MMI 133 Part 2.1

• The body's defense system against: Pathogens, cancers, organ transplants
• Functios to Keep microorganisms out, remove microogansims that get in, combat microorganisms that remain inside, fight cancer (mutated/transformed cells)
• Well balanced immune system should be able to: distinguish between SELF and NON-SELF

Distinguish between SELF and NON-SELF

• 1 st Line (Innate/Natural Immunity, non-specific responses): skin, mucuous membranes & secretion, normal flora
• 2 nd Line (also innate): Innate immune cells, inflammation, complement, antimicrobial substances
• 3 rd Line (Adaptive/Acquired Immunity, specific responses): Specialized Lymphocytes 1. B cells (produce antibodies) 2. T cells A. Helper T cells, B. Killer T cells

The physical barrier

• Thin and permeable barriers **line the respiratory, gastrointestinal (GI), and genitourinary tracts
• Mechanical Removal ciliated cells in the respiratory tract (ciliary escalator); goblet cells produce mucous; mucous/other secretions flush away microorganisms; prevent pathogen binding to host cells

• Flushing action of prevents infection
• Tears, saliva (lysozyme, breaks down peptidoglycan)
• Crevicular fluid, (flows into gingival crevice between teeth, similar composition to blood serum)
• Gastric juice (pH 1-2)
• Urine/vaginal secretions

• Compete for space and nutrients
• In the mouth (Staphylococcus epidermidis, Streptococcus salivarius, Lactobacillus sp), skin (Staphylococcus epidermidis, Candida albicans) and lower GI (Escherichia coli, Lactobacillus sp.)

• *Neutrophils (PMNL)
• Macrophages
• Dendritic cells
• *Basophils
• *Eosinophils
• Mast cells
• These cause direct destruction of pathogens
• Natural killer cells -> Destroy infected host cells (intracellular bacteria, virus or transforming cells)

• 60-70% of total WBC
• "eat cells" (phagocytosis)
• Fast moving, short life span ~ few days
• First to arrive and dominate initial phagocytosis at the infected site
• Have granules that contain anti-microbial proteins and inflammatory mediators

• 3-8% of total WBC
• Professional phagocytes (very efficient)
• Eat pathogens & damages cells
• In circulation -> called monocytes
• In tissue -> called macrophages (many types)
• Neutrophils are first to arrive, bu the macrophages are already present
• Can break down the infectious pathogen to peptides and bind these on it's surface (Antigen presenting cell or APC)

Macrophages that are in circulation

Macrophages in tissue

• Professional antigen presenting cell (APC)
• Phagocytic
• Important role inactivation of adaptive immunity (specific immune response)
• Presents peptides from organisms to lymphocytes to kick start the adaptive system

• Major role in defense against parasitic infection
• "spit out" cytolytic enzymes upon contact with pathogens
• Cells circulated in blood until recruited to inflamed tissue

• Most abundant in submucosal tissues
• Cell surface receptor for immunoglobulin E (IgE)
• Important role in allergic reactions
• Release histamine once IgE receptor is activated

• Found in blood
• Similar function to mast cells
• Release histamine from granules

• Lymphocytes that do not have memory
• First line of defense against intracellular pathogens: virally infected cells, intercellular bacteria/protozoa, tumor cells
• Release cytolytic granules = target cell destruction
• Kill infected host cells
• Kill cancer cells (cells that have lost surface expression of MHC class 1)

• "displays" self (self-peptides) normally; pathogen derived peptides in infection
• Expressed on all nucleated cells
• Provides a way for Tc cells to scan and detect intracellular infection
• Many viruses are able to decrease MHC class 1 expression to try to avoid detection by T cells
• But - the organisms are not that smart! (NK cells then detect these cells that lack MHC class 1 and kill them)
• All our cells have MHC

• Antigen presentation
• Found only on phagocytes (antigen presenting cells or APCs)
• Only macrophage and dendritic cells have this

These are digestive enzymes that breakdown endocytosed pathogens

• Phagocytosis, contain digestive enzymes (lysozyme) to breakdown endocytosed pathogen
• Neutrophil, Macrophage, and Dendritic cell

• Function to kill pathogens that are too big to eat (parasites)
• Contain chemical messengers that attract other immune cells (chemokines)
• Some contain inflammatory mediators (histamine)
• Neutrophil, Eosinophil, Basophil

Chemical messengers that secretory granules use to attract other immune cells

• 1. Mirgination
• 2. Diapedesis
• 3. Chemotaxis
• 4. Phagocytosis

Neutrophils get a chemical signal while they are in the blood vessels, marginate and stick to blood vessel walls

movement of cells out of the blood vessels by squeezing out through gaps in cells into tissues to track down the intruder

Directed movement of phagocytes towards a chemical gradient set up at the site of intectio or trauma

"phago" = eat and cyto = cell; ingestion of pathogens

• "immune defensive response to infection or physical agents"
• Breaching the first line of defense by physical trauma

• Swelling
• Heat - increased blood flow into site of injury
• A
• Redness - vasodilation
• Pain - pain on nerve cells

• Localized (cuts)
• Systemic (fever)
• Acute (trauma; S. aureus)
• Chronic (arthritis; M. tuberculosis)

• Damages cells release chemicals (like histamine)
• Histamine causes blood vessels to dilate (vasodilation)
• Expanding blood vessels get leaky; permeability increases
• Fluids move from blood into damaged area (edema)

• Protein rich fluid which oozes into tissue or on surfaces
• Also called inflammatory exudate
• Usually means that there is a local cause of inflammation

• Protein poor water fluid entering tissues causes swelling
• Usually due to systemic factors (eg. hemodynamic factors)

Exudates and transudates may form a fluid collection in a body space

• May develop 'abscesses' which are formed in a space formed from tissue destruction
• Or 'empyema' in a body space (eg. in pleural space of the chest between pleural membrane and lungs

• Fibrinous
• Purulent
• Hemorrhagic

formed in a space formed from tissue destruction

• in a body space
• eg. pleural space of the chest between pleural membrane and lungs

• Neutrophils are the defining cell of the inflammatory infiltrate (PUS)
• Specialized to go to site of tissue injury and infection
• Detect formylmethionine on bacterial proteins
• Chemotaxis: directed migration of a cell to a chemical gradient (eg. C5a)
• Ingest and digest pathogens

• Takes longer to develop (days to months instead of hours)
• More likely to involve specific recognition of pathogens (not the innate immune system)
• Cell infiltrate is mainly mononuclear; so monocytes, macrophages and lymphocytes
• Granuloma formation is typical
• More likely to have permanent damage to tissue

• Localized collection of mononuclear phagocytes
• Seen in TB and in fungal infections
• Also a characteristic of Crohn's disease and sarcoidosis
• Wall off infections from rest of body

• Toll-like receptors (TLRs) (also called pattern recognition receptors or PRRs)
• Recognize pathogen -associated molecule patterns (PAMPs) on microorganisms surface
• PAMPs: include lipopolysaccharide (LPS), peptidoglycan, flagellin, dsRNA and More!
• COMPLEX SIGNALING!!

Toll-like receptors, recognize pathogen-associated molecular pattern on microorganisms surface

Pathogen-associated molecular patterns; include lipopolysaccharide (LPS), peptidoglycan, flagellin, dsRNA and more!

• 1. chemokine release - calls in help from the circulation
• 2. proinflammatory cytokine release - activate neighbouring cells
• 3. increased microbiocidal activity - destroy ingested pathogens

A group of serum proteins produced by the liver in the circulation to destroy pathogens (when pathogens get into the circulation)

A substance, usually foreign, capable of provoking an immune response

The specific site on an antigen recognized by immune cells or antibodies

(aka. immunoglobulin or Ig). Protein produced by B-cells that recognizes a specific epitope or an antigen: leads to clearance of that antigen

• 1. Classical pathway
• 2. Alternative pathwas
• 3. Lectin pathway

• Consists of: >30 plasma proteins in an enzymatic cascade (produced by liver)
• Activated by: eg. LPS, antibody-antigen complex (alternative and classical pathways respectively)
• Alternative pathway has a cascade of things that chop up each proteins, causing the cells to swell and burst when C5b, C6, C7, C8 and C9 together form the membrane attack complex

• Membrane attack complex
• Result: LYSIS of cell!
• pore structure formed (MAC) which allows fluid (water) to move freely across membrane

• Function of complement:
• opsonisation, inflammation and lysis

• Opsonication (C3b) - Coats bacteria to enhance phagocytosis
• Chemoattractant (C5a) - recruit phagocytes
• Anaphylatoxin (C3a, C5a) - cause histamine release
• Membrane attack complex (MAC) (C5-C9) - kills pathogens

• Antimicrobial peptides (AMPs)
• -sweat, platelets, neutrophils, macrophages
• -form pores in bacterial plasma membrane, inhibit cell wall synthesis, breakdown DNA/RNA
• Acute phase proteins
• -produced in the liver during infections: increased levels indicate infection
• -C-reactive protein (CRP) produced in liver marks bacteria for enhanced phagocytosis (aka opsonisation)
• Interferons:
• -Antiviral proteins produced during a viral infection by the neighbouring cells.