Body Defenses

Immunity

• body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells
• consists of following activities:
• Defense against invading pathogens (viruses & bacteria)
• Removal of 'worn-out' cells (e.g., old RBCs) & tissue debris (e.g., from injury or disease)
• Identification & destruction of abnormal or mutant cells (primary defense against cancer)
• Rejection of 'foreign' cells (e.g., organ transplant)
• Inappropriate responses:
• Allergies - response to normally harmless substances
• Autoimmune diseases

Major targets of body defense system:

• Bacteria - induce tissue damage & produce disease largely by releasing enzymes or toxins that physically injure or functionally disrupt affected cells & organs
• Viruses - can only reproduce in host cells & cause cellular damage or death by:
• depleting essential cellular components
• causing cellular production of substances toxic to cell
• transforming normal cells into cancer cells
• inducing destruction of cells because infected cell no longer recognized as 'normal-self' cell

 

 

Bacteria

1 - Inflammation - response to tissue injury serving to defend against foreign invader

2 - Interferon - group of proteins that defend against viral infection

3 - Natural killer cells - lymphocyte-like cells that rather nonspecifically lyse & destroy virus-infected cells & cancer cells

4 - The complement system - inactive plasma proteins that, when activated, destroy foreign cells

Inflammation  (Check this animation)

• can be caused by microbial infections, physical agents (e.g., trauma, ultraviolet radiation, burns, or 'frostbite'), & tissue necrosis resulting from inadequate blood flow
• principle effects include:
• Redness - inflamed tissue appears red, e.g., skin affected by sunburn, due to dilation of small blood vessels within the damaged area
• Heat - an increase in temperature is seen in peripheral parts of the body, such as the skin. It is due to increased blood flow to the area as a result of vascular dilation and the delivery of warm blood to the area.
• Swelling -  results from edema (accumulation of fluid in the extra vascular space)
• Pain - results partly from the stretching and distortion of tissues due to edema and, in particular, from pus under pressure
• function is to destroy invaders & prepare area for healing & repair:

Interferon (check this animation - Antiviral activity of interferon):

• family of similar proteins
• interfere with replication of the same or unrelated viruses in other host cells
• Mechanism:

Natural killer cells

• lymphocyte-like cells
• destroy virus-infected cells & cancer cells by lysing their membranes upon first exposure
• mode of action similar to cytotoxic T cells (but latter can attack only cells to which they have been previously exposed)
• an important first line of defense against newly arising malignant cells and cells infected with viruses, bacteria, and protozoa. They form a distinct group of lymphocytes with no immunological memory. Natural Killer Cells constitute 5 to 16 percent of the total lymphocyte population. Their specific function is to kill infected and cancerous cells.

The Complement System

• activated by invading organisms &, more often, triggered by antibodies ('complements' action of antibodies)
• consists of 11 plasma proteins produced by liver

The complement cascade after activation by pathogens. Tthe complement cascade is usually activated by antibody complexes (classical pathway) or high-density mannose (lectin pathway) on the surface of pathogens. This activation leads opsonization and phagocytosis, as well as lysis as a result of the formation of the membrane attack complex (MAC). These combined actions of complement lead to the elimination of pathogenic cells (Ricklin and Lambris 2007).

• Functions:
1 - Membrane-attack complex proteins form a channel in membrane of invading cell. The resulting influx of water causes lysis (or bursting) of the invading cell.

2 - chemotaxins

3 - opsonins (bind with microbes & thereby enhance their phagocytosis)

Under certain circumstances of infection, bacteria or viruses may become coated with opsonins (C3b, a complement protein, or IgG, an antibody). Such microbes are said to be opsonized (opsonin comes from a Greek word meaning "sauce" or "seasoning"; they make the bacterium or virus more palatable and more easily ingested by a phagocyte.) Opsonins dramatically increase the rate of adherence and ingestion of a pathogen  (Source: http://www.bact.wisc.edu/Bact330/lecturecd2).

 
4 - inflammation

5 - activate kinins - reinforces vascular changes induced by histamine & act as powerful chemotaxins
 
 

Source: National Cancer Institute

Complement  The complement system consists of a series of proteins that work to "complement" the work of antibodies in destroying bacteria.  Complement proteins circulate in the blood in an inactive form. The so-called "complement cascade" is set off when the first complement molecule, C1, encounters antibody bound to antigen in an antigen-antibody complex. Each of the complement proteins performs its specialized job in turn, acting on the molecule next in line. The end product is a cylinder that punctures the cell membrane and, by allowing fluids and molecules to flow in and out, dooms the target cell.

Specific Immune Responses

• Selective attack aimed at "target" following prior exposure
• Two classes of responses:
• Humoral immunity - antibodies produced by B lymphocytes
• Cell-mediated immunity - activated T lymphocytes

B lymphocytes (or B cells) are most effective against bacteria & their toxins plus a few viruses, while T lymphocytes (or T cells) recognize & destroy body cells gone awry, including virus-infected cells & cancer cells.

  Clonal selection and expansion of the vertebrate immune response (Figure from Bergstrom and Antia 2006)

The adaptive immune response of vertebrates works by clonal selection. Independent of exposure to an antigen or pathogen, the immune system generates a repertoire of immune cell lineages or clones (labeled 1–8 in the above Figure), each encoding a receptor with a predetermined shape and specificity. The human immune system creates in excess of 10,000,000 different clones. As a first approximation, those that react with self-antigens (numbers 3, 5, and 8 in Figure I) are deleted shortly after they mature. When the individual is infected with a pathogen, those clones that are specific for the pathogen (number 2 in the above Figure) will proliferate, producing a pathogen-specific immune cell population that is large enough to control that pathogen. This process is known as clonal expansion. After the pathogen is cleared, some of the pathogen-specific immune cells survive and confer immune memory (Bergstrom and Antia 2006).

How do B & T cells recognize unwanted cells & other material?

• Antigen = foreign protein (e.g., an antigenic protein from the outer surface of the Lyme disease bacterium is pictured to the right)
• Each B & T cell has receptors on surface for binding with a particular antigen.

B-cells: Antibody-mediated immunity

• B-cells that bind with an antigen will subsequently differentiate into Plasma cells & Memory cells

• Plasma cells - begin to produce antibodies (up to 2,000 per second)
• Memory cells - remain dormant until a person is again exposed to the same antigen

Source: National Cancer Institute

Activation of B Cells to Make Antibody The B cell uses its receptor to bind a matching antigen, which it proceeds to engulf and process. Then it combines a fragment of antigen with its special marker, the class II protein. This combination of antigen and marker is recognized and bound by a T cell carrying a matching receptor. The binding activates the T cell, which then releases lymphokines—interleukins—that transform the B cell into an antibody- secreting plasma cell.     Plasma Cell

Humoral immunity  

Antibodies

• Grouped into 5 subclasses:
• IgM - B cell surface receptor for antigen attachment; secreted early in an immune response
• IgG - most abundant antibody; produced in large numbers
• IgE - mediator for common allergic responses (hay fever, asthma, & hives)

Source: NIAID

• IgA - found in secretions of digestive, respiratory, urinary, & reproductive systems, as well as in breast milk and in tears
• IgD - found on the surface of many B cells; function is unknown

Source: Check (2007).

Source: National Cancer Institute

IgA and IgM IgA -- a doublet -- concentrates in body fluids such as tears, saliva, and the secretions of the respiratory and gastrointestinal tracts. It is, thus, in a position to guard the entrances to the body.  IgM usually combines in star-shaped clusters. It tends to remain in the bloodstream, where it is very effective in killing bacteria.

• provide protection by:

1 - neutralization - binding with bacterial toxins to prevent them from harming susceptible cells; may also bind with viruses & prevent them from entering body cells (see example below)

2 - agglutination (see example to the right)

3 - Enhancing activities of other defense systems:

• activation of complement system
• enhancement of phagocytosis
• stimulation of killer cells

Plasma cells vs. Memory cells

(a) Development of memory B cells and effector B cells (plasma cells) occurs in two phases. Short-lived plasma cells that make mostly IgM (but some IgG) are generated during the primary response and occupy sites, such as lymph nodes. The second phase involves the formation of the memory B-cell pool and seeding of long-lived plasma cells to the bone marrow. Plasma cells do not give rise to memory cells. All arrows are driven by antigen and T-cell help. (b) Development of memory T cells. After activation, cells differentiate into effector T cells. Memory T cells might be generated by divergence from this pathway or directly from effector T cells. There might be two subsets of memory cells: quiescent, central memory cells that recirculate from blood to secondary lymphoid organs, and effector memory cells that migrate through tissues and deliver a very rapid response on reactivation with antigen (Gray 2002).

Plasma cells:

• prolific producers of customized antibodies (IgG antibodies)
• have lots of ROUGH ENDOPLASMIC RETICULUM (RER) because antibodies are proteins & RER is needed to make proteins (because of the associated ribosomes) and then transport them out of the cell
• formation and subsequent production of takes several days after exposure to an antigen & peak antibody production may occur a week or two after exposure. This is referred to as the PRIMARY RESPONSE.

Memory cells:

• remain dormant but respond quickly if exposed to the antigen a second time
• responsible for SECONDARY RESPONSE, a response so fast & effective that infection is typically prevented.
• form the basis for long-term immunity

Primary response vs. Secondary response:

Active immunity vs. Passive immunity

• Active ('natural') = production of antibodies as a result of exposure to an antigen (immunization)
• Passive = direct transfer of antibodies formed by another person (or animal), e.g., transfer of IgG antibodies from mother to fetus across placenta or in colostrum ('first milk') OR treatment for rabies or poisonous snake venom

Infants are born with relatively weak immune responses. They have, however, a natural "passive" immunity; they are protected during the first months of life by means of antibodies they receive from their mothers. The antibody IgG, which travels across the placenta, makes them immune to the same microbes to which their mothers are immune. Children who are nursed also receive IgA from breast milk; it protects the digestive tract. Passive immunity can also be conveyed by antibody-containing serum obtained from individuals who are immune to a specific infectious agent. Immune serum globulin or "gamma globulin" is sometimes given to protect travelers to countries where hepatitis is widespread. Passive immunity typically lasts only a few weeks.

"Active" immunity (mounting an immune response) can be triggered by both infection and vaccination. Vaccines contain microorganisms that have been altered so they will produce an immune response but will not be able to induce full-blown disease. Some vaccines are made from microbes that have been killed. Others use microbes that have been changed slightly so they can no longer produce infection. They may, for instance, be unable to multiply. Some vaccines are made from a live virus that has been weakened, or attenuated, by growing it for many cycles in animals or cell cultures.

T Lymphocytes: Cell-mediated Immunity    (Also see - Immunology: Proliferation of the T cell)

• defend against invaders that 'hide out' inside cells (where antibodies & complement system cannot reach them)
• must be in direct contact with their targets
• activated by foreign antigen only when present on surface of cell that also has "self-antigens" (except whole transplanted foreign cells)
• Three types of T cells:
• Cytotoxic (killer) T cells - destroy host cells bearing foreign antigen (e.g., host cells invaded by viruses and cancer cells)
• Helper T cells - enhance development of B cells into antibody-secreting cells & enhance activity of cytotoxic & suppressor T cells
• Suppressor T cells - suppress B cell antibody production & cytotoxic & helper T cell activity; effects are primarily the result of chemicals called CYTOKINES (or LYMPHOKINES)

Cytotoxic T cells:

• Most frequently target host cells infected with viruses
• Release PERFORIN molecules to destroy target cells --> PERFORIN molecules form channels in target cell membrane & inrush of water lyses cell

Helper T cells

• "Activation" requires MACROPHAGES --> Macrophage presents foreign antigen in combination with "self-antigen"
• secrete cytokines that "help" the immune response:
• B cell growth factor - enhances antibody-secreting ability of B cells
• Interleukin 2 - enhances activity of cytotoxic T cells, suppressor T cells, & even other helper T cells
• Chemotaxins - attract neutrophils & macrophages
• Macrophage-migration inhibiting factor - inhibits migration plus creates "angry macrophages"

Suppressor T cells:

• limit responses of other cells (B & T cells)
• make immune response self-limiting
• prevents excessive immune response which might be detrimental to body
• may also prevent immune system from attacking a person's own cells & tissues (= TOLERANCE)

1 - reduction in suppressor T cell activity

2 - normal self-antigens modified by drugs, environmental chemicals, viruses, or mutations

3 - exposure to antigen very similar to self-antigen ("molecular mimicry")

Major autoimmune diseases (Source: www.cdc.gov)

Red Blood Cells:

• ABO system of antigens
• Rh system of antigens

ABO system:

• Type A antigen
• Type B antigen

Source: ghr.nlm.nih.gov

Antibodies:

• produced if antigen is not present
• produced because common intestinal bacteria have A- & B-like antigens
• produced by age of about 6 months

If you mix anti-A antibodies with blood cells that have the A antigen OR mix anti-B antibodies with blood cells that have the B antigen, the results will be AGGLUTINATION (or clumping of red blood cells). This reaction can be used to type blood. You simply take two drops of 'unknown' blood and place a drop of anti-A antibody solution on one blood drop & a drop of anti-B antibody solution on the other blood drop. Then, look closely to see if any clumping occurs. If clumping occurs in the drop of blood where you added the anti-A antibodies, then you know that the A antigen is present (and, of course, if there is no clumping, then the A antigen is not present). If clumping occurs in the drop of blood where you added the anti-B antibodies, then you know that the B antigen is present (and, of course, if there is no clumping, then the B antigen is not present). Using this information, you can determine the blood type:
 

In the above chart, the blood types are listed with either a + or -. The + or - refers to the presence or absence of the Rh factor.

Type O:

• universal donor
• no antigens = no clumping

• universal recipient
• no antibodies = no clumping

Rh system:

• inherited independent of ABO system
• Rh positive = antigen present on RBCs (& no antibodies)
• Rh negative = no antigen & antibodies will be produced IF exposure occurs

Erythroblastosis fetalis (also called Rh disease):

• hemolysis of RBCs of fetus which can cause anemia or worse
• may occur when an Rh negative mother & Rh positive father have an Rh positive fetus

• treatment for Rh disease; contains antibodies specific for Rh positive antigen (a good example of passive immunity)
• injected within 72 hours after birth of Rh positive baby

Literature cited:

Bergstrom, C. T. and R. Antia. 2006. How do adaptive immune systems control pathogens while avoiding autoimmunity? Trends in Ecology and Evolution 21:22-28.

Related links:

Lifeblood

Acute Inflammation

Lymphatic System & Immunity

General Immunology

Introduction to Immunology

Cell Mediated and Humoral Immunity

Understanding the Immune System

Humoral Immunity

Immuno Biology Animations

Blood Types Tutorial

Back to 301 syllabus
 

Lecture Notes 1 - Cell Structure & Metabolism

Lecture Notes 2 - Neurons & the Nervous System I

Lecture Notes 2b - Neurons & the Nervous System II

Lecture Notes 3 - Muscle

Lecture Notes 4 - Blood and Body Defenses I

Lecture Notes 5 - Cardiovascular System

Lecture Notes 6 - Respiratory System

Literature cited:

Casadevall, A., E. Dadachova, and L.-a. Pirofski. 2004. Passive antibody therapy for infectious diseases. Nature Reviews Microbiology 2: 695-703.

Check, E. 2007. Immunology: pimp my antibody. Nature 446: 964-966.

Dranoff, G. 2004. Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews Cancer 4: 11-22.

Gray, D. 2002. A role for antigen in the maintenance of immunological memory. Nature Reviews Immunology 2: 60-65.

Ricklin, D. and J. D. Lambris. 2007. Complement-targeted therapeutics. Nature Biotechnology 25: 1265-1275.