Immunology: Lecture 12
Each B-cell produces an immmunoglobulin of __________ specificity?
.... of SINGLE specificity?
Contrast the structure and functioning of B-cell receptors and T-cell receptors?
1) A T-cell receptor (TCR) has only one antigen-binding site. Whereas a B-cell receptor (BCR) has two antigen binding sites (one on each arm of the Y-shaped immunoglobulin molecule) 2) A TCR is never secreted, whereas The BCRs (Immunoglobulins) can be secreted as antibody.
List the 5 classes of Immunoglobulins (antibodies)?
1) IgA 2) IgD 3) IgE 4) IgG 5) IgM
List the 2 types of epitopes?
1) Linear-Epitope. 2) Discontinuous-Epitope.
List the 3 general functions of antibody molecules?
1) Neutralization. 2) Cell-Mediated Phagocytosis 3) Complement Activation
Antibodies have three separate functions; describe them?
1)Neutralization. 2) Opsonization (immune cell recruitment). 3) Complement Activation.
Describe the 4 areas of variability in the heavy chain that constitutes the difference between the 5 classes of Immunoglobulins?
1. Difference in length of the heavy-chain C region 2. Difference in the location of the disulfide bonds 3. Presence or absence of the hinge region 4. Difference in the distribution of N-linked carbohydrate groups
Describe the structure of T-cell receptors?
A T-cell receptor (TCR) has only one antigen-binding site, and is composed of two chains, each possessing two respective domains, a Variable-region (V) domain, and Constant-region (C) domain. The alpha and beta chains are joined by a disulfide bond between their stalk segments which extend through the transmembrane region connect to the cytoplasmic tail protruding from the internal surface of the T-cell membrane.
How does the T-cell receptor function to recognize antigen?
A T-cell receptor (TCR) recognizes antigen in the form of a complex of a foreign peptide bound to an MHC molecule
How many types of light chains can an immunoglobulin posses, and how does it affect their functioning?
A given immunoglobulin has either lambda (l) chains and kappa (k) chains, never one of each. No functional difference has been found between antibodies having (l) chains and kappa (k) chains, and either type of light chain can be found in antibodies of any of the five major classes.
Define the term affinity?
Affinity is the strength of the interaction between a single antigen-binding site and its antigen.
What structural components constitute an Immunoglobulin molecule?
All antibodies are constructed in the same way from paired heavy and light polypeptide chains, and the generic term immunoglobulin is used for all such proteins.
How are the T-cell receptors and B-cell receptors similar?
Although B cells and T cells recog nize foreign molecules in distinct fashions, the receptor molecules they use for this task are very similar in structure. These T-cell receptors (TCRs) are related to immunoglobulins both in their protein structure—having both V and C regions—and in the genetic mechanism that produces their great variability.
Define an antigen?
An antigen is any molecule or part of a molecule that is specifically recognized by the highly specialized recognition proteins of lymphocytes.
What is an epitope?
An epitope is the part of an antigen to which antibody binds to (- it is is also called the antigenic determinant).
Describe how the enzyme pepsin interacts with the disulfide bonds of immunoglobulins confer greater antigen binding ability?
Another protease: Pepsin, cuts on the carboxy-terminal side of the disulfide bonds, producing a fragment called the Fab2 fragment, in which the two antigen-binding arms of the antibody molecule remain linked. Pepsin cuts the remaining part of the heavy chain into several small fragments. The Fab2 fragment has exactly the same antigen-binding characteristics as the original antibody but is unable to interact with any effector molecule. It thus has potential for therapeutic applications.
Describe the origin, composition and shape of Immunoglobulins (antibodies)?
Antibodies are the secreted form of B-cell receptors and originate from the effector-B-cells called plasma cells. They are Y-shaped and composed of 2 light chains and 2 heavy chains, the light chains have two domains; and the heavy chains have up to four domains. The Variable region (makes the arms of the Y-shaped molecule) and the Constant region (makes the stem of the Y-shape) respectively, and are held together by 3 disulfide-bonds.
What is antibody?
Antibodies are the secreted form of the B-cell receptor, immunoglobulin of the same antigen specificity as the B-cell's BCR is secreted as antibody by terminally differentiated B cells—the plasma cells.
Describe how antibodies function in facilitating antigen Neutralization?
Antibodies can bind to bacterial toxins and neutralize their destructive capabilities by inhibition their interactions with other molecules/cells. This also acts to opsonize the toxins for ingestion by a phagocytic cell such as a macrophage.
Describe how antibodies function in facilitating Complement Activation?
Antibodies coat an extracellular bacteria and signal complement activation, leading to the lysis of the cell via the MAC complex and its ingestion by phagocytic cells such as a macrophage.
Describe the shape of an antibody molecule and the functional purpose of its structure
Antibody molecules are roughly Y-shaped molecules consisting of three equal-sized portions connected by a flexible tether. The ends of the two arms of the Y—the V regions—vary in their detailed structure between different antibody molecules. These are involved in antigen binding. The stem of the Y—the C region—is far less variable and is the part that interacts with effector cells and molecules.
Describe a multivariant antigen?
Any antigen with more than one epitope, or more than one copy of the same epitope is a multivalent antigen
Define the term avidity?
Avidity is the strength of the interaction between two identical antigens binding simultaneously to two antigen binding sites.
Why is it that naive B-cells with bound BCRs can't have effector functions such as neutralization, opsonization, or complement activation?
Because they need to be activated by breaching a signaling threshold through antigen recognition on their antigen specific BCRs or be activated by IL-4 from T-Helper-cells in order to trigger their proliferate into their effector-form.
Which T-cells carry CD4+ co-receptors?
CD4 is carried by naive Helper T-cells whose function it is to activate other cells (such as B-cells, and other APCs) and recognized MHC-II molecules. CD4+ co-receptors bind MHC-II through a region that is located mainly on the lateral face of its first domain (D1).
Describe the CD4+ co-receptor?
CD4-coreceptor is a single-chain molecule composed of 4 immunoglobulin-like domains.
Which T-cells carry CD8+ co-receptors?
CD8+ co-receptors are carried by naive Cytotoxic T-cells and recognize MHC class I molecules. CD8+ co-receptors bind to an invariant-site in the α3-domain of the MHC-I molecule, but also interact with residues in the base of the α2-domain of the MHC-I molecule.
Describe the CD8+ co-receptor?
CD8-coreceptor has two different chains, called α and β, each containing a single immunoglobulin-like domain.
What is a Multivalent antigen?
Can have more than one epitope.
Describe the structure and function of the light chain of immunoglobulins (antibodies)?
Each immunoglobulin molecule (antibody) possesses two light chains each with 2 domains (a V-domain and a C-domain). There are two types of light chains, lambda-light-chains and kappa-light-chains. Each type of light chain has 2 gene-segment of multiple variations, V-gene segment and a J-gene-segment. A third gene segment is the C-gene segment.
What is the structural relation and importance of sulfide bonds in antibodies, B-cell receptors, and T-cell receptors.
Each immunoglobulin molecule is made up of two heavy chains and two light chains joined by disulfide bonds so that each heavy chain is linked to a light chain and the two heavy chains are linked together.
What are Fab fragments in context of immunoglobulins (antibodies)?
Each immunoglobulin molecule is made up of two heavy chains and two light chains joined by disulfide bonds so that each heavy chain is linked to a light chain and the two heavy chains are linked together. are responsible for its various functions. Limited diges-tion with the protease papain cleaves antibody molecules into three frag-ments. Papain cuts the antibody molecule on the amino-terminal side of the disulfide bonds that link the two heavy chains, releasing the two arms of the antibody molecule as two identical fragments that contain the antigen-binding activity. These are called the Fab fragments, for Fragment antigen binding.
MHC molecules are highly polymorphic, what does that mean?
Each type of MHC molecule occurs in many different versions within the population. Most people are therefore heterozygous for the MHC mole cules: that is, they express two different forms of each type of MHC molecule.
Define epitope, in context with antibodies, BCRs & TCRs.
Epitope are antigen-markers that can bind to pockets, grooves, or extended surfaces in antibody-binding sites.
Describe two conformational differing types of epitopes?
Epitopes can be linear-epitopes, or discontinuous-epitopes.
Where do the antibodies encounter the epitopes?
Epitopes for antibodies are exposed on the surface of pathogen (poliovirus)
How many genes do we have, to express MHC-I molecules, name them?
Every person has a total of 6 genes for MHC-I molecules; 3 genes from each parent, coding for MHC-I molecules, they are B, C, and A. The recombination of these 6 genes in addition to their codominant expression accounts for the great diversity of MHC-molecules.
How many genes do we have, to express MHC-II molecules, name them?
Every person has a total of 6 genes for MHC-II molecules; 3 genes from each parent, they are DP, DQ, and DR. The recombination of these 6 genes in addition to their codominant expression accounts for the great diversity of MHC-molecules.
List the five classes of Immunoglobulins?
Five different classes of immunoglobulins—IgM, IgD, IgG, IgA, IgE—can be distinguished by their C regions. regions. More subtle differences con-fined to the V region account for the specificity of antigen binding.
Describe the helpful trick in remembering the interactions between MHC class molecules and the two types of effector T-cells.
Helps to memorize the #8. CD8 x 1= 8. (MHC class I) CD4 x 2=8. (MHC class II)
Name the most abundant immunoglobulin (antibody) in the blood?
IgG
What is the most abundant antibody (immunoglobulin) in the blood?
IgG
IgG antibodies consist of four polypeptide chains, list and describe them
IgG antibodies are composed of two different kinds of polypeptide chains. One, of approximately 50 kDa, is called the heavy or H chain , and the other, of 25 kDa, is the light or L chain. Each IgG molecule consists of two heavy chains and two light chains.
Which antibody is the most abundant isotope in the plasma?
IgG is by far the most abundant immunoglobulin and has several subclasses (IgG1, 2, 3, and 4 in humans). The distinctive functional properties of the different classes and subclasses of antibodies are conferred by the carboxy-terminal part of the heavy chain, where it is not associated with the light chain.
Explicitly describe the polypeptide chains that constitute antibody molecules?
Immunoglobulin (antibody) molecules are composed of two types of protein chains: heavy chains and light chains. Each immunoglobulin molecule is made up of two heavy chains and two light chains joined by disulfide bonds so that each heavy chain is linked to a light chain and the two heavy chains are linked together.
Name the highly specialized recognition proteins of B cells are called what?
Immunoglobulins (Ig) which are produced by B cells in a vast range of antigen specificities.
What are the antigen-recognition molecules of B cells?
Immunoglobulins (Ig).
How does the structure and arrangement of the antibody molecule facilitate its ability to bind up to two identical antigens at a time?
In any given immunoglobulin molecule, the two heavy chains and the two light chains are identical, giving an antibody molecule two identical antigen-binding sites (see Fig. 4.1). This gives it the ability to bind simultaneously to two identical antigens on a surface and hence increase the total strength of the interaction
How many domains does each chain of an antibody molecule have?
Light chain have two domains; and the heavy chain has up to four domains
Which cells express MHC class I?
MHC class I are expressed in all nucleated human cells.
Which cells express MHC class II?
MHC class II are expressed in APC cells (Dendritic cells, macrophages, and B cells).
If MHC class I and class II peptide-binding regions are so similar, how can T cells functional distinguish between antigens presented by MHC class I and class II molecules?
MHC class-I molecules are recognized by CD8+ T-cells by the co-receptors. MHC class-II molecules are recognized by CD4+ T-cells by their co-receptors.
Describe the structural difference between MHC-I molecules and MHC-II molecules?
MHC-I molecules are formed from single Alpha-chain and a Beta-2-microglobulin. In contrast MHC_II molecules are formed by an Alpha-chain and a Beta-chain.
Describe the peptides that bind to the MHC class II molecules?
MHC-II accommodates a much greater variety of peptides than MHC-I. Peptides that bind to MHC-II molecules are at least 13 amino acids long and can be much longer (17 aa). For MHC II, there are no cluster of conserved residues that bind the two end of peptides, like in the case of MHC-I.
The antibody molecule has two separate functions, describe them?
One function is to bind specifically to the pathogen or its products that elicited the immune response; the other function is to recruit other cells and molecules to destroy the pathogen once antibody has bound.
How many B cell receptors types does each B-cell express.
One, each B-cell expresses only one type of B-cell receptor. Each B cell is covered in that ONE "type" of Receptor, and there are millions of B cells in your body at any given moment.
Describe how the enzyme Papain interacts with the disulfide bonds of immunoglobulins confer greater antigen binding ability?
Papain cuts the antibody molecule on the amino-terminal side of the disulfide bonds that link the two heavy chains, releasing the two arms of the antibody molecule as two identical fragments that contain the antigen-binding activity. These are called the Fab fragments , for Fragment antigen binding.
Describe the peptides that bind to the MHC class I molecules?
Peptides that bind to MHC class I molecules are usually 8-10 amino acids long. Peptides are bound to MHC class I molecules by their ends.
What is the effector B-cell responsible for antibody secretion called?
Plasma cells
MHC Class I and II are both....(what?)
Polygenic (many genes code for them) & Polymorphic (many variations in gene-arrangement possible)
How does the structure of the antibody molecule facilitate its recognition and effector functions?
Recognition and effector functions are structurally separated in the antibody molecule, one part of which specifically binds to the antigen whereas the other engages the elimination mechanisms.
Describe how antibodies function in facilitating cell mediated phagocytosis?
Specific antibodies coat bacteria or their antigenic products and recruit macrophages to ingest the opsonized bacteria.
Describe the structural similarities and functional differences of B-cells and T cells?
T-cell receptors (TCRs) are related to immunoglobulins (antibodies and BCRs) both in their protein structure—having both V and C regions—and in the genetic mechanism that produces their great variability (Somatic recombination). The T-cell receptor differs from the B-cell receptor in an important way, however: it does not recognize and bind antigen by itself, but instead recognizes short peptide fragments of protein antigens, which are presented by proteins known as MHC molecules on the surfaces of host cells.
What is the term for the additional dimension of antigen recognition provided by MHC interactions in T-cell receptor-antigen-recognition?
T-cell receptors recognize features of both the peptide antigen and the MHC molecule to which it is bound. This introduces an extra dimension to antigen recognition by T cells, known as *MHC Restriction , because any given T-cell receptor is specific for a unique combination of a particular peptide and a particular MHC molecule.
Which co-receptors are needed by each effector T-cell in order to respond to antigens?
The CD4-coreceptor (Helper) and CD8-co-receptor (Cytotoxic) are cell-surface proteins (co-receptors) of effector T cells, and are required to make effective responses to encountered antigens.
What are Fc fragments in context of immunoglobulins (antibodies)?
The Fc fragment contains no antigen-binding activity but was originally observed to crystallize readily, and for this reason it was named the Fc fragment, for Fragment crystallizable. It corresponds to the paired CH2 and CH3 domains and is the part of the antibody molecule that interacts with effector molecules and cells. The functional differences between heavy-chain isotypes lie mainly in the Fc fragment.
What are MHC molecules?
The MHC molecules are transmembrane glycoproteins encoded in the large cluster of genes known as the major histocompatibility complex (MHC).
Describe the T-cell receptor?
The T cell receptor resembles a membrane-bound Fab fragment. Each chain contain a C domain and a V domain.
How do the T-cell receptors and B-cell receptors differ?
The T-cell receptor differs from the B-cell receptor in an important way, however: it does not recognize and bind antigen by itself, but instead recognizes short peptide fragments of protein antigens, which are presented by proteins known as MHC molecules on the surfaces of host cells.
How does the T-cell receptor resemble an antibody?
The T-cell receptor resembles a membrane-bound antibody, with its antigen binding domains exposed
What region of the antibody is responsible for their binding to a wide variety of antigens?
The antibody is a Y-shaped molecule whose arms act as an antigen-binding site. This antigen-binding site is formed from the hypervariable regions of a heavy-chain and a light-chain V domain.
Name and describe the region of the antibody molecule responsible for antigen recognition?
The antigen-binding region varies extensively between antibody molecules and is known as the variable region or V-region.
How does the primary function of T-cell receptors differ from that of B-cell receptors?
The antigen-recognition molecules of T cells are made solely as membrane-bound proteins, which are associated with an intracellular signaling complex and function only to signal T cells for activation.
What determines the ultimate function and class of an antibody molecule?
The class, and thus the effector function, of an antibody is defined by the struc-ture of its heavy chain.
What is the primary function of the B-cell receptor?
The function of the B-cell receptor is to recognize and bind antigen via the V regions exposed on the surface of the cell, thus transmitting a signal that activates the B cell, leading to clonal expansion and antibody production.
What might an overabundance of lambda (l) chains be indicative of?
The ratio of the two types of light chains varies from species to species. In humans it is 2:1. The reason for this variation is unknown. Distortions of this ratio can sometimes be used to detect the abnormal proliferation of a clone of B-cells. These will all express the identical light chain, and thus an excess of lambda (l) chains in a person might indicate the presence of a B-cell tumor producing lambda (l) chains.
Name and describe the region of the antibody molecule responsible for its effector functions?
The region of the antibody molecule that engages the effector functions of the immune system does not vary in the same way and is known as the constant region or C region. It comes in FIVE main forms, each of which is specialized for activating different effector mechanisms. The membrane-bound B-cell receptor does not have these effector functions, because the C-region remains inserted in the membrane of the B cell.
What is the main effector function B-cells in adaptive immunity?
The secretion of antibodies, which bind pathogens or their toxic products in the extracellular spaces of the body, is the main effector function of B cells in adaptive immunity.
Describe the similarity and difference in the structure of a B-cell receptor and its corresponding antibody?
The structure of a B-cell receptor is identical to that of its corresponding anti-body except for a small portion of the carboxy terminus of the heavy-chain C region. In the B-cell receptor, the carboxy terminus is a hydrophobic amino acid sequence that anchors the molecule in the membrane, and in the anti-body it is a hydrophilic sequence that allows secretion.
Describe the structure of B-cell receptors?
The structure of a B-cell receptor is identical to that of its corresponding anti-body except for a small portion of the carboxy terminus of the heavy-chain C region. In the B-cell receptor, the carboxy terminus is a hydrophobic amino acid sequence that anchors the molecule in the membrane, and in the anti-body it is a hydrophilic sequence that allows secretion.
What is the most striking feature of MHC molecules?
Their most striking structural feature is a cleft in the extracellular face of the molecule, in which peptides can be bound.
How many classes of antibodies (Immunoglobulins) are there?
There are 5 classes: IgM, IgD, IgG, IgA, IgE.
How many heavy chains present in BCRs, and how many domains does each heavy chain posses?
There are two Heavy-chains, each with four domains.
Describe the structure and two functions of the heavy chain of immunoglobulins (antibodies)?
There are two Heavy-chains, each with four domains. The distinctive functional properties of the different classes and subclasses of antibodies are conferred by the carboxy-terminal part of the heavy chain, where it is NOT associated with the light chain. The structure of a B-cell receptor is identical to that of its corresponding anti-body except for a small portion of the carboxy terminus of the heavy-chain C region. In the B-cell receptor, the carboxy terminus is a hydrophobic amino acid sequence that anchors the molecule in the membrane, and in the anti-body it is a hydrophilic sequence that allows secretion.
How many classes/types of heavy chains are there, and what is the general term for each class of heavy chain? (hint: the heavy chain determines the class of antibody molecules, and there are 5 classes of immunoglobulins)
There are five main heavy-chain classes or isotypes , some of which have several subtypes, and these determine the functional activity of an antibody molecule. The five major classes of immunoglobulin are immunoglobulin-M (IgM), immunoglobulin-D (IgD), immunoglobulin-G (IgG), immunoglobulin-A (IgA), and immunoglobulin-E (IgE). Their heavy chains are denoted by the corresponding lower-case Greek letter (m, d, g, a, and e, respectively).
How are the 5 classes of Immunoglobulins defined?
These classes are defined by the structure of its heavy chain.
What type of B-cells secrete antibody?
Those whom have been stimulated by their Immunoglobulin-BCRs to differentiate into plasma cells (the effector B-cells).
How many types of light chains are found in antibodies, list them?
Two types of light chains, lambda (l) and kappa (k), are found in antibodies.
Membrane-bound immunoglobulin on the B-cell surface serves as the cell's receptor for antigen, and is known as ________...(WHAT)?
the B-cell receptor ( BCR ).
What type of antigen recognition molecule constitutes the B-cell receptor (BCR)?
the recognition proteins known as Immunoglobulins (Ig)
