Complement receptors (CR)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist

There are 4 types of complement receptors (CR):

- CR1 (CD35) promote phagocytosis of antigens coated by complement fragments
- CR2 (CD21) connect the innate and adaptive immune systems through humoral response
- CR3 (Mac-1, CD11b/CD18) (integrin receptors) promote both phagocytosis and leukocyte adhesion

- CR4 (gp 150/95, CD11c/CD18) is a market for dendritic cells

To remember: CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are affected in LAD type I.

CD55 (DAF) and CD59 are affected in PNH. Eculizumab (Soliris) is a humanized mAb against complement protein C5. It is used for treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Complement receptor 2 (CR2/CD21) is part of the B-cell coreceptor and expressed by mature B cells and follicular dendritic cells. CD21 is a receptor for C3d-opsonized immune complexes and enhances antigen-specific B-cell responses. Viruses, such as HIV and EBV, use the complement receptors (CR2) to the enter the cell. Genetic CD21 deficiency is associated with hypogammaglobulinemia (JACI, 2011).


Complement receptors (click to enlarge the image).

All of the following are correct pairings of complement receptors and function except:

A. CR1 (CD35) with phagocytosis, immune complex clearance

B. CR4 with phagocytosis

C. CR3 with EBV receptor, leukocyte adhesion, phagocytosis

D. CR2 (CD21) with B cell activation, trapping of antigens in germinal centers

Answer: C. EBV use CR2 (CD21) to enter the cell.

Place in increasing order the CD designation of complement receptors CR1, CR2, CR3, CR4:

A. CD21, CD35, CD11b/CD18, CD11c/CD18

B. CD35, CD21, CD11b/CD18, CD11c/CD18

C. CD35, CD21, CD11c/CD18, CD11b/CD18

D. CD11b/CD18, CD11c/CD18, CD21, CD35

Answer: B.

Deficiency of which component of the complement is among the causes of paroxysmal nocturnal hemoglobinuria (PNH)?

A. CR2 (CD21)

B. Factor I

C. DAF

D. MCP

Answer: C.

References

Allergy and Immunology MKSAP, 3rd edition.
Chapter 2. Innate immunity. Abbas et al: Cellular & Molecular Immunology, 6th Ed.

Published: 09/05/2010
Updated: 10/02/2011

CD59

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

CD59, or protectin, is a complement regulatory protein that inhibits the complement membrane attack complex (MAC) by binding C5b678 and preventing C9 from binding and polymerizing.

It is present on cells to prevent complement from damaging them.

CD59 is also called membrane attack complex inhibition factor (MACIF) or MAC-inhibitory protein (MAC-IP).


CD59 molecule, complement regulatory protein. Image source: Wikipedia, public domain.

Mnemonic

CD59 blocks
C5-9
components of the complement, MAC, from perforating the cell membrane


Complement receptors (click to enlarge the image).

Eculizumab (Soliris) is a humanized mAb against complement protein C5. It is used for treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Related reading

CD59. Wikipedia.

Published: 11/18/2009
Updated: 09/18/2010

Mnemonics: Complement

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

C3
All 3 complement pathways converge at C3 level

There are 3 pathways for activation of complement:

CAM

Classical
Alternative
Mannose-binding lectin (MBL)

CAM leads to MAC

CD59 blocks
C5-9
components of the complement, MAC, from perforating the cell membrane

References

Complement System
Complement Deficiencies

Published: 11/18/2009
Updated: 11/18/2009

Complement System

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Innate Immune System (click on the title for the full text).


The 2 arms of the immune system: innate immunity and adaptive immunity.


Overview of the innate immune system (a mind map).

Complement System

Complement system is a cascade of enzymes which leads to a membrane attack complex (MAC) which causes osmotic lysis of cells. Different fragments of the complement cascade act as inflammatory mediators.

There are 3 pathways for activation of complement:

CAM

Classical
Alternative
Mannose-binding lectin (MBL)


Mannose-binding lectin (MBL). Image source: Wikipedia.

The 3 pathways (CAM) converge at the point of cleavage of C3. Then C3b becomes an acceptor site for C5, and C5-9 form the membrane attacking complex (MAC). Thus, CAM leads to MAC:

CAM --> MAC

A complement protein attacking an invader. Image source: Wikipedia.

Classical and alternative complement pathways. Image source: Wikipedia.

C1 protein, showing subunits C1r, C1s, and the C1q tails. Image source: Wikipedia. Hereditary angioedema (HAE) is an autosomal dominant condition associated with episodic attacks of nonpitting edema. Patients with HAE have low levels of C1 inhibitor (a serine protease inhibitor). Edema is caused by unregulated generation of bradykinin.

MBL looks almost exactly like the "branching" C1 protein. The binding affinity of C1q decreases in the following order IgM, IgG3, IgG1, IgG2.

The likelihood of SLE development in complement deficiency: most common in C1q deficiency, then C4, and then C2.

HAE mnemonic:
1
C1 inhibitor is low
C1 q level is normal
11 chromosome
11 years is the mean age of onset
11 years before the diagnosis is made, on average

C
Classical pathway
C1
Cleaves
C4
Covalent bond to bacterial surface
Cleaves
C2
Complex C4b2a
C3
Convertase to MAC

C
Classical pathway
Complex Ag-Ab (IgG/M)

A
Alternative pathway
Adhesive cell walls
Antibody not needed for activation (different from classical pathway)

Click to see Wikipedia figures.

Alternative and MBL pathway

A
Alternative and MBL pathway

Antibody not needed for activation (different from classical pathway)

C3 - no receptor on any cell
C3b receptor - CD35 - CR1
C3a - small molecule

C3 continuously undergoes small scale cleavage in the plasma to C3b. This is called C3 tickover.

B cell activation

Complement receptor CD21 (CR2) activates BCR if the antigen is opsonized by C3b component of the complement.

CR2-CD19-CD81 complex is expressed on the surface of B lymphocytes.

When CD21 (CR2) interacts with C3d, the complex is brought into the BCR. CD19 has an ITAM that is phosphorylated, thus recruiting Lyn to enhance phosphorylation.

What is the rate-limiting step in the complement cascade?

C4. The liver can produce a finite amount of C4. In rare cases, when an angioedema attack is treated with large amounts of FFP, symptoms may worsen because of a temporary C4 depletion.

Complement receptors (CR) (click on the title for the full text).

Chemotaxis

C5a is the most potent mediator of basophil and cutaneous mast cell degranulation. C5a is chemotactic for neutrophils, eosinophils, monocytes, and basophils.

C3a is chemotactic for eosinophils only.

All of the following are correct pairings of complement deficiency and component of the complement system EXCEPT:

A. C2 or C4 deficiency with SLE-like syndrome

B. deficiency in the components of the alternative pathway of compliment with pyogenic bacterial infections

C. deficiency in the terminal components of complement with H. Influenzae infection

D. C1 inhibitor deficiency with angioedema

Answer: C. Deficiency in the terminal components of complement (C7-9) leads to Neisseria meningitidis infection.

References

Allergy and Immunology MKSAP, 3rd edition.
Chapter 2. Innate immunity. Abbas et al: Cellular & Molecular Immunology, 6th Ed.

Related Reading

Medical Immunology Syllabus. Columbia University.
Anaphylaxis Due to Contaminated Heparin Causes Multiple Deaths, Trigger Found. Allergy Notes, 04/2008.
FIT Corner Q & A from 5th edition of Cellular and Molecular Immunology, edited by Abul K. Abbas and Andrew H. Lichtman. ACAAI, 2004.
Chapter 6: The Complement System, Part 1 and Part 2. Allergy and Immunology Review Corner: Chapter 6, Part 1 of Middleton’s Allergy Principles and Practice, 7th Edition, edited by N. Franklin Adkinson, et al. FIT Corner Q&A.
Mnemonics: Complement

Videos


Classical Pathway Complement System


Alternative Pathway Compliment System


The Complement System.


Complement Proteins

Published: 12/05/2007
Updated: 09/05/2010