Elements of Innate and Acquired Immunity
 
 

The defenses of the body are traditionally divided into two branches:
 

1.) Innate / Nonspecific Defenses / Natural Immunity -

  • Many of these are the physical and biochemical barriers which prevent microbes from entering and establishing themselves.

 
 

2.) Adaptive / Specific Defenses / Acquired Immunity -

  • these defenses are based on T-cell and B-cell reponses. 
    • A key characteristic of these responses is that there is memory of the encounter.
      • A second encounter will cause a forceful response that is tailor-made for the organism.

 
 

Innate Defenses
 
 

A. Mechanical, Physical and Chemical Barriers
 

What are the examples of Physiologic and Chemical Barriers at the skin and mucous membranes?

Acid pH -- this also relates to the stomach

What is lysozyme?  Where is it found?  What does it do?

Hydrolytic enzymes?  Proteolytic enzymes?

Interferon refers to a group of proteins that can help prevent the spread of viruses.  There is one special one called gamma-interferon -- this one is a cytokine produced by TH cells.

Complement is a term that refers to a group of serum proteins that are normally found "inactive" in the serum. 

Antibody-antigen reactions  and the cell walls of certain microorganisms can "activate" complement. 
When this happens the active components can destroy cells in the area of complement activation.

Mucous producing membrane together with cilia help eliminate organisms = mucociliary escalator

Skin -

Tough, no bacteria can penetrate unaided.

Dry (most skin infections take place in the wetter areas).

Acid ( approximately pH 5), Low temperature, Skin cells are constantly shedding, high salt content.

Lysozyme in the pores.

Resident microflora.

Skin Associated Lymphoid Tissue
 

Mucous Epithelia -

    • GI
    • Respiratory
    • Urogenital
    • Eyes
  • These areas are warm and wet. They are sites of secretion and/or absorption and therefore cannot be thick like the skin.

 

  • mucus - contains polysaccharides and proteins which trap organisms. Ciliated cells and parastalsis and cough reflex moves trapped organisms out. (ie.: Muco-ciliary escalator in the lungs.)
  • Lots of lysozyme and lactoferrin (an enzyme that binds iron and keeps it away from microorganisms).

 

Attributes of Selected areas 

Mouth - rich resident normal flora -- these help to keep the bad guys out. 

Lungs - sterile if not compromised Otherwise this is a vulnerable area. If organisms get down into the alveolar area they have easy access to the blood.   Mucociliary escalator is very important

Stomach - Low pH is an important barrier

Small Intestine - Paneth cells in the crypts produce lysozyme and defensins (these are small proteins which inhibit bacterial growth).

Urethra - flow of urine important. 

Female Genitalia - microflora very important. Mucus plug in the cervix important in preventing movement of microbes into the uterus. Do you think that bacteria can piggyback on sperm cells?



B. Complex Biological Responses of Innate Immunity

Complex biological responses include:

·       Phagocytosis

·       Complement Activation

·       Inflammation and Fever

·       Interferon

First review the cells of the blood (Fig 2.1 Coico et. al.) and the structure of the immune system (Fig 2.6 Coico et. al.):

 

  • Erythrocytes - RBCs
  • Leukocytes - WBCs:
    • Granulocytes

·       Neutrophils - (polymorphonuclear leukocytes, polys, PMNs) most numerous; actively phagocytic; first on the scene.

Have granules loaded with digestive enzymes – Lysosomes

Also bombard ingested microorganisms with toxic compounds such as peroxide and superoxide.

·       Basophils / Mast Cells  These cells are filled with mediators of inflammation:

histamine - causes vasodilation (blood vessels dialate) and bronchoconstriction (because it causes smooth muscles to constrict)

heparin - inhibits blood coagulation

leukotrienes - prolonged constriction of smooth muscles, pain

prostaglandins - smooth muscle constriction and vasodilation, pain

·       Eosinophils -  These cells are active against helminth parasites; they are activated in chronic allergies and asthma.

 

·       Monocyte / Macrophage / Antigen Presenting Cell / APC. 

o      These cells may have special names in different tissues: 

§       kupffer cells

§       microglial cells 

§       alveolar macrophages

§       peritoneal macrophages

§       osteoclasts 

§       splenic macrophages

      •  Dendritic Cells including Langerhans cells of the skin are a special class of APC. Much of what we say about monocytes and macrophages will also be true of dendritic cells.

 

Macrophages can be resting or angry and they have several activation states in between. They are phagocytic cells and they are very important in antigen presentation.

By "antigen presentation" we mean that these cells digest antigen and then attach the pieces to MHC molecules on their surface. 

T-cell-receptors can only recognize antigen if it is properly presented....that means TcR's only attach to antigen which is itself attached to MHC  molecules. 

All nucleated cells have MHC class I.   It turns out that this is important for presentation to the TcRs on TC cells.  TC cells are CD8 + cells  they only recognize antigen presented on MHC class I molecules.

On the other hand,the TcR's on TH cells only recognize antigen when it is presented on MHC Class II molecules.  TH cells are CD4+ cells.  

In order for something to be phagocytosed, the macrophage much attach to the substance first. 

This means that some kind of receptor has to get engaged.
 
Macrophages do have receptors for many bacteria surface molecules and other bacterial products.

Many of these are called pattern recognition receptors because they bind to conserved molecules that are commonly found in microbes.  Some of these include:

The f-Met-Leu-Phe receptor

Mannan-binding lectin

Scavenger receptors

Toll-like receptors

Macrophages also have Fc-IgG receptors and complement receptors (the C3b receptor). 

These allow the macrophage to recognize and attach to bacteria which are themselves coated with IgG or with activated complement. 

These substances are called opsonins because they help the macrophage "eat" the bacteria.

 

  • Lymphocytes

    1. T-cells / Thymus derived
      1. CD4+ = Thelper (and Tdelayed hypersensitivity) cells
      2. CD8+ = Tcytotoxic (and Tsuppressor) cells.


These cells have a receptor for antigen - called the T cell receptor (TcR).

    1. B-cells / Bone Marrow derived.

These cells make antibody or immunoglobulin (Ig) 

Their antigen receptor is the antibody on their surface (sIg).

If a B-cell is actively secreting antibody, it is called a plasma cell.

    1. NK-cells / natural killer cells / (Large Granular Lymphocytes).

These cells kill virus infected cells and tumor cells.

They have an antigen receptor but it is still not completely understood. It appears that a negative signal is what triggers these cells to kill. 

The NK cell receptor is called the Killer Cell Inhibitory Receptor (KIR) and it normally binds to MHC class I on the surface of all the cells the NK cell meets.

(Remember that all nucleated cells have MHC class I). 

If the NK cell encounters a cell with diminished or no MHC class I proteins (which sometimes happens in viral infected cells or in cancer cells), then the NK cell releases substances to kill the defective cell.

 

 

  • Thrombocyte / Platelet
    • These are derived from megakaryocytes in the bone marrow. 
    • Platelets are active in blood clotting and they are rich in inflammatory mediators or mediators of inflammation.

 

PHAGOCYTOSIS and ENDOCYTOSIS
  (See Fig. 2.2 in Coico)

a.) chemotaxis -- phagocytic cells are attracted by

(1) microbial products,

(2) complement fragments generated when complement is activated,

(3) compounds liberated when mast cells and platelets become activated

(4) compounds and debris generated when tissues are damaged. (2 , 3 and 4 are commonly seen during inflammation.)

b.) adherence -- phagocytic cells "stick" to their targets by

(1) non-specific receptors

(2) C3b receptors if the target cell is coated with C3b

(3) Fc receptors if the target cell is coated with antibody

Coating target cells with either C3b or antibody so that phagocytes can adhere to them is called opsonization and the C3b or the antibody is called opsonin.

c.) endocytosis, killing and digestion

the phagosome and then the phagolysosome (the digestive vacuole) is formed.

A variety of enzymes and reactive compounds go to work on the ingested microbes: damaging cell walls and cell membranes, capturing any free iron and digesting the microbes.

d.) antigen presentation

Pieces of the digested microbe are displayed on the surface of the phagocytic cell for T-cells to see.

The pieces are placed onto the major histocompatibilty complex proteins (MHC proteins or MHC antigens ) which stud the surface of the phagocyte.

This function is very important in macrophages and dendritic cells. These cells are often called antigen presenting cells or APC's.

 

 

 

Complement
 

Complement consists of a number of serum proteins which exist in the serum in an inactive form. These proteins can be activated in a cascade-like fashion by

(1) microbial cells in either the alternative pathway or the lectin pathway

(2) antigen-antibody complexes in the classical pathway.


Once activated, complement can:

(1) destroy all cells (even host cells) in the activation area,

(2) cause inflammation (complement is an anaphylatoxin),

(3) opsonize microbial cells (complement is an opsonin) and

(4) attract leukocytes to the area (complement is a chemotaxin).


 

COMPLEMENT ACTIVATION PATHWAYS

 

complement activation pathways


INFLAMMATION
 
This is a very complex process initiated by any of the following.

  • Microbial infection 
  • tissue damage due to physical trauma
  • any of the mechanisms which lead to
    • complement activation,
    • basophile degranulation and/or
    • blood clotting (platelet activation)


Any of these will result in the release of a group of proteins called the acute phase proteins  - a general term for all the proteins which cause an acute inflammatory response (acute inflammation).

The purpose of inflammation is to limit damage, thwart and destroy invading organisms, and then promote tissue repair.

 

The mediators of inflammation (the acute phase proteins) include:

  • Chemokines - small proteins that control the adherence and migration of WBC's
    • Chemokines are often produced by damaged cells and by tissues under the stress of infection 
  • Tissue damage activates Hageman factor which in turn activates the Kinin System, the Clotting System and the Fibrinolytic System:
    •  
    • Bradykinin causes increase vascular permeability, vasodilation, pain, smooth muscle contraction
    •  
    • Fibrin and Fibrinopeptides causes increased vascular permeability and neutrophil chemotaxis
    •  
    • Plasmin activates complement and it also digests fibrin clots.  The digested fibrin peptides attract neutrophils
    •  
  • Activated Complement causes increased vascular permeability, smooth muscle contraction and attraction of neutrophils and monocytes

 

  • C-Reactive Protein – Binds to membranes of microorganisms and activates the complement system.
  •  Activated platelets and damaged cell membranes cause the production and release of thromboxane, prostaglandins, leukotrienes  and platelet activating factor.


These mediators lead to the classic signs of inflammation:

  • Erythema - Redness (rubor)
  • Accumulation of fluids - Edema and Swelling (tumor)
  • Pain (dolor)
  • Heat (calor)
  • Loss of function

These signs are due to:

  • Vasodilation
  • Increased vascular permeability
  • Accumulation of WBC's
  • Bronchoconstriction

Although the predominate cell type in acute inflammation is the polymorphonuclear leukocyte, macrophages may become involved. If macrophages do become involved, they will release Interleukin-1 (IL-1), Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-a). These cytokines have many functions including the ability to cuase the hypothalamus to reset the body's thermostat and cause fever.

Cytokines released by macrophages will also stimulates the liver to synthesize and release a variety of acute phase proteins.

C-reactive protein is one of these which damages bacterial cell walls and fixes complement.


 

In a successful inflammatory reponse, fibroblasts responding to a variety of cytokines, lay down collagen and scar tissue. Repair cytokines promote the regeneration of damaged tissues
 
 

If the acute inflammatory response does not resolve the problem, a chronic inflammatory response may be generated. In chronic inflammation, macrophages and T-cells become the predominate cell types. Granuloma and delayed hypersensitivity refer to particular types of chronic inflammation.

INTERFERON
 
 

Cells that are infected by virus can synthesize and secrete either alpha-interferon and/or beta-interferon (a-IFN, b-IFN). These interferons bind to other, still uninfected, cells and stimulate the uninfected cells to synthesize anti-viral proteins which interfer with and abort virus infections in those cells.
 
 


Structure of the Immune System:  

The lymphoid system is composed of

(1) the primary lymphoid organs -- the thymus and the bone marrow --where B-cells and T-cells are produced and mature.

The Thymus - Precursor T-cells arrive here from the bone marrow via the blood stream.  These immature T-cell make their T-cell-receptor here and they are tested for their ability to attach and recognize MHC class I or class II proteins here.  Most maturing T-cells fail to make the cut and are killed (by apoptosis) in the thymus.

The Bone Marrow - Precursor B-cells develop and mature here.  Each B-cell make its own unique antibody specificity here for the first time and then it moves out into the body.


(2) the secondary lymphoid organs -- a collection of lymph nodes dispersed throughout the body. The SALT and MALT (GALT, peyer's patches, appendix, tonsils) are secondary lymphoid organs as are all the lymph nodes and the spleen. The secondary lymphoid organs are connected by both lymphatic vessels and blood vessels. Interstitial fluid which percolates thru the tissues is collected by the lymphatic vessels and filtered through the lymph nodes before being shunted back into the bloodstream. Lymphatic fluid (lymph) is pumped through the vessels by skeletal muscle contraction.

lymphoid system