI anchored, so the affected red cells lose both regulators and are lysed by complement. Hemolysis is intravascular and worse at night because mild respiratory acidosis during sleep enhances complement activity. Patients present with dark morning urine, fatigue, and a striking tendency to venous thrombosis, including hepatic vein thrombosis.

Diagnosis is flow cytometry showing absent CD55 and CD59 on red cells and granulocytes. The old Ham test and sucrose lysis test are historical. Treatment is eculizumab or ravulizumab, monoclonal antibodies against C5 that stop MAC formation. Because they create a functional terminal deficiency, patients must be vaccinated against meningococcus before starting. PNH can evolve into aplastic anemia or acute myeloid leukemia.

UIT Exam Trap: Three Infections, Three Different Defects Recurrent Neisseria alone: terminal complement (C5 through C9) or properdin. Immunoglobulins and neutrophils are normal. Recurrent encapsulated bacteria from infancy: C3 deficiency if the immunoglobulins are normal. If IgG is low, think B cell defect. If there is a splenic story, think asplenia. Lupus like autoimmunity in a child: early classical component deficiency, most commonly C2. The immune complexes are never cleared.

Reading Complement Levels: CH50, AH50, C3 and C4

Complement labs are ordered in two settings on the exam: screening for a deficiency, and tracking immune complex disease. The logic is simple once you see it. CH50 tests the classical pathway from C1 all the way to the MAC, so any single missing classical or terminal component drops it. AH50 tests the alternative pathway from Factor B to the MAC, so it drops with alternative or terminal defects but not with early classical ones. C4 is consumed only by the classical and lectin pathways, so C4 is the switch that tells you which pathway is burning.

Table 5 gives the patterns. Memorize the C3 and C4 columns for the named diseases at the bottom, because those are the ones that show up as single best answer questions.

Scenario	CH50	AH50	C3	C4	Interpretation
Early classical deficiency (C1, C2, C4)	Low	Normal	Normal	Low or normal	Isolated classical defect
Alternative pathway deficiency (Factor B, D, properdin)	Normal	Low	Normal	Normal	Isolated alternative defect
C3 or terminal deficiency	Low	Low	Low if C3	Normal	Shared pathway defect
Active SLE	Low	Low	Low	Low	Classical consumption by immune complexes
Post streptococcal glomerulonephritis	Low	Low	Low	Normal	Alternative activation, C3 recovers in 6 to 8 weeks
Membranoproliferative GN (C3 nephritic factor)	Low	Low	Persistently low	Normal	Autoantibody stabilizes C3bBb
Hereditary angioedema	Low	Normal	Normal	Low	C4 consumed by unrestrained C1
Cryoglobulinemia, endocarditis	Low	Low	Low	Low	Immune complex consumption

How We Teach This We tell students to ask two questions in order. Is C4 low? If yes, the classical pathway is active or defective, so think lupus, hereditary angioedema, cryoglobulinemia or an early component deficiency. If C4 is normal but C3 is low, the alternative pathway is doing the work, so think PSGN, MPGN with C3 nephritic factor, or a C3 regulator problem. That single fork resolves nearly every complement lab question on the exam.

Complement Across Disciplines

Step 1 rarely asks a pure immunology question about complement. It embeds complement inside a pathology, microbiology or pharmacology stem. These are the connections that repay the time spent on them.

Table 6 maps the diseases and drugs where complement is the hidden mechanism the question is really about.

Topic	Where complement fits	The line that answers the question
Type II hypersensitivity	IgG or IgM on a cell surface activates the classical pathway, leading to lysis or opsonization	Hemolytic transfusion reaction, Goodpasture, rheumatic fever, hemolytic disease of the newborn
Type III hypersensitivity	Circulating immune complexes deposit in vessels and fix complement, C5a recruits neutrophils	Serum sickness, PSGN, lupus nephritis, Arthus reaction, polyarteritis nodosa
Systemic lupus erythematosus	Immune complexes consume classical components	Low C3 and C4 track disease activity, early component deficiency predisposes
Post streptococcal glomerulonephritis	Alternative activation by nephritogenic antigens	Low C3, normal C4, subepithelial humps, granular immunofluorescence
Membranoproliferative GN	C3 nephritic factor stabilizes C3bBb, persistent consumption	Persistently low C3, tram track appearance on light microscopy
Atypical HUS	Factor H, Factor I or CD46 defects allow alternative pathway to attack endothelium	HUS without diarrhea, treated with eculizumab
Neisseria infections	MAC is the primary defense	Recurrent meningococcemia or disseminated gonococcal infection
Encapsulated bacteria	C3b opsonization is the primary defense, needs a working spleen	Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis
Eculizumab, ravulizumab	Monoclonal antibodies against C5, block MAC formation	PNH, aHUS, generalized myasthenia. Vaccinate for meningococcus first
C1 INH concentrate, icatibant, ecallantide	Replace the inhibitor, block the bradykinin receptor, block kallikrein	Acute hereditary angioedema
Microbial evasion	Pathogens degrade or mimic regulators	Staph aureus protein A binds Fc and blocks C1q, Neisseria and Streptococcus recruit Factor H

The first two rows carry the most weight. If the hypersensitivity framework is still shaky, we work through all four types with the NBME traps for each.

Mnemonics That Actually Work

We are selective about mnemonics. A mnemonic that takes longer to decode than the fact it encodes is a liability. These four have survived years of student feedback.

OCEAN for the functions: Opsonization (C3b), Chemotaxis (C5a), Enhanced inflammation (C3a, C4a, C5a), Attack (MAC), Neutralization of immune complexes (C3b).

GM makes classic cars: IgG and IgM activate the classical pathway. IgA does not fix complement classically, which is why it works on mucosal surfaces without triggering inflammation.

C3 is the middle child, everyone depends on it: all three pathways converge on C3, so C3 deficiency is the most severe single component deficiency.

Late is for Neisseria, early is for lupus, C1 INH is for swelling: terminal deficiencies give Neisseria, early classical deficiencies give SLE like disease, and C1 esterase inhibitor deficiency gives hereditary angioedema. Say it out loud until it is automatic.

PNH: PIGA, GPI, DAF, CD59, dark urine, clots: the chain from gene to anchor to missing regulators to clinical picture, in the order the vignette usually reveals it.

Twenty Exam Pearls and Traps

We build this kind of list for every subject. See the high-yield Step 1 topics worth this treatment if you want to know where else the effort pays out.

These are the facts that appear in stems and answer choices. We have ranked them roughly by how often they decide the answer.

1. IgM is the most potent classical activator because a single pentamer provides the multiple Fc regions C1q needs. Two IgG molecules bound close together are required.
2. The lectin pathway uses the classical C3 convertase, C4b2b, not the alternative one. It is innate because it needs no antibody.
3. C3b is the opsonin. C5a is the chemoattractant. C3a and C5a are the anaphylatoxins. Do not swap them.
4. C5 through C9 defects produce recurrent Neisseria infections because Neisseria depends on the MAC for clearance. Other bacteria are handled by opsonization.
5. C2 deficiency is the most common inherited complement deficiency and presents with lupus like disease.
6. C3 deficiency is the most severe. It produces recurrent pyogenic infections from infancy plus immune complex disease.
7. Hereditary angioedema is autosomal dominant, driven by bradykinin, and shows low C4 with normal C3. There is no urticaria.
8. ACE inhibitors are contraindicated in hereditary angioedema because ACE is the enzyme that degrades bradykinin.
9. Danazol raises C1 INH synthesis and is used for prophylaxis of hereditary angioedema. It does not treat an acute attack.
10. PNH is an acquired PIGA mutation, not inherited. Flow cytometry for CD55 and CD59 is the diagnostic test.
11. Eculizumab creates a functional terminal complement deficiency. Meningococcal vaccination is mandatory before starting.
12. Low C3 with normal C4 points to alternative pathway consumption: PSGN or MPGN with C3 nephritic factor.
13. Low C3 and low C4 together point to classical consumption: active SLE, cryoglobulinemia, endocarditis.
14. CH50 tests the classical pathway end to end. AH50 tests the alternative pathway. A defect in C3 or the terminal components lowers both.
15. Properdin deficiency is X linked and produces the same Neisseria picture as terminal deficiency, but with a normal CH50 and low AH50.
16. Factor H deficiency or autoantibody causes atypical HUS. Look for HUS without bloody diarrhea.
17. Staphylococcus aureus protein A blocks complement by binding the Fc region of IgG so C1q cannot.
18. Encapsulated bacteria need C3b opsonization and a spleen. Asplenia and C3 deficiency produce overlapping infection profiles.
19. The hemolytic transfusion reaction is type II hypersensitivity with classical activation by preformed IgM against ABO antigens.
20. Transfusion or dialysis membrane reactions with flushing and hypotension are anaphylatoxin effects from C3a and C5a, not IgE.

USMLE Style Practice Questions

If these stems feel unfamiliar, start with our Step 1 study guide for beginners and come back to this section once you have worked a few blocks. Six vignettes in NBME style. Each answer includes why the correct option is right and why the distractors are wrong, because that is where the learning happens.

Question No: 1

Difficulty: Medium  |  Competency: Immunology, complement deficiencies

A 19 year old woman is admitted with fever, petechial rash and hypotension. Blood cultures grow Neisseria meningitidis. She had a similar episode at age 15 that was treated successfully. Serum immunoglobulins, CD4 count and neutrophil count are normal. Which of the following is the most likely underlying defect?

A. Deficiency of C2

B. Deficiency of C3

C. Deficiency of C8

D. Deficiency of the common gamma chain

E. Mutation in NADPH oxidase

Correct answer: C. Deficiency of C8

Recurrent invasive Neisseria infection in a patient with otherwise normal immune function is the signature of a terminal complement deficiency. C8 is one of the components of the membrane attack complex, which is the main defense against Neisseria.

Why the other options fail: 

• C2 deficiency produces lupus like autoimmunity rather than Neisseria.
• C3 deficiency produces severe pyogenic infections with encapsulated organisms from infancy, not isolated Neisseria in a teenager.
• Common gamma chain mutation causes X linked SCID with an abnormal lymphocyte profile.
• NADPH oxidase defects cause chronic granulomatous disease with catalase positive organisms and abscesses.

Question No: 2

Difficulty: Medium  |  Competency: Immunology and pharmacology, hereditary angioedema

A 24 year old man presents with painless swelling of his lips and tongue that began two hours ago. He has had three prior episodes of abdominal pain with facial swelling. There is no urticaria or pruritus. His father had similar episodes. Laboratory studies show a low C4 and normal C3. Which of the following medications is contraindicated in this patient?

A. Danazol

B. Icatibant

C. Lisinopril

D. Diphenhydramine

E. Fresh frozen plasma

Correct answer: C. Lisinopril

This is hereditary angioedema from C1 esterase inhibitor deficiency. Attacks are mediated by bradykinin. ACE inhibitors block the degradation of bradykinin and can precipitate or worsen attacks, so they are contraindicated.

Why the other options fail: 

• Danazol is used for prophylaxis because it increases C1 INH synthesis.
• Icatibant is a bradykinin B2 receptor antagonist used for acute attacks.
• Diphenhydramine is ineffective but not contraindicated.
• Fresh frozen plasma contains C1 INH and can be used when concentrate is unavailable.

Question No: 3

Difficulty: Hard  |  Competency: Hematology, complement regulation

A 34 year old woman presents with fatigue and dark urine that is most noticeable in the morning. She was recently treated for a hepatic vein thrombosis. Laboratory studies show hemoglobin 8.1 g/dL, elevated LDH, low haptoglobin and a negative direct antiglobulin test. Flow cytometry of red cells will most likely show absence of which of the following?

A. CD4 and CD8

B. CD19 and CD20

C. CD55 and CD59

D. CD18 and CD11a

E. CD3 and CD28

Correct answer: C. CD55 and CD59

Nocturnal hemolysis, venous thrombosis at an unusual site and a negative Coombs test point to paroxysmal nocturnal hemoglobinuria. A PIGA mutation removes the GPI anchor, so DAF (CD55) and MIRL (CD59) are absent and red cells are lysed by complement.

Why the other options fail: 

• CD4 and CD8 are T cell markers.
• CD19 and CD20 are B cell markers.
• CD18 and CD11a form LFA 1, absent in leukocyte adhesion deficiency.
• CD3 and CD28 are T cell receptor and costimulatory markers.

Question No: 4

Difficulty: Medium  |  Competency: Nephrology, complement lab patterns

A 7 year old boy develops periorbital edema, hypertension and cola colored urine two weeks after a sore throat. Urinalysis shows red cell casts. Serum C3 is low and serum C4 is normal. Which of the following best explains the complement pattern?

A. Classical pathway activation by immune complexes

B. Alternative pathway activation with C3 consumption

C. Deficiency of C1 esterase inhibitor

D. Inherited deficiency of C2

E. Autoantibody against the C5 convertase

Correct answer: B. Alternative pathway activation with C3 consumption

Post streptococcal glomerulonephritis consumes C3 through the alternative pathway, so C3 falls while C4, which is only used by the classical and lectin pathways, stays normal. C3 recovers within six to eight weeks.

Why the other options fail: 

• Classical activation would lower both C3 and C4, the pattern of lupus nephritis.
• C1 INH deficiency lowers C4, not C3, and does not cause nephritis.
• C2 deficiency lowers CH50 and predisposes to lupus but does not cause an acute nephritic picture after pharyngitis.
• C3 nephritic factor stabilizes the C3 convertase, not the C5 convertase, and causes persistent rather than transient C3 depression in MPGN.

Question No: 5

Difficulty: Easy  |  Competency: Immunology, complement functions

A researcher is studying the recruitment of neutrophils to a site of bacterial infection in a mouse model. Which complement fragment is the most potent chemoattractant?

A. C1q

B. C3a

C. C3b

D. C4a

E. C5a

Correct answer: E. C5a

C5a is the most powerful chemotactic factor in the complement cascade and also acts as an anaphylatoxin. C3a and C4a are anaphylatoxins with much weaker chemotactic activity, C3b is an opsonin, and C1q is a recognition molecule.

Question No: 6

Difficulty: Hard  |  Competency: Pharmacology, complement targeted therapy

A 40 year old man with paroxysmal nocturnal hemoglobinuria is about to start eculizumab. Which of the following should be done before the first dose?

A. Splenectomy

B. Meningococcal vaccination

C. Iron chelation

D. Bone marrow biopsy

E. Prophylactic acyclovir

Correct answer: B. Meningococcal vaccination

Eculizumab binds C5 and prevents formation of the membrane attack complex, producing a functional terminal complement deficiency. This creates the same susceptibility to Neisseria seen in inherited terminal deficiencies, so meningococcal vaccination is required before treatment.

Why the other options fail: 

• Splenectomy would worsen susceptibility to encapsulated organisms and has no role here.
• Iron chelation is for iron overload, and PNH patients tend to lose iron in urine.
• Bone marrow biopsy may be part of the workup but is not a prerequisite for the drug.
• Acyclovir prophylaxis addresses herpesviruses, which are not the risk created by C5 blockade.

Frequently Asked Questions

Q1. What is the most high yield fact about the complement system for Step 1?

That terminal complement deficiency causes recurrent Neisseria infections. If we had to bet on one complement question appearing on your form, it would be a variation of that vignette. The second most likely is the C3 versus C4 pattern in PSGN and SLE.

Q2. Which complement deficiency is the most common?

C2 deficiency is the most common inherited complement deficiency in the general population. It presents with lupus like autoimmunity and sometimes recurrent infections. On the exam, however, terminal deficiencies are asked about far more often because the Neisseria link is so clean.

Q3. Why does IgM activate complement better than IgG?

C1q needs to bind at least two Fc regions that are close together. A single pentameric IgM molecule offers five, so one bound IgM is enough. IgG is a monomer, so two IgG molecules must land near each other on the same antigen. IgA and IgE do not activate the classical pathway at all.

Q4. Is the lectin pathway part of innate or adaptive immunity?

Innate. Mannose binding lectin recognizes a sugar pattern on microbes directly and needs no antibody. It shares the classical C3 convertase, C4b2b, but not the classical trigger.

Q5. What is the difference between CH50 and AH50?

CH50 measures the ability of serum to lyse antibody coated sheep red cells, which requires every classical and terminal component from C1 through C9. AH50 uses rabbit red cells in conditions that activate only the alternative pathway, so it needs Factor B, Factor D, properdin, C3 and the terminal components. A low CH50 with normal AH50 isolates the defect to C1, C2 or C4. Both low means C3 or a terminal component.

Q6. Why is C4 low in hereditary angioedema if the disease is about bradykinin?

C1 esterase inhibitor also holds C1 in check. Without it, C1 is constantly active and cleaves C4 in the background, so C4 stays low even between attacks. The swelling itself comes from bradykinin, but the lab clue comes from complement.

Q7. How does PNH connect to complement if it is a hematology disease?

The red cells in PNH are missing DAF and CD59, the two GPI anchored regulators that normally protect host cells from complement. Without them the alternative pathway, which is always ticking over, builds MAC on the red cell membrane and lyses it. The problem is not too much complement, it is too little protection.

Q8. What do eculizumab and ravulizumab do?

Both are monoclonal antibodies against C5. They block cleavage of C5 so no C5a or C5b is produced and no membrane attack complex forms. They are used in PNH, atypical HUS and some autoimmune conditions. Because they mimic terminal deficiency, meningococcal vaccination is required before starting.

Q9. Do complement levels go up or down in active lupus?

Down. Immune complexes activate the classical pathway and consume C3 and C4 faster than the liver can replace them. Falling levels track flares and rising levels suggest response to treatment. Low C3 and C4 with a high anti dsDNA titer is the classic active lupus nephritis pattern.

Q10. Which bacteria escape complement, and how?

Staphylococcus aureus protein A binds the Fc portion of IgG so C1q cannot attach. Streptococcus pyogenes M protein and several Neisseria strains recruit Factor H to their surface, which shuts down C3 convertase formation. Capsules physically block C3b deposition, which is why encapsulated organisms are the classic pathogens of opsonization defects and asplenia.

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