Immunology The Complement System Chapter 6

Systemic lupus erythematosus (SLE) is what?

A deficiency of C2 and C4 (often seen). Decrease in circulating C3 is used to confirm active disease.

Pyogenic infections with encapsulated bacteria is caused by what?

A deficiency of C3.

Paroxysmal nocturnal hemoglobinuria (PNH) is what?

A deficiency of DAF, where RBCs are lysed when the MAC forms on cell surfaces.

Which pathways are antibody independent, in other words, do not require an antibody to begin?

Alternative pathway/Properdin pathway and Lectin pathway are the two pathways that are antibody independent.

What are the end products of the activation unit?

Anaphylatoxins (C3a, C4a, and C5a).

The classical complement pathway is activated by what?

Antigen Antibody complexes.

Why is IgM important in the classical pathway?

Because IgM has the most binding sites.

Why is complement not activated with anti Rh (D) antibodies?

Because Rh antigens are too far apart on RBCs.

Why is MAC important?

Because it forms a pore in the cell, it leads to the rupture of the cell through osmotic lysis.

Why is complement activation is referred to as a "cascade"?

Because numerous proteins in the complement system are sequentially activated.

What occurs in the recognition unit?

C1 protein, which consists of C1q, C1r, and C1s, binds to IgM or IgG that is then bound to a bacterial cell surface. It is stabilizes by calcium. Once the last C1 protein, C1s, is fixed, the activation unit begins.

The recognition unit consists of C1q, C1r, and C1s, binding occurs at Fc region of antibody molecules, and the subunits require calcium for binding together. However, C1q does NOT become what?

C1q does NOTbecome an active esterase.

The structure of MBL is similar to?

C1q.

C4b2a, C3bBb, and iC3Bb refer to what?

C3 convertase.

Which protein is the major constituent of the complement system, as well as the pivotal point for ALL three pathways?

C3.

What is immune adherence in regards to the end products of activation unit?

C3b adherence to immune complexes and surfaces of substances to aid in removal of immune complexes.

Which proteins are opsonins in the activation unit?

C3b and C4b which enchances phagocytosis.

Which protein is the second most abundant complement protein in the activation unit?

C4.

The Membrane Attack Complex is comprised of what?

C5b, C6, C7, C8, and C9.

What tests are used in complement activities?

CH50 and AH50.

What are the three pathways that may activate complement?

Classical Pathway, Alternative Pathway (Properdin Pathway), and Lectin Pathway

Which pathway is antibody dependent, in other words, requires an antibody to begin?

Classical pathway is the only one that is antibody dependent.

What's a fun fact about complement fixation test?

Complement itself can be used as a reagent to detect viral, fungal, or rickettsial antibodies.

What occurs in the activation unit?

Composed of C4, C2, and C3, it ends with the production of C5 convertase which cleaves C5 to C5a and C5b. C5b then is deposited on the bacterial cell surface, which begins the membrane attack complex (MAC).

What is most effective in preventing bystander lysis of RBCs?

DAF.

A lack of CR2 on cell membranes wold result in what?

Decreased antibody production.

Hereditary angioedema is caused by what?

Deficiencies in C1INH.

Recurrent infections with Neisseria sp. is caused by what?

Deficiencies in the MAC proteins.

What is the procedure to complement fixation testing?

Destory complement through heating to 56C for 30 minutes prior to testing. Dilutions of serum (unknown) + known antigen + measured amount of guinea pig complement. If patient's antibody is present, it will combine with reagent antigen and complement is bound. Then add sheep RBCs (coated with anti sheep hemolysin).

The CH50 test measures what?

Dilution of patient serum required to lyse 50% of a standard concentration of sensitized sheep RBCs, functioning of both the classical and alternative pathways, and genetic deficiencies of any of the complement components.

Factor H acts by competing with what for the same binding site?

Factor B.

CR1 is a cell bound regulator similar to what and how?

Factor H through binding to C3b. It mediates transport of immune complexes to the liver and spleen. Tissue macrophages strip immune complexes from RBCs, returning them intact to circulation.

What are the two types of regulators in complement?

Fluid phase (plasma component) and cell bound phase.

C3a, C4a

Function as anaphylatoxins.

C3b, C4b

Function as opsonins.

C5a

Function as the most powerful anaphylatoxin, as well as having chemotactic properties.

C5b

Function to bind with proteins that help initiate the MAC attack.

What are the results for complement fixation testing?

Hemolysis occurs = patient negative for antibody (guinae pig complement free to lyse RBCs) Hemolysis doesn't occur = patient positive for antibody (no guinae pig complement free to lyse RBCs)

Lack of individual components can have an adverse effect through how?

Hereditary deficiency of any complement protein (except for C9) usually manifests itself in increased suspectibility to infection and delayed clearance of immune complexes.

What are the positive and negative results of a complement fixation test?

If there is hemolysis, indicating that either antigen or antibody was not present, it is a negative test. If there is a lack of hemolysis, it is a positive test.

Decreased CH50 levels may be caused by what?

Inadequate refrigeration of specimen, coagulation associated complement consumption, and autoimmune disease process.

What is the general trend when it comes to the complement cascade?

Inflammation > Phagocytosis > Lysis.

What does chronic activation lead to?

Inflammation and tissue damage that occurs in an autoimmune disease.

Complement combats infection by amplifying phagocytosis, but in some cases, it can cause what?

It can actually contribute to tissue damage or death.

How in what ways can the complement system be harmful?

It can be activated systemically on a large scale as in gram negative septicemia, activated by tissue necrosis (tissue decay) such as myocardial infarction, and lysis of RBCs through cold autoimmune hemolytic anemia.

The functions of the complement system include lysis of foreign cells, increase in vascular permeability, and migration of neutrophils to tissues. What does it not do in regards to antigen antibody complexes?

It does NOT decrease clearance of antigen antibody complexes.

What major role does the complement system play in the inflammatory response?

It helps with the direction against foreign antigens, because it "complements" the action of antibody in destroying microorganisms.

C5a, which is an anaphylatoxin, induces what?

It induces the migration of neutrophils and monocytes to the site of infections, which is important to the site of inflammation.

What is the mannose binding lectin (MBL)?

It is a key lectin that binds to mannose in a Ca+ dependent manner to initiate the Lectin Pathway. It's produced in the liver and contributes to an acute phase protein (goes up during the initial protein response).

What other facts are necessary to know about the complement system?

It is a system of proteins that play a major role in host defense, is synthesized in the liver, and involves the process of the complement attaching to the Fc portion of the immunoglobulin molecule.

What other functions does DAF serve?

It protects host cells from "bystander lysis" through inactivating C3 or C3b (discrimination of self from nonself).

What is the role of properdin in the alternative pathway?

It stabilizes the C3/C5 convertase.

What is most important to know about the MAC?

It's associated with the hole forming in the cell wall of the foreign microbe, which ultimately leads to the lysis of the foreign microbe when it reaches to the protein C9.

What describes the amplification loop in complement activation?

It's found in the alternative pathway, iC3 binds Factor B to generate amplification, and C3b is the product that is increased.

A lack of CR1 receptors on RBCs would result in what?

Lack of clearance of immune complexes by the spleen.

Zymogens are another name for what?

Latent/inactive proteins.

What occurs in the Lectin Pathway?

Lectins bind to carbohydrates, which activate the complement without an antibody present.

What leads to the activation unit in the Lectin Pathway?

MBL binds to a cell surface, which autoactivates C1s. This leads to C4 & C2 being cleaved. The rest of the pathway is same to the Classical Pathway.

What does MAC stand for?

Membrane Attack Complex.

What does the complement system promote?

Opsonization and the lysis of foreign cells as well as immune complexes.

DAF is found on what?

Peripheral blood cells, endothelial cells, fibroblasts, and different types of epithelial cells.

What three units consist of the classical pathway?

RAM (recognition unit, activation unit, and MAC unit).

Classical Pathway

Requires the antigen antibody or AgAb complex to be activated, it consists of components (proteins), which add up to a total of 9 proteins (C1 to C9) in the activation cascade. IgM and IgG 1, 2, and 3 are the immunoglobuins associated with this pathway.

What is the two stage process of complement fixation testing?

Test system with antigen and antibody (only one of which is unknown), an indicator system consisting of sheep RBCs coated with hemolysin (will lyse in presence of complement). If complement has not been tied up in the first reaction, lysis of the cell occurs.

What does NOT activate the Alternative Pathway?

The AgAb/antigen antibody complex.

Which pathway plays a role in infancy antibody defense?

The Lectin Pathway, which serves as protection for the baby once it loses maternal antibody.

What is common to both pathways?

The MAC/Membrane Attack Complex.

Factor H blocks the activation of what?

The alternative pathway of complement by binding to C3b, which prevents the binding of Factor B.

Decay Accelerating Factor (DAF) prevents what?

The assembly of active C3 convertase.

The generation of C5b leads to what?

The beginning of the MAC unit or Membrane Attack Complex.

What does activation refer to?

The conversion of several latent/inactive proteins to an enzymatic form.

S protein prevents what?

The formation of the MAC, making it unable to inset into the cell membrane or produce cell lysis. It's also known as vitronectin.

The activation of the Alternative Pathway involves what?

The initiation when C3b is deposited on a bacterial cell surface.

C9 polymerizes to form the transmembrane channel best characterizes what?

The membrane attack complex (MAC).

C1 inhibitor inhibits what?

The production of C3b by combining with and inactivating C1r and C1s.

What are lectins?

They are the proteins significant in binding in the Lectin Pathway.

What do anaphylatoxins do?

They cause basophils and mast cells to degranulate and release histamine as well as other components.

What is the interesting fact about the proteins involved in the Membrane Attack Complex?

They do not have any enzymatic activity.

Characteristics of complement components are mainly synthesized in the liver, are heat labile, normally present in serum, and NOT present as what?

They're NOT present as active enzymes.

How do CH50 and AH50 test the complement system?

Through assessing functional ability of serum complement in the classical pathway.