Innate Immunity

immunity

ability to ward off disease

susceptibility

lack of resistance to a disease

innate immunity

• defenses against ANY pathogen

• rapid

• present at birth

adaptive immunity

• immunity or resistance to a SPECIFIC pathogen

• slower to respond

• has a memory component

immunity diagram

1. pathogens (viruses, bacteria, fungi)

2. skin, mucous membranes, antimicrobial substances

3. inflammation, fever, phagocytes

4. humoral and cellular immunity

first line of defense (innate immunity)

• intact skin

• mucous membranes and their secretions

• normal microbiota

second line of defense (innate immunity)

• natural killer cells and phagocytic WBCs

• inflammation

• fever

• antimicrobial substances

third line of defense (adaptive immunity)

• specialized lymphocytes: T cells and B cells

• antibodies

when your body is challenged by microbes you are defended by

both innate and adaptive immunity

basophil

• innate granulocyte

• releases histamines that causes inflammation

eosinophil

• innate granulocyte

• kills parasites with oxidative burst

mast cell

• innate granulocyte

• antigen-presenting cell

• produce antibacterial peptides

• involved in inflammatory responses and allergic reactions

neutrophil

• innate granulocyte

• first responders

• phagocytizes bacteria and fungi

monocyte

• innate agranulocyte

• precursor to macrophages

• cause inflammation in organs and tissues

• perform phagocytosis

• present antigens to T cells

dendritic cell

• innate agranulocyte with surface projections

• phagocytizes bacteria in skin and respiratory/intestinal mucosa

• presents antigens to T cells

natural killer (NK) cell

• innate agranulocyte (lymphocyte)

• kills cancer cells and virus infected cells

dermis

inner portion of the skin made of connective tissue

epidermis

outer portion of the skin made of tightly packed epithelial cells containing keratin (protective protein)

skin as a physical factor

• shedding and dryness of it inhibits microbial growth

• formidable barrier → microbes rarely penetrate the intact healthy epidermis

• infections of the skin frequently occur as a result of burns, stab wounds, etc. that break the skin

mucus membrane as a physical factor

• epithelial layer that lines the gastrointestinal, respiratory, and genitourinary tracts

• mucus trap microbes and prevent tracts from drying out

ciliary escalator

transports microbes trapped in mucus upward toward the throat

lacrimal apparatus

drains tears; washed eye

epiglottis

prevents microorganisms from entering the lower respiratory tract

earwax

prevents microbes from entering the ear

urine

cleans the urethra via flow

vaginal secretions

move microorganisms out of the vaginal tract

peristalsis, defecation, vomiting, and diarrhea

expel microbes

chemical factors

• Sebum forms a protective film and lowers the pH (3–5) of skin

• Lysozyme (enzyme) in perspiration, tears, saliva, mucus, urine, destroys bacterial cell walls

• Low pH (1.2–3.0) of gastric juice destroys most bacteria and toxins

• Low pH (3–5) of vaginal secretions inhibits microbes

• Antimicrobial Peptides: small antimicrobial peptides; broad spectrum

  • e.g., Defensins

Iron-Binding Proteins

• Most pathogenic bacteria require iron for growth and reproduction

• Pathogens may compete with host for available iron

• Host proteins bind iron tightly with iron-binding proteins:

  • Transferrin: found in blood and tissue fluids

  • Lactoferrin: found in milk, saliva, and mucus

  • Ferritin: found in the liver, spleen, and red bone marrow

  • Hemoglobin: located in red blood cells

• Some bacteria produce siderophores to compete with iron- binding proteins

Antimicrobial Peptides (AMPs)

• Short peptides produced in response to protein and sugar molecules on microbes

• Broad spectrum of activity; innate immunity

• Over 600 different peptides have been discovered in plants and animals

  • Inhibit cell wall synthesis

  • Form pores in the plasma membrane causing lysis

  • Destroying DNA and RNA

• Examples:

  • Dermcidin (by skin), defensins (by a wide range of cells), cathelicidins (by neutrophils, macrophages), thrombocidin (by platelets)

normal microbiota

• compete with pathogens via microbial antagonism (competitive exclusion)

  • competitive advantage for space and nutrients

  • produce substances harmful to pathogens

  • alter conditions that affect pathogen survival

  • prevent the overgrowth of harmful microbes

  • play and important role in the development of the immune system

commensalism

one organism benefits while the other (host) is unharmed

opportunistic pathogens among the normal microbiota

e.g. E. coli, S aureus, S. epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa and oral streptococci

probiotics

live microbial cultures administered to exert a beneficial effect

prebiotics

chemicals (nutrients) that selectively promote the growth of beneficial bacteria

formed elements in blood

• cells and cell fragments suspended in plasma

  • erythrocytes (RBCs)

  • leukocytes (WBCs)

  • platelets

• created in red bone marrow stem cells via hematopoiesis

  • forms either myeloid progenitor cell (becomes innate immunity cells) or lymphoid progenitor cells (becomes adaptive immunity cells)

granulocytes

• leukocytes with granules in their cytoplasm that are visible with a light microscope

  • neutrophils: highly phagocytic → most active in early stages of infection

  • basophils: release histamine; work in allergic responses

  • eosinophils: phagocytic; toxic against parasites and helminths through oxidative burst

agranulocytes

• leukocytes with granules in their cytoplasm that are NOT visible with a light microscope

  • monocytes: mature into macrophages in tissues where they are phagocytic

  • dendritic cells: found in the skin, mucous membranes, and thymus; phagocytic

  • lymphocytes: T cells, B cells, and NK cells; B and T cells play a role in adaptive immunity

the lymphoid system

• consists of:

  • lymph

  • lymphatic vessels

  • structures and organs containing lymphoid tissue

  • red bone marrow and thymus

• lymphoid tissue contains lymphocytes and phagocytic cells

• lymph carries microbes to lymph nodes were B and T cells, macrophages, and dendritic cells encounter and destroy the pathogen

steps of phagocytosis

1. chemotaxis

2. adherence

3. ingestion

4. digestion

chemotaxis of phagocytosis

• chemical signals attract phagocytes to microorganisms

• include microbial products, components of WBCs, damaged cells, complement

adherence of phagocytosis

• attachment of a phagocyte to the surface of the microbes or other foreign material

• PAMPs (pathogen associated molecular patterns) on microbes attach to TLRs (Toll- like receptors) on phagocyte surfaces

  • Examples of PAMPs: LPS, flagellin, peptidoglycan, bacterial DNA, viral DNA and RNA

• opsonization: microorganism is coated with serum proteins, making adherence easier

  • opsonins include complement components, antibodies

ingestion of phagocytosis

• pseudopods (cytoplasmic projections on the phagocyte) extend out and engulf the microbes or particles

• engulfed microorganism is enclosed in a phagosome

digestion

• lysosomes fuse with phagosome → forms phagolysosome

  • lysosomes provide numerous enzymes and toxic oxygen products (oxidative burst)

• microorganism is digested inside the phagolysosome

• indigestible material forms a residual body that is removed from the cell by exocytosis

inflammation

• a local defensive response triggered by damage to tissues

  • damage may include microbial infection, physical agents (heat, electricity, sharp objects) or chemical agents, acids, bases, gases)

  • signs and symptoms (PRISH) → pain, redness, immobility, swelling, heat

• functions

  • eliminate injurious agent, or

  • limits its effects of injurious agents on the body

  • repairs and replaces tissue damaged by the injurious agent

  • if dysregulated or prolonged, it can contribute to tissue pathology and disease

process of inflammation

1. vasodilation and increased vascular permeability

   1. vasoactive mediators

2. phagocyte migration and phagocytosis

3. tissue repair

acute inflammation

develops rapidly, last for few days to few weeks

chronic inflammation

• develops more slowly

• lasts months to years

• may be severe and progressive

• often becomes detrimental

• ex: granulomas formed around the bacteria to contain the infection in tuberculosis

key events in the process of inflammation

1. chemicals released by damaged cells cause vasodilation and increased vascular permeability

2. vasoactive cytokines are also released by activated macrophages

3. cytokines are part of a positive feedback loop, stimulating cells to release more cytokines

4. vasodilation: blood vessels dilate immediately after tissue injury

5. increased permeability of blood vessels: enables defensive substances and cells to pass through vessel walls to the injured area

6. margination is the sticking of phagocytes to blood vessels of endothelium in response to cytokines at the site of inflammation

7. phagocytes squeeze between endothelial cells of blood vessels via Diapedesis

8. phagocytosis

   • pus forms

9. tissue repair phase

   • scar may be formed by fibroblasts

fever

• abnormally high body temperature

• the hypothalamus is normally set at 37 degrees Celsius

• cytokines released from endotoxins travels to the hypothalamus → causes it to release prostaglandins: set the hypothalamus to a higher temp

• body maintains the higher temp until cytokines are eliminated

• a chill indicates a rising body temp

• when body temp falls (crisis) → causes vasodilation and sweating

fever can be considered a defense up to a certain point

• phagocytes and T cells work better at a slightly higher temp

• higher temps intensify the effect/production of antimicrobial substances → like interferons, transferrins

• higher temps may slow the growth of pathogens

• increased metabolic rate speeds repair processes

complications of fever

• tachycardia, acidosis, dehydration, seizures, coma

• body temp greater than 44-46 degrees C is FATAL

the complement system

• system of over 30 serum proteins produced by the liver that enhances the immune system in destroying microbes

  • act in a cascade in a process called complement activation

• proteins are designated with an uppercase C and numbered in order of discovery

  • activated fragments are indicated with lowercase a and b

• 3 pathways (classical, alternative, lectin) reach a common point where they activate C3, which splits into activated C3a and C3b

• part of the innate immune system → BUT it can be recruited by the adaptive immune system

• lack of complement proteins causes susceptibility to infections

the classical pathway

initiated by antigen-antibody complexes → activates C1

• C1 splits and activates C2 and C4

  • C2 splits into C2a and C2b

  • C4 splits into C4a and C4b

• C2a and C4b combine and activate C3

  • C3a: functions in inflammation → smaller fragment

  • C3b: functions in cytolysis and opsonization → larger fragment

the alternative pathway

activated spontaneously by the hydrolysis of C3

• C3 present in the blood combines with B, D, and P factors on the surface of the microbe

• C3 splits into C3a and C3b → does the same as the classical pathway

  • inflammation (C3a) and cytolysis/opsonization (C3b)

the lectin pathway

triggered by the recognition of microbial carbohydrates (mannose) by mannose-binding lectin (MBL)

• macrophages ingest pathogens → release cytokines that stimulate lectin production in the liver

• MBL (lectin) binds to mannose on bacteria and some viruses → activates C2 and C4

• C2 splits into C2a and C2b

• C4 splits into C4a and C4b

• C2a and C4b combine and activate C3

  • C3a: functions in inflammation

  • C3b: functions in cytolysis and opsonization 

cytolysis

activated complement proteins create a membrane attack complex (MAC) that can lyse targeted cells

• C3 starts → not part of MAC but splits to form C3b

• C3b attaches to the microbe

• C3b helps build C5 convertase (enzyme complex)

• C5 convertase cleaves C5 → makes C5b

• C5b starts the MAC ring formation → ring of C5b, C6, C7, C8, C9

• MAC ring inserts into pathogen’s cell membrane → acts as a pore

• pore lets lots of water and ions rush in → microbe swells and bursts (cytolysis)

opsonization

process where microbes are coated with molecules that make them easier for phagocytes to recognize and attach

• ex: coating microbes with C3b molecules so that the CR1 receptor of a phagocyte can recognize it

inflammation

activated complement proteins bind to mast cells, causing them to release histamine and other inflammatory cytokines

• any of the 3 pathways occur → eventually C3 is split into C3a and C3b

  • C3a → binds to receptor to cause inflammation

  • C3b: functions in cytolysis and opsonization 

    • attaches to microbe → helps form C5 convertase

  • C5 convertase cleaves C5 → makes C5a and C5b

    • C5a → strong inflammation

    • C5b → begins MAC ring formation for cytolysis

interferons (IFNs)

• cytokines produces by host cells → have antiviral activity

• NOT virus-specific

• 3 types

  • IFN-a and IFN-b: produced by virus-infected host cells through IFN-mRNA

    • cause uninfected neighboring cells to produce antiviral proteins (AVPs) that inhibit viral replication (inhibit protein synthesis)

      • aka warns them to protect themselves BEFORE they get infected 

  • IFN-y: made by immune cells to activate other immune cells (like macrophages) to kill bacteria