Specific Defenses of the Host

Specific Defenses of the Host
Adaptive or Acquired Immunity

Specific Defenses of the Host
Also called acquired or adaptive immunity. Although one is born with the ability to respond to foreign invasion of the body, the specific response is developed during a person’s lifetime. Immunity, unlike resistance, involves the production of a specific defensive response against the foreign organisms or substances that have invaded the body.

The immune system Contains two components
The humoral arm of the immune system Involves antibodies (also called immunoglobulins) that are dissolved in blood and lymph Antibodies are produced by B lymphocytes upon exposure to a foreign antigen (an antigen will be discussed in more detail later, but it is basically anything that can stimulate a specific immune response)

The Structure of a Monomeric Antibody

Immune system, continued
B cells have antibodies on their cell surface and the antibody acts as a surface receptor for the antigen. The antibody actually only recognizes a small region of the antigen called the antigenic determinant or epitope. Each antigen has many different antigenic determinants.

Antigenic determinants

Immune system, continued
Each B cell has many antibodies on its surface, but the specificity of each antibody on the surface of a single B cell is the same. In other words, all of the antibodies on the surface of a single B cell recognize the same antigenic determinant. After binding of the antigen (specifically, the antigenic determinant) to the antibody on the B cell surface, the B cell is stimulated to produce and secrete antibody of the same specificity that was on the surface of the B cell.

Antigens and B cell receptors

Secretion of antibody following B lymphocyte stimulation

Immune System, continued
Therefore, the B cells produces antibody that will specifically react with the antigen (specifically, the antigenic determinant) that stimulated its production. Antibodies (or B cell receptors) can recognize and bind to linear proteins, folded proteins (may recognize non-linear sequences), polysaccharides, or nucleic acids.

Linear Versus Non-linear Antigenic Determinants

The second arm of the immune system is called the cell mediated arm of the immune system. Involves T lymphocytes that are found in blood and lymphoid tissues. T cells, like B cells, have receptors on their cell surface (called the T cell receptor) that recognize and bind to antigens (or, more specifically, antigenic determinants). The T cell receptor is similar in structure to an antibody.

Structure of the T cell receptor

All of the T cell receptors on the surface of a single T cell recognize the same antigenic determinant. The T cell receptor is only capable of recognizing antigenic determinants that are linear pieces of proteins (peptides). The significance of this will become clear later in the lecture. After binding of the T cell receptor with its specific antigenic determinant, the T cell will be stimulated to differentiate into an activated effector cell. There are several different types of effector cells (helper, supressor, cytotoxic, etc.)

T helper cells produce cytokines that help stimulate their own proliferation as well as the proliferation and differentiation of B cells and cytotoxic T cells. The cytokines are also involved in the activation of macrophages and they contribute to the development of inflammation. Cytotoxic T cells act to kill target cells, which may be infected cells or tumor cells. T supressor cells act to suppress the immune response.

Effector T cells

Acquired immunity There are four different types of acquired immunity:
Naturally acquired, active immunity Occurs when a person’s immune system comes in contact with microbial antigens in the course of daily life and the immune system responds by producing antibodies or sensitized T cells. Immunity may be lifelong (measles, chickenpox), or may last only a few years (diphtheria, tetanus), or even for only a short period of time (pneumococcal pneumonia) Naturally acquired, passive immunity

Acquired immunity Artificially acquired, active immunity
Involves the natural transfer of antibodies from an immunized donor to a nonimmunized recipient such as mother to child transfer through the placenta or through breast milk, particularly colostrum. Usually last only a few weeks or months. Artificially acquired, active immunity Results from vaccination Artificially acquired, passive immunity Gained by injection of antibodies (serum) from an outside source. Serum is the fluid remaining after blood has clotted and blood cells and clotted material have been removed. Most of the antibodies remain in the serum. The term antiserum is often used when referring to serum containing antibodies. The half-life of injected antibodies is ~ three weeks.

Types of acquired immunity

Acquired immunity If serum is subjected to electrophoresis, it will separate into , , and  globulins as well as albumin. The antibodies are found in the gamma fraction. Gammaglobulin is a term used to describe this antibody rich serum component.

What is an antigen? An antigen is also called an immunogen and it causes the body to produce a highly specific immune response in the form of antibodies and/or specially sensitized effector T cells. It should be noted that the body can distinguish between “self” and “nonself” antigens so that an immune response is not generated against “self” antigens.

What is an antigen? Most antigens are proteins, nucleoproteins, lipoproteins, glycoproteins, nucleic acids, or large polysaccharides. Notice that these are all structural components of an invader. The invader does not have to be a microorganism. It could also be transplanted tissue or blood cells.

What is an antigen? An antigen usually has a molecular weight >10,000 kd. As stated earlier, antibodies are formed against only a small region of the antigen, called the antigenic determinant or epitope. Antigenic determinants typically have a molecular weight of 200-1,000 kd.

What is an antigen? The valence of an antigen is the number of antigenic determinant sites on the surface of an antigen. Most antigens are multivalent and contain more than one kind of antigenic determinant. An antigenic determinant cannot function to stimulate an immune response by itself, but if an immune response has already been generated, it can combine with antibodies generated against it.

Antigenic determinants (epitopes)

What is an antigen? A foreign substance with a low molecular weight (hapten) is often not antigenic unless it is bound to a carrier molecule such as a serum protein. The combination of the hapten and the carrier molecule can stimulate an immune response against the hapten. The classic example of this is penicillin.

Haptens

What is an antibody? Antibodies are proteins secreted by B lymphocytes (or, more specifically, as will be discussed later, plasma cells) in response to the presence of an antigen. They combine specifically with the antigen that stimulated their secretion. Antibodies always have >1 antigen-antibody combining site or valence. A bivalent antibody molecule is called a monomer. Monomers often combine via a J chain, to form multimers.

Antibody monomers and multimers

What is the basic structure of a monomeric antibody?
A monomeric antibody is composed of four polypeptide chains held together by disulfide bonds. There are two short chains called the light chains and two long chains called the heavy chains. There are two basic types of light chains, called kappa () and lambda (). The two light chains in a single antibody molecule are always of the same basic type ( or ) and they have the same sequence as each other.

There are five basic types of heavy chains called alpha (), gamma (), mu (), delta () and epsilon (). The two heavy chains in a single antibody molecule are always of the same basic type (, , , , or ) and they have the same sequence as each other. The type of heavy chain that an antibody contains determines the class of the antibody, IgA, IgG, IgM, IgD, and IgE, respectively (more later on this).

The two sections at the ends of the arms of the antibody are called the variable region (labeled V) and it is here that you find the antigen binding sites (two per monomer). Variations in the amino acid sequence in these regions of the heavy and light chains are what determines the specificity of the antibody for a specific antigenic determinant.

The region on the antibody that is labeled C is the constant region because for each type of basic light or heavy chain, the amino acid sequence in this region is invariant. For example, all kappa chains have the same amino acid sequences in this region, all gamma chains have the same amino acid sequence in this region, etc. It is the sequence of the C region that determines if a light chain is of the kappa or the lambda type or if a heavy chain is an alpha, gamma, mu, delta, or epsilon type.

The stem of the antibody which contains part of the C regions of the heavy chains only is called the Fc region of the antibody and it participates in the opsonization and complement fixation activities of the antibody. The hinge region of the antibody is what gives the antibody its flexibility.

What are the functions of the different classes of antibodies?
As previously stated there are five different classes of antibodies and the class of the antibody is based on the type of heavy chain that the antibody contains. Each class of antibody plays a different role in the immune response: IgG antibodies account for about 80% of the antibodies found in serum. They are found as monomers and can cross the placenta to protect or attack the developing fetus. They can move out of the blood vessels into the tissue fluids.

They can participate in complement fixation and opsonization activities. They are important in protecting the host from circulating bacteria, viruses and toxins. They have a relatively long half life of 23 days IgM antibodies make up about 5-10% of the serum antibodies. They are found as pentamers joined together by a J chain (what is their valence?). They can’t cross the placenta or move out of the blood vessels into the tissues, in part because of their large size. IgM antibodies are the first antibodies to appear the first time an antigen is encountered, but they have a short half life of 10 days.

They can participate in complement fixation and opsonization activities. They are very effective in agglutinating antigens IgA antibodies make up 10-15% of the serum antibodies and are the antibodies found in body secretions and in breast milk. They are usually found as a dimer held together by a J chain. The IgA found in secretions, sIgA, is complexed with a secretory component (SC) that protects it from enzymatic degradation. They do not participate in complement fixation or opsonization activities.

They function locally to protect mucosal surfaces by preventing the attachment of pathogenic bacteria and viruses. IgD makes up about .2% of the serum antibodies. They are found as monomers. They have no known function in serum and cannot participate in complement fixation or opsonization activities. They are present on B cell surfaces where they may act as antigen receptors. IgE makes up .002% of the serum antibodies They are found in a monomeric form attached by their Fc region to receptors on mast cells and basophils which are cells that participate in allergic reactions.

When an antigen attaches to an IgE molecule bound to a mast cell or a basophil, the cells will release granules containing histamine and other chemical mediators that cause the localized dilation of blood vessels and contraction of smooth muscles seen in allergic reactions. This may be protective in instances where the antibodies bind to parasitic worms because the chemicals released attract IgG, complement, and phagocytic cells to the site.

The different classes of antibodies

Summary of antibody functions

What is the difference between a primary and a secondary humoral response?
The primary humoral response is the response in terms of antibodies produced the first time an antigen is encountered. The secondary humoral response is the response in terms of antibodies produced the second or subsequent time that an antigen is encountered.

IgM antibodies are the first antibodies to appear in response to an initial exposure to an antigen. However, the high IgM concentration rapidly declines and the IgG concentration then increases. Upon a secondary exposure to the same antigen, the IgM response is the same as with the primary response, but the IgG response is much quicker and higher than with the primary response. This is called a memory or anamnestic response and it is due to memory cells produced during the primary response (more on this later).

Mechanisms of the Immune Response
Both B and T cells have an antigen independent and an antigen dependent phase of maturation. Antigen independent maturation Pluripotential stems cells in the bone marrow produce immature B cells that mature to immunocompetent B cells in the bone marrow. Immunocompetent B cells have antibody receptors on their surface(IgM and IgD) and are capable of functioning in an immune reaction.

Mechanisms of the Immune Response, continued
Pluripotential stem cells in the bone marrow produce immature T cells that move to the thymus where they mature into immunocompetent T cells which have CD4 (for T4 cells) or CD8 (for T8 cells) and T cell receptors on their surface that are capable of interacting with an antigenic determinant in an immune response. In the thymus the T cells learn to distinguish between self-antigens and non-self antigens. Thus, the immune system does not normally produce a specific immune response against self-antigens.

Antigen independent maturation

Antigen dependent maturation Antigen dependent maturation begins when antigen (antigenic determinant) binds to an antibody receptor on the surface of a B cell or the T cell receptor on the surface of a T cell. Binding of the antigen will activate the B or T cell and help to stimulate a clonal expansion (proliferation) and differentiation of the B or T cell. In most cases a second signal provided by a helper T cell is required for the proliferation and differentiation to occur. B cells will differentiate into either plasma cells that will secrete antibody of the same specificity (recognizes the same antigenic determinant) that was on the surface of the original B cell or, in the case of T-dependent antigens (more on this later), to memory B cells

Antigen dependent maturation of B cells

T cells will differentiate into either an activated effector cell {helper (CD4+), supressor (CD8+), cytotoxic (CD8+), etc} or to a memory T cell. Memory cells are responsible for the anamnestic or secondary response that occurs the next or subsequent times that the same antigen is encountered. As previously shown with the humoral response, the anamnestic response is usually much quicker or stronger than the primary or original response.

Antigen dependent maturation of T cells

B cells often work together with T cells and macrophages during an immune response. When an antigen comes in, B cells and macrophages will process the antigen and present pieces of it (antigenic determinants) to the B or T cell for activation.

Many antigens require T cell interaction for B cell stimulation and production of secreted antibodies. T dependent antigens require T help (T helper cells) to stimulate the proliferation and differentiation of the B cell. Stimulation of the B cell requires two signals. One signal comes from the binding of the antigen itself to the B cell receptor (antibody) which is a membrane bound IgM or IgD. This binding will activate the B cell. The second signal comes from an interaction of the B cell with a T helper cell. The interaction causes the T cell to release cytokines that provide the second signal. This stimulates a clonal expansion of the B cells, isotypic switching (different class of antibody, but same antigen combining site) from IgM to IgG (or IgA), and differentiation to plasma cells or memory B cells which have membrane bound IgG receptors.

Mechanisms of the Immune Response, T Dependant Antigens

B cell clonal expansion and differentiation into plasma cells

T helper cells have CD4 on their cell surface. The significance of this will be explained later. The T cell must be armed or activated by previous exposure to the same antigen. The T cell is restricted in that it can only help its own B cells. This is because the T cell can only recognize the foreign antigen in the context of a self-antigen (more on this later).

Mechanisms of the Immune Response, T Dependant Antigens

B-T interaction

T independent antigens don’t require T help for B cell stimulation. T independent antigens usually contain some sort repeating subunit like a polysaccharide. Binding by this type of antigen somehow provides both signals that are required for B cell stimulation, probably by extensive cross-linking the surface antibodies. The outcome from this type of stimulation is clearly different than that which occurs in T-dependent stimulation, since with the T-independent stimulation no memory cells are made. There is no anamnestic response for T-independent antigens because memory B cells are not formed.

T-independent activation of B cells

Antigens also require T cell interaction (T helper cell) to stimulate the proliferation and differentiation of T cells. Stimulation of the T cell requires two signals. One signal comes from the binding of the antigen itself (in the context of a self antigen) to the T cell receptor. This binding will activate the T cell. The second signal comes from cytokines, such as interleukin 2, released from activated T helper cells. This stimulates a clonal expansion of the T cell, and differentiation to T helper cells (for T4 cells) or cytotoxic T cells (for T8 cells) plus memory T cells.

T4 proliferation

T8 proliferation

Cytotoxic T cells have CD8 on their surface (significance will be described later) and they act to destroy target cells, including infected cells, cancer cells, and tissue transplants. Cytotoxic T cells are like T helper cells in that, in order to function, they can only recognize a foreign antigen in the context of a self-antigen. The T cell restriction (for both T helper cells and cytotoxic T cells) involves antigens encoded in the Major Histocompatibility Complex (MHC).

The MHC This is a region of highly polymorphic genes found, in humans, on chromosome 6. The products of the MHC are found on a variety of cell surfaces and are called histocompatibility antigens. The histocompatibility antigens function as peptide receptors. In humans these antigens are collectively called the Human Leukocyte Antigens (HLA) and they include three classes of genes.

Class I genes encode the class I histocompatibility antigens that are found on the surfaces of most nucleated cells. Class II genes encode the class II histocompatibility antigens that are found on cells involved in immune functions (B cells, macrophages, among others) Class III genes encode the complement components and other gene products that have various functions in the immune system.

The MHC Regions for Humans and Mice

All of the genes in the MHC are tightly linked and they are inherited as a block. Each allele is given a numerical designation and the total set of alleles on each chromosome (1 from mom and 1 from dad) is called a haplotype. The alleles are co-dominant. Individuals studying tissue transplant rejection first discovered the histocompatibility antigens. They are the principle determinants of tissue transplant rejections.

Their discovery led to an understanding of T cell restriction. T cells can only recognize foreign peptides if they are noncovalently bound to self-antigens, the MHC molecules. The T cell receptor reacts with amino acid side chains from both the bound peptide and the MHC molecule itself. This explains why T cells cannot recognize antigens in a free or soluble form and why they only recognize linear peptides. The MHC molecule “presents” the antigenic determinant to the T lymphocyte.

How do the MHC class I molecules function? MHC class I antigens - Foreign antigens synthesized within the cell (such as viral proteins) bind to MHC class I antigens and help to stimulate cytotoxic (CD8+) T cells which act to destroy the cell displaying the foreign peptide by secreting perforins and granzymes which together cause the infected cell to undergo apoptosis. Both the binding of the T cell receptor to the MHC molecule and the bound peptide, and the binding of the CD8 molecule to the MHC molecule are required for T cell activation.

MHC Class I Interaction with CD8+ T Cell

Presentation of Foreign Antigen Made Within the cell to CD8+ T Cells

Killing by cytotoxic T cell

In humans there are three functional class I loci, called A, B, and C. Assuming heterozygosity, every individual has six different class I molecules.

These class I molecules which are found on the surface of all nucleated cells participate in the destruction of virus infected cells and in graft rejection. The class I molecules consist of two separate polypeptide chains, alpha and beta. Only the alpha chain is MHC encoded. The alpha chain has four separate domains or regions: the peptide binding domain, the immunoglobulin-like domain, the transmembrane domain, and the cytoplasmic domain.

Structure of the MHC Class I Molecule

The peptide binding domain This region interacts with foreign peptides to form complexes that are recognized by CD8+ T cells. Almost all of the polymorphic residues (the differences between different alleles) lie in the region where peptide binds. Other polymorphic residues are where the T cell receptor interacts with the MHC molecule itself. Differences here provide the basis for T cell restriction.

Polymorphism in the MHC Class I Molecule

Every MHC class I molecule can bind more than 1 different peptide. In terms of the peptides that each MHC class I molecule binds: All are 9-11 amino acids in length. All peptides that interact with a single allelic form of a class I molecule share common structural features. The shared features of the peptides that can bind to one allelic form of MHC class I molecules are different from the features shared by peptides that can bind to another allelic form. The term loose specificity is used to describe this phenomena. That is, each MHC molecule has loose specificity for its peptides. To summarize: each MHC class I molecule can bind many different peptides, but all the peptides that each binds have common structural features.

The extraordinary polymorphism within the MHC region that exists within the population, protects the population, as a whole, from disease. A microorganism spreading through a population will have to adapt to each new host. It will not be able to mutate and therefore be resistant to everyone’s immune system. The immunoglobulin-like domain (alpha 3 region) This region is highly conserved among class I molecules and is homologous to the constant domain of immunoglobulin molecules. This is the region where the CD8 molecules on the surface of cytotoxic T cells interact with the MHC class I molecule. In Summary: MHC class II molecules present foreign peptides synthesized inside the cell to CD8+ T cells.

Structure of the MHC Class I Molecule

MHC Class I Interaction with CD8+ T Cell

How do MHC class II molecules function? MHC class II antigens – these molecules bind foreign antigens that are synthesized outside the cell and have entered the cell via endocytosis. They trigger an immune response by helping to stimulate helper CD4+ T cells. Both the binding of the T cell receptor to the MHC class II molecule and the peptide as well as the binding of the CD4 molecule to the MHC class II molecule are required for stimulation of the T cell. The genes that encode these molecules are called immune response genes and they determine whether an individual can mount an antibody response to T-dependent antigens.

MHC Class II Interaction with CD4+ T Cells

Presentation of Foreign Antigens Made Outside the Cell to CD4+ T Cells

The MHC class II molecules, like the class I molecules, consist of two polypeptide chains called alpha and beta. Both the alpha and the beta chain are encoded in the MHC class II region. There are 3 functional loci – DR, DQ, and DP. Each locus encodes alpha chains and beta chains.

Since one inherits (assuming heterozygosity), 6 different loci, and since each locus encodes both alpha and beta chains, individuals can express different MHC class II molecules/cell. DR, DQ, and DP beta chains associate mainly with alpha chains from their own family. The alpha and beta chains can be divided into 4 separate domains or regions: the peptide binding domain, immunoglobulin-like domain, transmembrane domain, and cytoplasmic domain.

The Structure of the MHC Class II Molecule

The peptide binding domain This region has a structure similar to that of the peptide binding domain of class I molecules In terms of the peptides they bind, since the ends of the cleft are open, bound peptides can extend beyond the cleft. The peptides that bind to the MHC class II molecules can range in size from amino acids.

Each MHC class II molecule can bind more than 1 different peptide, but as with the class I molecules, all peptides that bind a single class II molecule will share structural features. The MHC class II molecules therefore, are said to bind their peptides with loose specificity. All polymorphic residues are found within the cleft where the peptide binds or where the T cell receptor interacts with the MHC class II molecule. Differences here provide the basis for T cell restriction. The class II molecules are not as polymorphic as the class I molecules.

Polymorphisms within the MHC Class II Molecules

The immunoglobulin-like domain This region is highly conserved among class II molecules and is homologous to the constant domain of immunoglobulin molecules. This is the region where the T cell CD4 molecule interacts with the MHC class II molecule (at the beta 2 region) In summary: MHC class II molecules present peptides synthesized outside the cell to CD4+ T cells.

The Structure of the MHC Class II Molecule

Presentation of Foreign Antigen Made Within the cell to CD8+ T Cells

Specific Defenses of the Host

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