This lesson is the continuation of Immunology 1: General principles and nonspecific immune responses.
A specific immune response is an attack on a target that is particular to that target with the goal of eliminating
or neutralizing the target. In general, we can say that the immune system has been specially prepared to attack that
target by prior exposure to it. You may notice a small problem with this description in considering the first time
the immune system is exposed to the target, but that will become clear later.
Specific immune responses exhibit three distinctive characteristics:
Self/non-self discrimination - the immune system normally distinguishes between self and non-self and only reacts against non-self.
Memory - The immune system “remembers” if it has seen an antigen before, and it reacts to secondary exposures to an antigen in a manner different than after a primary exposure. Generally only an exposure to the same antigen will generate this memory response.
Specificity - A response to a particular antigen is specific for that antigen or a few closely related antigens.
There are two types of specific immune response:
Humoral, or antibody-mediated immunity involves the production of antibodies by differentiated B cells called plasma cells.
Cell-mediated immunity results from the formation of activated T cells, which participate in behavior to attack and destroy the target.
internship and residency of lymphocytes
Recall that lymphocytes released from the bone marrow are immunologically incompetent, and this competency must be acquired by residency in either another bone marrow compartment (B cells) or the thymus (T cells). For example, the T cells which enter the thymus are CD4-/CD8-, become double positive, CD4+/CD8+ cells expressing low levels of the T cell receptor (TCR). Positive selection for interaction with self MHC-I or MHC-II molecules occurs in the cortical epithelium of the thymus. (As you might suspect, MHC molecules are the determinants of self, i.e., not foreign.) The majority of the cells are unselected and undergo apoptosis (self-programmed death). The cells that remain either interact with MHC-I and lose their CD4 antigen (becoming CD8+ T cells) or interact with MHC-II and lose their CD8 antigen (becoming CD4+ T cells). Autoreactive cells are then removed as a result of their interaction with self antigen peptides that are presented by cells in the corticomedullary junction and the medulla of the thymus.
antigens and immune triggering
An immunogen is a substance that induces a specific immune response.
An antigen (Ag) is substance that reacts with the products of a specific immune response; i.e., antibodies or specific T cells. The word “antigen” is a coined term, implying antibody & generating.
The antigenic determinant (or epitope) is that particular part of an antigen that combines the components of the specific immune response. This is important because it implies that (often ?) the truly antigenic part of an organism, might only be a very small part of the whole.
A hapten is a substance, almost always very small in molecular terms, that by itself is non-immunogenic, but that can react with the products of a specific immune response. If a hapten is administered by itself, it cannot induce an immune response (thus, haptens are not immunogens). If the hapten combines with a carrier, then the combination is immunogenic. Also, free haptens can react with products of the immune response after such products have been formed (thus, haptens possess antigenicity).
An antibody (Ab) is a specific protein (immunoglobulin) which is produced in response to an immunogen and which reacts with an antigen.
To be immunogenic, the antigen must possess certain properties, such as:
First, it must (should) be foreign. There are mechanisms within the immune system that normally discriminate self and non-self, with the result that only foreign molecules are immunogenic.
Second, bigger is better when it comes to immunogenicity, even though there is no known absolute size above which a substance would become immunogenic. Proteins and large carbohydrates are typically immunogenic.
Third, the more complex the chemistry, generally the more immunogenic the substance will be. Fourth, particulate antigens are more immunogenic than soluble ones, and, strangely, denatured antigens appear more immunogenic than the native state.
And fifth, easily phagocytosed antigens are usually more immunogenic. Why? Because for most antigens, a really effective immune response involves helper T cells, and they depend on antigen presentation by the APCs, which means the antigen had to have been gobbled up first.
B lymphocytes and antibody-mediated immunity
We know that antibodies are formed even before an antigen is ever seen; we also know that the particular antibody is selected for by the antigen. Thus, what exists is a collection of B lymphocytes capable of responding to any conceivable antigen; guesses put this number in the vicinity of no more than 108 antigens. Each lymphocyte is programmed to make one, and only one, antibody. The B cell places this antibody on its plasma membrane, where it acts as a receptor. Each lymphocyte has about 105 antibody molecules on its surface. (As an aside, the possible number of TCRs appears to be as much as 1016!)
When an antigen enters the body, it meets the suite of lymphocytes, each bearing different antibodies; understand that each antibody has a unique recognition site. The antigen will only bind to those receptors with which it makes a good fit (sort of like in the Brothers Grimm fairy tale Aschenputtel or Cinderella).
plasma cell differentiation
Lymphocytes whose receptors have bound antigen are stimulated into developing into antibody-forming plasma cells. Since the B cell that was programmed to make only one type of antibody, the derived plasma cell will also make only that antibody.
Immunoglobulins are glycoprotein molecules produced by plasma cells in response to an immunogen and which
function as antibodies. The immunoglobulins get their name because they migrate with globular proteins when
antibody-containing serum is placed in an electrical field. When we speak of different classes of immunoglobulin,
such as immunoglobulin G, we shorten the name to IgG.
Immunoglobulins bind specifically to one or a few closely related antigens. Each immunoglobulin actually binds to a specific antigenic determinant of the antigen called the epitope. Antigen binding by antibodies is the primary function of antibodies and can result in protection of the host.
When we speak of the valency of an antibody, we are refering to the number of antigenic determinants that an individual antibody molecule can bind. The valency of all antibodies is at least two; sIgA has a valency of four, IgM ten.
Often the binding of an antibody to an antigen may have no direct biological effect. Rather, the significant biological effects are a consequence of secondary “effector functions” of antibodies. The immunoglobulins mediate a variety of these effector functions. Usually the ability to carry out a particular effector function requires that the antibody bind to its antigen. Not every immunoglobulin will mediate all effector functions. Some of the effector functions are given after the description of the immunoglobulin classes.
All immunoglobulins have a
four-chain structure as the basic unit.
They are composed of two identical light chains (molecular weight 23 kDa) and two identical heavy chains
(molecular weight 50-70 kDa). There are inter- and intra-chain disulfide bonds:
The heavy and light chains and the two heavy chains are held together by inter-chain disulfide bonds and
by non-covalent interactions The number of inter-chain disulfide bonds differs among immunoglobulin molecules.
Each of the polypeptide chains also has intra-chain disulfide bonds. The heavy and light chains can be
divided into two regions based on variability in the amino acid sequences. These are the:
1. Light Chain - VL (110 amino acids) and CL (110 amino acids)
2. Heavy Chain - VH (110 amino acids) and CH (330-440 amino acids)
There is a hinge region where the arms of the antibody molecule form a Y; there is some flexibility in the molecule at this point.
The three-dimensional structure of the Ig molecule is not a nice flat Y, but rather, it is folded into globular regions (domains), each of which contains an intra-chain disulfide bond:
1. Light Chain Domains - VL and CL
2. Heavy Chain Domains - VH, CH1 - CH3 (or CH4)
Carbohydrates are attached to the CH2 domain in most immunoglobulins. Carbohydrates may also be attached at other locations.
Treating Ig molecules with the enzyme papain breaks the molecule in the hinge region before the H-H inter-chain disulfide bond. The result is two identical fragments that contain the light chain and the VH and CH1 domains of the heavy chain.
antigen-binding fragment (Fab)
The Fab fragments contain the antigen binding sites of the antibody. Each Fab fragment is monovalent, whereas the original molecule was divalent. The combining site of the antibody is created by both VH and VL. An antibody is able to bind a particular antigenic determinant because it has a particular combination of VH and VL. Different combinations of a VH and VL result in antibodies that can bind a different antigenic determinants.
constant (Fc) region
The Fc fragment contains the remainder of the two heavy chains, each containing a CH2 and
CH3 domain (this was called Fc because it was easily crystallized).
Different domains of the Fc region of the Ig molecule mediate the several effector fucntions.
Immunoglobulins are divided into five different classes, based on differences in the amino acid
sequences in the constant region of the heavy chains. All immunoglobulins within a given class will
have very similar heavy chain constant regions.
1. IgG - Gamma heavy chains
2. IgM - Mu heavy chains
3. IgA - Alpha heavy chains
4. IgD - Delta heavy chains
5. IgE - Epsilon heavy chains
IgG has molecular weight of 150 kDa and consists of a monomer with four subclasses. The subclasses differ in the number of disulfide bonds and length of the hinge region. IgG is the most abundant immunoglobulin of internal body fluids, particularly the extravascular spaces where it combats microorganisms and their toxins. IgG is also the most versatile immunoglobulin because it is capable of carrying out all of the functions of immunoglobulin molecules. IgG fixes complement in the classical pathway, although not all subclasses are equally effective; for example, IgG4 does not fix complement at all. IgG molecules can cross the placenta. This forms the basis for establishing neonatal passive immunity. Transfer is mediated by receptor on placental trophoblast cells for the Fc region of IgG. Again, not all subclasses cross equally; for example, IgG2 does not cross well. Macrophages, monocytes, PMNs, and some lymphocytes have Fc receptors for the Fc region of IgG. Not all IgG subclasses bind equally well - IgG2 and IgG4 do not bind to Fc receptors. A consequence of binding to the Fc receptors on PMNs, monocytes, and macrophages is that the cell can now internalize the antigen better. The antibody has prepared the antigen for phagocytosis (opsonization). Binding of IgG to Fc receptors on other types of cells results in the activation of other functions.
IgM has a molecular weight of 970 kDa and consists of a pentamer of four-peptide units. Generally the first Ig produced in the immune response, it is a very effective agglutinator and provides the first line of defense against bacteremia. It is the best at fixing complement in the classical pathway, but does not fix complement in the alternate pathway. IgM cannot cross the placenta, does not sensitize mast cells and basophils, and does not bind to macrophages and PMNs. It constitutes about 5-10% of circulating antibody. IgM is the first Ig made by the fetus.
IgA has a molecular weight of 160 kDa, but twice that in its dimeric form. Serum IgA exists as the monomer. In secretions, dimeric IgA has another protein associated with it (called the secretory piece or T piece). Unlike the remainder of the IgA molecule, which is made in the plasma cell, the secretory piece is made in epithelial cells and added to the IgA as it passes into the secretions. The secretory piece helps IgA to be transported across the mucosa and also protects it from degradation in the secretions. IgA is the major class of Ig in secretions - tears, saliva, colostrum, mucus. Because of its presence in secretions, IgA is important in seromucosal immunity. It does not fix complement, unless aggregated. IgA does not cross the placenta, but does bind to some macrophages and PMNs. It constitutes about 15% of circulating antibody.
IgE has a molecular weight of 190 kDa and consists of a monomer with an extra domain in the Fc region. IgE binds very tightly to Fc receptors on basophils and mast cells even before interacting with antigen. Its initial role in immunity was probably in parasitic helminth infections; serum IgE levels rise dramatically in parasitic diseases, so measuring IgE titers is helpful in diagnosis of parasitic infections. Eosinophils have Fc receptors for IgE so the binding of eosinophils to IgE-coated helminths causes degranulation of the eosinophil, and death of the parasite. Since IgE is bound to basophils and mast cells, it is also involved in allergic reactions. Binding of the allergen to the IgE on the cells results in the release of the various pharmacological mediators (histamine, for one) that result in allergic symptoms. IgE does not fix complement. Nor does it cross the placenta. Usually, it constitutes only about 0.002% of circulating antibody (because most of it is bound to cells).
IgD has a molecular weight of 175 kDa and consists of an ordinary looking monomer. IgD is mostly found on the B cell surface where it functions as an antigen receptor. IgD on the surface of B cells has extra amino acids at the C-terminal end for anchoring to the membrane. It also associates with the Ig-alpha and Ig-beta chains. IgD does not fix complement, does not cross the placenta, and does not bind to macrophages and PMNs. It constitutes 0-1% of the circulating antibody, but its role in the serum is unknown.
modes of action
interfering with antigen effect
This is a physical thing, preventing the antigen from exerting its harmful effects. These hinderance mechanisms probably only play a minor role in the body; it is through the augmentation of the already-initiated nonspecific effects that they become most important.
By combining with the toxin, the antibody renders the toxin, in its Ab-toxin form, harmless. Another action would be to interfere with viruses, blocking their ability to gain access to cells.
Sometimes antibody can cross-link antigen into long chains, forming antigen-antibody complexes. IgM works to clump together up to ten cells bearing the antigen for which it is specific. This is the process which occurs when a blood transfusion is made with the wrong cell type (for example, transfusing type A blood into a type B host).
Antibodies against tetanus toxin form an antigen-antibody complex lattice that is so large that
it can no longer remain in solution, and so precipitates, thus inactivating it.
These last two effects can be exploited clinically to detect the presence of an antigen. For example, pregnancy tests use an antibody formed against the hormone chorionic gonadotropin.
augmenting nonspecific immune effects
In this manner, the antibodies tag the foreign material, making it more clearly the target for the action of these nonspecific effects. Some of these have already been discussed.
activation of complement system through C1
enhancement of phagocytosis
stimulation of killer (K) cells
The are probably the same as the NK cell described earlier, but we’re not quite ready to say so. Certainly, though, they kill in exactly the same way.
Under normal circumstances, the antigen-antibody (Ag-Ab) complexes are removed by phagocytes. Sometimes, not all goes as planned, and if Ag-Ab complexes sit around, they will continue to stimulate, among other things, the complement system. This overzealous activation of complement and other inflammatory process substances can result in damage to nearby healthy tissue. In addition, the Ag-Ab complexes can travel, eventually becoming trapped in distant sites, such as the kidney. At these new sites, there will be new inflammatory responses and tissue damage.
clonal selection theory of B cell production
Because we can make such a large number of different antibody molecules (recall: some think up to 108), it is not practical to have too many lymphocytes producing each antibody type. To compensate for the paucity of lymphocytes, those which are triggered by contact with antigen undergo successive waves of proliferation to build up a large clonal set of plasma cells which will be making the antibody for which the triggered lymphocyte was programmed. By this system, large quantities of antibody can be produced for effective elimination of the antigen.
The primary antibody response has four phases: 1. Inductive, latent, or lag phase - Antigen is recognized as foreign and the cells begin to proliferate and differentiate in response to the antigen. The duration of this phase will vary depending on the antigen but it is usually 5-7 days. The plasma cells begin to secrete antibody. 2. Log or Exponential Phase - As more B cells proliferate and differentiate into antibody secreting cells, the antibody concentration increases exponentially. The plasma cells initially secrete IgM antibody. Eventually some B cells switch from making IgM to IgG, IgA or IgE. 3. Plateau or steady-state phase - As antigen is depleted, T and B cells are no longer activated. In addition, mechanisms which down-regulate the immune response come into play. Furthermore, plasma cells begin to die. When the rate of antibody synthesis equals the rate of antibody decay the stationary phase is reached. 4. Decline or decay phase - The rate of antibody degradation exceeds that of antibody synthesis and the level of antibody falls. Eventually the level of antibody may reach base line levels.
The secondary, memory, or anamnestic* antibody response also has four phases:
1. Inductive, latent, or lag phase - This is normally shorter than that observed in a primary response.
2. Log or Exponential Phase - The log phase in a secondary response is more rapid and higher antibody levels are achieved.
3. Plateau or steady-state phase - No difference.
4. Decline or decay phase - The decline phase is not as rapid and antibody may persist for months, years or even a lifetime.
* What a bizarre word: “amnestic” = “loss of memory”, “an-” = “not”, so “anamnestic” = “not loss of memory”
Not all of the T and B cells that are stimulated by antigen during primary challenge with antigen die. Some of them are long lived cells and constitute what is refer to as the memory cell pool. Both memory T cells and memory B cells are produced, and memory T cells survive longer than memory B cells. Upon secondary challenge with antigen, not only are virgin T and B cells activated, the memory cells are also activated, and thus, there is a shorter lag time in the secondary response. Since there is an expanded clone of cells being stimulated, the rate of antibody production is also increased during the log phase of antibody production, and higher levels are achieved. Also, since many, if not all, of the memory B cells will have switched to IgG (IgA or IgE) production, IgG is produced earlier in a secondary response. Furthermore, since there is an expanded clone of memory T cells which can help B cells to switch to IgG (IgA or IgE) production, the predominant class of Ig produced after secondary challenge is IgG (IgA or IgE).
The production of antibodies as result of exposure to an antigen is called active immunity. An individual can, however, acquire antibodies that were actively made by another individual (or animal). This direct transfer of another’s antibodies is what we term passive immunity. Two examples: Maternal IgG molecules cross the placental barrier into the fetal blood stream, conferring a protective immunity on the neonate, whose own immune system does not start functioning for at least a month. A second example would be the administration of an antitoxin or antivenom to some agent to which you might have been exposed, such as being bitten by a cottonmouth snake. You would make antibodies against that snake venom, given the couple of weeks or so required; but the venom is a lot faster acting, and you’d be ... well, dead.
natural immunity as a special case of actively acquired immunity
Natural immunity refers to the presence of preexisting antibodies within the body even without previous exposure to the antigen.
ABO blood groups as example
The major blood group system is termed the ABO system. (Bear in mind, the whole system is a lot more complicated than I am going to indicate here.) Erythrocytes (RBCs) may have carbohydrate moieties on their surfaces that act as antigens. If the RBCs have an A-antigen, then the blood type is A. If there is a B-antigen, type B. If both are present (and, yes, both can be), the blood type is AB. If neither is expressed, then the blood type is O. Interestingly enough, after about six months of age, the blood acquires antibodies to the antigens that are not present on the RBCs. Thus, type A blood has anti-B antibodies; type B blood has anti-A antibodies; type O blood has anti-A and anti-B antibodies; but type AB blood has neither antibody. How can this be? The answer appears to be the exposure of developing immune system to the bacterial flora within the gut. Many of these express carbohydrate moieties that mimic the blood group antibodies; they are called phytohemagglutinins.
This is the agglutination (clumping, sticking together) and hemolysis (rupture of the RBCs) that may occur when donor blood of the wrong type is introduced into the recipient. For example, imagine the immunologic scenario if type AB red cells are introduced into an adult with type O blood. Since the recipient blood has anti-A and anti-B antibodies, the donor cells are attacked. The effects are devestating, particularly in the kidneys.
The Rh factor is a different case. In this case, the marker is a protein, so there is no incidental preexposure. One either has the factor, Rh+, or one doesn’t, Rh-. (Yes, once again I am oversimplifying.) For transfusions, it is important to get it right. But there is another case where it can be a problem, and that concerns maternity. Suppose mother is Rh-, and father is Rh+. If he is homozygous Rh+/Rh+, then all conceptions will be phenotypically Rh+; if he is heterozygous Rh+/Rh-, then half the conceptions will be of Rh+ phenotype. The first pregnancy with an Rh+ conceptus is generally not a problem. At parturition, however, there is no way to avoid fetal blood mixing with maternal blood, and so mother will be exposed to the Rh-antigen, and generate circulating anti-Rh IgG molecules. If the next pregnancy is an Rh+ conceptus, these anti-Rh IgG molecules will cross the placenta, destroying the fetal erythrocytes, resulting in erythroblastosis fetalis or hemolytic disease of the newborn. The drug RhoGam® is essentially an anti-(anti-Rh IgG) IgG.
antigen processing and presentation
B cells generally cannot produce antibody without help from macrophages and, usually, T cells. A B cell clone cannot recognize a raw antigen. It has be “introduced” to the B cell as something foreign.
It is the function of the antigen-presenting cell to gobble up the antigen, process it intracellularly, and then present the processed antigen is such a way that neighboring B cells can recognize, and respond, to it. (For T cells, there is a similar antigen presentation using macrophages and dendritic cells.)
For presentation, the APC digests the antigen into fragments. Each fragment is bound to an MHC molecule. These molecules are synthesized in the APC’s ER-Golgi complex. An MHC molecule has a groove into the antigenic fragments can be placed.
compartment for peptide loading (CPL) organelle
This is the organelle responsible for placing the antigenic fragments onto the MHC molecule of the APC.
interleukin 1 and B cell proliferation
Besides presenting the antigen on the MHC molecule, the APC secretes IL-1, which in turn enhances the differentiation and proliferation of the B cell clone.
TH cells and B cell growth factor
Antigen presented to helper T cells results in their producing B cell growth factor, which works in concert with IL-1 to promote B cell function.
T lymphocytes and cell-mediated immunity
Many microorganisms live inside host cells where it is impossible for the humoral antibodies to reach them.
Obligate intracellular parasites like viruses have to replicate inside cells; facultative intracellular parasites
like Mycobacterium and Leishmania can replicate within cells, particularly within macrophages, even
though they don’t have to; life is much better for them if they stay hidden and protected! A totally separate
acquired immunity system has evolved to deal with this situation based on the lymphocyte subpopulation made up of
T cells. Because T cells are specialized to operate against cells bearing intracellular organisms, T cells only
recognize antigen when it is on the surface of a body cell. Thus, the T cell surface receptors, which are different
from the antibody molecules used by B cells, recognize antigen plus a surface marker which informs the T cell
that it is in contact with another cell. These cell markers belong to an important group of molecules known as the
major histocompatibility complex (MHC), originally identified through their ability to evoke powerful
transplantation reactions in other members of the same species. Naïve T cells must be introduced to the
antigen and MHC by a special dendritic APC before they can be initiated into the rites of a primary response. Once
primed, however, they are activated by antigen and MHC present on the surface of other cell types such as
macrophages. Note that a T cell can be activated only if the antigen is presented in context of self.
Here are a few of the things T cells take care of:
viral and fungal infections
tumors and xenograft rejection
A good of example of T cell regulation is how cytokine-producing T cells help macrophages to kill intracellular parasites. These parasites can only survive inside macrophages because they subvert the innate killing mechanisms of these cells. Nonetheless, they cannot prevent the macrophage from processing small antigenic fragments and placing them on the cell surface. A subpopulation of T cells, the helper T cells, if primed to that antigen, will recognize and bind to the combination of antigen with so-called class II MHC molecules on the macrophage surface, resulting in the production of soluble factors called cytokines, such IL-2. One of these cytokines, γ-interferon (IFNγ), acts as a macrophage activating factor to switch on the subverted microbicidal mechanisms of the macrophage and bring about the death of the parasite.
T cell types
cytotoxic T cells (CD8+ or TC cells)
These cells destroy host cells harboring anything foreign and thus bearing foreign antigen, such as body cells invaded by viruses, cancer cells that have mutated proteins resulting from the malignant transformation, and xenografts (cells transplanted from another host). Besides the perforin method, cytotoxic T cells appear to be able indirectly to bring about the death of infected host cells by producing chemicals that induce them to self-destruct (a process called apoptosis). After the cell is destroyed, the released viral particles can be easily dealt with by other elements of the immune system, and the T cell can merrily move on to its next victim.
The direct means used by cytotoxic T cells is the same as used by NK cells - releasing perforin molecules which penetrate into the target cell’s surface membrane and join together to form large porelike channels. If this sounds familiar, it should. It’s the same idea as used by the MAC in the complement cascades. Also, maybe the approach used by Dementors.
helper T cells (CD4+ or TH cells)
These cells enhance the development of antigen-stimulated B cells into antibody-secreting plasma cells, enhance the activity of cytotoxic and suppressor T cells, and activate macrophages. They do all these things, and more, by releasing chemicals, the by now well-known cytokines:
B cell growth factor
This enhances the antibody-secreting ability of the activated B cell clone. Without helper T cells, antibody secretion is greatly reduced. Knowing that HIV (human immunodeficiency virus) infects, and disables, CD4+ cells, how well do you suppose an AIDS (acquired immunodeficiency syndrome) patient responds to an infection? HIV also invades macrophages, and sometimes enters brain cells.
T cell growth factor (interleukin 2 [IL-2])
IL-2 augments the activity of cytotoxic T cells, suppressor T cells, and even other helper T cells responsive to the invader. So, IL-1 from macrophages will enhance B and T cell clones, but also stimulate IL-2 production by activated T helper cells.
Chemotaxins lure more neutrophils and macrophages-in-waiting to the action arena.
macrophage-migration inhibition factor (MMIF)
Once the macrophages are on scene, it’s really important to keep them there. So, MMIF from the helper T cells inhibits the normal outward migration of these phagocytes. In addition to causing a large gathering to form, MMIF also confers a greater phagocytic power to the gathering, creating the so-called angry macrophages. Lest you think this unimportant, nonactivated macrophages cannot kill some bacteria, such as the cause of tuberculosis.
Some helper T cell interleukins activate eosinophils and promote the development of antihelminthic IgE antibodies.
helper T cell subsets
The helper T cell subsets augment different parts of the immune system by secreting different types of cytokines.
helper T cell naïveté
Helper T cells produced in the thymus are naïve until they encounter the antigen for which they are specific. When the dendritic cell presents the antigen to the naïve helper T cell, it also secretes an interleukin, IL-4 or IL-12, which determines to which subset the helper T cell will belong. (One is reminded of the Drazi Dro’hannan where two factions are formed by individuals randomly choosing a green or purple sash from the great barrel. But I digress...)
T helper 1 (TH1) cells
TH1 cells are formed from the naïve pool by secretion of IL-12 by the presenting dendritic cell. These TH1 cells secrete IFNγ to activate macrophages, promoting a cell-mediated (cytotoxic T cell) response, and thus, are best suited for responding to intracellular microbial infections. Of equal importance, IFNγ produced by TH1 cells inhibits proliferation of TH2 cells cells
T helper 2 (TH2) cells
TH2 cells are formed from the naïve pool by secretion of IL-4 by the presenting dendritic cell. These TH2 cells promote a humoral (B cell) response, and produce IL-4 and IL-5 that increases production of eosinophils and mast cells and enhances production of antibody, especially IgE. Similar to what happens with TH1 cells, IL-10 produced by TH2 cells cells inhibits production of IFNγ and, IL-4 inhibits the production of TH1 cells.
suppressor T cells (TS cells)
These are the least well-known of T cells. Suppressor T cells do not have to be presented antigen to become active. They seem to limit immune reactions, providing what approximates a negative feedback loop on the system. They may have a very important role in tolerance, autoimmune disorders, and certain cancers.
Tolerance refers to the specific immunological non-reactivity to an antigen resulting from a previous exposure to the same antigen. While the most important form of tolerance is non-reactivity to self antigens, it is possible to induce tolerance to non-self antigens. When an antigen induces tolerance, it is termed tolerogen. Tolerance is different from non-specific immunosuppression and immunodeficiency. It is an active antigen-dependent process in response to the antigen. Like immune response, tolerance is specific and like immunological memory, it can exist in T-cells, B cells, or both, and, like immunological memory, tolerance at the T cell level is longer lasting than tolerance at the B cell level. Tolerance may be induced to all epitopes or only some epitopes on an antigen and tolerance to a single antigen may exist at the B cell level or T cell level or at both levels.
The exact mechanism of induction and maintenance of tolerance is not fully understood. Experimental data, however, point to several possibilities.
Functionally immature cells of a clone encountering antigen undergo a programmed cell death; for example, auto-reactive T cells are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection). Recent studies have shown that a variety of antigens are expressed in thymic epithelial cells. Likewise, differentiating early B cells become tolerant when they encounter cell-associated or soluble self antigen. B cells expressing only IgM (no IgD) on their surface when exposed to antigen are more prone to tolerance induction than immune response. Clonal deletion has been shown to occur also in the periphery (i.e., lymph nodes).
Auto-reactive T cells, when exposed to antigenic peptides which do not possess co-stimulatory molecules (B7-1 or B7-2), become anergic to the antigen. Note that this is implying that the T cell must receive two specific simultaneous signals to be activated, one from the antigen and the other from the surface of the APC, B7. Also, B cells when exposed to large amounts of soluble antigen down-regulate their surface IgM and become anergic. These cells also up-regulate the Fas molecules on their surface. An interaction of these B cells with Fas-ligand-bearing cells results in their death via apoptosis. (In this usage, the word “anergy” means a reduction or lack of an immune response to a specific antigen.)
inhibition by TS cells
Both low and high doses of antigen may induce suppressor T cells which can specifically suppress immune responses of both B and T cells, either directly or by production of cytokines, most importantly, TGF-β and IL-10.
antigen sequestration (or clonal ignorance)
T cells reactive to self-antigen not represented in the thymus will mature and migrate to the periphery, but they may never encounter the appropriate antigen because it is sequestered in inaccessible tissues. Such cells may die out for lack of stimulus. Auto-reactive B cells that escape deletion may not find the antigen or the specific helper T-cells and hence not be activated and die out. A few examples of sequestered antigens: proteins within the lens, shielded by the capsule; thyroglobulin within the thyroid follicles; and enzymes forming on the acrosomes of developing spermatozoa on the other side of the blood-testis barrier. (There is evidence that the first two examples may also have granted privilege for there appears to be a specific plasma membrane protein that triggers apoptosis of attacking lymphocytes.)
granting of immune privilege
The uterine endometrium appears to be such a site, particularly with respect to xenografts. That makes sense; what is the implanting conceptus but something chimerically foreign?
Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self. Such an immune response may not always be harmful (e.g., anti-idiotype antibodies). However, in numerous autoimmune diseases it is well recognized that products of the immune system cause damage to the self.
human leukocyte-associated (HLA) antigens
The HLA antigen locus on chromosome 6 in the human was found to be a large complex of multiple genes (currently about 100 are known), many of which are highly polymorphic. (This was first studied in the mouse; the region in that species is called H-2 and is on chromosome 17.) These genes code for the three classes of the major histocompatibility complex. Class III MHC seems to contain genes for complement components, a couple of heat shock proteins, and a couple of cytokines; we will ignore it.
major histocompatibility complex (MHC)
In transplantation studies, MHC gene products were identified as responsible for graft rejection.
In studies on responses to antigens, MHC gene products were found to control immune responses, called the
immune response (Ir) genes. It was determined that antigen-specific T cells recognize portions of protein
antigens that are bound non-covalently to MHC gene products. Specifically, helper T cells recognize peptide
bound to class II MHC gene products, and cytotoxic T cells recognize peptide bound to class I MHC gene products.
The class I MHC molecule contains two polypeptide chains with four separate regions. Class I MHC glycoproteins are found on the surface of virtually all nucleated body cells.
The class II MHC molecule also has two polypeptide chains with four separate regions, but its appearance is very different. Class II MHC glycoproteins are restricted to the surface of a few special types of immune cells, such as B cells, cytotoxic T cells, and macrophages.
This activity, the recognition and destruction of newly formed, potentially cancerous tumor cells before they have a chance to multiply and spread, is another function of the T cells. Unrestricted growth of a single tumor cell results in a tumor, a clone of the original mutated cell.
A benign tumor is a slow growing mass that stays put in its original location and does not infiltrate the surrounding tissue.
Malignant tumors are those that do not play nice. Their cells divide and multiply rapidly and form invasive masses (cancers). Malignant tumor cells also do not adhere well to neighboring cells, with the result that they may break away from the pack and emigrate elsewhere.
A metastasis is such an emigration to another part of the body.
immune neuroendocrinology and neuroendocrine immunology
Recent research points that there may be important interactions between the immune system and the two controlling systems of the body, endocrine and nervous systems. Two quick examples:
interleukin 1 promotes cortisol release
neuroendocrine receptors are found on lymphocytes and macrophages
An immune deficiency reduces the ability of the body to resist invasion by foreigners.
This implies that the immunodeficiency was present at birth. For example, DiGeorge Syndrome (DGS):
This the most clearly defined T-cell immunodeficiency and is also known as congenital thymic aplasia/hypoplasia, or immunodeficiency with hypoparathyroidism. The syndrome is associated with hypoparathyroidism, congenital heart disease, low-set notched ears, and fish-shaped mouth. These defects result from abnormal development of the fetus during 6th-10th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed. No genetic predisposition is clear and not all DiGeorge syndrome babies have thymic aplasia. A thymic graft taken from an early fetus (13-14 weeks of gestation) can be used for treatment. Older grafts may result in graft-vs.-host reaction. In severely immunodeficient DiGeorge patients, live vaccines may cause progressive infections. DiGeorge syndrome is caused by a deletion in chromosome 22. The deletions are of variable size, but size does not correlate with severity of disease. In about 6% of cases, the chromosome 22 microdeletion is inherited but most cases result from de novo deletion which may be caused by environmental factors. Some effects, for example the cardiac problems and some of the speech impairments, can be treated either surgically or therapeutically, but the loss of immune system T-cells ...
An acquired immunodeficiency is nonhereditary. It might be caused by trauma or disease. It might involve impairment of the humoral immunity, cell-mediated immunity, or both.
Cellular abnormalities of lymphocytes: There is a decrease in the number of helper-inducer
(CD4+) T cells, and consequently a reversal in CD4+/CD8+ T cell ratio. Natural killer cell number is within
normal range but their activity is reduced.
Functional abnormalities seen in vivo: AIDS patients have an increased susceptibility to infections with opportunistic organisms (Pneumocystis carinii, Toxoplasma gondii, Cryptococcus neoformans, herpes simplex, herpes zoster, cytomegalovirus, Mycobacterium avium-intracellular, &c.). These patients also have increased incidence of neoplasms (Kaposi’s sarcoma). Delayed hypersensitivity response to common antigens (tetanus, diphtheria, streptococcal antigen, tuberculin, Candida antigen, trichophyton, &c.) is decreased in AIDS patients. They fail to produce antibody in response to various antigenic challenges (KLH, tetanus toxoid, pneumococcal polysaccharide).
severe combined immunodeficiency (SCID)
This is a rare congenital disorder in which both B and T cells are absent. Such individuals have extremely limited ability to fight pathogens and usually die in infancy, unless kept within a germ-free environment (think “bubble boy”).
inappropriate immune attacks
|juvenile-onset diabetes||pancreatic beta cells|
|multiple sclerosis||myelin in the central nervous system|
|rheumatic fever||heart valves|
|myasthenia gravis||acetylcholine receptors at the neuromuscular junction|
|male infertility (some)||spermatozoa|
|systemic lupus erythematosis||most organs|
|amyotrophic lateral sclerosis||motor neurons in the spinal cord|
These should be familiar from the last lesson.
An allergy is the acquisition of an inappropriate specific immune response, or hypersensitivity, to normally harmless environmental substances, such as pollen or dust. The hypersensitivity results from damage done to the body by the immune response. Many immune responses damage the body during antigen removal, causing swelling and pain from inflammation or lysis of virus-infected cells by cytotoxic T cells. When the damage is too great, however, hypersensitivity can become life-threatening. Hypersensitivities are classified into four types based on the mechanism of tissue damage. Most of what we call "allergy" is immediate (type I) hypersensitivity, in which IgE is produced in response to an antigen called an allergen.
immediate hypersensitivity (type I)
The most common allergens are pollen grains, bee stings, penicillin, certain foods, molds, dust, feathers, and animal fur. For reasons unclear, these allergens bind to and elicit the synthesis of IgE antibodies rather than IgG. When first exposed, the compatible helper T cells of the individual secrete IL-4, which prods compatible B cells to synthesize the IgE antibodies specific for the allergen. During this initial sensitization period, there are no symptoms, but the memory pool has been created, and it’s all down hill from there:
IgE molecules attach to mast cells/basophils
slow-reactive substance of anaphylaxis (SRS-A)
SRS-A induces prolonged and profound contraction of smooth muscle, particularly in the small respiratory bronchioles.
eosinophil chemotactic factor
Eosinophils actually release enzymes that inactivate SRS-A and may also inhibit histamine’s action.
hay fever vs. asthma
Hay fever is nasal congestion caused by histamine-induced localized edema and sneezing and runny nose caused by irritation; asthma is the constriction of the bronchioles.
If the allergen becomes blood-borne or if very large amounts of the chemicals are released into the circulation, the extremely serious situation of profound hypotension occurs that can lead to circulatory failure.
T cell mediated
Poison ivy oil is a hapten that combines with skin proteins. Harmless to the skin itself, it activates T cells specific for the toxin, including the formation of memory cells. Next exposure, scratch away ...
If you have questions, please e-mail me,
and I will post them here.
Make sure to check back before Monday’s class.