The Complement System

The ___ form in the complement classical pathway are anaphylatoxins that mediate inflammation and recruitment of MQ

A

Why is IgM more efficient in activating the complement classical pathway than IgG?

A soluble IgM is a pentamer. When attached to the antigen on the pathogen's surface, it provides a read staple for binding the C1q. A soluble IgG is a monomer but many IgG units may bin the antigen close together and cause the formation of a staple for C1q.

The _____ pathway is constitutively active; the cascade increases upon spontaneous hydrolysis of the C3 protein component

Alternative

Which pathway or protein complement deficiency causes decreased opsonization ability and increased risk of infection by encapsulated bacteria

Alternative pathway (factor D, B, P, and C3)

The ___ form in the complement classical pathway binds to complement receipts and mediates opsonization and CIC clearing

B

The lectin pathway is activated by ______

Binding of mannose binding lectin (MBL) to mannose residues on a pathogens surface

Hereditary angioedema (HAE) is caused by deficiency in ______ resulting in overproduction of C4a&b and C2a&b proteins. C4b is rapidly inactivated in serum thus cannot form C3 and C5 convertase. The C2b & bradykinin cause swelling.

C1 inhibitor

Subsequent to ____ binding, the antibody-antigen complex initiates the complement activation cascade.

C1q

Which pathway or protein complement deficiency causes defective opsonization, deficient leukocyte chemotaxis, and inability to form MAC. Leads to overwhelming infections with encapsulated bacteria and has a high correlation with developing the immune complex disease.

C3

Which two anaphylatoxins mediate histamine release?

C3a and C5a

Complement role in the enhancement of immune response: TI-B cell activation— The ____ complement protein deposited on the pathogens surface is broken down into C3d and C3c by Factor I-Alternative Pathway). C3d binds to ____ receptor on the B cell and cross links the Ag/Ig binding. Initiation of signaling through CD19 and activation of B cell.

C3b, CR2

What is the starting native protein for the membrane attack complex/lytic pathway

C5

Which complement receptors will cause inflammation

C5aR and C3aR

Initiates the assembly of the membrane attack complex (MAC)

C5b

____ is the initiator of MAC (membrane attack complex) formation in complement terminal pathway

C5b

In the membrane attack complex/lytic pathway, the ____ complex binds to the pathogens membrane

C5b67

In the membrane attack complex/lytic pathway, ___ binds to the C5b67 complex (located on the pathogens membrane) and inserts into the cell membrane

C8

_____ and _____ are very important inhibitors of complement activity. They block MAC on our cells.

CD55, CD59

_____ receptor is located on erythrocytes, MQ, monocytes, B cells, polymorphonuclear leukocytes, follicular dendritic cells (FDCs), podocytes (visceral epithelial cells) in kidneys. Stimulates phagocytosis, erythrocyte transport of immune complexes, and promotes decay of C3b and C4b proteins. Ligand are C3b and C4b

CR1

Which complement receptors aid in opsonization

CR1, CR2, CR3, and CR4

Which complement receptor is a part of B cell co-receptor

CR2

Which pathway in the complement system is activated by immunoglobulin?

Classical

What are the three complement cascade pathways?

Classical, lectin, and alternative

Subsequent to the MBL binding to bacterial carbohydrates, the MBL/sugar complex initiates the

Complement activation cascade

Hypocomplementemia is the deficiency of _______ and leads to an under active response to infections//higher susceptibility to bacterial infections

Complement activators

Hypercomplementemia is the deficiency of ______ and includes hereditary angioedema (HAE), hemolytic-uremic syndrome, and paroxysmal nocturnal haemoglobinuria (PNH)

Complement receptors

The activated complement receptors are detected by cells of the immune system via _______

Complement receptors

Composed of proteins circulating in the bloodstream and expressed on a cell surface (total of >30 proteins)

Complement system

In PNH, ______ is caused by C3b that opsonization RBC and tag them for phagocytosis (liver and spleen)

Extravascular hemolysis

____ is used for emergent treatment of thromboembolism d/t PNH and ____ is an oral anticoagulant used for maintenance therapy.

Heparin, Coumadin

In ______, there is an unbalanced blow of body fluids between the vascular system and body tissues. Most common presentations are episodic attacks of edema formation (some having catastrophic consequences)

Hereditary angioedema (HAE)

Ruconest, Lanadelumab, and Icatibant are all potential treatments for

Hereditary angioedema (HAE)

A bradykinin receptor antagonist used to treat HAE

Icatibant

The antibodies activating the complement classical pathway are _____ (most efficient) and ____ (somewhat less efficient)

IgM, IgG

Deficiency of C3 protein activity leads to:

Impaired immune response to T cell dependent (TD) and T cell independent (TI) antigens

The Complement System is part of the ______ immune system dedicated to clearing the pathogen and immunocomplexes

Innate

Complement role in clearance of the immune complexes: Complement proteins bind into _________. The C3b, iC3b, and C4b bind to complement receptor 1 (CR1) on circulating erythrocyte. RBC transport bound CICs into the liver and spleen. CICs are released from erythrocytes = and phagocytized by ____ (spleen) or ______ (liver). Erythrocytes return to blood circulation.

Insoluble Ab/Ag complexes, MQ, MQ-like cells

Eculizumab (Soliris) and Ruvulizumab (note: also considered in terminally ill COVID 19 patients). Anti-complement antibody that targets the C5 complement component. Alleviates ONLY the _____ hemolysis, partially eliminating complications of PNH.

Intravascular

In PNH, _________ is caused by C5b mediated MAC formation in RBCs.

Intravascular hemolysis

Why is the membrane attack complex (MAC) an essential mechanism?

It eliminates bacteria resistant to phagocytosis (Neisseria spp.; particularly N. Meningitis)

Why is it important for abdominal HAE to be monitored closely?

It may have an undefined set of symptoms and if not treated can lead to death

A monoclonal antibody that blocks plasma enzyme kallikrein (inducer of kin in system). Tx for HAE.

Lanadelumab

Pathogens activated by the _____ pathway include: encapsulated bacteria (Neisseria, Salmonella), non-capsulated bacteria (Listeria), fungi (Candida, Cryptococcus), or viruses (HIV or RSV)

Lectin

Serum complement proteins are synthesized in the ____ and circulate in the blood as ______(inactive proteins)

Liver, precursors

The membrane attack complex forms channels in pathogen membrane leading to

Lysis of cells

The membrane attack complex is also known as the _____ pathway

Lytic

Which pathway or protein complement deficiency leads to an increased risk of infection by N meningitis

MAC

Which pathway or protein complement deficiency leads to an increased risk of infection with encapsulated bacteria and yeast infections

MBL

In ___________, red cells lack CD59-MAC inhibitor and/or CD55 DAF. These cells can, therefore, be used by MAC

Paroxysmal nocturnal haemoglobinuria (PNH) (aka Marchiafava-Micheli syndrome)

Chronic disease arising from deficiency of terminal pathway inhibitors. Specifically, the RBCs lack GPI, a connector protein for CD55 and/or CD59. Can be inherited or acquired. Most common presentation is anemia w/ dark colored urine and thrombosis. 50% mortality rate

Paroxysmal nocturnal haemoglobinuria (PNH) (aka: Marchiafava-Micheli syndrome)

Accumulation of C3b, iC3b, or C4b complement proteins on the pathogen surface acts as a tagging process for ________________.

Phagocytes to phagocytize the microbe

In the membrane attack complex/lytic pathway, after C8 binds to the C5b67 complex and inserts into the cell membrane, C9 molecule binds to the complex and _____. Approx. 16 molecules of C9 bind to form a pore in the membrane.

Polymerizes

The classical pathway is activated by _______

Presence of antigen-antibody complexes

When stimulated, the circulating precursors are activated by ______ or protein-protein interaction and become proteases themselves. Activation of the complement results in a rapid cascade.

Proteolytic cleavage

People who have alternative complement pathway deficiency present with

Recurring and severe meningitides

A recombinant human C1 inhibitor used for treatment of acute symptomatic attacks of HAE I in adults and adolescents

Ruconest

True or false: ALL THREE complement pathways produce anaphylatoxins.

True

True or false: the activation of C4 and the subsequent steps of the cascade are identical for the classical and lectin pathways.

True

Which type of HAE is most common and caused by lack of C1 inhibitor?

Type I

Which type of HAE is less common and is caused by production of atypical-ineffective C1 inhibitors

Type II

Which pathway or protein complement deficiency leads to an increased predisposition to developing autoimmune disease (immune complex diseases) such as SLE, cryoglobulinemia, RA, Scleroderma, and Sjorgen's syndrome

classical (C1q, r, s, and C2)