The Immune System

There are physical, chemical, and cellular defenses against invasion by viruses, bacteria, and other agents of disease.

During the early stages of an infection, there is an inflammatory response

• Non-specific attack
• Phagocytes active ("eat" pathogen)

During later stages, leucocytes produce immune responses

• Antigen - a foreign substance which triggers an immune response
• Some WBC's produce antibodies in huge amounts
  • Antibodies - substances which bind to specific antigens and tag them for destruction
  • Other WBC's (executioner cells) directly destroy body cells

The first two lines of defense are called Innate Immunity

The last line of defense is called Acquired Immunity

Surface coverage - the first line of defense

• The body is protected from pathogens by the skin and mucous membranes
  • Skin - dead cellular layer - dry, low pH
  • Mucous membranes contain lysozymes (enzymes which break down bacteria)
  • Other cells contain cilia which filter pathogens and particulates

Non-specific responses - the second line of defense

• Non-specific responses are generalized responses to pathogen infection - they do not target a specific cell type
• The non-specific response consist of some WBC's and plasma proteins
• Neutrophils - phagocytize bacteria
  • Also secrete chemicals (lysozyme) which degrades bacterial cell walls
• Eosinophyls - secrete enzymes to kill parasitic worms
• Basophils - secrete histamine to enhance inflammation
• Mast Cells - secrete signals to decrease blood flow right at the wound (so you don't bleed to death) but increase blood flow and capillary permeability nearby to allow phagocytes to be able to enter the interstitial fluid near the wound
• Macrophage - "big eaters" phagocytize just about anything
  • Possess MHC (major histocompatibility proteins) which can display foreign antigens
  • Secrete cytokines, which attract still more macrophages and neutrophils and induces fever

• Inflammation
  • Pathogens enter wound
  • Platelets release blood clotting proteins
  • Injured tissues and macrophages release cytokines to recruit help
    • Changes in capillary wall structure allow interstitial fluid and WBC's to leak out in tissue
    • Stimulate bone marrow to make and release additional nutrinophils and macrophages
    • Attract other immune system cells to the cite
    • Activate cells involved in tissue repair and wound healing
    • Induce fever
  • Mast cells release factors that constrict blood vessels at wound and dilate vessels nearby
  • Neutrophils arrive and begin phagocytizing pathogens
  Leukocytes arrive and mature into macrophages

Animation - the First Two Lines of Defense

The Immune System (Specific Responses) - the third line of defense

• Called into action when nonspecific methods are not enough and infection becomes widespread

Types of cells involved in the immune system:

• Macrophages - engulf foreign objects
  • Inform T lymphocytes at a specific antigen is present
• Helper T cells - produce and secrete chemicals which promote large numbers of effector and memory cells
• Cytotoxic T cells - T lymphocytes that eliminate infected body cells and tumor cells
• B cells & plasma cells- produce antibodies (secrete them in the blood or position them on their cell surfaces)

Each type of virus, bacteria, or other foreign body has molecular markers which make it unique

• Host lymphocytes (i.e. those in your body) can recognize self proteins (i.e. those which are not foreign)
• When a nonself (foreign) body is detected, mitotic activity in B and T lymphocytes is stimulated
  • While mitosis is occurring, the daughter populations become subdivided
    • Effector cells - when fully differentiated, they will seek and destroy foreign
    • Memory cells - become dormant, but can be triggered to rapid mitosis if pathogen encountered again

Thus, immunological specificity and memory involve three events:

(1) Recognition of a specific invader

(2) Repeated cell divisions that form huge lymphocyte populations

(3) Differentiation into subpopulations of effector and memory cells

• Antigen - a nonself marker that triggers the formation of lymphocyte armies
• Antibodies - molecules which bind to antigens and are recognized by lymphocytes

Antigen-presenting cell - a macrophage which digests a foreign cell, but leaves the antigens intact. It then binds these antigens to MHC molecules on its cell membrane. The antigen-MHC complexes are noticed by certain lymphocytes (recognition) which promotes cell division (repeated cell divisions)

T cells (Helper T cells and Cytotoxic T cells)

• T cells arise from stem cells in the bone marrow - they then travel to the thymus where the differentiate and mature. At maturity, they acquire receptors for self markers (CD4 and CD8 markers) and for antigen-specific receptors. They are then released into the blood as "virgin" T cells.
• T cells ignore other cells with MHC molecules and they ignore free-floating antigens. However, they will bind with a antigen-presenting macrophage (a macrophage possessing a MHC-antigen complex). This binding promotes rapid cell division and differentiation into effector and memory cells (all with receptors for the antigen)

• Effector helper T cells secrete interlukins (stimulate both T and B cells to divide and differentiate)
• Effector cytotoxic T cells recognize infected cells with the MHC-antigen complex. They then destroy the cell with perforans (enzymes which perforate the cell membrane, allowing cytoplasm to leak out) and other toxins which attack organelles and DNA

B cells, Plasma Cells, and Antibodies

• B cells also arise from stem cells in the bone marrow. As they develop and mature, they start synthesizing a single type of antibody
• Antibodies are proteins which recognize and bind antigens
• The virgin B cell produces antibodies which move to the cell surface and stick out
• The virgin or memory B cell floats in the blood - when it encounters the specific antigen it becomes primed for replication
• The B cell must receive an interleukin signal from an effector helper T cell which has already become activated by a macrophage with a MHC-antigen complex. This promotes clonal cell division (rapid cell division)
• The B cell population then differentiates into effector B cells (aka plasma cells) and memory B cells
• The effector B cells (plasma cells) then produce a staggering amount of free-floating antibodies
  • When these free-floating antibodies encounter an antigen, they tag it for destruction by phagocytes and complementary proteins
  • These types of responses are only good for extracellular toxins and pathogens - they cannot detect pathogens or toxins located inside of a cell
• The memory B cells remain inactive for this invasion.  During subsequent pathogen infections, they can become active much more rapidly than the first response involving just a virgin B cell

Antibody-mediated immune response

 

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Summary of the Immune Response

The Clonal-Selection Theory

Scientific evidence showed early researchers:

• B cells can produce antibodies to a seemingly limitless number of antigens
• Each antibody is sepcific to an antigen
• The immune respone intensifies through time after an infection begins
• The immune response is "remembered" - individuals do not get sick at all, or recover extremely quickly, if they are exposed to the same pathogen again

To explain these patterns, researched developed the clonal-selection theory, whihc made several key claims about how the adaptive immune system works:

• Antigens are recognized by receptors on B cells and T cells.
• Lymphocytes are activated by antigen-receptor binding
• Activated Lymphcytes are cloned - rapid cell division
• Activated lymphcytes endure - memory system

The History of Vaccinations

Edward Jenner (1749-1823)

• country doctor in Gloucestershire
• the area was facing an epidemic of smallpox
  • http://www.bt.cdc.gov/agent/smallpox/
  • http://www.smallpox.gov/
• noticed that milk maids previously infected with cowpox rarely got smallpox
• he performed an experiment
  • First, he obtained pus from a cowpox ulcer from a woman named Sarah (and her cow was named Blossom - this is completely irrelevant, but I love the fact that they know the cow's name)
  • Then he purposesly infected an 8 year old boy named James Phipps
  • James became ill with cowpox, but he recovered
  • Jenner then repeatedly infected James with smallpox, but he never became ill
• To his credit, Jenner refused to patent the treatment, so it could be made available to everyone, rich and poor
  • Trivia - vaccination comes from the latin vacca, which means cow
  • Trivia - smallpox has been all but eradicated - the only known samples of the virus remain in the CDC in Atlanta, GA and in Moscow