8: Effector Mechanisms of Humoral Immunity

Can antibodies function at locations distant from where they are produced?

Yes. Antibodies can travel away from their site of production and perform protective functions in other tissues

When are protective antibodies first produced during an immune response?

During the primary immune response to a microbe.

How does antibody production differ between primary and secondary immune responses?

Protective antibodies are produced during primary responses and in larger amounts during secondary responses.

What is the primary function of the Fab region of an antibody?

To bind specific antigens on microbes and toxins and block their harmful effects

• Antigen recognition

What is the primary function of the Fc region of an antibody?

To activate diverse effector mechanisms that eliminate microbes.

• Tells you what type of antibody

What two processes enhance the protective functions of antibodies?

Isotype switching and affinity maturation

What are the major effector functions of antibodies?

• Neutralization

• Opsonization and phagocytosis

• ADCC

• Complement-mediated microbial lysis

• Complement-mediated phagocytosis

• Inflammation.

What is antibody-mediated neutralization?

Antibodies bind microbes or toxins and prevent their harmful interactions with host cells.

What is opsonization?

Coating microbes with antibodies or complement fragments to promote their recognition and ingestion by phagocytes.

What is antibody-mediated phagocytosis?

The ingestion of antibody-coated microbes by phagocytes that recognize antibody Fc regions

What immune cells can recognize antibody-coated microbes through Fc receptors?

Phagocytes, including macrophages and neutrophils.

What is antibody-dependent cellular cytotoxicity (ADCC)?

Killing of antibody-coated target cells by immune cells, particularly natural killer (NK) cells.

What antibody-associated mechanism can directly lyse microbes?

Activation of the complement system

Which complement fragment shown in the diagram promotes microbial phagocytosis?

C3b

How does C3b promote microbial elimination?

C3b coats microbes and binds complement receptors on phagocytes, promoting phagocytosis

What inflammatory response can result from complement activation?

Recruitment and activation of inflammatory immune cells.

What are the major effector functions of IgG?

• Neutralization

• Opsonization

• Classical complement activation

• NK-cell-mediated ADCC

• neonatal immunity

• feedback inhibition of B-cell activation.

How does IgG neutralize microbes and toxins?

It binds microbial or toxin antigens and prevents harmful interactions with host cells

Which phagocytes are identified as participating in IgG-mediated opsonization?

Macrophages and neutrophils

Which complement pathway can IgG activate?

The classical complement pathway.

Which immune cells mediate IgG-dependent ADCC?

Natural killer (NK) cells.

How does IgG contribute to neonatal immunity?

Maternal IgG is transferred across the placenta and gut, providing passive protection

What regulatory function does IgG perform in B-cell responses?

Feedback inhibition of B-cell activation.

What is the major effector function of IgM?

Activation of the classical complement pathway

What is the major function of IgA?

Mucosal immunity through neutralization of microbes and toxins in the gastrointestinal and respiratory tracts.

Where is IgA secreted to provide mucosal protection?

Into the lumens of the gastrointestinal and respiratory tracts

What is the major protective function of IgE?

Eosinophil- and mast-cell-mediated defense against helminths.

What is the function of FcRn?

FcRn protects IgG from degradation and lengthens its half-life in serum

What happens to IgG and other plasma proteins during the initial step in half-life serum?

They are internalized into an endocytic vesicle

Where does IgG bind FcRn during recycling?

Inside the endosome.

What happens after IgG binds FcRn in the endosome?

IgG–FcRn complexes are sorted into recycling endosomes

What happens to plasma proteins that are not protected through FcRn recycling?

They are degraded in lysosomes

What happens to IgG when the recycling endosome reaches the cell surface?

IgG is released from FcRn into the extracellular environmen

Why does FcRn recycling increase IgG serum half-life?

It prevents IgG from undergoing lysosomal degradation and returns IgG to the extracellular environment.

What are the major steps of FcRn-mediated IgG recycling?

Endocytosis → binding to FcRn in acidic endosomes → sorting into recycling endosomes → release at extracellular pH greater than 7.

What does anti-TNF IgG bind?

Tumor necrosis factor (TNF).

What region of anti-TNF IgG binds TNF?

The antigen-binding region of the antibody.

What is a TNFR–IgG Fc fusion protein?

A fusion protein containing a TNF receptor component linked to an IgG Fc region.

What part of the TNFR–IgG Fc fusion protein binds TNF?

The TNF receptor component

What structural component is shared by anti-TNF IgG and the TNFR–IgG Fc fusion protein?

The IgG Fc region

How do the TNF-binding portions of anti-TNF IgG and TNFR–IgG Fc fusion proteins differ?

Anti-TNF IgG uses antibody antigen-binding regions, whereas the fusion protein uses TNF receptor domains.

What feature of the Fc region makes it useful in fusion proteins?

It can support FcRn-mediated recycling, helping prolong the circulating half-life of the fusion protein.

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What happens when a microbe binds its receptor on a tissue cell in the absence of neutralizing antibodies?

The microbe can infect the tissue cell

What is the outcome when antibodies successfully neutralize a microbe?

The microbe cannot bind to and infect the tissue cell through the blocked interaction.

Does neutralization require a microbe to be phagocytosed?

No. Antibodies can prevent infection directly by blocking microbial attachment

Which antibody region directly binds microbial antigens during neutralization?

The Fab region

What happens when a toxin binds its cell-surface receptor without neutralizing antibodies?

The toxin can produce a pathological effect in the target cell.

• EX: cell necrosis

How do neutralizing antibodies prevent toxin-mediated cellular damage?

They bind toxins and prevent their attachment to cellular receptors.

What is the ultimate protective result of toxin neutralization?

Prevention of the toxin's pathological effect on the target cell.

How does neutralization of toxins differ from neutralization of microbes?

Toxin neutralization blocks toxin-receptor interactions and pathological effects, while microbial neutralization blocks attachment and infection.

What is the antibody-binding affinity of FcγRI (CD64)?

High affinity.

Which IgG subclasses bind FcγRI?

IgG1 and IgG3.

Which cells express FcγRI (CD64)?

Macrophages and neutrophils.

What are the major functions of FcγRI (CD64)?

Phagocytosis and activation of phagocyte

What is the affinity of FcγRIIB (CD32) for immunoglobulins?

Low affinity

Which cells express FcγRIIB (CD32)?

• B lymphocytes

• Dendritic cells

• Mast cells

• Neutrophils

• Macrophages.

What are the functions of FcγRIIB (CD32)?

Feedback inhibition of B cells and attenuation of inflammation.

What is the affinity of FcγRIIIA (CD16) for immunoglobulins?

Low affinity.

Which cells express FcγRIIIA (CD16)?

Natural killer (NK) cells.

What is the major function of FcγRIIIA (CD16)?

Antibody-dependent cellular cytotoxicity (ADCC).

Which Fc receptor allows NK cells to recognize antibody-coated target cells?

FcγRIIIA (CD16).

Which antibody isotype binds FcεRI?

IgE with high affinity

Which cells express FcεRI?

Mast cells, basophils, and eosinophils

What is the major function of FcεRI?

Activation and degranulation of mast cells and basophils

Which Fc receptors listed are low-affinity receptors?

FcγRIIB (CD32) and FcγRIIIA (CD16).

Which Fc receptors listed are high-affinity receptors?

FcγRI (CD64) and FcεRI.

What is the first step of antibody-mediated opsonization and phagocytosis?

IgG antibodies bind and coat the microbe.

Which Fc receptor recognizes IgG-coated microbes?

FcγRI

What happens after IgG binds the microbial surface?

The IgG-coated microbe binds Fc receptors on a phagocyte.

Which portion of IgG is recognized by phagocyte Fc receptors?

The Fc region

What happens when Fc receptors bind an IgG-opsonized microbe?

Fc receptor signaling activates the phagocyte

Which antibody isotype mediates ADCC?

IgG

What is the first step of ADCC?

IgG binds surface antigens on a target cell.

Which Fc receptor allows NK cells to bind IgG-coated target cells?

FcγRIII (CD16).

What part of the antibody is recognized by FcγRIII on NK cells?

The Fc region of IgG

What happens when an NK cell recognizes an antibody-coated target cell?

The NK cell becomes activated and kills the antibody-coated cell.

Which antibody isotype participates in eosinophil-mediated helminth killing?

IgE

Which immune cell releases IL-5?

A Th2 helper T cell.

Which cytokine promotes eosinophil activation?

IL-5

Which immune cell is activated during IgE-mediated helminth killing?

An eosinophil.

Which Fc receptor is on the eosinophil?

FcεRI

What happens after the eosinophil is activated?

It releases eosinophil granule contents, which kills a helminth

Which two immune components cooperate to promote helminth killing?

Th2 cells producing IL-5 and IgE-associated eosinophils

What is the sequence of IgE/eosinophil-mediated helminth killing?

Th2-derived IL-5 promotes eosinophil activation → IgE interacts with FcεRI → eosinophil granules are released → helminth dies.

What are the three complement activation pathways?

Alternative, classical, and lectin pathways

Which complement enzyme initiates the late stages of complementation?

C5 convertase

What happens when C5 convertase acts on C5?

C5 is cleaved into C5a and C5b

What is the function of C5a?

Promotion of inflammation

Which complement fragment initiates membrane attack complex assembly?

C5b

Which complement components first associate with C5b?

C6 and C7.

What forms after C5b binds C6 and C7?

The C5b67 complex.

Which complement component binds after C5b67 forms?

C8

Which complement component polymerizes to form the membrane pore?

C9

What does poly-C9 mean?

Multiple C9 molecules assembled into a polymeric pore structure.

Which complement proteins make up the membrane attack complex (MAC)?

C5b, C6, C7, C8, and multiple C9 molecules.

What is the primary function of the membrane attack complex?

To form pores in target-cell membranes, resulting in cell lysis

• Breaking down or destruction of a cell's outer membrane or cell wall

What are the three major functions of complement?

1. Opsonization and phagocytosis

2. Complement-mediated cytolysis

3. Stimulation of inflammatory reactions

Which complement fragment is responsible for opsonization?

C3b

What happens when C3b binds a microbial surface?

The microbe becomes opsonized

Which phagocyte receptor recognizes C3b-coated microbes?

CR1, a C3b receptor.