Basics of ImmunityAssoc. Prof. Edyta Mądry MD.PhD

Department of PhysiologyPoznań University of Medical Sciences

Innate defense

The innate immune response is the first line of defense against invading microorganisms. This system is not specific for a given pathogen, but can aid in the induction of cell-mediated immunity (antibody and specific killer cells).

Nonspecific Body Defenses

1. Physical Barriers -Mechanical (skin, mucus, cilia in respiratory tract, sebum, cerumen

( earwax) )2. Chemical Barriers (low pH – stomach, vagina, genito-urinary tract,

sweat/ high pH –small intestinal juice3. Others: vomiting, diarrhea, sneezing, coughing

Nonspecific Defenses

• Phagocytes (eg. macrophages)• Complement• Fever• Inflammation• NK cells• Lysozyme• Interferons

Innate defense

Lysozyme

Lysozyme protects us from the ever-present danger of bacterial infection.It is a small enzyme that attacks the cell walls of bacteria. Lysozyme breaks the carbohydrate chains of bacterial walls, destroying their structural integrity. The bacteria burst under their own internal pressure.•tears•mucus •blood•salive•urine

Interferons

IFN-alpha-is made by almost all type of cell infected with virus( fibroblsts are the principal source of INFα)INFα recently is used in treatment:AIDS,hair cell leucemia, hepatitis B and hepatitis C

IFN-beta treats autoimmune disease: multiple sclerosis.

INF-gamma-produced by activated T-lymphocytes and NK cells.Currently is used to treat chronic granulomatous disease and rare hereditary disease of blood

                       

                                                                              

Interferon alpha

Interferons

Complement

Complement- Membrane Attack Complex

After cleavage by the C5 convertase, C5b is loosely membrane associated. Additional interaction with C6 and C7 leads to the formation of a complex that can insert itself into a cell's lipid bylayer. When C8 associates, the complex is capable of initiating lysis, but further assoication with C9 is required for full MAC (membrane attack complex) generation. Four molecules of C9 confer full lytic activity, but as many as 15 can associate to make larger pores. The animation below demonstrates how this pore formation works.

Complement- Activation by a PathogenAn invading bacteria initiates the complement response.The C3bBb3b complex is the C5a convertase; an enzyme that is able to cleave C5 to C5a and C5b.

ComplementA critical byproduct of complement fixation is the C5a peptide. This small protein has a large number of functions and its receptor is expressed in many different cell types. Since it is an enzyme, the C5 convertase complex continually cleaves C5 to C5a, increasing a concentration gradient. The concentration of C5a is highest near the area of production, decreasing farther from this region. This gradient can lead to the chemotactic migration of immune effector cells including macrophages, which can then kill bacteria and initiate an immune response.

Complement-macrophage migration to C5a

After the C5 convertase cleaves C5 to C5a and C5b, the C5a protein diffuses away from the production area to set up a concentration gradient. Different cell types including macrophages, neutrophils and mast cells can recognize this gradient and "crawl" toward the area of activation. .

Complement -Tissue specific cell migrationAfter migrating to the area of C5a production, the macrophages can then phagocytize the offending microorganism. At that point, the cell must make a choice. "Do I stay and find some more goodies to eat?" OR "Do I move out of this area, become a professional antigen presenting cell (dendritic cell), and go to a local lymph node?”

Complement

Inflammation

• Bodies response to tissue injury• Classic signs

• Heat• Redness• Swelling• Pain• Impairment of function

Skin

Blood

Tissue Damaged

Histamine Released

Capillary More Permeable

Plasma Leaks Out

Capillary More Permeable

Antibodies Leaks Out

Capillary More Permeable

WBCs Leave by Diapedesis

Wall of Fibrin Forms

Pus Forms

Lymphatic System Capillaries

Functions of Lymphatic System

• Drain fluid from around cells• Absorb fat from intestines• Circulate lymph• Filter lymph• Immunity

Lymphatic System

Right Lymphatic Duct

Thoracic Duct

Lymphatic organs -Lymph Nodes

• Filter lymph• Microorganisms• Cancer cells

• Lymphocytes• Monocytes

Lymphatic organs - Thymus

• Programs some lymphocytes to develop into T-cells

Lymphatic organs -Spleen

• Filters blood• Worn out RBC• Bacteria

• Lymphocytes• Monocytes

Lymphatic organs - Bone Marrow

T Cells B Cells

Lymphatic organs – GALT70% of human lymphocytes is localized in GALT

Antigenicdeterminants

RCBAntigen A

Binding sites

Variableportion

Hingeregion

Lightchain

Constantportion

Disulfidebonds

Heavy chainCarbohydrate

FcBinding site

Antibody A

Antigen-antibody complex(agglutinated RBC)

Antibodies are made by B cells;

basic unit : 2 identical light chains; 2 identical heavy chains; stabilized and linked by disulfide bonds-form a Y-shaped molecule

Each chain has constant and variable region; Ag binds to variable region on each arm.

Light chains exist in 2 forms: kappa and lambda

Heavy chains exist in 5 forms: alpha, gamma, delta, epsilon and mu.

Fc of the haevy chains can bind complement and receptors on macrophages,monocytes, neutrophils and natural killer cells

IgG • The major immunoglobulin in normal blood (9-14 g/L),

• 4 types, monomers • Can cross the epithelium and placenta,

are secreted with mother’s milk • It contributes immunity against many

kinds of pathogens, including bacteria, viruses, and fungi.

• Distributed evenly between the blood and extravascular fluids.

•After IgG1, IgG3 bind the bacteria they initiate the classical pathway of complement reaction

•include anti-Rh antibodies

IgM• primary importance in

bacterial defense • initiate the classical

pathway of complement activation

• pentamer –consist of 5 monomers

• can NOT cross the epithelium

• always produce as 1st• antibodies of ABO system

are IgM immunoglobulins.

Ig M – ALWAYS 1st,IgG indicates old infection (" G for Grandmother ")

IgA • Provides „mucosal immunity”• found in various secretions, such as

mucus (respiratory and digestive tract), blood, saliva, milk ( COLOSTRUM !). tears, and fluids secreted into the genitourinary and digestive tracts.

• IgA antibodies provide defense against pathogens that contact the body surface or are ingested or inhaled.

• Monomer or dimer or trimar ( we discuss DIMERIC Ig A)

• IgA does NOT activate the complement-has NOT properties to kill bacteria

•They prevent bacteria to adhere to mucosa, they neutralize viruses and toxines

Function

IgE • 0.3x10-3 g/L (1000x more in people with

allergy)• rarely are found as free circulating

antibodies but commonly are found on the surface of basophils and mast cellls of connective tissue (bind by Fc)

•When engaged by an antigen, IgE stimulate basophils and mast cells to release histamine that mediate the allergic response .• important role in defense against parasites (worms) • are produced in tonsills, lymph nodes, mucosa of GI tract. • are involved directly in diseases characterized by hypersensitivity( eg.asthma, hay fever)

IgD • monomer• present on the plasma

membranes of many circulating B-lymphocytes

• Involved in differentiation and development of plasma cells and memory cells from B-lymphocytes.

AQUIRED vs. INNATE IMMUNITY

3 main characteristics that differ aquired and innate immunity :

1.MEMORY 2. SPECIFISITY 3. TIME DEPENANCE