Immune Function 1

Immunity

Immunity is the ability of the body to resist invasion by foreign organisms, the ability to eliminate those organisms, the ability to neutralize and eliminate potentially damaging agents produced by those organisms, and, in its more advanced development, the ability to survey the body for rogue elements of the body itself, such as cancer cells.
The evolutionary origins of immunity are obscure, but elements of it are extremely widespread amongst the Animalia. For example, insects use three primary lines of defense to avoid infection:  there is a physical barrier between the internal and external environments formed by the cuticle and lining of the gut; there are humoral responses requiring several hours for their full expression, and involving induced synthesis of anti-bacterial proteins that disrupt bacterial cell membranes and synthesis of lysozymes; and there are cellular defense mechanisms, mediated by hemocytes, include phagocytosis, nodule formation, and encapsulation. Quite an armatorium!
Within the vertebrates, the first defense mechanisms to evolve probably dealt with parasitic infestations; these mechanisms most likely included phagocytosis and cell lysis, with the introduction of signaling chemicals that would evolve into antibodies and leukokines.

pathogens

A pathogen is a disease-producing microorganism. I suspect, if pressed, we should include helminthic invasions (worms) as well, even though some of them, such as the pig roundworm, get to be quite large.

bacteria

Along with viruses, one of the major pathogens in industrialized nations (various parasitic infections are likely to be at least as significant, if not more so, in nonindustrialized countries). Bacteria are prokaryotes. When they invade the body, they cause tissue damage mostly through enzymes or toxins they release, those agents disrupting the normal functioning of body cells.

virulence

Virulence is a measure of the power of a pathogen to produce disease in the host.

viruses

Viruses are not cells and cannot reproduce without living cells. They consist of a core of nucleic acid (DNA or RNA) surrounded by a protein coat. The protein coat not only protects the core nucleic acids, but also provides recognition markers that can combine with cell-surface receptors allowing internalization of the virus into the host cell. Some viruses may be oncogenic.

host cell

The host cell is a cell infected by an intracellular pathogen (bacteria, viruses, or protists). In the case of viruses, the host cell provides the factory and machinery for the viruses replication.

protists

The agents of malaria, syphilis, and sleeping sickness, to mention but a small number, are single-celled eukaryotes. Some live within tissues or fluids; some, like malaria, complete much of their complex life cycles with red blood cells. The gene for sickle-cell anemia is maintained in tropical malaria-infested regions because the malarial protist cannot successfully reproduce in a cell containing HbS.

parasites

Although the apicomplexan protists are generally regarded as parasitic, as are some fungi, many parasites are animals (multicellular eukaryotes). A good rule to keep in mind about parasites is “a good parasite does not kill its host!”

cancer cells

Immune surveillance is the defense mechanism that identifies and destroys abnormal or mutant cells.

“clean-up”

This is the removal of things like tissue debris from an injury or effete red blood cells.

External defenses

The simplest way to avoid infection by microorganisms is to prevent their gaining access to the body. A well-built fortress with a surrounding moat can withstand many waves of attack from Sauron’s minions.

skin

An intact skin is almost impermeable to most infections agents. In addition, the surface is reasonably inhospitable due to the low pH from the lactic acid in sweat. The various epidermal components of the immune system are known as the SALT (skin-associated lymphoid tissue).

epidermis

Recall, it’s the outer epithelial covering of the skin.

keratinocytes

These are the dead, outer cell layers, the cells of which are filled with the protein keratin. This keratinized layer is airtight and fairly impervious to most chemicals. Its importance in retaining fluid within the body cannot be overstated, just witness what happens when large portions of it are lost in severe burns.
In addition, keratinocytes secrete interleukin 1 and influence the maturation of T cells that localize in the skin.

melanocytes

The melanocytes produce (from tyrosine) and distribute the pigment melanin to the keratinocytes. After exposure to UV light rays from the sun, additional melanin is transiently produced and distributed; this shows up as a “tan,” which protects by absorbing harmful UV rays.

Langerhans cells

Langerhans cells originate in the bone marrow and migrate to the skin. They are antigen-presenting cells (APCs) to helper T cells, thus promoting skin immunologic responses.

Granstein cells

Granstein cells are also APCs (origin?) but appear to interact with suppressor T cells, modulating a skin immunologic response.

dermis

sweat glands

Sweat contains lactic acid and fatty acids, lowering the fluid’s pH.

sebaceous glands

Sebum, the product of the sebaceous gland, is an oily secretion that lubricates the hair shaft and the skin; without it, the skin becomes dried and cracked, making for a much easier invasion.

saliva

Saliva not only flushes the oral cavity, but also contains an enzyme that lyses some ingested bacteria.

mucosal modifications

Along the length of the upper respiratory tract is the BALT (bronchus-associated lymphoid tissue) and along the gut tube is the GALT (gut-associated lymphoid tissue).

mucus

Secretion of mucus, a very sticky substance, is extremely common; it is produced in the upper respiratory tract, all along the gut tube, and by the genitourinary tracts. View it as like flypaper, ensnaring tiny organisms that will then be flushed or gobbled up by phagocytes.

alveolar macrophages

These phagocytic cells patrol the alveoli (air sacs) in the lungs. Unfortunately, they can be immobilized and killed by cigarette smoke or severe air pollution.

Resistance to infection

The body’s ability to resist invasion and infection depends on barriers, chemicals, and cells.

white blood cells (leukocytes)

The leukocytes are cellular players in the immune system. To call them “blood cells” is a misnomer because they really are not denizens of the blood; rather, they are lymphoid tissue derivatives which just happen to use the blood stream as a convenient highway system to get around.

polymorphonuclear leukocytes

These are all members of the granulocyte cell lineage, the common precursor cells for which reside in the hematopoietic bone marrow. There are three types, based on the characteristics of their granules when treated with Romanovsky stains.

neutrophils

The commonest leukocyte, the neutrophil is a very mobile, highly efficient phagocyte.

eosinophils

Eosinophils are noted for their large acidophilic granules. These contain chemicals that are released when the eosinophil is signaled that there helminthic invaders present. At least that was what eosinophil appear to have evolved for:  kill the parasitic worms! But in industrial societies, eosinophilia usually doesn’t connote rampaging parasites; hayfever or some other allergy is much more likely.

basophils vs. mast cells

Basophils are leukocytes, derived from a granulocytic precursor, having granules that contain histamine, heparin, serine proteases, prostaglandins, leukotrienes, and cytokines. Degranulation of these promotes the early stages of an inflammatory response. Are tissue mast cells, which have the same chemicals and do the same things, identical to the granulocytic basophils? Some research indicates both derive from a bone marrow precursor cell with marker CD34; other research indicates there are two different precursor cells. It’s still too soon to make a definitive answer.

monocytes

Monocytes are bone-marrow derived phagocytes, and also APCs. If they take up residency in tissues, they are called histiocytes.

lymphocytes

Lymphocytes are also bone-marrow derived, but from a different precursor lineage. There many different forms, recognizable by the markers displayed (such as CD4+, CD8+). It is customary to divide them into sets, based on the finishing school to which they go to achieve immunological competency. Naïve B cells apparently leave the hematopoietic compartment and go to another bone marrow compartment (unknown) where they mature and achieve competency. Then they go off for residency in lymphoid tissue (lymph nodule, lymph node, spleen, &c.).
[Note:  This is not why they are called B cells. The real reason is that early immunologists studied lymphocytic development in chick embryos. In the chick embryo, there is an organ off the cloaca -- think of the cloaca as a combined rectum/urinary bladder/vagina, it’s the single structure into which the digestive and urogenital systems empty -- yes, off the cloaca is a structure called the bursa of Fabricius. That’s where the naïve chicken B lymphocyte goes to mature. Hence, bursal-equivalent or B cell.]
Naïve T cells, on the other hand, leave the hematopoietic compartment and prance off to that “useless” organ in the anterior mediastinum, the thymus. The holds for the chick, as well -- thymic or T cell.

B cells

B lymphocytes are transformed into plasma cells, which secrete antibodies.

T cells

T lymphocytes are responsible for the operations of cell-mediated immunity, involving the direct destruction of mutated or virally infected cells. In addition, they have other “helper” and “suppressor” roles.

NK cells

NK (natural killer) cells are nonB-nonT lymphocytes that destroy mutated or virally infected cells without prior exposure to antigen. We know how they work but not their precise lineage. It is said they share a common early progenitor with T cells, express CD2 and CD56, and have interleukin 2 receptors; but they also express CD16 and do not develop in the thymus.

properties

The leukocytes share certain properties which allow them to get to where the action is. Not all of these may be present in any given leukocyte.

margination

Margination is the sticking of blood-borne leukocytes to the endothelial lining of the capillary wall. One particular cell adhesion molecule used in margination is selectin, which causes the passing monocytes and neutrophils to slow down as they pass. Another CAM, integrin, will bind them firmly (sort of like the One Ring).

ameboid motion

Ameboid motion is the method of locomotion whereby the cell, by protoplasmic streaming and probably lots of cytoarchitectural rearrangements and myosin/actin interactions, projects the pseudopodia so classic of the protist Amoeba.

diapedesis

By using the ameboid movement, the leukocyte is able to pinch a long narrow projection through a capillary pore; the remainder of the cell flows forward into this projection. In this way, the leukocyte is able to wiggle itself through the tiny pore.

chemotaxis

Chemotaxis is the attraction of a leukocyte to the action by chemicals, surprise!, called chemotaxins. Binding the chemotaxin to the leukocyte receptor increases Ca2+ entry into the leukocyte, which, in turn, switches on ameboid motion.

phagocytosis

Phagocytosis is the swallowing up and breakdown of foreign particles by the macrophages and neutrophils.

enzymatic digestion

Most phagocytosed material will be degraded by lysosomes (membrane-bound organelles containing hydrolytic enzymes) fusing with the phagosome. In some cases, such as tattoo dyes or the lysosomally-resistant tuberculosis bacterium, the material will be retained within the phagosome, unaltered. The body will form granulomas, walled-off structures containing phagocytes within which are the undestroyed material. When large numbers of phagocytes fall to the cause, as in an infected wound, pus may accumulate -- living and dead phagocytes, cellular debris, and (mostly dead) bacteria.

peroxisomes

If the phagocyte has engulfed toxic bacterial compounds, then it may combine the peroxisome (containing oxidative enzymes) with the phagosome.

reticuloendothelial system

The reticuloendothelial system (RES) is a diffuse group of cells having the ability to take up and sequester inert particles and vital dyes. This includes the macrophages or macrophage precursors, specialized endothelial cells lining the sinusoids of the liver (Kupffer cells), spleen, and bone marrow, and the reticular cells of lymphatic tissue (macrophages) and of bone marrow (fibroblasts).

Nonspecific immune responses:  innate immunity

The innate, nonspecific immune defenses come into play whether or not there has been a prior exposure to the offending agent. The four processes are described below:

inflammation

Inflammation is the nonspecific response to tissue injury, foreign invasion, or both. The goal of the inflammatory response is to bring phagocytes, plasma proteins, and other cells to the area that can halt the invaders and immobilize or destroy them, remove whatever debris remains, and prepare the area for repair. What follows are the preliminary steps in the response:

defense by resident tissue macrophages

The resident tissue macrophages are the first line of defense. Although usually fixed, they can be moved to other areas for engagement of the invaders.

localized vasodilatation

Tissue mast cells at the site of insult will almost immediately release histamine, causing a localized vasodilatation, and bringing more leukocytes and plasma proteins to the scene.

increased capillary permeability

The histamine also enlarges the capillary pores, facilitating the passage of plasma proteins through the endothelium.

localized edema

The leakage of plasma proteins into the tissue spaces creates an osmotic pressure to attract still more fluid to the area. Thus, histamine induces the familiar localized swelling in an inflammation. Two other familiar effects, redness and heat, are due to the increased blood flow (vasodilatation); and the pain is caused by a combination of distention and tissue-damage elements stimulating the nociceptors.

walling-off of inflamed area

The leaked plasma proteins include not only the complement and kinin proteins, but also proteins involved in the clotting cascade.

tissue thromboplastin

Tissue thromboplastin and specific chemicals secreted by the on-scene phagocytes cause the conversion of fibrinogen (the soluble final factor in the clotting cascade) to fibrin, forming clots in the interstitial spaces, thus walling off the injured region. Some bacteria, such as streptococci, produce enzymes that work on plasminogen to convert it into plasmin, the clot-dissolving enzyme.

emigration of leukocytes

The leukocytes are attracted to the site by the chemotactic factors, and make their way into the site.

leukocyte proliferation

Within a few hours of the onset of the inflammatory response, there is an increase in the bone marrow production of leukocytes. This mostly results from chemical mediators released from the area of inflammation.

leukocytic destruction of bacteria

As already described, the neutrophils and macrophages gobble up the bacteria and destroy them. Remember that with a large infection, pus may be formed.

opsonization

Opsonization is a process whereby foreign particles may be coated with chemical mediators that make them more attractive to the phagocytes. Think Roquefort salad dressing.

phagocyte-secreted chemical mediation

Phagocytes that have been stimulated by foreign organisms will release many chemicals that serve as mediators of the inflammatory response, causing effects from local to systemic scope.

direct action

This set of substances directly kills any foreigners that have not already been phagocytosed.

NO (nitric oxide)

Toxic to nearby microbes, it may also serve to reduce clotting locally.

lactoferrin

Lactoferrin binds iron. So? you ask. Well, bacterial multiplication is dependent on high concentrations of iron. Deprive them of it, and they can’t reproduce.

release of histamine

Phagocytic secretions promote the release of histamine from mast cells. And that causes vasodilatation and increased capillary permeability.

triggering of clotting/anticlotting mechanisms

Remember, conversion of soluble fibrinogen into fibrin. But almost as important:  When the clot is not longer needed, as when all the foreigners have been killed, there should be a mechanism to dissolve it. Which, of course, there is.

formation of active kinins from kininogens

Some phagocytic secretions split kininogens (inactive precursor proteins in the plasma that have been synthesized by the liver) into kinins. Once activated, the kinins can stimulate steps in the complement system, reinforce the vascular changes induced by histamine, activate pain receptors, and act as strong chemotaxins. Ouch!

kallikrein

This agent is produced by neutrophils.

endogenous pyrogen (EP)

Phagocytes release EP, which is then thought cause the release of prostaglandins within the hypothalamus, turning up the hypothalamic “thermostat,” with fever as the result. There is a lot of debate over what good fever is, some arguing that there is nothing beneficial about fever at all. And yet, one is left to wonder, with its ubiquity in disease states, why, if it were of no benefit, it would exist. Anyhow, there are a couple tantalizing ideas for fever:  first, enzymatic reactions, including those of the phagocytes, go faster at the slightly elevated temperatures of fever; and second, increased temperature increases the bacterial requirement for iron, but at the same time makes less of it available. Obviously, though, very high fevers are not good.

secretion of leukocyte endogenous mediator (LEM)

Macrophages secrete LEM. Strangely, if not the same, it is very closely related to EP. Here are the effects of LEM:

reduction of plasma iron concentration

This is accomplished by altering iron metabolism in the liver, spleen, and elsewhere.

promotion of granulopoiesis

Makes sense.

acute-phase proteins

Acute-phase proteins are any protein whose plasma concentration increases (or decreases) by 25% or more during certain inflammatory disorders. The acute-phase proteins include C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, and alpha 1-acid glycoprotein. Perhaps the best known of these acute-phase proteins is CRP, a plasma protein that rises in the blood with inflammation. The level of CRP in blood plasma can rise as high as 1000-fold with inflammation. Conditions that commonly lead to marked changes in CRP include infection, trauma, surgery, burns, inflammatory conditions, and advanced cancer. Moderate changes occur after strenuous exercise, heatstroke, and childbirth. Small changes in CRP occur after psychological stress and in several psychiatric illnesses. C-reactive protein is a test of value. Marked rises in CRP reflect the presence and intensity of inflammation. An elevation in CRP, however, is not a telltale sign pointing to just one disease.

interleukin 1 (IL-1)

IL-1 enhances the proliferation of both B and T cells. These can then respond with specific humoral and cell-mediated effects. IL-1 also appears to be identical (or closely related) to EP and LEM.

tissue repair

The goal of the inflammatory response is to destroy the causative agent and clear the area for tissue repair. In many tissues, healthy organ-specific cells in the neighborhood divide and fill in the damaged areas, often perfectly. This is what we see in liver, bone, and skin.

scar tissue in nonregenerative tissues

In the nonregenerative tissues, like muscle and nerve, there are no mitotically capable cells, so repair is left to the connective tissue fibroblasts. They will divide rapidly and secrete lots of ground substance and collagen fibers to fill in the spaces. This makes a solid repair, but the esthetics and, of course, functioning are lost.

salicylates and glucocorticoids

Numerous drugs can suppress the inflammatory response; the most effective are the salicylates (e.g., aspirin) and the glucocorticoids (e.g., cortisol). Salicylates interfere with the inflammatory response by decreasing the release of histamine, thus reducing the redness, swelling, and pain. Also, by blocking prostaglandin synthesis in the hypothalamus (in response to EP), they reduce fever. The glucocorticoids interfere with all aspects the inflammatory response. They also destroy lymphocytes in lymphoid tissue and decrease the production of antibody. This is fine if you are dealing with an acute immune problem, such as an allergic reaction or arthritic inflammation or a multiple sclerosis flareup, but long-term they are not good. Not only do they limit inflammatory reactions, but they also severely cut into the ability of an individual to fight the day-to-day microbes that come along. Glucocorticoids must be used carefully.
There is some evidence that adrenocortical cortisol does exert some anti-inflammatory activity at physiological levels. It probably serves to modulate stress-activated immune responses, reining them in just enough so as not to get out of hand.

interferon

Interferon is released from virus-infected cells. It is not a single type of molecule, but a family of similar proteins. When a virus invades a cell, one thing that happens is, because of the presence of viral nucleic acids, the infected cell produces interferon, which is then secreted into the extracellular fluid. The circulating interferon binds with receptors on neighboring (or even distant) cells. These cells now synthesize viral blocking enzymes that can break down viral mRNA. The enzymes remain inactive until the cell is invaded by the virus (note that interferon does not prevent invasion, it only prevents the virus from taking over the machinery of the host), at which time the presence of viral nucleic acid activates the enzymes.
In addition, interferon can enhance the phagocytic activity of macrophages, stimulate antibody production, enhance the activity of NK and cytotoxic T cells, and slow cell division, suppressing tumor growth.

NK cells

Natural killer (somehow a movie comes to mind here), or NK, cells are lymphocyte-like cells that nonspecifically destroy virally infected cells and cancer cells by lysing their membranes. This is a role very similar to the cytotoxic T cell, but the latter requires previous exposure and a maturation period before execution.

complement

The complement system, originally so named because its actions complemented the actions of antibodies, plays an essential role in the inflammatory process and in body defense. It consists of about 20 plasma proteins that are synthesized in the liver; these are either enzymes or binding proteins, but circulate in the bloodstream in an inactive form.

classical pathway

The classical pathway is activated by the binding of antibody molecules (IgM, IgG1,IgG2, and IgG3) to a foreign particle. Note:  the classical pathway is antibody-dependent.

Ag-Ab complex activates C1

What begins the process is the binding a protein, C1q, to the Fc region of the antigen-bound IgG or IgM molecule.
The proteins C1r and C1s attach to C1q to form C1, the first enzyme in the pathway.
Activated C1 enzymatically cleaves another protein, C4, into the fragments C4a and C4b.
C4b binds to neighboring proteins and carbohydrates on the antigen; C4b then binds C2.
The activated C1 cleaves C2 into C2a and C2b, forming C4b2a, the C3 convertase.
Our classical pathway is now activated. C3 convertase can now cleave hundreds of molecules of C3 into C3a and C3b.
Some molecules of C3b bind to C4b2a, the C3 convertase, to form C4b2a3b, a C5 convertase that cleaves C5 into C5a and C5b.

opsonization and phagocytosis  [C3b]

C3b and, to a lesser extent, C4b can function as opsonins. That is, they can attach antigens to phagocytes. One portion of the C3b binds to proteins and polysaccharides on microbial surfaces; another portion attaches to CR1 receptors on phagocytes, B cells, and dendritic cells to enhance phagocytosis.

lysis  [C5b6789n]

C5b binds to the surface of the target cell and subsequently binds C6, C7, C8, and a number of monomers of C9 to form the Membrane Attack Complex (MAC), C5b6789n.
The MAC is able to destroy gram-negative bacteria as well as human cells displaying foreign antigens (virus-infected cells, tumor cells, &c.) by lysing them.

agglutination

C3b and, to a lesser extent, C4b help to remove harmful immune complexes from the body. C3b and C4b attach the immune complexes to CR1 receptors on erythrocytes. The erythrocytes then deliver the complexes to fixed macrophages within the spleen and liver for destruction. See, erythrocytes are good for more than just transporting oxygen around the blood stream. Immune complexes can lead to a harmful Type III hypersensitivity reaction.

viral neutralization

The MAC (C5b6789n) can damage the protein coat of viruses.

chemotaxis  [C5a]

C5a also functions as a chemotactic agent for phagocytes. Phagocytes will move towards increasing concentrations of C5a and subsequently attach, via their CR1 receptors, to the C3b molecules attached to the antigen.

basophil/mast cell activation  [C3a, C4a, C5a]

C5a is the most potent complement protein for triggering inflammation. It causes mast cells to release histamine. To a lesser extent, C3a and C4a can also trigger mast cells and basophils.

inflammatory effects

C5a and, to a lesser extent, C3a and C4a increase the expression of adhesion molecules on leukocytes and the vascular endothelium so that leukocytes can diapedese; they cause neutrophils to release toxic oxygen radicals for extracellular killing; and they induce fever.

alternate (or alternative) pathway

The alternate pathway is of major importance in host defense against bacterial invasion. Unlike the classical pathway, the alternate pathway does not require the formation of antibody; it is activated directly by the invader. Note:  the alternate pathway is antibody-independent. Thus, the alternative pathway is a humoral component of natural defense against infections; it can operate without antibodies. Six proteins -- C3, B, D, H, I, and P -- perform the functions of initiation, recognition, and activation of the pathway, the end result of which is the formation of activator-bound C3/C5 convertase

large polysaccharides react with factors B and D

The alternate complement pathway is mediated by C3b, produced either by the classical or lectin pathways or from C3 hydrolysis by water. (Water can hydrolyze C3 and form C3i, a molecule that functions in a manner similar to C3b.)
Activation of the alternate complement pathway begins when C3b (or C3i) binds to the cell wall and other surface components of microbes. (C3b can also bind to IgG antibodies.)
Alternate pathway protein Factor B then combines with the cell-bound C3b to form C3bB.
Factor D then splits the bound Factor B into Bb and Ba, forming C3bBb.

formation of activation product that activates C3

A serum protein called properdin then binds to Bb to form C3bBbP that functions as a C3 convertase capable of enzymatically splitting hundreds of molecules of C3 into C3a and C3b.
The alternate complement pathway is now activated.

If the complement discussions seem a little confusing, I highly recommend the
animation showing the assembly of C1 during the classical pathway,
animation showing the assembly of C3 convertase,
animation showing the cleavage of C3 and the formation of C5 convertase,
animation showing the formation of the MAC,
animation showing the benefits of C5a and C3b,
animation of the lectin pathway,
animation of the alternative pathway and formation of C3 convertase, and
animation of the formation of C5 convertase.



This lesson continues as Immunology 2:  Specific immune responses and the adaptive immune system.

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