Test 3 - Chapter 9 - Antibody Functions

Comparison of monomers, dimers and pentamers 1) What is a monomer? 2) Types of antibodies that can form a monomer? 3) What is a dimer? 4) What antibody can be a dimer? 5) What is a pentamer? 6) What kind of antibody can be a dimer?

1) A single antibody 2) IgD, IgE, IgG, and IgA 3) Two antibodies linked together 4) IgA 5) Five antibodies linked together 6) IgM

Infants have a limited supply of IgG (and IgA) in the first year 1) What happens the first six months after birth? 2) What does the timeline for antibody production look like for babies?

1) After birth, maternal IgG declines during the first 6 months. 2) Infants start to make their own IgM before birth and IgG and IgA at around 3 months.

Fc receptors bind to the Fc fragment of an antibody 1) Different cells have different...?

1) Fc Receptors

Mast cells, eosinophils and basophils bind IgE and function in defense against parasites and in type I hypersensitivity reactions 1) IgE binds to _______ and awaits antigen binding. 2) What happens when IgE on mast cells finally does bind antigen? (a) What does this promote? (b) What else does it do?

1) Fcε receptors on mast cells 2) When IgE on mast cells binds antigen, the mast cell secretes inflammatory mediators (a) Promote bodily functions that aim to flush out the parasite, e.g., vomiting, diarrhea, increased mucus production. (b) Recruit other cells

IgM 1) What are IgM first in? 2) IgM has relatively low...? (a) Why? 3) How does IgM increase its overall binding strength? 4) How are other antibody classes produced and what do they have?

1) First antibody class to be produced during an immune response (from primary focus). 2) affinity for antigen (a) Because it is produced prior to somatic hypermutation. 3) It forms pentamers to increase overall binding strength. The pentamer form gives it ten antigen binding sites. 4) Other antibody classes (IgG, IgA and IgE) are produced through class switching in the germinal center and have a higher affinity antigen binding site.

What is the most abundant antibody class in 1) the body and 2) blood serum?

1) IgA due to the large amount of IgA that is produced to protect mucosal surfaces. 2) IgG. It is a good 'all round' antibody class able to perform various functions (see table in handout).

IgG to Fcγ receptors on NK cells promotes antibody-dependent cell-mediated cytotoxicity (ADCC) 1) Natural killer cells have a receptor for...? 2) What do natural killer cells recognize? 3) What do they do when they recognize it? 4) What other function does this process complement?

1) IgG 2) NK cells recognize host cells coated with IgG 3) It kills the infected cell 4) Complements the function of CD8 T cells

Binding of IgG antibody to Fcγ receptors promotes phagocytosis 1) What antibodies function in opsonization?

1) IgG and Monomeric IgA. Dimeric IgA is not because there are no phagocytes present at mucosal surfaces. Therefore, it is not a major function of the IgA class as a whole)

Location of Antibodies 1) What kind of antibodies circulate in the blood? 2) What kind of antibodies are the primary classes that protect extravascular tissues? 3) What kind of antibody protects mucosal surfaces? 4) What kind of antibody is transported across the placenta 5) What do IgE antibodies do? 6) What kind of antibody is transferred through breast milk and why?

1) IgG, monomeric IgA and IgM circulate in blood. 2) IgG and monomeric IgA are the primary classes that protect extravascular tissues. 3) Dimeric IgA protects mucosal surfaces 4) IgG is transported across the placenta 5) IgE binds to mast cells underlying surfaces and surrounding blood vessels 6) Dimeric IgA is transferred through breast milk to an infant to protect mucosal surfaces

Antibodies operate in distinct places 1) What antibodies protect extravascular (outside the blood) tissues? (a) Two antibodies are better at protecting extravascular tissues. What are they and why? (b) What is the most abundant class of antibody in the blood? 2) What kind of antibody protects mucosal surfaces? (a) What is the most abundant antibody class in the body? (b) Where do most pathogens enter the body? 3) What kind of antibody is able to be transported across the placenta?

1) IgG, monomeric IgA and IgM protect extravascular (outside the blood) tissues (a) IgG and IgA are smaller than IgM and diffuse more easily into tissues (b) IgG is the most abundant class in the blood 2) Dimeric IgA protects mucosal surfaces (a) Dimeric IgA (b) Mucosal surfaces are expansive, and most pathogens enter through mucosal surfaces 3) IgG is transported across the placenta

IgM and IgG activate the classical complement pathway 1) How do IgM and IgG activate the classical complement pathway? 2) When do they not interact with C1?

1) IgM and IgG bind to the pathogen surface and recruit C1, which activates the classical complement pathway. 2) They do not interact with C1 when not bound to the pathogen surface.

Hyper IgM syndromes 1) What happens? 2) What kind of deficiency? 3) How is it inherited and how common is it? 4) Role of CD40L? 5) Symptoms? 6) Treatments?

1) Individuals produce only low affinity IgM antibody. They can't make high affinity antibodies through class switching. 2) CD40L deficiency 3) X linked, affects ~2 in 1,000,000 4) needed for affinity maturation and class switching in the germinal center. Also needed to up-regulate macrophages 5) susceptible to infections with extracellular bacteria and fungi, defective clearance of intracellular pathogens (such as M. tuberculosis and P. jirovecii). 6) regular infusions of antibody antibiotics to treat infections

X-linked agammaglobulinemia (XLA) 1) How common? 2) What happens? 3) Role of B-cells? 4) Symptoms? 5) Treatments?

1) affects ~1 in 200, 000 2) Defective B cell receptor signaling during B cell development results in no functional B cells. 3) produce antibodies 4) susceptible to infections with extracellular bacteria and fungi recurrent infections can lead to tissue and organ damage not particularly vulnerable to viral infections 5) regular infusions of antibody and antibiotics to treat infections.

Selective IgA deficiency 1) Prevalence? 2) What's the problem? 3) What compensates? 4) Symptoms?

1) affects ~1 in 500 Caucasians 2) Individuals do not produce IgA antibodies (can't class switch from IgM to IgA). 3) IgM compensates at mucosal surfaces 4) Many do not have symptoms. Estimated that 25-50% of patients are more prone to infections (ear infections, sinusitis, bronchitis and pneumonia most common).

Mast cells, eosinophils and basophils bind IgE and function in defense against parasites and in allergic reactions 1) Parasites are too large to...? 2) How do eosinophils and IgE work together?

1) ingest 2) Binding of an eosinophil to an IgE coated parasite triggers exocytosis of granules.

What is an Fc receptor?

A receptor that binds the Fc portion (heavy chain constant region) of an antibody.

What is AID needed for?

AID is needed for somatic hypermutation and class switching.

Hyper IgM syndromes can come about through...?

Activation-induced cytidine deaminase (AID) deficiency ▪ AID is needed for somatic hypermutation and class switching.

How do errors in producing antibodies affect us?

Antibodies protect our body fluids against extracellular pathogens so errors in that makes us more susceptible.

Summary of IgD?

Binds to basophils in the respiratory tract and functions in defense against respiratory pathogens

Summary of IgE?

Defense against parasites- works with mast cells, eosinophils and basophils

B-cell immunodeficiency leads to...?

Deficiency in producing antibodies

What is the most abundant antibody class in the body?

Dimeric IgA

What do heavy chains regions do?

Heavy chain regions (blue) determine class

____________ prevent attachment of microbes, toxins and venoms to cell surfaces (and therefore prevent entry into cells).

High affinity neutralizing antibodies

What kind of antibodies are IgA and IgG?

IgA and IgG are high affinity neutralizing antibodies

What are the 5 antibody classes?

IgA, IgG, IgM, IgD, IgE

Which antibody class protects against parasite infections? Which effector cells does the antibody interact with?

IgE. Mast cells, basophils and eosinophils have receptors for binding IgE. We will discuss IgE mediated responses to parasites and allergens a lot more in the fourth part of the course.

What is the most abundant antibody in blood serum?

IgG

Infants have a limited supply of...?

IgG (and IgA) in the first year

How many subclasses does IgG have? What does that make IgG?

IgG has 4 different subclasses. It makes it an all around good antibody.

Which antibody classes are most effective at activating the classical complement pathway?

IgM and IgG Monomeric IgA can activate the classical complement pathway, but most IgA is dimeric IgA found at mucosal surfaces where complement proteins are not found. The primary function of IgA is neutralization.

What is the first class of antibody to be secreted?

IgM is the first class to be secreted

Why are young infants vulnerable to infections in the first year?

IgM levels gradually rise during the first year, but it takes time to develop high levels. IgG that came from the mother steadily declines after birth: an infant starts to produce appreciable levels of its own IgG at approximately 3 months, but levels are relatively low until ~1 year of age. Levels of IgA also start to steadily rise from about 3 months but are relatively low until ~ 1 year if age. However, an infant can be supplied with maternal IgA from breast milk until its levels are high.

Which antibodies activate the classical complement pathway?

IgM, IgG, and monomeric IgA

Where is the primary focus?

In the medullary cords

What is antibody dependent cell mediated cytotoxicity (ADCC)? Which antibody class mediates ADCC, and which effector cell is involved?

Infected host cells display pathogen antigens on the surface on MHC class I. IgG antibodies (that were generated against antigens when the pathogen was outside the cell) bind to their antigen when presented on the host cell surface. Natural killer cells have an Fcγ receptor that binds to the IgG at the host cell surface. Binding to IgG through its Fc receptor causes the natural killer cell to destroy the infected host cell. ADCC complements the function of cytotoxic T cells during the adaptive immune response.

What is neutralization? Which antibody classes are effective at neutralization and why?

It involves the binding of antibodies to surface structures that are used by an organism or toxin to enter a cell. Therefore, neutralization prevents attachment to host cells. IgG and IgA are effective neutralizing classes because they are high affinity antibodies that have undergone affinity maturation. IgG is the primary neutralizing antibody class in systemic tissues, and IgA is the primary neutralizing antibody class at mucosal surfaces. If antigens are present at low concentration, we must have high affinity antibodies. IgM can also function in neutralization, but it is a lower affinity antibody, and it does not move into tissues as easily due to its size, so it is less effective.

What antibodies function in neutralization?

Mainly IgG and IgA but IgM can perform neutralization much less effectively than the other too.

What kind of cells are able to bind IgE and for what function?

Mast cells, eosinophils and basophils bind IgE and function in defense against parasites and in type I hypersensitivity reactions

What primary symptoms would you expect in patients that do not produce functional B cells, or only produce low affinity IgM antibodies (hyper IgM syndromes)?

Susceptibility to extracellular infections. Although antibodies are also involved in combating intracellular infections (i.e., antibodies are required for ADCC and they can recognize viruses during the extracellular phase), individuals still have other defenses for combating intracellular infections,(cytotoxic T cells, NK cells) although the infections may not be dealt with as quickly and efficiently in the absence of antibodies

What is opsonization? What are the primary effector cells that respond to opsonized pathogen?

The coating of an antigen with a molecule (e.g., antibody and/or complement) that facilitates uptake of the antigen by phagocytes. The phagocytes that ingest opsonized pathogens are macrophages and neutrophils. The IgG class is the most important class that functions in opsonization. Monomeric IgA can also be an opsonizing antibody, but most IgA is dimeric IgA found at mucosal surfaces where there are no macrophages or neutrophils.

In a newborn infant, where do the IgM, IgG and IgA antibody classes come from?

The infant produces its own IgM, which begins before birth and steadily rises during the first year. IgG comes from the mother; it is transported across the placenta during fetal development. At birth, an infant has the same IgG antibodies in circulation as the mother. After birth, maternal IgG gradually declines until there is little left by about 6 months at which point the infant's own IgG levels have begun to rise and continue to steadily rise throughout the first several years of life. IgA to protect mucosal surfaces comes from the mother through breastmilk. An infant begins producing its own IgA after birth and levels steadily rise throughout the first several years.

Monomeric IgA can also activate the classical complement pathway, but dimeric IgA does not. Why?

There are no complement proteins present at mucosal surfaces. Therefore, it is not a major function of the IgA class as a whole.

How do the four subclasses of IgG differ in structure?

They differ in the structure of the hinge.

Binding of IgG to Fcγ receptors on NK cells promotes...?

antibody-dependent cell-mediated cytotoxicity (ADCC)

Antibodies operate in...?

distinct places

4 different subclasses with distinct functions make IgG a...?

good all-around antibody

High affinity neutralizing antibodies prevent...?

organisms and toxins binding to host cells

Binding of IgG antibody to Fcγ receptors promotes...?

phagocytosis

Fc receptors bind to...?

the Fc fragment of an antibody

Summary of IgM?

▪ First antibody class to be secreted ▪ Relatively low affinity binding site and functions as a bulky pentamer ▪ Effective at activating the classical complement pathway ▪ Contributes to neutralization and protection of mucosal surfaces

Summary of IgG?

▪ Most abundant antibody class in the blood ▪ Protects extravascular tissues and is transferred across the placenta ▪ Good all-around antibody class ➢ Opsonization, neutralization, activation of classical complement pathway, ADCC ➢ Doesn't play a major role in defense against parasites

Summary of IgA?

▪ Most abundant antibody class in the body; dimeric IgA is the primary class that protects mucosal surfaces ▪ Overall, its primary function is neutralization ▪ (Monomeric IgA contributes to other functions- opsonization, neutralization, activation of complement system)