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system that enables us to resist infections and resist damage from foreing substances
what are the two major subdivisions/categories of the immune system and what's the difference?
- 1. innate or non specific resistance:
- -mechanical mechanisms: prevent entry or remove microbes... skin, tears, saliva, mucous membranes, mucus
- -chemical mediators: promote phagocytosis and inflammation
- -cells: involved in phagocytosis and production of chemicals
- 2. adaptive or specific immunity:
- -specificity: ability to recognize a particular substance
- -memory: ability to remember previous encounters with a particular substance and respond rapidly
non-specific defenses vs specific defenses
- non-specific defenses-born with it
- -first line of defense
- -always involved
- -limited action
- -prevent the approac
- -deny entry
- -limit the spread
- specific defenses-acquired
- -called into action if needed
- -not always involved
- -discriminating and specific
- -knock off invaders that breached the non-specific defenses
what are the 7 categories of NON-specific defenses?
- 1. physical barriers: prevent approach of and deny acces to pathogens
- 2. phagocytes: remove debris and pathogens (fixed macrophage, neutrophil, free macrophage, eosinophil, and monocyte)
- 3. immunological survailance: destroys abnormal cells (nk cell)
- 4. interferons: increase resistance of cells to viral infection; slow the spread of disease (released by activated lymphocytes, macrophages or virus-infected cells)
- 5. complement system: attacks and breaks down cell walls; attracts phagocytes; stimulates inflammation
- 6. inflammatory response: multiple effects... MAST CELL --> (1) increase blood flow, (2) phagocytes activated, (3) capillary permeability increased, (4) complement activated, (5) clotting reaction walls off region, (6) regional temperature increased, (7) specific defenses activated
- 7. fever: mobilizes defenses, accelerates repairs, inhibits pathogens
first line of defense: physical barriers... just overview of skin and mucous membranes...
- skin is most visible barrier
- covers majority of surfaces in obvious contact with environment
- mucous membranes = barrier that lines digestive tract, respiratory tract, and genitourinary tract (mucus protects these surfaces from infections)
-how is it a physical barrier?
-how is it a chemical/microbial barrier?
- 1. physical barrier
- a. epidermis: mutiple layers for protection, outer layer is mostly dry (keratin)
- -tightly connected together and to underlying basal lamina
- -takes 15-30 days for skin to be removed... if pathogen is stuck to skin, it will be rubbed of when top layer comes off
- b. hairs: protect against abrasion and direct contact with skin
- 2. chemical & microbial barriersa. lysosomes, phosphoplipases
- b. lactic acid and fatty acids
- c. normal skin flora
- -dermis contains a lot of sebacious glands that are associated with hair follicles that produce CEBUM
- -cebum comes with lactic and fatty acids that decrease skin pH and makes it harder for pathogens to live in that environment
BARRIER: mucous membranes
-how is it a physical barrier?
-how is it a chemical/microbial barrier?
- 1. physical barrier:
- -covers "external" inner layer not covered by skin
- -not as hearty as skin; moist and delicate epithelia
- -flow of fluid washes epithelium
- 2. chemical & microbiological barrier:
- -mucus: traps & transports, lysozymes, phospholipases
- -chemicals: HCl
- -normal mucosal flora
mucus membranes in respi tract, gi tract, eyes and urogenital tract
- respiratory tract: mucus (flow and antibacterial enzymes), cilia, nose hairs, couging and sneezing
- gastrointestinal tract: saliva (flow and antibacterial enzymes), gastric acid, mucus (stomach and intestine), digestive enzymes, peristalysis, gi flora, vomiting & diarrhea
- eyes: tears (flow and antibacterial enzymes)
- urogenital tract: pH, urine flow, one-way valve, vaginal flora
first line of defense: antimicrobial substances
- antimicrobial substances are found on both skin and mucus membranes to protect them from a variety of antimicrobial substances including...
- lysozyme: enzymes that degrade peptidoglycan; found in tears, saliva, blood and phayocytes
- peroxidase: breaks down hydrogen peroxide to produce reactive oxygen; found in saliva, body tissues and phagocytes
- lactoferrin: sequesters iron from microorganisms... iron is essential for microbial growth; found in saliva, some phagocytes, blood and tissue fluids
- defensins: antimicrobial peptides inserted into microbial membrane... small peptides that can poke holes on microbial membranes; found on mucous membranes and phagocytes
contain granules that contain cytotoxic compounds; secretory vesicles and lysosomes
- the -phils... basophil, eosinophil, neutrophil
what is degranulation? and what are the two different ways?
- degranulation: loss of cytotoxic granules during attack
- 1. granules fuse with vesicle containing engulfed bacteria (phagolysosome = what's formed when granules combine with bacteria)
- 2. granules are exocytosed... eosinophils (exocytose toxic compounds such as nitric oxide and cytotoxic enzymes... eosinophils are known to fight worms, can't really engulf worms so it attacks it by shooting granules at it)
- the different pathways depend on size of what they're trying to target
neutrophil granules (4)
- 1. superoxide and hydrogen peroxide (H2O2): respiratory burst- accompanies production of highly reactive oxygen species, consumption of O2 increases during generation of ROS... increase metabolic rate and consumption of O2 to increase production of highly reactive O2 species when it combines with antigen
- 2. defensins: creates holes in pathogens... small peptides that envelop the pathogen, forms channels... will hit anything, attack and fill a whole in it
- 3. neutrophil elastase: degrade microbial cell membrane
- 4. prostaglandins & leukotrienes: increase vascular permeability to recruit more WBCs to the crime scene
peroxidase, RNase (to kill RNA viruses), NO
- histamine (potent vasodilator)
- heparin (prevent coagulation to get inflammatory mediators in)
which cell types are phagocytes?
- never eat monkeys
- neutrophils, eosinophils and monocytes/macrophages
term: phagocytes responding to domestic disturbances (cellular debris) and foreign invasion (foreign particle, pathogen) by engulfing material
- 1st line of cellular defense
monocyte vs macrophage
-location and lifespan?
- monocyte: circulate blood and lymphy... 24 hrs in circulation... migrate to tissue and are now called macrophage... large with large kidney shaped nucleus, uses bloodstream for transport but only there for 24 hrs
- macrophage: differentiated monocytes located in tissue... lifepsan = MONTHS! can be fixed or free
- when monocytes become macrophages they get larger, they're intracellular organelles increase, increase phagocytotic activity, may start secreting soluble factors, so not just a name change... monocytes are very aggressive phagocytic cells once they get into tissue
fixed marophage vs free macrophage
- fixed macrophage: ~immobile resident of tissues (kind of immobile but will move out of the tissue if they have to)
- present in most tissues but may have special names... liver = kupffer cells, cns=microglia
- free macrophage: mobile resident of tissue/travel to the crime scene... wandering macrophage
- -present n most tissues.. lung = alveolar macrophage, abdominal cavity = peritoneal macrophage
overview of monocyte/macrophage functions (2)
- 1. secrete cytokines and chemokines-attract others to crime scene (chemotaxis)
- -chemokines = cytokines that cause chemotaxis.. will make the macrophage attracted to that particular substance
- 2. antigen (Ag) presentation-present a piece of engulfed pathogen (Ag) on cell surface to 'specific immune cells'
- -"professional" anitgen-presenting cell
- -linkage to specific immunity
- -when a macrophage engulfs a pathogen, the pathogen will have antigen on it (impt for specific immune cell) but macrophages bridge non-specific immune system and specific immune system
- -just know that macrophages don't just spit up antigen but they're wrapping it in a bow... will discuss later
- -besides just phagocytosing, they take up antigen, break it up and present it to MHC (major hisocompatibility complex)
macrophages have receptors for: (4)
- 1. lipopolysaccaride: gram negative bacteria
- 2. peptidoglycan: gram positive bacteria
- 3. mannose: sugars on bacteria
- 4. scavenger receptors: gram -&+ bacteria, other targets
term: on macrophage, recognizes gram - & + bacteria, LPS, flagellin, dsRNA... resulting in activation of NFkB and transcription of cytokine genes
- TOLL-LIKE RECEPTORS (TLR)tlr are also found on dendritic cells, neutrophils, nk cells, mucosal epithelial cells and endothelial cells
- you have tlrs on macrophages that recognize both GP and GN bacteria and fungi
- similar in how extracellular domain is leucine rich BUT have a broad range of specificity... recognizes certain things about different pathogens, turn on transcription and call in other players
what two things enhance recognition of macrophage to antigen?
- 1. pathogen marked with COMPLEMENT... macrophages have complement receptors!
- 2. pathogen marked with ANTIBODY (Ab)... macrophages have Fc receptors
- so antibody has two receptors... one that can bind complement receptor and one for Fc receptor... both help macrophage bind to antigen
term: process where the pathogens are tagged with compounds that make them more attractive to pathogens (ex. complement or antibodies)
- anything that makes a pathogen or particle more readily phagocytized
- pathogen has receptors for complement and Fc portion of antibody and are therefore more likey to attack that compound
describe the steps of phagocytosis
- phagocyte recognizes and attaches the bad guy
- psuedopodia (cytoplasmic extensions) endocytose foreign object
- then surround object to form phagosomephagosome fuses with lysosome to make phagolysosome (acid, no, defensins, digestive enzymes and H2O2)
- foreign object is degraded and contents of phagolysosome are exocytosed
- antigen fragments are presented on the macrophage membrane!!!
next step... what happens when the macrophages have the antigens on their cell surface?
- ANTIGEN PRESENTATION
- macrophage express class II major histocompatiblity complex (MHC) on their cell surface and are therefore 'professionals' at presenting antigen to lymphocytes
- macrophages travel to secondary lympjhoid tissue and present antigen fragments to lymphocytes via MHC II
- ex of lymphoid tissue = lymph nodes and splee
- initiate adaptive, specific immune response
- so part of antigen is exocytosed and absorbed in lymph system... MHC class II acts like a hotdog bun and presents the leftover to T cells... macrophage will travel to lymphoid tissue and bring it to lymphocytes in lymph tissue... start ball rolling for specific immunity
term: circulating PMNS and monocytes response to signals generated at site of infection... process when phagocytes leave the circulation and enter the tissue
- monocytes cross to become macrophage
- activated phagocytes cross in response to inhury/infection
what are the 4 stages of diapedesis?
- 1. activation
- 2. margination
- 3. adhesion
- 4. extravasation
what happens at the first stage of diapedesis: activation?
- activated phagocytes and damaged tissue secretes cytokines/chemokines
- chemokines increase expression of cellular adhesion molecules (CAM) on circulating phagocytes and endothelial cells
- endothelial cells will express I-CAMs and selectin receptor
what happens at the second stage of diapedesis: margination?
selectin on phagocytes weakly bind to selectin receptors on endothelial cells and cause phagocytes to slow down and roll along endothelium (rolling)
what happens at the 3rd stage of diapedesis: adhesion?
- ingerin CAMs are now expressed (phagocytes and endothelium) which ahve stronger bonds
- causing phagoyctes to stop rolling and adhere to endothelium
- adhered phagocytes hears "the call" to enter damaged tissue
- chemotaxis: movement towards a stimulus, chemical gradient, pathogen or host produced
what happens at the 4th stage of diapedesis: extravasation?
- migration out of blood vessels
- how? chemokines result in changes in...
- (1) cytoskeletal proteins (psuedopodia)
- (2) relax junctions between endothelial cells
constant monitoring by natural killer cells; monitoring in peripheral tissues (recognizing and destroying abnormal cells when they appear); destruction of abnormal cells expressing abnormal surface antigens
characteristics of NK cells?
- nks are great as a 1st defense & constant surveyors (bec they are less selective than t cells)
- nk cell assault is quicker than t or b cell mediated attack (bec nks don't need antigen-presentation process and they respond immediately)
- nk cells will attack ANY abnormal membrane (very versatile)
describe NK cell activation steps
- 1. abnormal surface markers stimulates nk cell to adhere to abnormal celll
- 2. golgi apparatus turns to face abnormal cell, produces vesicles containing perforin
- 3. exocytosis of vesicles... perforins diffuse to abnormal cell... perforins form a pore on cell surface... granzymes are proteases from nk that enter abnormal cell and causes protein denaturation!
- 4. annihilation of abnormal cell
- -protectin released on surface that binds perforin... so that perforin doesn't poke nk cell
what does the complement do?
- it "complements" the actions of antibodies
- 20 protein/protein classes
- synthesized in the liver
- reside in inactive form in the serum
- complement proteins interact with each other to cause a cascade rxn
describe some actions of activated complement proteins: C5a, C3a/C5a, C3b, C5-C9
- C5a: increase histamine release from mast cells/basophils
- C3a/C5a: attract phagocytes to injury
- C3b: increases binding for phagocytosis
- C5-9: destroy cell membranes
- a=other activity
what are the 3 effects of the complement cascade?
- 1. enhance inflammation
- 2. enhance phagocytosis
- 3. lysis of target cell
classical complement pathway vs alternative complement pathway
- classical pathwayeffective, rapid activation
- begins when C1 binds to an antibody that's presently bound to its antigen
- C1 becomes activated
- activated C1 acts like an enzyme an sets off cascade reaction with oter complement proteins
- ultimately leads to activation of C3 (aka C3b)
- alternative pathwayless effective, slower activation
- antibodies NOT involved
- surface of microbe, venom, etc result in enzymatic interactions between C3, properdin and factors B&D
- ultimately leads to activation of C3 to C3b
what does C3b result in? what does it form?
- C3b results in formation of Membrane Attack Complex (MAC)
- C3b binds to C6,7,8,9 sequentially... these insert into the bacterial membrane to form MAC
- MAC is lipophilic
- leads to pore formationin pathogen
- causes lysis of pathogen
what are the 4 cardinal signs of inflammation?
- 1. swelling (tumor)
- 2. redness (rubor)
- 3. heat (calor)
- 4. pain (dolor)
why is mast cell so important? what do mast cells release?
- mast cells are impt in inflammatory response and mast cell degranulation results in release of histamine & prostaglandins, and heparin
- histamine & prostaglandin: increase vascular permeability and blood flow... which then increase the ability of phagocytes, complement and clotting factors enter area
- rubor, calor causes increase enzyme activity, increase phagocyte ctivity, denature and remove foreign proteins
- tumor, dolor causes swelling and pain due to above
- heparin: delays clotting until the necessary players can enter the damaged site and do the work