The Immune System: Innate and Adaptive Body Defenses
I. Innate Defenses
A. Surface Barriers: Skin and Mucosae
1. Skin, a highly keratinized epithelial membrane, represents a physical barrier to most microorganisms and their enzymes and toxins.
2. Mucous membranes line all body cavities open to the exterior and function as an additional physical barrier.
3. Secretions of the epithelial tissues include acidic secretions, sebum, hydrochloric acid, saliva, and mucus.
B. Internal Defenses: Cells and Chemicals
1. Phagocytes confront microorganisms that breach the external barriers.
a. Macrophages are the main phagocytes of the body.
b. Neutrophils are the first responders and become phagocytic when they encounter infectious material.
c. Eosinophils are weakly phagocytic but are important in defending the body against parasitic worms.
d. Mast cells have the ability to bind with, ingest, and kill a wide range of bacteria.
2. Natural killer cells are able to lyse and kill cancer cells and virally infected cells before the adaptive immune system has been activated.
Inflammation is a bodily response to cell damage (physical trauma, intense heat, irritating chemicals, or infection by viruses, fungi, or bacteria).
The four cardinal signs of inflammation, as described by the Roman physician and science writer Celsus, are:
The fifth sign, which is somethimes present, is loss of function, or functio laesa - this was originally described and added to the four signs described by Celsus by another Roman physician and science writer, Galen, but was popularized in the 1800s by Rudolph Virchow, the "Father of Modern Pathology".
Functions:
The release of inflammatory chemicals causes vasodilation, which increase blood flow to the area, increased vascular permeability, which allows fluid containing clotting factors and antibodies to enter the tissues, sensitize and even directly stimulate pain receptors, and act as chemotactic factors for phagocytes (neutrophils and macrophages).
A brief explanation of how some of this inflammation/phagocytosis/complement activation gets started:
Pattern recognition receptors (PRRs) are receptors that recognized conserved (common) molecular sequences associated with a number of different pathogens (PAMPs - pathogen associated molecular patterns). PRRs are found on the surface and in the cytoplasm of macrophages, dendritic cells, mucosal epithelial cells, endothelial cells, and lymphocytes. Some secreted molecules recognize PAMPs and act as PRRs as well.
For a moderate list of the PRRs click here.
Secreted PRRs:
Circulating acute phase proteins, like C-reactive protein, mannose-binding lectin, and complement proteins C3b and C4 bind to PAMPs on the surface of a number of different pathogens. This causes opsonization and phagocytosis of the pathogen and activation of the complement cascade.Cytoplasmic PRRs:
Intracellular receptors recognize nucleic acid sequences, cell wall components of gram-positive and gram-negative bacteria, and a number of other pathogen associated molecules. Interaction with their ligands activates cytokine production and HLA upregulation.
Phagocytosis Receptors:
Macrophages have cell-surface receptors that recognize certain PAMPs, including, those containing mannose. When a pathogen displays a cell surface polysaccharide containing mannose it is engulfed into a phagosome.Toll-Like Receptors (TLRs):
Surface membrane receptors that recognize a number of different PAMPs. There are at least 10 different TLRs.
Binding of the pathogen to the PRRR initiates a signaling pathway leading to the activation of the transcription factor NF-κB. NF-κB turns on cytokine genes, such as those for tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and chemokines, which attract white blood cells to the site. All of these effector molecules lead to inflammation at the site.
Mast cells, injured tissue cells, neutrophils, lymphocytes, and basophils all release inflammatory mediators as well.
The release of histamine, kinins, and prostaglandins causes vasodilation and increased permeability of blood vessels.
Histamine causes vasodilation, increases vascular permeability, and is chemotactic for eosinophils.
Kinins cause clotting, vasodilation, increased vascular permeability, and pain.
- Factor XII (Hageman Factor) is activated by endotoxin, uric acid, calcium pyrophosphate, and basement membrane proteins (collagen).
- XIIa activates Factor XI to initiate clotting and cleaves prekallikrein to kallikrein.
- Kallikrein converts plasminogen to plasmin, HMW kininogen to bradykinin, and cleaves C5 to release C5a and C5b.
- C5a stimulates inflammation
Arachidonic acid metabolites
Cyclooxygenase products
- Prostaglandins:
- PGE2 increases vascular permeability, sensitizes to pain, and is pyrogenic.
- PGI’s cause vasodilation.
- Thromboxanes cause vasoconstriction.
Lipooxygenase products
- Leukotrienes are produced by mast cells, basophils, macrophages, and eosinophils.
- LTB4 (SRS-A) is chemotactic, causes vasoconstriction, and increases endothelial stickiness.
- LTC and LTD cause bronchoconstriction, allergy, increase vascular permeability
Blood clots can form around an abscess to prevent dissemination of the infection.
Epithelial mucosal cells increase their release of b- defensins (broad spectrum antimicrobial proteins) when the epithelial barrier has been breached and the underlying connective tissue is inflammed.
Chemotaxis of Phagocytes
Phagocytes have the ability to stick to the lining of the blood vessels (margination, pavementing).
They also have the ability to squeeze through blood vessels (emigration or diapedesis).
PMNs show up first and release ROI (reactive oxygen intermediates), like superoxide anions, hydroxyl ions, hydrogen peroxide, and the enzyme myeloperoxidase, which converts hydrogen peroxide to hypochlorous acid (HOCl, which dissociates to H+ and OCl-, the hypocholorite anion, basically bleach). PMNs also release defensins and are phagocytic.
Pus is the accumulation of damaged tissue and dead microbes, granulocytes, and some macrophages. Generally macrophages show up late to clean up the cellular debris (debride the wound) and set the stage for wound healing.
A tissue is repaired when the stroma (supporting tissue) or parenchyma (functioning tissue) produces new cells.
Stromal repair by fibroblasts produces scar tissue.
4. Antimicrobial proteins enhance the innate defenses by attacking microorganisms directly or by hindering their ability to reproduce.
a. Interferons are small proteins produced by virally infected cells that help protect surrounding healthy cells.
b. There are three types of human interferon: alpha-IFN, beta-IFN, and gamma-IFN. Recombinant interferons have been produced.
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* INFs also enhance the activity of phagocytes and natural killer (NK) cells, inhibit cell growth, and suppress tumor formation; they may hold promise as clinical tools in AIDS and cancer treatment once they are more fully understood.
* Gamma-IFN activates neutrophils and macrophages to kill bacteria and activates Th1 cells, which stimulate cell-mediated reactions.
* Lack of gamma-IFN results in activation of Th2 cells, which are humoral mediators.
* Very high levels of gamma-IFN stimulates NK cells and CTLs.
c. Complement refers to a group of about 20 plasma proteins that provide a major mechanism for destroying foreign pathogens in the body.
5. Fever, or an abnormally high body temperature, is a systemic response to a bacterial or viral infection.
Bacterial endotoxins and interleukin-1 can induce fever.
A chill indicates a rising body temperature; crisis (sweating) indicates that the body’s temperature is falling.
II. Adaptive Defenses
A. Aspects of the Adaptive Immune Response
1. Specific: The adaptive defenses recognize and destroy the specific antigen that initiated the response.
2. Systemic: The immune response is a systemic response; it is not limited to the initial infection site.
3. Has Memory: After an initial exposure the immune response is able to recognize the same antigen and mount a faster and stronger defensive attack.
4. Humoral immunity is provided by antibodies, which are produced by plasma cells and are present in the body’s “humors” or fluids.
Plasma cells arise from B-lymphocytes after B-cell activation.
5. Cellular immunity is associated with T-lymphocytes and has living cells as its protective factor.
B. Antigens are substances that can mobilize the immune system and provoke an immune response.
1. Complete antigens are able to stimulate the activation process that leads to proliferation of specific lymphocytes and antibody production; they are recognized by activated lymphocytes and the antibodies they have stimulated production of.
2. Haptens are incomplete antigens that are not capable of stimulating the immune response, but if they interact with proteins of the body they may be recognized as potentially harmful.
3. Antigenic determinates or epitopes are a specific part of an antigen that are immunogenic and bind to free antibodies or activated lymphocytes.
C. Cells of the Adaptive Immune System: An Overview
1. Lymphocytes originate in the bone marrow and when released become immunocompetent in either the thymus (T cells) or the bone marrow (B cells).
2. Antigen-presenting cells engulf antigens and present fragments of these antigens on their surfaces where they can be recognized by T cells.
III. Humoral Immune Response
A. The immunocompetent but naive B lymphocyte is activated when antigens bind to its surface receptors.
1. Clonal selection is the process of the B cell growing and multiplying to form an army of cells that are capable of recognizing the same antigen.
2. Plasma cells are the antibody-secreting cells of the humoral response; most clones develop into plasma cells.
3. The clones that do not become plasma cells develop into memory cells.
B. Immunological Memory
1. The primary immune response occurs on first exposure to a particular antigen with a lag time of about 3–6 days.
2. The secondary immune response occurs when someone is reexposed to the same antigen. It is faster, more prolonged, and more effective.
C. Active and Passive Humoral Immunity
1. Active immunity occurs when the body mounts an immune response to an antigen - effector cells and memory cells are generated.
a. Naturally acquired active immunity occurs when a person suffers through the symptoms of an infection.
b. Artificially acquired active immunity occurs when a person is given a vaccine.
2. Passive immunity occurs when a person is given preformed antibodies - no lymphocyte activation, no effector cells, no memory cells.
a. Naturally acquired passive immunity occurs when a mother’s antibodies enter fetal circulation.
b. Artificially acquired passive immunity occurs when a person is given preformed antibodies that have been harvested from another person.
D. Antibodies or immunoglobulins are proteins secreted by plasma cells in response to an antigen that are capable of binding to that antigen.
1. The basic antibody structure consists of four looping polypeptide chains linked together by disulfide bonds.
2. Antibodies are divided into five classes based on their structure: IgM, IgG, IgA, IgD, and IgE.
3. Embryonic cells contain a few hundred gene segments that are shuffled and combined to form all of the different B cells that are found in the body.
4. Antibody Targets and Functions
a. Complement fixation and activation occurs when complement binds to antibodies attached to antigens, and leads to lysis of the cell.
b. Neutralization occurs when antibodies block specific sites on viruses or bacterial exotoxins, causing them to lose their toxic effects.
c. Agglutination occurs when antibodies cross-link to antigens on cells, causing clumping.
d. Precipitation occurs when soluble molecules are cross-linked into large complexes that settle out of solution.
5. Monoclonal antibodies are commercially prepared antibodies specific for a single antigenic determinant.
IV. Cell-Mediated Immune Response
A. The stimulus for clonal selection and differentiation of T cells is binding of antigen, although their recognition mechanism is different from B cells.
1. T cells must accomplish a double recognition process: they must recognize both self (an HLA molecule of a body cell) and nonself (antigen) at the same time. (HLA molecules are Human Leukocyte Antigens , you may be more familiar with the term MHC)
2. T-cells bind and recognize their specific antigen through an antigen receptor, which is known as the T-cell receptor (TCR).
The TCR will bind to the antigen it is specific for only when the antigen is bound to an HLA molecule on the surface of some other cell.
Human Leukocyte Antigens, or tissue antigens, are glycoproteins that are present on almost every cell in the body. HLA molecules have a groove along the top of the molecule (the peptide binding site) that binds a small piece of protein, typically between 8 and 15 amino acids long.
The presence of peptide in the peptide binding site of an HLA molecule such that T-cell receptors can bind to the HLA-peptide complex is known as antigen presentation.
There are two classes of HLA molecules, Class I and Class II.
Class I HLAs are coded for by three different genes, Class I A, Class I B, and Class I C. Class I molecules are present on all nucleated cells in the body and are recognized by CD8+ T-cells.
Class I HLAs present "internal foreign antigens" like viral antigens and tumor antigens (which look foreign because they are mutant normal peptides).
Class II HLAs are coded for by three different genes as well, the DR, DP, and DQ genes. Class II molecules are present on antigen presenting cells (APCs), which include macrophages, dendritic cells, and B-cells.
Class II HLAs are recognized by CD4+ T-cells.
Class II HLAs present "exogenous foreign antigens", things that have been phagocytized and broken down within APCs.
Normally, HLA molecules have a small piece of endogenous self-peptide, a piece of some normal self protein that has "worn out" and been recycled, bound to their antigen binding site.
T-cells "dock" with the HLA-peptide complex, recognize it as "self", and go on about their business. This is called immune survellience.
If a foreign peptide is bound to the antigen binding site of the HLA molecule the T-cell will recognize the complex as "foreign" and respond appropriately.
But - In order to respond to an antigen, the T-cell has to be activated first.
T Cell Activation
a. The first step in T-cell activation is binding of the T-cell to HLA-antigen complex it is specific for on the surface of an APC (thats why they're called antigen presenting cells).
b. The second step is the requirement for the T-cell to recieve a co-stimulatory signal. Co-stimulation may be the result of interaction of the CD28 protein on the surface of T-cells and B-7 proteins on the surface of APCs or stimulation of the T-cells by cytokines, in particular IL-2, or a number of other interactions (this is somewhat simplified, but go with it).
Without co-stimulation the T-cell won't respond to its antigen - it becomes anergized or tolerized.
Since non-antigen presenting cells don't have co-stimulatory molecules, like B-7, on their surface they can't activate T-cells.
The bottom line here is this: In order to become activated, naive T-cells must contact their specific antigen by binding between their T-cell receptor and the appropriate HLA-antigen complex on the surface of an APC.
c. Once activated, a T cell enlarges and proliferates to form a clone of cells that differentiate and perform functions according to their T cell class.
3. Cytokines include hormonelike glycoproteins released by activated T cells and macrophages.
B. Specific T Cell Roles
1. Helper T-cells (CD4+)
Th1 secrete IL-2, IFN-g, TNF-ß
Drives cell-mediated responses (stimulates CD8+ T-cells and high levels of IFN-g will stimulate phagocytes to kill internal pathogens)
Th1 also secrete IL-3 and GM-CSF to stimulate bone marrow to produce more leukocytes
Th2 secrete IL-4, IL-5, IL-6, IL-10
Drives humoral responses (stimulates antibody production by activated B-cells)
Th1 and Th2 cytokines are antagonistic in activity.
The Th1 cytokine IFNg inhibits proliferation of Th2 cells, while IFNg and IL-2 stimulate B cells to secrete IgG2a and inhibit secretion of IgG1 and IgE.
The Th2 cytokine IL-4 stimulates B cells to secrete IgE and IgG1; IL-10 inhibits Th1 secretion of IFNg and IL-2; it also suppresses Class II MHC expression and production of bacterial killing molecules and inflammatory cytokines by macrophages.
The balance between Th1 and Th2 activity helps drive the immune response in the direction of cell-mediated or humoral immunity.
Antigen presenting cells phagocytize external antigens, break them down in phagolysomes, and put peptide fragments in the peptide binding site of Class II HLAs.
The Class II HLA-peptide complex is then moved to the surface of the APC where it can be recognized by an appropriate CD4+ T-cell.
The act of phagocytosis will stimulate macrophages to secrete IL-1, which will co-stimulate CD4+ T-cells when they bind to the HLA-peptide complex.
When CD4+ T-cells are activated in this way they secrete IL-2, which stimulates macrophages, stimulates CD8+ T-cells, stimulates B-cells, and self stimulates the activated CD4+ T-cells. IL-2 works like a growth factor.
2. Cytotoxic T-cells (CD8+)
What about antigen presentation and activation of CD8+ T-cells?
Same deal, except the antigen is presented bound to a Class I HLA molecule. APCs can take up viral particles by phagocytizing virally-infected host cells or through gap junctions between the APC and virally-infected cell.
B7 proteins on APCs bind CD28 on the T-cells and costimulate them to become activated.
CD8+ T-cells kill virally infected cells and tumor cells when activated by secreting perforin, granzymes, and expressing a protein called FAS-ligand on their cell surface.
- Perforin creates channels in the target cell membrane.
- Granzymes enter the target cell through the channels and turn on enzymes that induce apoptosis in the target cell.
- FAS-ligand binds to a receptor protein on the target cell called FAS. This interaction also stimulates the tartet cell to undergo apoptosis.
3. Regulatory T cells release cytokines that suppress the activity of both B cells and other types of T cells.
May be CD4+ or CD8+
4. Gamma/delta T cells are found in the intestine and are more similar to NK cells than other T cells.
5. Without helper T cells there is no adaptive immune response because the helper T cells direct or help complete the activation of all other immune cells.
C. Organ Transplants and Prevention of Rejection
1. Grafts
a. Autografts are tissue grafts transplanted from one body site to another in the same person.
b. Isografts are grafts donated to a patient by a genetically identical individual such as an identical twin.
c. Allografts are grafts transplanted from individuals that are not genetically identical but belong to the same species.
d. Xenografts are grafts taken from another animal species.
2. Transplant success depends on the similarity of the tissues because cytotoxic T cells, NK cells, and antibodies work to destroy foreign tissues. Tissue typing for HLA matching and blood typing for ABO matching are important parts of preparing for transplantation. An example: Tissue typing for bone marrow transplantation.
V. Homeostatic Balances of Immunity
A. Immunodeficiencies are any congenital or acquired conditions that cause immune cells, phagocytes, or complement to behave abnormally.
1. Severe combined immunodeficiency (SCID) is a congenital condition that produces a deficit of B and T cells.
2. Acquired immune deficiency syndrome (AIDS) cripples the immune system by interfering with helper T cells.
B. Autoimmune diseases occur when the immune system loses its ability to differentiate between self and nonself and ultimately destroys itself. There is often involvement of HLA type in susceptibility to autoimmune disease.
C. Hypersensitivities, or allergies, are the result of the immune system causing tissue damage as it fights off a perceived threat that would otherwise be harmless.
1. Immediate hypersensitivities (Type I or anaphylactic) begin within seconds after contact and last about half an hour. IgE antibodies bind to the Fc receptor on basophils and mast cells and when allergen binds to the IgE molecules and crosslinks them they cause degranulation and release of histamine, leukotrienes and prostaglandins, which cause inflammation.
There are two basic kinds of reactions: systemic anaphylaxis and localized reactions.
Systemic anaphylaxis is anaphylactic shock and can be counteracted by epinephrine injection.
Localized reactions include allergic rhinitis (hay fever) accompanied by itchy and teary eyes, congestion, coughing and sneezing; asthma, accompanied by wheezing and shortness of breath; and hives, a skin rash usually due to food allergies.
Anaphylactic reactions can be prevented by determination of the specific allergens that a patient is sensitive to and injecting small amounts of the allergens over an extended period of time (desensitization). This causes the production of blocking antibodies, which are IgG.
The only other treatment is symptomatic, such as with antihistamines.
2. Subacute hypersensitivities (Types II and III) take 1–3 hours to occur and last 10–15 hours.
Type II, or cytotxic
Cytotoxic reactions are mediated by IgG or IgM and complement.
The antibodies are directed toward cellular antigens on foreign cells or foreign antigens on host cells.
The antigen-antibody complexes cause complement fixation resulting in cell lysis and phagocytosis.
Examples include transfusion reactions and drug induced hemolysis.
Type III, or immune complex
Antigens involved are not part of host cells but soluble antigens.
The antigens are bound by IgM or IgG antibodies and the antigen-antibody complexes precipitate and lodge in basement membranes.
Complement fixation leads to inflammation and cell lysis.
Example: Glomerulonephritis
Inflammation of the glomeruli due to immune-complex disease.
Occurs as a sequel to a beta-hemolytic streptococcal infection (group A).
Antigen-antibody complexes cause inflammation and damage to the glomerular membrane.
Other Immune Complex Diseases:
- Systemic lupus erythematosus
- Rheumatoid arthriti
3. Delayed hypersensitivity reactions take 1–3 days to occur and may take weeks to go away.
Delayed-type hypersensitivity (TDTH) T-cells are involved.
Sensitized T-cells secrete lymphokines in response to antigen.
Lymphokines attract macrophages and initiate tissue damage.
Examples:
- Tuberculin skin test
- Allergic contact dermatitis
VI. Developmental Aspects of the Immune System
A. Embryologic Development
1. Stem cells of the immune system originate in the liver and spleen during weeks 1–9 of embryonic development; later the bone marrow takes over this role.
2. In late fetal life and shortly after birth the young lymphocytes develop self-tolerance and immunocompetence.
B. Later in life the ability and efficiency of our immune system declines.
