BSI: Immunology Acquired Immunity

The specific, acquired or adaptive immune response which is mediated primarily by lymphocytes.

This response to potential infection normally requires several days to develop fully during which time the innate responses are crucial.

• The specificity of the immune response is due to specific antigens which individual lymphocytes have been “programmed” to respond to.
• Antigens via Antigen-Presenting Cells (APC’s) are “presented” to the lymphocytes, but only the“correctly matched” antigen causes activation. To ensure the correct antigen is present, a complex, direct contact, “double hand-shake” occurs. The purpose of the "double hand-shake is to recognize a“foreign” or potentially pathogenic organism or toxin and differentiate it from a self-antigen (causing potentially lethal autoimmune conditions).
• Once activated B-lymphocytes (now as Plasma cells) produce specific circulating antibodies (which mark pathogens for destruction), while various “killer” T-lymphocytes kill and/or neutralize pathogens directly.
• However for a full and effective response, “Helper” T-lymphocytes must also be specifically activated (another safeguard against developing an autoimmune disease). Activated T cells produce a very significant enhancement of lymphocyte function via released lymphokines in a + feedback loop.
• The significance of these “Helper”cells is underscored by the fact that these are the cells affected in AIDS.

• The mechanisms employed by the acquired response are often far more effective than those of the innate.
• For instance, “memory cells” of previously activated lymphocytes are retained so if challenged by the same antigen again, the immune response is far more rapid and effective (this is the basis of immunization).

Cells involved in the Acquired Response:

• 1) Lymphocytes
• Site produced: Mature in bone marrow (B cells and NK cells) and thymus (T cells); activated in peripheral lymphoid organs.
• Function: Recognition cells in specific immune responses and are essential for all aspects of these responses.

• 2) B Cells
• Site produced: Mature in Bone marrow
• Function: 1) Initiate antibody immune responses by binding specific antigens to the B cell's plasma membrane, which are immunoglobulins; 2) During activation are transformed into plasma cells, which secrete antibodies 3) present antigen to helper T cells

• 3) Cytotoxic T Cells (CD8 cells)
• Site produced: Thymus
• Function: Bind to antigens on plasma membrane (virus-infected cells, cancer cells and tissue transplants) and directly destroy the cells.

• 4) Helper T Cells (CD4 cells)
• Site produced: Thymus
• Function: Secrete cytokines that help to activate B cells, cytotoxic T cells, NK cells and macrophages.

• 5) Natural Killer (NK) Cells
• Site produced: mature in bone marrow
• Function: 1) Bind directly and non-specifically to virus infected cells and cancer cells and kill them; 2) Function as Killer Cells in antibody-dependent cellular cytotoxicity (ADCC)

• 6) Plasma Cells
• Site produced: Peripheral lymphoid organs; differentiate from B cells during immune responses
• Function: Secrete antibodies

Acquired Immune Response is the response of the body via lymphocytes to foreign invading organisms or pathogens.

Acquired or adaptive immunity requires specific recognition of the invader resulting in a specific response which requires time to develop upon initial exposure (unlike innate immunity which responds instantly).

The body (via lymphocytes) has the ability to generate immunity against invading bacteria, viruses, toxins and foreign tissue by the formation of specific antibodies and/or specifically activated lymphocytes that attack and destroy the invader.

These two basic, closely-related mechanisms are mediated by two different types of lymphocytes:

• 1) B-lymphocytes produce a humoral response by synthesizing circulating antibodies that target the invader for destruction by various means
• (immunoglobulins/gamma globulins)

2) T-lymphocytes produce activated “Killer cells” that directly destroy the invaders.

In order to mount these specific responses the invader must be first recognized as “foreign.”

● Molecules that are identified as foreign and produce an immune response are called antigens.

Typically antigens have a mw >8,000 and often posses repeating/reoccurring molecular groups called epitopes often observed in proteins and large polysaccharides.

• ● Acquired immunity is the function of lymphocytes. If a person is born with a lack of lymphocytes for whatever reason, then death usually occurs within days due to massive bacterial infections confirming that lymphocytes are essential
• for survival.

● Lymphocytes are found primarily in bone marrow, lymph nodes and lymphoid tissues throughout the body. Lymph nodes filter the lymph, while the spleen, thymus, bone marrow and liver filter the blood (like the innate response).

● The two principal types of lymphocytes (B's and T's) are derived as for all blood cells from pluripotent hematopoietic stem cells (as are all blood cells). Nearly all lymphocytes reside in lymphoid tissues throughout the body, but prior to this they must go through an essential maturation or programming called“processing.”

● Potential T-lymphocytes first migrate to the thymus (hence the “T?”) for processing while B-lymphocytes are processed in the liver prior to birth and then bone marrow (hence the “B?”) after and throughout life.

● After migrating to the thymus, T-lymphocytes divide rapidly and diversify extensively in preparation to respond to a huge array of potential antigenic substances. Each T-lymphocyte develops specific reactivity to one antigen.

• ● T-lymphocytes then migrate throughout the body to the various lymphoid tissues where they attack
• antigenic material directly (cell-mediated immunity).

• ● While in the thymus, T-lymphocytes are “checked” to ensure that they do not respond to any of the body’s own tissues or “self-antigens” which
• can prove disastrous (by causing an autoimmune
• response). The lymphocytes are exposed to virtually all self-antigens and any that react are destroyed and/or phagocytized (can be >90% of lymphocytes formed!).

● This vital processing occurs principally just prior to and after birth. After this, the thymus can actually be removed if necessary because after that, it doesn't do much.

• ● B-lymphocytes function differently from T-lymphocytes in two ways (much less is known about B-lymphocyte processing in the liver and bone marrow than for T-lymphocytes):
• 1) B-lymphocytes secrete antibodies that interact specifically with antigens (humoral immunity)
• 2) B-lymphocytes exhibit even greater diversity than the processed T-lymphocytes.

● After processing, B-lymphocytes migrate throughout the body similarly to T-lymphocytes to similar but not identical locations in lymphoid tissues.

• ● When either type of processed lymphocyte comes into contact with the specific antigen it has been
• “programmed” to respond to, they become activated. This causes rapid cell division which produces  no. of lymphocytes with identical specificity (clones).

• ● The mechanism of activation involves the specific binding of the antigen to surface-expressed antibodies (B-lymphocytes) or similar molecules
• called Surface Receptor Proteins (also called T-cell markers on T-lymphocytes).

● This great diversity of potential antigens (>106!) is achieved despite being encoded for by only 100-1000 genes. It is due to the “shuffling” of gene segments during processing.

• Encounter and Recognition
• First, a B cell, a helper T cell, or a cytotoxic T cell will enounter an antigen.

• Activation
• Second, the helper T cell will be stimulated to replicate and produce cytokines.
• The cytokines produced from the helper T cell stimulate B cells to divide and mature into plasma cells, which will then release antibodies. The cytokines also stimulate cytotoxic T cells to divide and replicate.

• Attack
• The antibodies released from Plasma cells help guide phagocytes, complement and NK cells to attack antigen-bearing cells or to neutralize free antigen.
• The cytotoxic T cells will directly attack antigens.

● Many millions of macrophages are also present in lymphoid tissues where they are the first responders to invaders which they phagocytize and partially digest (innate response).

● These partially digested products are still highly antigenic and the macrophages subsequently “present” them by cell-to-cell contact directly to lymphocytes so activating the specific lymphocyte clones programmed to respond to that specific antigen.

● But be aware that other cells can also present antigens including B-lymphocytes and the so-called Dendritic cells (collectively known as Antigen Presenting Cells [APC's]).

● Macrophages also secrete Interleukin-1 (IL-1) that promotes further reproduction and growth of lymphocyte clones (processed lymphocytes).

• 

Summary of the role of Macrophages:

1) In nonspecific inflammation, macrophages phagocytize particulate matter, including microbes. They also secrete anti-microbial chemicals and protein messengers (cytokines) that function as local inflammatory mediators. The inflammatory cytokines include IL-1 and TNF.

2) Macrophages process and present antigen to cytotoxic T cells and helper T cells.

3) The secreted cytokines IL-1 and TNF stimulate helper T cells to secrete IL-2 and to express the receptor for IL-2.

4) During specific immune responses, macrophages perform the same killing and inflammation-inducing functions as in the nonspecific (innate immunity), but are more efficient because antibodies act as opsonins and because the cells are transformed into activated macrophages by IL-2 and interferon-gamma, both secreted by helper T cells.

5) The secreted IL-1, TNF and IL-6 mediate many of the systemic responses to infection or injury.

• ● Most presented antigens can activate both types of lymphocytes simultaneously. However some specialized T-lymphocytes called “Helper T cells”
• secrete lymphokines after presentation/activation which enhances the activation of processed B-lymphocytes.

● Without this “enhancement,” the amount of antibodies secreted by B-lymphocytes would be small and probably insufficient so Helper T cells are crucial in producing an effective response.

• B Cells: Do NOT interact with MHC proteins.
• Helper T Cells: Interact with Class II MHC proteins, which are found only on macrophages, macrophage like-cells (dendritic cells), and B cells.
• Cytotoxic T Cells: Interact with Class I MHC proteins, which are found on all nucleated cells of the body.
• NK Cells: Interaction with MHC proteins is NOT required for activation of NK Cells.

• The Primary Response
• ● The primary response is the detailed story of B cells transforming into Plasma cells, which secrete antibodies.

● Fully activated B-lymphocytes enlarge and become Lymphoblasts → Plasmoblasts → Plasma cells.

● After becoming Plasmoblasts, the ER proliferates greatly (for increased protein synthesis) and the Plasmoblasts begin to divide at an increased rate (~ once every 10 hours).

● Plasmoblasts soon to give rise to an increased no. of Plasma cells, which then start to produce specific antibodies (specific to the antigen they were first programmed with) extremely rapidly (~ 2,000 molecules/second!).

● These antibodies are carried from lymphoid tissues via the lymph to the blood where they can circulate for days to weeks until the plasma cells become exhausted: this is the primary response.

● Some of the activated B-lymphocytes do not become Plasma cells but are retained together with a small number of original processed/programmed B-lymphocytes.

● These original programmed (for a specific antigen) B-lymphocytes again circulate throughout the body to the various lymphoid tissues where they remain dormant until activated again by the same specific antigen.

• ● These cells are called “Memory cells” and on subsequent exposure to the same antigen can produce a far more rapid and effective response: this
• is the secondary response.

• ● This picture shows the time course and relative effectiveness (by estimating the amounts of
• antibodies produced) of the primary vs. secondary responses to the same antigen. Note the delay ~1 week for the primary response plus the lower quantity of antibodies produced as compared to the secondary response, which begins within hours and results in significantly more antibody production.

● Note that the production of antibodies is more prolonged with the secondary response (typically lasting many months compared to days or weeks for the primary).

● This helps explain how effective immunizations work. They are designed to prepare the immune system for an effective secondary response to an antigen, which is accomplished by giving multiple exposures to the antigen (in a safe form) with weeks to months in between.

• ● Immunizations have been used for many years to produce acquired immunity against specific potentially lethal diseases. It eliminates the time
• lag (primary response) required for specific recognition of an invader by lymphocytes.

● This response is normally induced by injecting dead organisms that are no longer pathogenic but still possessing the living organism’s antigenic properties. Immunizations are used to protect against conditions such as Typhoid fever, Whooping cough, Diphtheria and many other bacterial infections.

● Immunizations can also be produced using chemically-neutralized toxins which still retain their specific antigenic properties used to immunize against Tetanus, Botulism, etc.

• ● Immunization can also be induced by using a live “attenuated” organism that has been sufficiently mutated so as not to be pathogenic but still
• retains it’s antigenic properties. Such is the case as in: Poliomyelitis, Yellow fever, Measles, Smallpox and many other viral pathogens.

A passive immunization involves the injection of specific antibodies produced from another source or specifically activated T-lymphocytes or both.

The antibodies can survive ~2-3 weeks before degradation while T-lymphocytes can survive several weeks if from a human source but only hours to days if from an animal source (more “foreign”).

• ● Antibodies are gamma globulins called immunoglobulins (Ig) that have a mw ~160,000 to 970,000 and normally comprise ~20% of all plasma
• proteins.

• ● All antibodies are composed of combinations of so-called “light” and “heavy” polypeptide chains. Most are composed of two of each, but some can
• have up to ten (hence the range of mw).

● Usually antibodies are bivalent with two separate sites that bind to two separate antigens but some have up to ten binding sites (antibodies with 10 polypeptide chains).

● In all types of antibodies, each heavy chain is aligned parallel with a light chain at one end.



● Part of this heavy-light pairing is termed the “variable portion” and determines the antigenic specificity and is unique to each antibody.

• ● The remainder of the antibody is termed the “constant portion” and determines other general properties of the antibody such as tissue access, interactions with the Complement system,
• etc.

• ● The specificity of the antigen binding sites of the variable portion is due to the appropriate amino acids forming a highly specific binding site analogous to a drug receptor or enzyme active site (3-D and stereospecific). Weak molecular forces/interactions form the basis of the binding and include hydrogen bonding, ionic attraction, hydrophobic bonding, van der Waals forces,
• etc. (same interactions that help determine the 3-D structure [tertiary structure] of proteins).

● The affinity of an antibody for its specific antigen is described similarly to these other interactions:

• Affinity (Ka) = [concentration of bound antibody-antigen complex] / [(conc. free antibody) x (conc. free antigen)]
• 

• ● There are 5 general
• classes of antibodies (immunoglobulins):
• 1) IgD
• 2) IgG
• 3) IgA
• 4) IgM
• 5) IgE

● Most significant is IgG which is bivalent and comprises ~75% of all antibodies in the body.

• ● IgE and IgM are found in much lower concentrations but are significant because IgE is involved in allergic reactions while IgM is produced during the primary response and is particularly effective due to possessing ten binding sites.

Synthesis of antibodies (or immunoglobulins) occurs in the lymphoid organs.

• ● Antibodies have two general mechanisms of destroying/inactivating the antigenic material they specifically bind to:
• 1) directly
• 2) via the Complement system

Direct action of Antibodies:

● Because all antibodies have two or more binding sites and because most antigenic material (whether a protein or an entire organism) expresses multiple copies of the antigen, several types of interaction can occur:

1) Agglutination: occurs when large invaders such as bacteria or even RBC's become bound together via antibodies into a clump.

2) Precipitation: occurs when the linked molecules (such as toxins) become so large that they become insoluble.

3) Neutralization: This occurs when binding antibodies cover and therefore inactivate toxic sites on the invader.

4) Lysis: Upon binding, some antibodies can actually rupture the cell membranes of invading organisms (direct physical effect).

● However, the direct actions listed above are often insufficient or ineffective on their own and require the “amplifying” effect of the Complement system.

● The Complement System is similarly to the blood-clotting Intrinsic and Extrinsic pathways. It is a system of ~20 proteins that forms a cascade of proteins/enzymes that activate each other sequentially.

● Of particular significance are 11 proteins (C1 → C9 + “B” and “D”) which are all normally present in the blood. These can leak out of capillaries into the Extra Cellular Fluid, or ECF (similar to the clotting factors).

● The so-called “classic” Complement pathway is initiated by specific antibody-antigen interactions which “reveals” a special site on the constant portion of the antibody that now binds Complement factor C1 and activates it.

● Activated C1 now initiates sequential activation of this pathway. Increasing amounts of these factors are activated which produces an amplification effect (similar to one adenylate cyclase producing many molecules of the secondary messenger cAMP).

Several very important mechanisms are initiated at various stages of this cascade:

• ● Opsonization and Phagocytosis: Factor C3b (a fragment of active C3) strongly stimulates
• phagocytosis of the invaders marked by antibodies (normally a bacterium) via both neutrophils and macrophages (enhancement up to x100 normal).

• ● Lysis: Activated Complement factor fragment
• C5b + C6→C9 form the so-called Membrane
• Attack Complex (MAC: also known as the Lytic Complex) which directly ruptures the cell membranes of invading bacteria and other organisms.

● Agglutination: Activated Complement factors can alter the external surface of invading organisms to promote agglutination.

● Neutralization of Viruses: The Complement system can render some viruses inactive/non-virulent.

● Chemotaxis: Activated Complement factor fragment C5a causes chemotaxis of both neutrophils and macrophages (along with increased phagocytosis) towards the site of the antibody-antigen reactions stimulating the Complement cascade.

• ● Activation of Mast Cells and Basophils: Activated Complement factor fragments C3a, C4a and C5a activate Mast cells and
• basophils towards the site of antibody-antigen reactions stimulating the Complement cascade where they then release substances causing inflammation. Here a process first associated with innate immunity is involved in the acquired response.

● Direct Inflammatory Response: In addition to the above effects, several other activated Complement factors contribute directly to the inflammation response at the site ( increased blood flow and capillary “leakage,” etc.).

1) In secondary lymphoid organs, bacterial antigen binds to specific receptors on the plasma membranes of B cells.

2) Simultaneously, antigen-presenting cells (APCs), for example, macrophages (a) present to helper T cells processed antigen complexed to class II MHC proteins on the APCs, (b) provide a co-stimulus in the form of another membrane protein, and (c) secrete IL-1, TNF, and other cytokines, which act on the helper T cells.

3) In response, the helper T cells secrete IL-2, which stimulates the helper T cells themselves to proliferate and secrete IL-2 and other cytokines. These active antigen-bound B cells to proliferate and differentiate into plasma cells. Some of the B cells differentiate into memory cells rather than plasma cells.

4) The plasma cells secrete antibodies specific for the antigen that initiated the response, and the antigens circulate all over the body via the blood.

5) These antibodies combine with antigen on the surface of the bacteria anywhere in the body.

6) Presence of antibody bound to antigen facilitates phagocytosis of the bacteria by neutrophils and macrophages. It also activates the complement system, which further enhances phagocytosis and can directly kill the bacteria by the membrane attack complex (MAC). It may also induce antibody-dependent cellular cytoxicity (ADCC) mediated by NK cells that bind to the antibody's Fc portion (also known as the "stem").

● Macrophages/APC's “present” antigenic material to T-lymphocytes as well as B-lymphocytes.

● As for B-lymphocytes, this induces increased proliferation and activation of the appropriately programmed T-lymphocyte clone.

• ● These now activated T-lymphocytes circulate
• throughout the body first via the blood and then via the lymph after entering tissues and then back to the blood. They repeat this journey many times over months or even years.

• ● As with B-lymphocytes, T-lymphocyte “Memory” cells are also formed and are distributed throughout lymphoid tissues ready to respond
• immediately to another invasion by their specific antigen.

Three events are required for activation of Helper T-Lymphocytes:

1) Presentation of an antigen bound to MHC II protein on APCs.

2) Binding of matching non-antigenic proteins on the Helper T Cell and APC.

3) Secretion by APC of cytokines, including IL-1 and TNF, which act on the Helper T lymphocyte.

● B-lymphocytes respond to relatively “complete” antigens (binding to surface immunoglobulins prior to internalization), but T-lymphocytes only respond when the antigen is bound to special surface molecules called Major Histocompatibility Complexes (MHC's) on the external surfaces of APC's in lymphoid tissues.

• ● There are 3 major types of APC's:
• 1) macrophages
• 2) B-lymphocytes
• 3) Dendritic cells which are the most effective.

● Dendritic cells are found throughout the body and their only known function is antigen presentation.

● Direct cell-cell contact initiated by cell adhesion molecules (remember “Notch” signaling) is vital for the antigen presentation process.

• ● MHC proteins are coded for by a large gene family. They bind the peptide fragments that have been previously partially digested after phagocytosis
• and then transported back to the cell surface.

● There are two general classes of MHC proteins: MHC I's present to Cytotoxic T-lymphocytes while MHC II's present to T-Helper cells.

● The receptors for the MHC-antigen complexes are similar to the variable portion of antibodies with their specificity, but the “stem” of the antibody is firmly located in the T-lymphocyte membrane (may express ~1000 of these receptors on a single T-lymphocyte!).

● In addition there must be a second "handshake" between T-Helpers and APC's by binding of matching, non-antigenic proteins (confirmation? safety factor? Helpers now act in a +feedback manner!).

• ● Finally secretion by the APC of cytokines (especially IL-1 and TNF) fully active the
• T-Helper cells.

• There are four known major types of T-lymphocytes: these include so-called
• 1) Helper T cells
• 2) Cytotoxic T cells
• 3) Suppressor T cells
• 4) Natural Killer (NK) cells

● Helper T cells are the most numerous type of T-lymphocyte (~75%). As their name implies, they help the immune system function effectively and are involved in regulating virtually all immune functions. Because of this they are crucial for proper immune system, and especially acquired responses.

● They release various lymphokines which act throughout the immune system and bone marrow, which include Interleukins 2 → 6, Granulocyte-monocyte Colony-stimulating factor and Interferon-gamma.

● Without these substances the immune system is virtually inoperative!

• ● This can be fully appreciated by the fact that in Acquired Immunodeficiency Syndrome (AIDS),
• the virus destroys principally these Helper cells.

• ● Specific functions of Helper cells include effective activation of both Suppressor and Cytotoxic T-lymphocytes (principally via Interleukin 2) and the stimulation of B-lymphocyte growth and differentiation into antibody-secreting Plasma cells (antibody production is significantly
• reduced especially in the absence of Interleukins 4, 5 and 6).

● Lymphokines also help prevent migration of macrophages previously attracted by chemotaxis away from the invaded tissue and increase their effectiveness at phagocytosis.

● In addition some Interleukins (especially IL-2) produce a + feedback loop by stimulating Helper cells themselves so increasing immune response overall.

● Cytotoxic T cells, as their name implies, actually kill invading microorganisms directly.

● Surface receptors allow them to bind strongly and specifically to organisms expressing the antigen they were programmed with.

● They then kill their specific targets by punching a hole through their membranes (thus creating a channel) via proteins called Perforins.

● Cytotoxic T-lymphocytes also release cytotoxic substances directly into their targets. This process can be repeated many times by these cells.

● These cells can also kill the body’s own cells if they have been previously infected by viruses that become trapped in the cell membrane and whose antigenic properties can be therefore accessed.

● These cells can also destroy certain cancerous cells and unfortunately “foreign” tissues used in transplants ("rejection").

● Much less is known about the function of these lymphocytes but they can decrease function or effectiveness of both Cytotoxic and Helper T-lymphocytes and they can help suppress autoimmune responses.

● Together with Helper cells they are classified as regulatory T-cells.

● Natural Killer T-lymphocytes (NK's) are considered a distinct class of lymphocytes although they are similar in function to Cytotoxic T-lymphocytes. Their main targets are virus-infected and cancerous cells.

• ● Like Cytotoxic T-lymphocytes, NK's attack and kill their target cells directly after binding to them. However, unlike Cytotoxic T-lymphocytes, NK's
• are not antigen specific and do not posses normal T-Lymphocyte receptors or the surface-expressed immunoglobulins of B-Lymphocytes.

• ● The receptors identifying NK targets are as yet unknown but it is known that MHC proteins are not involved in their activation. However, they are considered part of the specific immune response
• (acquired/adaptive immunity) because their
• participation is enhanced either by certain antibodies or cytokines secreted by Helper T-lymphocytes
• which are triggered by specific antigens.

• ● The major signals/cytokines from Helper T-lymphocytes to NK's that cause them to
• proliferate and secrete their cell-killing chemicals are IL-2 and Interferon-gamma. These also act on macrophages to produce so-called "activated" macrophages that, in addition to phagocytosis and antigen presentation, also release many different cell-killing chemicals to kill virus-infected and cancerous cells.

● The general systemic effects of infection are mediated by a "cocktail" of cytokines in particular IL-1, IL-6 and TNF acting humorally (as opposed to acting auto- or paracrine).

• ● General responses include:
• 1) increased WBC production
• 2) increased plasma fatty acids (for fuel)
• 3) amino acids (for repair)
• 4) increased acute phase proteins (for inflammation and tissue repair)
• 5) increased cortisol (the "stress" hormone which actually decreases immune function long-term)

● The effects on the brain appear counter-intuitive, but generation of a fever (increasing body temperature) appears to enhance many of the immune responses.

● Making sure the body does not attack its own cells is primarily the role of lymphocytes that develop in the thymus (T-lymphocytes) and bone marrow (B-lymphocytes).

● Inappropriate responses to our own antigens can cause severe consequences and even death (examples include the Rh system, Multiple sclerosis and Myasthenia gravis). Luckily our immune system normally does not recognize it’s own antigens and this is called tolerance.

• ● Most tolerance develops during the processing of T and B-lymphocyte clones in the thymus and
• bone marrow respectively. All or virtually all lymphocytes that respond to these “self-antigens” destroy themselves due to the constant and repeated exposure to these antigens.

● Occasionally people lose this toleranc (especially older people) after some form of tissue damage which releases significant quantities of self-antigens triggering an acquired response.

● This loss of tolerance can cause several acute disease conditions. These include:

● Rheumatic fever when the body becomes sensitized in particular to tissues in joints and heart valves after exposure to specific Streptococcal toxins whose antigenic properties are very similar to the affected tissues (remember multiple sclerosis is probably due to a virus with similar antigenic properties to myelin).

• ● In a certain type of Glomerulonephritis (the glomeruli are the individual blood filtering structures in the kidney), sensitivity develops to the glomerular
• basement membrane (the actual “filter”).

● In the condition known as Lupus erythematosus, sensitivity to many self-antigens occurs which can cause extensive damage and often death.

● Sometimes people express an inappropriate (too severe) immune response which manifests as an allergic response or some other form of hypersensitivity.

• ● This can be caused by T-lymphocytes as with Poison Ivy toxin. The initial exposure induces a
• mild response (appropriate) but after subsequent repeated exposures the response becomes so extreme that healthy tissue is actually harmed (this scenario is analogous to the Rh antigen problem with pregnancy: subsequent Rh+ babies through later pregnancies are at increasingly endangered risk because of the production of an increasingly severe response).

● Some people have an “allergic tendency” which is inherited and characterized by excessive IgE antibody levels in the blood. These antibodies are called Reagins or sensitizing antibodies to distinguish them from the more common IgG type.

• ● When an “allergen” (a specific antigen that
• reacts with IgE antibodies) enters the body it induces an “allergen-reagin” reaction which causes the allergic response.

• ● IgE antibodies often attach themselves to Mast cells and basophils causing them to rupture (possibly caused by the direct physical deformation of the cell membrane due to multiple binding sites) and release various substances including:
• 1) histamine
• 2) proteases
• 3) Slow-reacting Substance of Anaphylaxis
• 4) Eosinophil Chemotactic Substance
• 5) Neutrophil Chemotactic Substance
• 6) heparin
• 7) platelet activating factors

● These substances cause effects such as local vasodilation and increase capillary permeability (basically inflammation), chemtactic attraction of eosinophils and neutrophils, and contraction of local smooth muscle. The reactions observed depend on the tissue affected.

Anaphylaxis

• ● This is an extreme response triggered in tissues
• immediately surrounding small blood vessels due to Mast cells and eosinophils that rapidly spreads throughout the circulation and associated tissues. In extreme cases this can cause circulatory shock and death unless treated rapidly with adrenalin which opposes this principally histamine-induced crisis (antihistamines alone are not sufficient!).

• ● Slow-reacting Substance of Anaphylaxis can cause muscle spasms in the smooth muscle in the walls of the bronchioles (lung airways) eliciting an asthma-like attack which has the potential to kill by
• suffocation.

Urticaria

• ● This is triggered by antigens (allergens) entering certain skin areas and the subsequent release of histamine causing swelling and a red “flare” due to the inflammatory response. These swellings are
• commonly known as “hives” and can be prevented by anti-histamines.

Hay fever

● In this case the allergen-reagin reaction occurs in the nasal passages with released histamine causing a similar effect to that described previously and sneezing as the body tries to eject the causative agent.

Asthma

● In this case the allergen-reagin reaction again occurs in the bronchioles (like anaphylaxis), but is less severe. Normally the bronchiole spasm is effectively treated by a b2-adrenergic agonist that causes bronchiole dilation.

● Of particular interest to pharmacists is the fact that patients' can exhibit allergy-like symptoms when given certain drugs; penicillin is a good example.

• ● It is thought that the drug, or part of the drug, structure mimics an antigenic epitope and therefore
• produces a response. However, this seems very difficult to predict based solely on the drug's chemical structure.

● There may be other mechanisms involved such as a "general" stimulation of the inflammation response. A patient may have an allergic pre disposition.

● If an allergic response is suspected then another drug should be selected if possible.

• ● It is sometimes possible to desensitize a patient to a drug by repeated administration, initially at a very low dose, increasing slowly until reaching the desired plasma level. This is a current area
• of intense research.

Lymphocytes mediate specific immune responses.

The acquired immune response deals with B and T lymphocytes. B-lymphocytes are produced and programmed in the bone marrow while T- lymphocytes develop in the thymus and are programmed primary lymphoid organs.

Programmed lymphocytes circulate via the blood → tissues → lymphoid tissues waiting to be activated by their specific (programmed) antigen.

1) Preprogrammed lymphocyte encounters its specific antigen which binds to specific membrane receptors.

2) Lymphocyte is now activated and subsequently divides and differentiates.

3) Many lymphocytes now attack specific antigens either directly (cell-mediated) or indirectly via antibodies.

1) B-lymphocytes

2) T-lymphocytes

3) “Natural Killer” lymphocytes (NK cells) [originate in the marrow]

- Activated B-lymphocytes → Plasma cells → antibodies.

- Cytotoxic T-lymphocytes directly attack infected cells.

- Helper T-lymphocytes required for proper activation of these cells.

• •B-lymphocyte cell membrane receptors are
• copies of the antibodies that cell has been programmed to produce. These receptors are:

• - Unique to that B-lymphocyte (or all its
• clones).

- “Variable” binds antigen or ”Constant” activates Complement, etc.

• T-lymphocyte cell membrane receptors are not immunoglobulins but do have specific receptors:

• - Receptors bind antigens only when complexed
• with MHC proteins.

- MHC I proteins found on all nucleated cells (for Cytotoxic T’s).

- MHC II proteins only on APC’s (for Helper T’s).

• Antigen presentation is required for T lymphocyte activation:

- Antigen is internalized by APC’s → peptide fragments → MHC II’s.

- MHC II’s → membrane + nonspecific co- stimulus + cytokines.

- Virus-infected/cancer cells act as APC’s for Cytotoxic T’s (MHC I’s).

•NK cells have similar targets to Cytotoxic T-Lymphocytes but are not antigen-specific. The mechanisms of identifying targets of NK cells are not currently understood.

• Immune tolerance is the result of clonal deletion and inactivation.

• • In antibody-mediated responses, B-lymphocyte
• surface receptors bind antigen together with a Helper T-lymphocyte which presents the same antigen complexed with the MHC II protein on an APC:

• 1) The Helper T-lymphocyte is activated by
• a combination of the specific antigen (+MHC II), nonspecific co-stimulus, IL-1 and TNF secreted by the APC.

2) The activated Helper T-lymphocyte then secretes IL-2 which causes its own proliferation which in turn secrete more cytokines.

3) These cytokines then stimulate the previously specifically activated antigen-bound B-lymphocytes to proliferate and differentiate into antibody secreting Plasma cells.

• • Five major classes of circulating antibodies are:
• 1) IgD
• 2) IgG
• 3) IgA
• 4) IgM
• 5) IgE

*Note that IgG and IgM are most important against bacteria and viruses.

• Antibodies circulate humorally until they encounter and combine with their specific antigen.

• Antigen-antibody complexes enhance the inflammatory response principally via activation of the Complement system.

• Complement factors also act as opsonins and kill cells directly via the MAC.

• IgG can act directly as opsonins and link targets directly to NK cells.

• Antibodies also neutralize toxins and “free” virus particles.

• • Virus-infected and cancer cells are targeted
• and killed by Cytotoxic T-lymphocytes, NK cells and activated macrophages:

1) Cytotoxic T-lymphocytes bind to cells via surface receptors presenting the viral or cancer-associated antigen combined with MHC I protein.

2) Cytotoxic T-lymphocytes also require cytokines from Helper T-lymphocytes which themselves have been activated by APC’s and MHC II presentation.

3) Finally they release Perforin which destroys the target cell by making its membrane permeable.

4) NK cells and macrophages are also stimulated by Helper T-lymphocyte cytokines (in particular IL-2 and Interferon-gamma) to attack and kill virus-infected or cancerous cells.