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USMLE Step 1ImmunologyEP 07 of 14

Complement deficiencies: C1q, C3, C5–C9 and C1 inhibitor

Each missing complement component predicts its own disease. Work out the infection or syndrome from the job that is lost, and the CH50, C3 and C4 pattern follows.

  • 5:15 video
  • 3 min read
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  • Published 15 Nov 2026
Video lesson · 5:15 · Watch on YouTubeSeries: Immunology · @medservatory
Chapters (10)
By the end of this lesson

Predict the infection or disease that follows deficiency of the early classical components (C1q, C2, C4), C3, the terminal components (C5–C9) and C1 inhibitor, from the job each component does.

The short version

  1. The infection or disease pattern follows the job that is lost.
  2. Early classical deficiency (C1q, C1r, C1s, C4, C2) gives lupus-like autoimmunity, and C3 deficiency gives severe recurrent bacterial infection.
  3. Terminal component deficiency (C5–C9) gives recurrent or disseminated Neisseria infection.
  4. CH50 is the classic screening test: absent in early classical, C3 and C5–C8 deficiencies, only reduced in C9 deficiency.
  5. C1 inhibitor deficiency gives hereditary angioedema from bradykinin, with usually low C4 and normal C3.

The puzzle: swelling with no hives

A woman's lips and face swell, again and again, often after dental work. There are no hives and no itch, and antihistamines, steroids and epinephrine do nothing. A missing complement regulator can cause this. Which one, and why?

This lesson covers complement deficiencies: what follows when the early components, C3, the terminal components or C1 inhibitor are missing. The rule that ties them together is simple: the infection pattern follows the job that is lost.

Recall the roles: early classical, C3, the pore and the brake

  • Early classical pathway: C1q, C1r, C1s, C4 and C2.[1]
  • C3: the hub where all three pathways meet, and the component that opsonises microbes.[1][2]
  • C5 to C9: these make the membrane attack complex, which punches holes in a target.[1][2]
  • C1 inhibitor: a brake on C1r, C1s and the lectin enzymes, and also on the contact system enzymes (plasma kallikrein and factor XIIa) that make bradykinin.[1][3][4]

Keep these four jobs in mind. Each deficiency in this lesson removes one of them, and the disease that results follows from the job that is missing.

Early classical and C3 deficiency: autoimmunity and bacterial infection

The early classical components, C1q, C1r, C1s, C4 and C2, clear immune complexes and dying cells. Without them, complexes and cell debris linger, so the result is lupus-like autoimmunity.[3]

C1q deficiency is the classic cause of this lupus-like picture. There is also a risk of infection with encapsulated bacteria.[3]

C3 is the hub, so its loss means no opsonisation and no C5 convertase from any pathway. The result is recurrent severe bacterial infections, plus immune-complex glomerulonephritis. C3 deficiency therefore hits opsonisation, the central job of complement.[3]

The two groups can look alike at first, because both involve the early part of the cascade. The difference is the main job lost: early classical components deal with debris and immune complexes, so the leading problem is autoimmunity, with some encapsulated infections; C3 is the opsonin and the hub, so the leading problem is severe infection.

Terminal complement deficiency (C5–C9): recurrent Neisseria

In terminal component deficiency, opsonisation is intact, so ordinary infections are not the problem. What is lost is the pore. Gram-negative Neisseria are especially sensitive to lysis by the membrane attack complex.[2][3]

So terminal deficiency means recurrent or disseminated Neisseria infection, meningococcal or gonococcal. The clue is the organism and the repeat: Neisseria, again.[3][5]

The reasoning runs in three steps. Opsonisation still works, so most bacteria are handled. The pore cannot form, so organisms that depend on lysis for their clearance are not handled. Neisseria are the classic example, so the pattern is Neisseria infection that keeps coming back.[2][3]

CH50: the screening test for complement deficiencies

The classic blood test is CH50, which measures total classical-to-terminal complement activity. It is the first-tier screen when a complement disorder is suspected.[5][6]

CH50 by deficiency
DeficiencyCH50
Early classical componentsAbsent
C3Absent
C5 to C8Absent
C9Only reduced

This table follows the IUIS listing: CH50 activity is absent when any component from C1 to C8 is missing, and only reduced when C9 is lost, because C5b-8 without C9 can still lyse the test red cells slowly.[3]

C1 inhibitor deficiency: hereditary angioedema and bradykinin

C1 inhibitor deficiency causes hereditary angioedema. It is autosomal dominant.[3][4]

Without the brake, C1 stays active and consumes C4 and C2, so C4 is usually low and C3 is normal. The same missing brake lets the contact system make too much bradykinin.[3][4]

Notice that the problem here is not a lost defence but a lost brake. The missing brake lets two cascades run unchecked: complement, which uses up C4 and C2, and the contact system, which makes bradykinin.[3][4]

Bradykinin, not histamine, causes the swelling. That is why there are no hives, and why antihistamines fail. A dental procedure is a classic trigger, and the airway can swell, so it can be life threatening.[4]

That is the woman from the opening: usually low C4, normal C3, and bradykinin-driven swelling.

Putting the complement deficiencies together

What follows each deficiency
MissingJob lostWhat follows
Early classical (C1q, C1r, C1s, C4, C2)Clearing immune complexes and dying cellsLupus-like autoimmunity; C1q is the classic cause
C3Opsonisation, the hub of all pathwaysRecurrent severe bacterial infections; immune-complex glomerulonephritis
C5 to C9The membrane attack complex poreRecurrent or disseminated Neisseria
C1 inhibitorThe brake on C1r, C1s, the lectin enzymes and the contact systemAngioedema from bradykinin; C4 usually low, C3 normal

When a vignette describes a repeat infection, name the organism first. Neisseria again points to the terminal pore. Severe infection with many kinds of bacteria points to C3. Lupus-like disease, sometimes with encapsulated infections, points to the early classical components, and C1q is the classic cause. Swelling without hives points to C1 inhibitor and bradykinin.

Practice question

Original · USMLE style
Your turnQB-MS-S1-IMM-002-01

A 19-year-old man is admitted with meningococcal meningitis. One year ago he had a previous episode of meningococcal meningitis. He has no history of other severe infections, and has no rash, joint pain or kidney disease. His CH50 is undetectable; his serum C3 and C4 concentrations and immunoglobulin levels are within normal limits.

Which of the following is the most likely underlying deficiency?
Pick one option. Your answers stay on this device.

Common questions

Which complement deficiency causes recurrent Neisseria infections?

Terminal component deficiency, C5 to C9. Opsonisation is intact but the membrane attack complex pore is lost, and Gram-negative Neisseria are especially sensitive to lysis by it.

Which complement deficiency is classically linked to lupus-like disease?

C1q deficiency is the classic cause. Early classical components clear immune complexes and dying cells, so without them complexes and debris linger.

Why do antihistamines not work in hereditary angioedema?

Bradykinin, not histamine, causes the swelling. The missing C1 inhibitor lets the contact system make too much bradykinin, so there are no hives and antihistamines fail.

What does CH50 measure?

CH50 measures total classical-to-terminal complement activity. It is absent in early classical, C3 and C5 to C8 deficiencies, and only reduced in C9 deficiency.

What are C3 and C4 in C1 inhibitor deficiency?

C4 is usually low and C3 is normal, because without the brake C1 stays active and consumes C4 and C2.

Transcript

Read the full narration, by chapter592 words

0:00The puzzle: swelling with no hives, and a missing complement regulator

A woman's lips and face swell, again and again, often after dental work. There are no hives and no itch, and antihistamines, steroids and epinephrine do nothing. A missing complement regulator can cause this. Which one, and why? Today: predict what follows when the early

0:17Today's goal and the complement funnel: early classical, C3, C5-C9, C1 inhibitor

components, C3, the terminal components, or C1 inhibitor are missing. Recall the cascade. C1q, C1r, C1s, C4 and C2 make up the early classical pathway. C3 is the hub where all three pathways meet, and it opsonises microbes. C5 to C9 make the membrane attack complex, which punches holes in a target. C1 inhibitor is a brake on C1r, C1s and the lectin enzymes. Rule: the infection pattern follows the job that is lost. Early classical components,

0:58Early classical deficiency (C1q): lupus-like disease

C1q, C1r, C1s, C4 and C2, clear immune complexes and dying cells. Without them, complexes and cell debris linger, so the result is lupus-like autoimmunity. C1q deficiency is the classic cause of this lupus-like picture. There is also a risk of infection with encapsulated bacteria. Next, C3.

1:25C3 deficiency: no opsonisation, severe bacterial infection

It is the hub, so there is no opsonisation, and no C5 convertase from any pathway. The result is recurrent severe bacterial infections, plus immune-complex glomerulonephritis. C3 deficiency therefore hits opsonisation, the central job of complement. Now the terminal components,

1:46Terminal deficiency (C5-C9): recurrent Neisseria

C5 to C9. Opsonisation is intact, so ordinary infections are not the problem. What is lost is the pore. Gram-negative Neisseria are especially sensitive to lysis by the membrane attack complex. So terminal deficiency means recurrent or disseminated Neisseria infection, meningococcal or gonococcal. The clue is the organism and the repeat: Neisseria, again.

2:16CH50: the screening test

The classic blood test is CH50, which measures total classical-to-terminal complement activity. It is absent in early classical, C3, and C5 to C8 deficiencies. In C9 deficiency it is only reduced. Finally, C1 inhibitor deficiency:

2:33C1 inhibitor deficiency: hereditary angioedema and bradykinin

hereditary angioedema. It is autosomal dominant. Without the brake, C1 stays active and consumes C4 and C2, so C4 is usually low and C3 is normal. The same missing brake lets the contact system make too much bradykinin. Bradykinin, not histamine, causes the swelling, which is why there are no hives, and why antihistamines fail. A dental procedure is a classic trigger, and the airway can swell, so it can be life threatening. That is our woman: usually low C4, normal C3, and bradykinin-driven swelling.

3:16Practice question

Your turn. A 19-year-old man is admitted with meningococcal meningitis. A year ago he had another episode. He has no history of other severe infections, and has no rash, joint pain or kidney disease. His CH50 is undetectable, his serum C3 and C4 concentrations are normal, and his immunoglobulin levels are normal. Which of the following is the most likely underlying deficiency? A, C1q. B, C3. C, C7. D, C1 inhibitor. E, decay-accelerating factor. Pause here and decide.

4:00Answer and explanation (C7 deficiency)

A is out: C1q deficiency gives lupus-like disease, and he has no rash, joint pain or kidney disease. B is out: C3 would give repeated severe bacterial infections of many kinds, and a low C3. D is out: C1 inhibitor deficiency causes angioedema, with a usually low C4. E is out: losing decay-accelerating factor lets complement attack the body's own red cells, a haemolytic anaemia, not meningitis. So the answer is C. Recurrent meningococcal disease with no CH50 and normal C3 points to a terminal component, here C7.

4:45Recap and next lesson

Three things to keep. One: early classical deficiency gives lupus-like disease, and C3 gives severe recurrent bacterial infection. Two: terminal deficiency gives recurrent Neisseria. Three: C1 inhibitor deficiency gives angioedema from bradykinin, with usually low C4 and normal C3. Next, hypersensitivity: the four types.

Sources

Numbers in the text, e.g. [1], point here
  1. Complement System Part I: molecular mechanisms of activation and regulation. Front Immunol 2015. europepmc.org/article/PMC/PMC4451739
  2. Complement System Part II: role in immunity. Front Immunol 2015. europepmc.org/article/PMC/PMC4443744
  3. IUIS Expert Committee on Inborn Errors of Immunity, 2017 report (Table 8, complement deficiencies). europepmc.org/article/PMC/PMC5742601
  4. WAO/EAACI guideline for the management of hereditary angioedema, 2021 revision. europepmc.org/article/PMC/PMC9023902
  5. Case report: recurrent meningococcal disease and total complement activity (CH50). europepmc.org/article/PMC/PMC12886615
  6. Review: first-tier complement screening with CH50 and AH50. europepmc.org/article/PMC/PMC13601826
  7. Review: paroxysmal nocturnal haemoglobinuria (loss of CD55 and CD59, complement-mediated haemolysis). europepmc.org/article/PMC/PMC13753068
  8. Review: decay-accelerating factor (CD55) and convertase decay. europepmc.org/article/PMC/PMC13078055
  9. Background: en.wikipedia.org/wiki/Complement_system · en.wikipedia.org/wiki/Complement_deficiency

The hook patient and the practice question are original teaching vignettes with synthetic values. The CH50 tubes, kinin chain and funnel diagrams are schematic.

The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.

Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): Dentist, Syringe, Skin, Normal joint, Kidney, Antibody, Meningitis, Larynx front view. NIAID NIH BioArt Source (bioart.niaid.nih.gov), public domain: Complement C1 Complex, Bacteria, Cell Death, Macrophage, Red Blood Cell, Mast Cell. "edema capillaries" icon by Servier via bioicons.com, CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/), adapted. The patient's face, hive and tablet icons, the complement funnel, protein bars, CH50 tubes and table, the kinin chain, the cards and all handwriting are drawn in code (original). No AI-generated teaching images.

Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-IMM-002.

For exam study only, not medical advice. Read the medical disclaimer.

In this series

Playlist on YouTube
← Previous · EP 06Complement system explained: three pathways, one ending
  1. EP 01MHC I vs MHC II: how antigen presentation works5:03
  2. EP 02T-cell activation: the two-signal model4:58
  3. EP 03Th1, Th2, Th17 and Treg: helper T-cell subsets5:13
  4. EP 04Antibody isotypes and class switching5:13
  5. EP 05Central vs peripheral tolerance: how lymphocytes learn self-tolerance5:26
  6. EP 06Complement system explained: three pathways, one ending5:24
  7. EP 07Complement deficiencies: C1q, C3, C5–C9 and C1 inhibitor5:15
  8. EP 08Hypersensitivity types I to IV: the four effectors5:20
  9. EP 09B-cell vs T-cell immunodeficiency: predict the infections5:24
  10. EP 10Hyper IgM syndrome: CD40 ligand and class switching5:19
  11. EP 11Chronic granulomatous disease: NADPH oxidase and the respiratory burst5:20
  12. EP 12Leukocyte adhesion deficiency: CD18 and neutrophil extravasation5:01
  13. EP 13Transplant rejection explained: hyperacute, acute, chronic and GVHD5:51
  14. EP 14Vaccine types explained: live, inactivated, conjugate and mRNA5:41