Innate immunity - inborn; always present; nonspecific

Immunity → Resistance & Susceptibility

Non specific immunity: Innate Immunity

• First line of defense: Intact skin, mucous membranes and their secretions, normal microbiota

• Second line of defense: phagocytes, inflammation, fever, antimicrobial substances (cell based and processes)

  • Complement - come together to cause different reactions

Specific immunity: Adaptive Immunity (recognition and binding)

• Third line of defense: specialized lymphocytes: T cells and B cells, Antibodies

  • Stimulated by the presence of an antigen

Toll-like receptors (TLR) on host cells recognize pathogen associated molecular patterns (PAMPS) → Activates innate immunity

• PAMPS: LPS layer of gram negatives, peptidoglycan, flagella, viral RNA/DNA

• Induces release of cytokines which regulates the immune response

  • Cytokines - a term for a number of different chemicals that are involved in different aspects of the immune response.

    • Activate macrophages, Chemotactic effects, inflammatory response/fever, Activate T, B cells

    • Acts as an attractant or signal for immune cells to arrive at the sight of infection

First Line of Defense:

Physical factors:

• Skin - comprised of epidermis & dermis; protective keratin layer on epidermis

  • Subcutaneous infection - when skin is penetrated

• Mucous membranes - Line GI, GU, & respiratory tracts; epithelial and connective tissue layers

  • Mucus - traps microbes and moistens surfaces

  • Tears & Saliva - prevent colonization of microbes

  • Hairs (nose) & Cillia (respiratory tract) - trap microbes

    • Mucociliary escalator - both cilia and mucus produced; mucus serves to trap the microbes and the cilia is used to push them out of the lungs, moving them upwards and out of the lungs when they’re coughed out.

  • Epiglottis, earwax, digestion - eliminates microbes

Chemical factors:

• Skin: sebum (oily secretions) forms a film on skin

  • contain fatty acids, low pH → prevent colonization of pathogens

  • Perspiration: high salt; contain lysozyme (also in tears, saliva, etc)

    • lysozyme breaks down peptidoglycan which is part of some microbes’ cell wall leading to bacterial cell death

• Mucous membranes:

  • Saliva: lysozyme, urea, uric acid, antibody

  • Gastric juice (stomach): pH 1-3 due to HCl

  • Vaginal secretions: acidic pH

  • Urine: lysozyme, pH 6

• Normal microbiota: microbial antagonism, alteration of physical, chemical conditions → prevent colonization by pathogens

Second Line of Defense:

Blood →

• plasma → antibodies complements

• Formed elements → erythrocytes (red blood cells)

Platelets - cell fragments

Leukocytes (white blood cells) →

• Granulocytes: neutrophils, basophils, eosinophils

• Agranulocytes: Monocytes → macrophages, dendritic cells, lymphocytes

  • Lymphocytes: NK cells, T & B cells

Granulocytic Leukocytes:

• Neutrophils (polymorphonuclear leukocytes): phagocytic; active in initial stages of infection

  • can exit blood and enter infected tissue

  • 70% of white blood cells

• Basophils: release components promoting inflammatory & allergic responses (histamine)

  • 1% of white blood cells blood

• Eosinophils: phagocytic & exit blood; release toxins. Also deal with large multicellular pathogens (microscopic worms, certain protozoans, etc)

  • 3-5% of white blood cells

Agranulocytic Leukocytes: (makes up 25% of white blood cells)

• Monocytes: differentiate (change) into macrophages and dendritic cells in lymphatic tissue depending on the infection or inflammation signals they get after entering the bloodstream

  • phagocytic cell types

  • Are also antigen presenting cells (work w/ adaptive immune system)

  • Macrophages “eat” pathogens and clear out dead cells

  • Dendritic cells are essential for adapting immunity as they capture antigens from the pathogens and presenting them to the T cells

  • Macrophages and Dendritic cells can work as both innate and adaptive

• Lymphocytes: (B cells & T cells)

  • Natural Killer Cells: kill infected body cells & some tumor cells; recognize abnormalities in the plasma membranes which signals it to kill that cell

    • destroy host cells that are infected and cancerous; those that lack MHC antigens

      • Binding of NK cells to target: stimulates secretion of perforins(perforates or causes holes); inserts in membrane of target cell causing lysis

      • Also release granzymes; induce apoptosis (programmed cell death) in target cell

  • T cells - modulates specific immune response

    • Intracellular pathogens

  • B cells - produce antibodies to bind antigens

    • Extracellular

Major Histocompatibility Complex (MHC)

Self-antigens; collection of genes that encode for a genetically diverse number of glycoproteins

Molecules that help the body recognize what’s part of it and what isn’t

All cells have these. It’s used by the body to understand what’s supposed to be in the body and what’s not. Think A, B and O blood types

If receiving blood or an organ, that organ or blood has to be compatible with your body’s self-antigens

• MHC Class II: macrophages, dendritic cells, B cells

  • Antigen presenting cells

  • MHC Molecules present pieces from pathogens these cells have "eaten" or encountered to the cell surface. This alerts helper T-cells, which help coordinate the immune response.

• MHC Class I: all other cell types that are not class II

  • Nucleated mammalian cells

  • The cell displays pieces of itself on its cellular membrane. If it’s healthy, it will display normal “self” pieces or antigens, but if it’s not, then it will display unusual "or “non-self” pieces that would alert T cells that it’s infected.

Red Blood cells have their own way of ID-ing itself. The glycoproteins are unique to that system and it’s the ABO blood types.

There are different T cell types depending on the MHC Class types. These T cells have different effects or responses depending on the class type.

Some virus infected cells or cancerous cells lack MHC antigens. In this case, the body finds it abnormal and natural killer cells are used to dispose of it.

Lymphatic Systems

• Lymphoid tissues/organs present throughout the body

  • Protect against inhaled, ingested microbes

  • Contain T cells, B cells, dendritic cells, macrophages

Lymphatic Fluid is fluid that carries extra fluids, waste, and immune cells from tissues and carries them through lymph vessels. The fluid is filtered through the lymph nodes before returning back into the bloodstream.

Exchange of material between the lymphatic system and the circulatory system occurs in capillaries or capillary beds.

There are lymphatic tissues in the intestinal tract in places called the Peyer’s patch. The lymphoid tissues in Peyer’s patches contain M cells which serve to trap antigens before being taking up by macrophages

The spleen also has lymphatic tissue to filter through the blood for potential microbes

Phagocytes & Phagocytosis

One of the major defense mechanisms we have against pathogens

• Granulocytes and monocytes migrate to the site of infection

  • Monocytes differentiate into macrophages; fixed & free (wandering) macrophages

Process of Phagocytosis:

• Chemotaxis

  • Chemotactic chemicals: get the immune cells to the site

    • Chemotactic chemicals are released will draw these cell types to the sites of infection

    • Cytokines and other signaling molecules create a chemical gradient that attracts additional immune cells to the site of infection.

    • Microbial products, components of damaged tissue, cytokines are examples of these chemicals.

• Adherence - immune cells stick to the pathogen

  • Via PAMPS to Toll-like receptors

    • Causes release of cytokines

    • Opsonization facilitates phagocytosis

    • Target coated with serum proteins (opsonins), eg., antibodies, complement

• Ingestions - phagosome formation

• Digestion - fusion of phagosome with lysozyme; enzymatic digestion & production of oxygen radicals & peroxides

(GET BETTER EXPLANATION)

Opsonins

Not all pathogens can be easily be phagocytized; those with capsules can be more resistant to phagocytosis

Phagocytosis is enhanced by opsonization - a combination of innate and adaptive immune responses. (activated via complement/antibodies)

• Engulfment of capsulated bacteria via anticapsular antibodies

• Phagocytic cells recognize & ingest bacteria

Antibodies or complements are produced in response to the capsule. The antibodies or complements will bind onto the virus , marking it for destruction and facilitating its recognition by phagocytic cells, which will then proceed to engulf and eliminate the pathogen. Phagocytic cells have an Fc region in which the antibodies or complements can use to bind onto, effectively adhering the capsuled antigen to the immune cell. This will allow the whole structure to become phagocytized.

Inflammation - damage induced by microbial infection, chemical or physical agents - triggers inflammation.

• Signs and symptoms:

  • redness/pain/heat/swelling/may or may not have loss of function

  • acute and chronic inflammation

    • chronic inflammation develops more slowly and occurs for a longer period of time. Can lead to more damage over time in terms of tissue or organ functioning

    • acute inflammatory response occurs on a local or particular part of the body where infective agents are introduced. Immune system cells are brought to the sight of infection and phagocytize the infective agents before repairing the tissue that’s been damaged

• Functions: destroy/remove agent, confine agent to local area, repair/replace damage tissue

Early stage of inflammation:

• Cytokine release - TNF tumor necrosis factor → induces formation of acute-phase proteins

Stages:

• Vasodilation (manipulation of blood vessels) → phagocyte migration (phagocytes migrating out of the blood and into the surrounding tissue) → phagocytosis → repair

Vasodilation:

• increases blood flow in the area (redness & heat)

• Triggered by chemicals - histamines, kinins - to increase the diameter of the blood vessels

  • Blood vessels get larger and closer to the skin

• Making blood vessels larger will allow for less blood flow resistance, allowing for more blood to flow to the area at a much quicker rate. This is important because our blood is what contains the phagocytes that’s fighting the infection.

• Increased permeability permits entry of blood cells into site (edema, swelling) due to kinins, leukotrienes (mast cells)

• Prostaglandins intensify effect of chemicals; heightens the pain response

• Clotting elements of blood arrive to form clot; may have pus formation & abscess

In response to cytokines, phagocytes stick to blood vessel walls (margination)

• process of slowing the phagocytes down to allow it to go through diapedesis

Diapedesis - phagocytes squeeze between cells, exiting blood vessel

Monocytes later enter the area & develop into free macrophages

Phagocytosis removes microbes, damaged tissue; pus formation

Tissue repair: replacement of dead, damaged tissue

Fever

The hypothalamus: body thermostat; regulates body temp

Pyrogens - substances that cause fever, a natural, induced rise in the body’s temperature setpoint

• Exogenous pyrogens: outside the body (bacteria, viruses, others)

• Endogenous pyrogens (interleukin - 1): act on the hypothalamus, raising the temperature set point

Elevated temperature does what?

• slows pathogen growth

• Increases T cell activity

  • controls the adaptive immune response

• lowers concentration of available iron

Complement

The complement cascade relies on soluble protein factors in blood to attack bacterial pathogens

• Complement consists of about 20 proteins that activate each other via proteolytic cleavage

• Activation of C3, C5 are the major ones

• C3 → C3a, C3b

• C3a → C5 → C5a, C5b

Complements can work with the adaptive immune system

Can be activated in three different ways with three different outcomes

• can bring about inflammation

• can serve as an opsonin to facilitate phagocytosis

• Have an effect called cytolysis

Classical pathway - complement activation due to antibodies

• Antibodies bound to pathogen will then activate a compliment

• C3 activated by contact between complement and pathogen via antibodies

Alternate pathway - activation of complement through binding of compliment glycolipid/glycoprotein molecules on the surface of the pathogen

• C3 activated by contact between complement & pathogen via surface glycolipid complexes

Lectin pathway - C3 activated by lectin

• Lectin - molecule produced by liver. Mannose containing carbohydrates

• C3 activated by contact between lectin and pathogen via surface specific carbohydrates

Effects of Complement:

• Opsonization - activated C3b proteins bind microbe; phagocyte binds to C3b → enhances phagocytosis

• Cytolysis - C3b proteins split into C5 → C5a + C5b; c5b promotes formation of a complement protein complex that inserts in the plasma membrane of microbe

  • Form membrane attack complex (MAC)

  • Channels form in microbe, causing lysis

  • More common to happen in gram negative cells. More susceptible because of thinner cell wall compared to gram positive cells

• Inflammation - C3a & C5a bind mast cells; cause release of histamine, kinins, etc. C5a also acts as a chemoattractant for phagocytes

Interferons - cytokines that interfere with viral replication; produced in response to infection; action is host-specific, not virus specific.

Two classes of interferons:

• Type 1: high antiviral potency; bind receptors on uninfected host cell; renders them resistant to viral infection

  • can either degrade the viral genome that’s released or otherwise inhibit translation

  • Not long acting; not very stable and toxic in high doses

  • Effective in acute viral infections; cannot help virus-infected cells

• Type 2: activated neutrophils and macrophages; increases MHC antigens on their surface

  • the increase of MHC antigens on cell surface increases the potential of showing more antigens to the bod and make the immune system aware of the potential infections

Antimicrobial Substances - Iron binding proteins

• Transferrins, Lactoferrins, Ferritin, Hemoglobin: bind free iron in the human body

• Compete with pathogens for iron; required as a cofactor for many enzymes; pathogens produce siderophores to bind iron

• Iron needed for pathogens to continue → iron is binded and out of reach from pathogens → pathogens die

Antimicrobial peptides (AMPS)

• 12-50 amino acids long, AMPS have a broad spectrum of activity

  • Synthesis triggered by protein, carbohydrate molecules on microbial cell surface → disrupts microbial membranes

  • Act against bacteria, viruses, fungi, eukaryotic parasites

  • Kill by lysing cells, inhibiting cell wall synthesis; hydrolyzing DNA, RNA

  • Also attract dendritic cells, mast cells