Module 2, pt. 1: Inflammation and immunity alterations (Ch. 7, 8 and 9)

Video lecture

1st line of defence

• physical and mechanical barriers
• biochemical barriers
• normal microbiome

2nd line of defence

• inflammation

inflammation

• quick, nonspecific, localized most of the time
• goals; in order
  • neutralize, limit cause of injury
  • clean (phagocytosis)
  • heal

response

• injury = vasodialation = release of cytokines (controls other immune cells) = endothelial cell contraction and leukocyte diapedesis (passage of blood cells through capillaries) = allow passage of leukocytes (including macrophages) in to site where injury happened = phagocytosis, removal, neutrolizing = activation of adaptive immunity

inflammatory and immune cells

• neutrophils
  • neutralize destroy
  • capture and destory invading bacteria or microorganisms by ingesting
  • travel through blood stream and will know how to exit through the injury site
  • body will react with inflammation
• monocytes
  • later become macrophages (eats microorganisms) or dentritic cells (antigen presenting, informs to fight pathogens)when invading a germ or bacteria entered in body
  • either kill it or alert other blood cells to help kill it
  • experts on phagocytosis
• eosinophils
  • allergies
• lymphocytes
  • lymphocyte

inflammatory cells in action: neutrophils and macrophages

• cell injury activates tissue macrophages
• produces cytokines
  • small proteins that sends a message to endothelial cells to sticky to white blood cells
• neutrophil will bind and migrate towards activated macrophages through chemotaxis
• macrophages to attract neutrophils and they'll know where to go
• between the neutrophils an macrophages, phagocytosis happens
  • eat bacteria, in to phagosome
• recognition and attachment
  • opsonization
    • when phagocytosis is coded by antibodies of compliment proteins that will help macrophages phagocytosis better
    • it tags pathogens so neutrophil and macrophages can find them easier
    • without opsonization (immunocompromised), phagocytosis will still happen but just inefficently
    • without complement proteins (liver disease), less efficient inflammation

the compliment system: helping the inflammatory cells

• compliment produces opsonization
• a bunch of proteins that are all produced by liver
• latent in plasma normally as long as we have healthy liver
• gets activated by bacteria, antibodies, pathogens
• when activated, cascade of activations
  • induces chemotaxis, attract neutrophils in injury site
  • polymerize, membrane attack complex: polimer of proteins binding to bacteria and opens a hole in the bacteria (destroys it)

chemical mediators of inflammation

• vasodilation
  • prostaglandin
    • produced during inflammation
    • vasodilators
    • inhibit with asprin
  • histamine
    • increases vascular permeability
    • anti histamine for allergies induces vasoconstriction
  • nitric oxide
• pain
  • prostaglandin
    • activates nociceptors
    • aspirin is an analgesic blocks pain similar to inflammation
• fever
  • systemic effect
  • IL-1, IL-6, TNF and prostaglandis are produced
  • can escape inflammatory site and in to bloodstream, up to brain stem
  • brain stem is where thermoregulation is
  • fever is good, other enzymes for metabolism thats not essential will slow down, give time for body to regroup
• wound healing
  • relate to production of collagen and new blood vessels
• phagocytosis
  • ways to increase

acute inflammatory response

• tissue injury = activation of macrophages = produces cytokines, inflammatory mediators = redness, swelling, pain
• can also activate blood vessels to make sure the cells needed arrive = vasodialators

chronic inflammatory response

• acute inflammation = resolution = termination of inflammation = homeostasis
• ineffective resolution/persistent injury = contiuation of inflammatory process = chronic inflammatory disease
  • ex. arthritis, TB, tendinitis

chronic inflammatory response

• neutrophils will keep going = they ask for help from lymphocytes and fibroblasts = lymphocytes will try to isolate the acute inflammation happened = if not resolved, fibroblasts deposits collagen to the inflammatory site, seals it off = can sometimes lead to deformation of scars

phases wound healing

1. clotting to stop bleeding
2. inflammation to clean up the mess and neutralize (neutrophils, lymphocytes, macrophages)
3. inflammation will decrease and heal through proliferation (rapid reproduction of cells)
   1. angiogenesis: formation of new blood vessels
   2. fibroblasts: produces collagen
   3. granulation tissue: the wound rebuilding itself from the bottom up. it also protects the surface from microbial invasion and more injury
      1. what someone wants to see clinically with wound healing
4. remodelling
   1. epithelium closes again
   2. when not ideal, scar formation or contracts

wound repair by primary intention

• edges are closely re-approximated, most of the time intentional
• most of the time, minimal scarring
• ex. sutures = fibrin clot = neutrophils will clean up and neutrolize = fibrobalst will start rebuilding from the floor up

wound repair by secondary intention

• when the wound had to be left open rather than being stitched together
• usually leaves a scar
• ex. necrosis = angiogenesis (formation of new capillaries) = macrophages cleans up = formation of granulation tissue (red, full of blood vessels, pushes upwards) = fibroblasts deposits collagen but might not know where to stop producing collagen = might leave a scar/keloid

Adaptive immunity

• lymphoid tissues
• thymus shrinks through puberty

overview of immune response

• two types of immuno response
  • cell mediated immunity
    • b and t cells formed in thymus
    • ready to detect a new antigen and differentiate that can help the immune response by remembering the antigen
  • humoral or antibody mediated immunity
    • produces in antibodies 5 different types
    • produced by plasma cells
      • differentiated B cells
      • differentiate to plasma cells
    • when exposed to antigen = B cells will look at the antigen and develop to plasma cells = plasma cells will produce antibodies specific to that antigen

humoral immunity response

• antibodies
• IgG and IgM are most common, look for it in the blood
  • exposure to vaccine = body is not use to it = immune system develops IgG and IgM so body will be prepared for REAL exposure
  • primary response: when we get vaccinated
  • secondary response: being exposed to the real thing. its faster
    • IgG is big, IgM is small = can cross the placenta, passive immunity to fetus in utero
• IgA
  • found in membranes in many epithelium
  • ex. crying, mucus, saliva, human milk
  • this is another way to give passive immunity to baby
• IgE
  • allergies

functions of antibodies

• why is it good?
  • neutrolizes viruses
  • neutrolizes toxins (even bacterial) ex. tetanus
  • complement mediated killing activated by antibodies (immune complex)
  • phagocytosis

cellular immunity

• cytotoxic T cells
  • can kill cells
  • ex. cancer cells, transplants
  • helped by T helper (Th1)cells. motivates other cells, orchastrating alot of the immune system
    • poroduces cytokines to make cytotoxic T cell be more efficient

Hypersensitivity

• anltered immonologic response to an antigen that results in disease or damage to the individual
• four types

1. IgE-mediated type 1

• allergies, anaphylaxis, athsma
• antigen detected by dendritic cells (antigen presenting cells) = presents itself to T helper cells = it stimulates formation og IgE antibodies, these antibodies bind to IgE receptors that are on top of mast cells (mast cells produce vasoactive mediators like histamine) = mucose secretion, smooth muscle spasm
• histamine blockers = no reaction

2. tissue specific type 2

• when specific cell gets targeted
• blood transfusion reactions, hymolytic disease of new borns
• wrong blood cells received = Igm and IgG will recognize its foreign = binds to it and activates the compliment = polymerizes and membrane attack complex (opens a hole in to the cell, osmoticlysis, destroying it)

3. Immune complexes mediated type 3

• immune complexes
• systemic lupus etithematosus, rheumatic fever, rheumatoid arthritis
• vascular plasma had immune complexes floating around = gets stuck in an organ by the organ trying to remove them = compliment will be activated = C5A will attract neutrophils = compliment activation inflammation

4. cell mediated type 4

• mediatedby the cytotoxic t cells, meant to kill other cells
• t cells get close to target cell = bind to it = produces perforin, opens the cell with a hole
• important with organ transplant
  • not compatible organ = immune system develop cytotoxic t cells = destroys the organ
  • transplant receivers need to me immunosuppressed

Module 2, pt. 2: AIDS

Immune deficiency: failure of immune or inflammatory response

• increased susceptibility to infections
• primary: genetic defect
• secondary: caused by another condition

opportunistic infections

• caused by non-pathogenic microorganisms, become pathogenic with immuno deficit human
• recurrent
• clinically atypical

primary immune deficiency

• rare, congenital
• ex. combined and antibody deficiency, immune dysregulation, phagocyte and innate immunity defects etc.

secondary immune deficiencies

• common, acquired
• ex. pregnancy, againg, psychological stress, trauma, dietary insufficiencies etc.,

HIV

• HIV: human immunodeficiency virus
  • attacks bodys immune system, can lead to AIDS when not treated
  • destroys CD4 T cells
• important molecules
  • RNA, reverse transcriptase (gives it pathogenicity, replicates in body), proteins (gp 120, gp41)
• life cycle
  • attaches to cells (proteins important) = lock to cell is protein CD4 = reverse transcription = integration of provirous (generic material of a virus) into host genome (haploid sets of chromosomes in microorganism) = synthesis of HIV proteins = assembly of virion core
  • T helper CD4 positive cells as main HIV target
    • perosn with HIV has less T helper cells = immunodeficient
• pathogenesis of HIV
  • HIV infects dentritic cells and Th in lymph nodes = burst of viremia (pressence of virus in blood) = infected Th cells circulate the blood = cytotoxic kill infected Th in circulation and in the gut = Th cells in get are also infected = reactivation of HIV replicaiton = HIV viral toxicity destroys bone marrow precursor cells = HIV infects memory cells (latency)
• clinical progression of HIV
  • 1-6 weeks, plasma viremia rises
  • viral replication neutralizes, latent (delay)
  • clinical goal is to keep someone latent, delay replication as much as possible
  • replication starts again when symptoms of AIDS begin
  • CD4 contiues to decrease
• how to know if HIV positive
  • looking for antibodies as they appear later and become stable
  • viruses aren’t present in latency so you cant find it
  • antibodies dont develop immediately

AIDS: Acquired immunodeficiency syndrome

• caused by HIV, late stage of the infection
• when CD4 is sevearly depleated
• clinical manifestation
  • 9000/mm3 WBC count (normal is 4000-11000)
  • opportunistic infections
    • protoza, fungi, bacteria, viruses
  • cancer
    • kaposi sarcoma (most common)
    • brain lymphoma
    • cervical cancer
  • fever means immune system is not severely altered since theres a response

Module 2, pt. 3: Infection

examples of emerging infections

• COVID from SARS-CoV-2
• “MAD COW” from prion

infection: key terms concepts

• pathogenicity: ability of an agent to produce disease by causing harm
• opportunism: benign microorganisms becomes pathogenic because of decreased human resistance
• virulence: capacity of a pathogen to cause severe disease
  • ex. ebola, cause death very fast
• agent-host: microorganisms pathogenicity combines with hose defence mechanism
  • combine with host defence mechanism
  • ex. covid after being vaccinated can cause mild disease since human defence mechanism is strong
• zoonosis: infections harbored in animals and spread to humans
  • ex. rabies

clinical stages of infection

• incubation period: between exposure to onset of symptoms
  • virus has entered but no symptoms yet
• prodomal stage: non specific infectious symptoms
• invation period: specific signs and symptoms
  • person can feel weak and fever then develop a more severe and specific
• convalescence: resolution and recovery
  • immune and inflam. sys. succeed

pathogenesis of fever and acute phase response

• infection = fever first symptoms
• pyrogen turns up temperature of the body, to the hypothalamus
  • TNF, IL1, IL6, IFN, PGE2
• elevating temp. cause febrile response
  • slows downbody so gives body enough time and activate other things for the recovery will be faster
• c reactive protein (CRP) is used as indicator that acute phase response is on
  • non specific

process of an infection

• colonization
  • contact and entry
• invasion
  • invade or evade
• multiplication
  • once they invade, they grow
  • viral replication
• dissemination
  • when it speads

biofilm

• bacteria can stay and hide and grow and disseminate in other areas
• mucus basically houses bacteria
• encourages recurrent infections
• ex. bronchial disease

classes of infectious microorganisms

• bacterial infections
  • no nucleus but nucletic acid
  • shape is cocci (round), bacilli (elongated), spirochetes (spiral)
  • gram positive vs gram negative
    • depending on cell wall
• lipopolysaccharides LPS: lipids with alot of sugar residues
  • present in outer membranes of gram negative bacteria
  • very toxic
  • activated macrophages easily
  • endotoxins, not released when bacteria is alive but when theyre dead
• bacteria can grow aerobic or anaerobic
  • anaerobic are more aggressive
• bacteriaemia
  • bacteria in blood
• septicemia
  • when bacteria causes infection’
• some bacterias can resist phagocytosis
  • can remain latent

stains

• gram positive is purple
• gram negative is pink

staphylococcus aurerus

• gram positive bacteria, non pathogenic but sometimes, it can become pathogenic
• depending on where it is and how affected the skin is, can cause different diseases
• produces exotoxins
  • its on the skin latent (nonpathogenic). when theres a wound, it can go in (pathogenic)
• the same bacteria either cause different diseases depending on where it is, resistance of host and if it produces exotixins or not

effects of pathogenicity by endotoxins from gram negative

• they have LPS in outer membrane of cell wall
• LPS activates macrophages, produces activation of cytokines
  • depending on quantity
  • low: cause local inflammation
  • moderate: fever
  • high: activate macrophages everywhere at the same time = inflammatory response everywhere (lungs, all blood vessels) = septic shock

fungal infections

• “mycoses”
• superficial
• nonpathogenic, nonaggressive microorganisms
• frequently opportunistic
• 2 types
  • molds
  • yeats: single cells

candidiasis

• superficial mycoses
  • doesnt cause disease
  • but immunosuppressent can cause mucosal infections
  • can be trated with anti micotic

parasitic infections

• protoza (uni cellular) vs helminths (multicellular)
• hosts: person that will develop the disease
• vector: one who houses the host
• life cycle: toxoplasmosis

malaria: parasitic disease

• affects red blood cells
• vector is mosquito
  • neutralize mosquito

viral infections

• obligatory intracellular microorganisms (really small)
• tissue specific
• cause disease by getting in to the cell
  • respiratiry virus can get in to the airways
  • hepatitis can get in to liver cells
  • herpes virus can get in to neurons
  • HIV can get in to T cells
• RNA or DNA and
• (the one who hold the “key” to get in to specific cells)

stages of viral entrance during infection of cell

• come with capsid with the fusion proteins (keys) = receptor mediated endocytosis = uncoats capsid = it goes in to nucleic acid = replicate and use the synthetic machinery of the cell to asssemble the virus = synthesize viral proteins = form new particles = the new particles and exit and the cycle continues

antigenic shifts in influenza virus

• viruses have a way to mutate that causes antigenic shifts
• viruses will have slightly altered genes and antigens, because of this they shift alot
  • different variants for covid
  • can be detected every year

Module 2, pt. 4: Coronoavirus

SARS: severe acute respiratory syndrome

MERS: middle east respiratory syndrome

CODIC-19: coronavirus disease 2019

Covid pathophysiology

• block spike from binding to ace2
  • spike protein becomes most important because it is the protein that allows virus to get in to cells but also for immunity
• Mrna teaches cells to produce spike proteins and create antibodies
  • worried about variants that change the spike protein = vaccinated people are no longer immune
• ill continue this later im too lazy rn

Module 2, pt. 5: stress and disease

stress response key terms

stressors

• physiologic and psychogenic
• general adaptation syndrome (GAS)
  • allows adaption to stressors, non specific
  • ex of signs: tachycardia, more alert
  • acute vs chronic
• GAS stages
  • alarm
  • resistance or adaptation
    • most common
  • exhaustion

general adaptation syndrome

• alarm phase
  • when body senses the stressor
  • generates flight or fight response
• resistance phase
  • stress remains, body adaps
  • remains on guard
• recovery phase
  • stress is removed
  • body functions return to normal
  • homeostasis
• exhaustion phase
  • stress continues
  • bodys resources to the combat is depleted
  • immune sys. compramaised
  • stress related illness can occur

good side of the stress spectrum

• spike in good/short term stress
• turns to bad stress when long term (chronic)
  • lifestyle factors
  • psychosocial buffers
  • activities
• goal
  • optimize good stress
  • maximize resting zone
  • minimize bad stress
• results
  • productive immunity
  • increase physical performance
  • increases health

allostasis: process of achieving homeostasis

• chronic social and envi. stress
• physiological stressors
• major life events and trauma
• depends ofn differences in vulnerability and behavioural response: adaptive or maladaptive
• result of this is achieving allostasis

diversity of responses to stress

• repeating stressor builds endurance
• repeating stressor can also lead to less adaptation
• stress might also get prolonged
• inadequate response

physiology of the acute stress response

• alarm reaction
  • neural (fast)
    • sympathetic response/fight or flight response
    • centered in brain stem
    • fight or flight response facilitated by the connection of the brain step to the adrenal medulla = release catecholamines, epinephrine and norepinephrine = generates response
  • hormonal (slow)
    • pituitary gland
    • hypothalamus = releases CRH (corticol releasing hormone) = anterior pituitary gland produces ACTH (adrenocorticotropic hormone) = this will go to the adrenal cortex = adrenal cortex will produce cortisol (glucocorticoids)
    • we need the slow one because corticoids morbilizes glucose
      • fight or flight response needs glucose

sympathetic nervous system response

• sympathetic activation (vasomotor tone) = adrenal medulla activation = increased strength
• sympathetic activation (vasomotor tone) = contraction of arteriolar smooth muscle = vasoconstriction = increased peripheral resistance = increased blood pressure

hormonal structures involved in response to stressors

• slower but more regulated, always have a feedback loop
• (explained above)

cortisol response

• metabolic response
  • more cortisol, more mobilization of glucose = increased energy
  • increased glucocegenesis, glycogenolysis, proteolysis, lipolysis
• cardiovascular effects
  • increased myocardial contractility, cardiac output, bp

drug role of adrenal gland in the stress response

• adrenal is involved in both hormonal and neural
• medulla produces epinephrine that will increase HR and produce fight or flight response
• adrenal cortex is also stimulated to release more glucose and produce mor cortisol
• some conditions where adrenal gland is damaged meaning theres no stress results
  • neurological condition where brain stem is damaged, no stress results

summary of the stress response