Lecture -3

What are Interferons? They are glycoproteins in nature. Secreted by eukaryotic cells in response to viral infections, tumors, and other biological inducers. Produce clinical benefits for disease states such as hepatitis, various cancers, multiple sclerosis, and many other diseases. Structurally, they are part of the helical cytokine family which are characterized by an amino acid chain that is amino acids long.

- They are particularly effective against virus with RNA genome. -  and  interferons are present early in viral infections, whereas  interferon appears some what later in the course of infection.

- Interferons are small proteins released by macrophages, lymphocytes, and tissue cells infected with a virus. - When a tissue cell is infected by a virus, it releases interferon. Interferon will diffuse to the surrounding cells. - When it binds to receptors on the surface of those adjacent cells, they begin the production of a protein that prevents the synthesis of viral proteins. This prevents the spread of the virus throughout the body. General Action of Interferons

Interferons do not protect the cells that secret them, these cells are already infected with virus. Instead, IFN produce protective steps in neighboring uninfected cells. They are:(types) α- Interferon, produced by leucocytes. β-Interferon, produced by fibroblasts.  -Interferon produced primarily by activated TH cell.

Blood There are three major components to human blood. Human blood is approximately 55% plasma, which is the “fluid” part of the blood with ions, proteins and other substances dissolved in it. The “cellular elements” blood make up the other 45%. Almost 95% of these are red blood cells (erythrocytes) that carry oxygen in the blood. About 4% of the cellular elements in blood are platelets. These are cell pieces that are used for blood clotting Much less than 1% of blood contains white blood cells, (leukocytes), they are vitally important in fighting infection.

granulocytes neutrophils eosinophils basophils agranulocytes lymphocytes monocytes White Blood Cells There are 5 major types of white blood cells (leukocytes)

Lymphocytes about the size of RBC large spherical nuclei thin rims of cytoplasm They are divided into three categories -Natural killer cells attack tumor cells and some cells that have been infected with viruses. -B-lymphocytes develop in the bone marrow. -T-lymphocytes develop in the thymus.

Lymphocytes Natural Killer cells –Large lymphocytes (not B or T) –Kills tumor cells –Kills cells infected with certain viruses (intracellular pathogens)

Monocytes largest blood cell. kidney-shaped or oval nuclei leave blood stream to become macrophages. elevated in typhoid fever, malaria, tuberculosis.

Granulocyte –Cytoplasmic granules Polymorphonuclear Phagocytosis Short life span (hours) Very important at “clearing” bacterial infections (PMN)Neutrophils

Kills Ab-coated parasites through degranulation Involved in allergic inflammation Double Lobed nucleus Orange granules contain toxic compounds Eosinophils

Basophils deep blue granules is basic stain contain toxic and inflammatory compounds. release histamine release heparin less than 1% of leukocytes Important in allergic reactions

Highly specialized Process antigen and display peptide fragments on cell surface Involved in T-cell activation Antigen-presenting cells(APC) The immune system contains of three types of antigen presenting cells (APC's). 1- Macrophages 2- Dendritic cells 3- B cells

Phagocytosis and killing of microorganisms. Function as antigen presenting cells (APC) In the blood and tissues – mature and migrate to the lymph nodes Dendritic cells

Phagocytosis is the process by which phagocytic cells ingest and destroy invading particles as bacteria. Two types of phagocytic cells: -Microphages ( PMN) found circulating in the blood. - Macrophages: found throughout the body circulating in the blood and fixed in tissues. Second line defense

Second line of defense: 1.Attachment of the bacterium to the long membrane evaginations, called pseudopodia. 2.Ingestion of the bacterium forming a "phagosome," which moves toward the lysosome. 3.Fusion of the lysosome and phagosome, releasing lysosomal enzymes into the phagosome. 4.Digestion of the ingested material. 5.Release of digestion products from the cell.

Activation: Resting phagocytes are activated by inflammatory mediators. -As a result, the phagocytes produce surface glycoprotein receptors -These glycoprotein molecules known as endocytic pattern- recognition receptors, are so named because they recognize and bind to pathogen-associated molecular patterns-(PAMP) components of common microbial molecules as peptidoglycan, teichoic acid and L.P.S

Chemotaxis: Positive chemotaxis involves the use of pseudopodia to move toward microorganisms at the site of an infection. Chemotactic factors Bacterial factors ( protein, capsule, cell wall or endotoxins) Complement components (C 5a ) Cytokines as IL-8

Attachment Attachment of M.O is necessary for ingestion. -May be: 1- unenhanced attachment. 2- enhanced attachment. 1- Is a general recognition of what called pathogen- associated molecular patterns- components(PAMP) of common microbial molecules. 2- the attachment of microbes to phagocytes by way: -Antibody molecule called IgG -Or complement proteins ) C 3b &C 4b ).

Examples of opsonins: antibodies and some serum components of complement ( C 3b ), this process called opsonization The attachment and ingestion are greatly enhanced by a variety factors called opsonins. Enhanced attachment is much more specific and efficient than unenhanced

Ingestion:( engulfment) It begins with the extension of pseudopodia by the phagocytes. The pseudopodia surround the organism and totally engulf it. this sac called a phagosome. Digestion :(intracellular killing) Digestion begins when lysosomes within the phagocyte fuse with the newly formed phagosomes to form phagolysosomes.

Intracellular killing: is achieved by two mechanisms: (1) The oxygen-dependent system `respiratory burst`: (major) At the time of phagocytosis there is a burst of metabolic activity within the phagocyte in which the stores of glycogen in the cytoplasm are metabolized and the oxygen consumption is increased. This metabolic activity results in the formation of excess NADPH which when oxidized result in the generation of highly toxic oxygen metabolites, include super oxide anion, hydrogen peroxide, hydroxyl radical which are powerful bactericidal and virucidal agents

(2) The oxygen- independent mechanisms of intracellular killing: Involves killing by: low pH lysozyme, lactoferrin, defensins and cationic protein, hydrolytic and proteolytic enzymes

Some M. O are more resistant to phagocytic effect 1- Capsules can resist unenhanced attachment by preventing the endocytic- pattern recognition receptors on phagocytes from recognizing the bacterial cell wall components, e.g Streptococcus pneumoniae

3- Some bacteria are able to kill phagocytes as Staph. aureus and Strep. Pyogenes produce the exotoxin, Leukocidin which damages either the cytoplasmic membrane of the phagocyte or the membranes of the lysosomes. 2- Some bacteria have virulence factors, such as M protein of Streptococcus pyogenes ( hinder adherence of phagocytes by degradation of opsonin C3b, and thereby increase the virulence of the bacteria ).

Determinants of innate immunity Innate immunity is genetically controlled and varies widely with species, race and to less extent between individuals. a)Species and race: -Man and guinea pigs are highly susceptible to diphtheria while rats are not. -Man is susceptible to common cold while dogs are not. -American Indian and Negro are more susceptible to tuberculosis than white races.

B) Individual differences: Age: the very young and aged are particular liable to infection. Nutrition: Malnutrition and starvation predispose to infection by decreasing the total white cell count and phagocytosis. Hormones: Some endocrine diseases cause a decrease in resistance to infection such as diabetes mellitus, hypothroidism and adrenal dysfunction.