HSS 3305 Midterm
Disease
disturbance of structure/function of the body
Organic Disease
explained by deficit in something essential in the organ
Functional Disease
abnormal symptoms or changes in function but with no measurable changes in tissues
(movement disorders, mental illnesses, headaches, vertigo, spasms, hypertension, IBS)
→ Congenital/hereditary
congenital - present since birth
hereditary - genetic, inherited (not always congenital)
→ Inflammatory
innapropriate inflammatory reaction
autoimmune diseases
in infection cell injury produces inflammatory response
→ Metabolic
role of mitochondira
→ Neoplasm
irregular cell growth/proliferation
benign (not dangerous), malignant (dangerous)
cancer
→ Degenerative
aging
eyes, joints
abnormal degen, occurs in advance of aging process
→ Endocrine
too much, too little hormones (imbalance)
genetic issues with transporters, receptors
→ Malnutrition
deficiencies
obesity
→Obstructions/deposits
cholesterol, mineral deposits
bodies making weird things
Disease cont.
What happens? → cells are damaged by a pathogen, an injury, the environment (exposed to a stressor)
cells attempt to adapt to said stressors → cells may adapt, be injured or die
cell death is hallmark of disease progression
Pathology (study of whats wrong)
study of disease
Pathophysiology (whats wrong)
derange dysfunction in individual (or organ) due to a disease
Pathogenesis (why its wrong, how it is wrong)
the way disease develops
Pathogen (little guy that makes it wrong)
microorganism that causes disease → bacteria, virus, fungi
Morphological changes
changes in cellular level → all disease includes these changes (able to be diagnosed by these changes through microscopy)
Morphology
structure or architecture of tissue or organ
Disease mechanisms
identifying patterns
ex. if something is a cancer: A, B, C will happen
may be used to classify/group diseases
DETERMINANTS OF HEALTH
income, social status
social support networks
education and literacy
employment/working conditions
social environments
physical environments
personal health practices, coping skills
health child development
biology and genetic
health services
gender
culture
Diagnosis
determination of condition based on
Signs, symptoms
Disease Manifestations
Symptoms → pain
Subjective
Signs/Physical findings → blood test
Objective
Clinical history
current illness history (onset of symptoms, severity)
past med history
fam history
social history
review of symptoms
Physical exam
Diagnostic tests
ex. MRI, CT, blood tests, X-Ray, ECG
Lab tests:
organic damage (enzymes), organic dysfunction (creatinine), metabolic perturbation (serum/urinary glucose), electrolyte anomaly, endocrine perturbation (cortisol, thyroid hormone) → typically female (menstrual, ovulation), infection (PCR, bacteria culture), diagnostic biomarkers (tumour markers)
Used to evaluate:
concentrations of substances (in blood, urine)
organ function, (ex. O2 → pulmonary function)
Microbiologic tests → detect presence of pathogens
Serologic tests → detect presence of antigens
Invasive vs. non-invasive
invades body (pain, discomfort): endoscope, needles, catheters
must be sure the test is worth the discomfort
no risk, minimal risk to patient: urinalysis, chest x ray
Tests of electrical activity:
measure electrical impulses (ECG, EEG, EMG)
Ultrasound:
mapping echoes (fetal development, heart function)
X-rays:
x rays passed through the body (mammogram, angiogram)
bone absorbs rays
Computed tomography (CT):
images of body in cross section, rotating x ray tube around patient
detection of abnormalities of internal organs
Magnetic resonance imaging (MRI):
produce images of organs/tissues
strong magnet
Positron emission tomography (PET):
study body functions NOT STRUCTURE
using an isotope, injected to detect radiation output
Cytologic and histologic exams:
exam of cells identified in fluid or secretions (pap smear)
biopsy: histologic exam of small sample removed from tissue/organ
Screening Tests: detecting it early
Genetic screening → gene carriers of heritable genetic diseases
Amniocentesis
hollow needle inserted through abdomen, sucking out fluid from fetal sac
detect chromosomal disorders (downs, spina bifida)
Diagnostic Signs
most skin care guidelines mainly pertain to patients with light skin
“Colour blindness”
disregarding skin colour does not provide equal care for all patients
skin colour related classic signs can still provide key information abt severity of condition
missed diagnosis, staging bruising
Flushing (redness), erythema
vasodilation → increased blood flow
in dark skin → skin warm to touch, hyperpigmentation, hypopigmentation
Brusing, bleeding under skin
damaged blood vessels
Petechiae
pinpoint bleeds in tiny capillaries
in dark skin → examine soles of feet, conjunctiva, oral mucous membranes for subtle petechiae
Blue colour change
cyanosis → blue gray skin, lips and nails
low oxygen levels
dark skin → examine nails, oral mucous
White colour change
diascopy → detecting early pressure sores
test: pushing on skin, release, called “blanching”
if no blanching → hemorrhagic lesions and nonvascular lesions (negative diascopy)
dark skin → blanch test over bony prominence
does not blanch if blood flow is ALREADY interrupted
pallor → anemia, headache, frostbite, endocrine disorders, cardiovascular system disorders
Yellow colour changes
Jaundice → high level of bilirubin, neonatal jaundice
dark skin → yellowing of eyes
blanch test appears yellow
Tan-Bronze colour changes
addison disease
increased production of melanocyte stimulating hormone
The idea that sex does not equal gender: differences in sexes/genders
are we talking about sex as a biological factor, or gender (how people move through the world)
Pharmacokinetics and drug response
Hormonal differences
Anatomical differences
Symptom presentation
Reproductive health
Immune system function
Trans people
both biological and social barriers
underuse of health services
effects of gender affirming care on disease risk
sex-specific organs and cancer risk
minority stress/chronic stress
barriers to gender affirming care
violence/trauma
economic insecurity/homelessness
survival sex work risk, HIV risk
Disease = cell injury
if a cell is unable to adapt to a stressor, disease will occur
every day cell has small stressors, and have mechanisms to adapt and recover
Cell stress can either result in:
Injury
there is a point of no return, where the injury is no longer reversible
ex. epidermal injury (sunburn) from UV radiation → cell death (irreversible damage)
stressors can also trigger cell death (necrosis, apoptosis)
Adaptation
through changes in metabolism, protein function, gene expression
want to achieve homeostasis
ex. melanocyte production in response to UV radiation
→ Depending on dose intensity and cell vulnerability
some cells are more sensitive than others
lip skin vs feet skin
duration of exposure → longer = more damage
Disease-producing cell stressors:
Hypoxia → no oxygen in tissues
interrupted blood supply (ex. blood clot), heart failure, anemia
depletes cellular ATP, generates free radicals (biological stressor)
Chemical injury
2 mechanisms
direct injury from chem
harmless compound but metabolites are toxic (ex. acetaminophen OD toxic to liver)
Physical agents
many physical injury harmful to cells/tissues
every possible thing that could ever hurt/injure you
Infection
pathogenic virus, bacteria, fungi
Immune reactions
exaggerated immune reaction
anaphylaxis, autoimmunity
Nutritional imbalance
deficiencies
Genetic abnormalities
developmental defects
Disease at the Cellular Level:
Adaptive structural changes
cells adapt to enviro stresses by modifying
size/shape
pattern of growth
metabolic activity
→ may help cell function better, but also might be detrimental
Atrophy → decrease in size
lower rates of metabolism, decreased protein synthesis
less structural proteins, fewer mitochondria, less ER
NOT DEAD, less metabolic activity makes them less vulnerable to injury
Hypertrophy → increase in size
increase in cell size, accelerated synthesis of proteins and structural components of cells
Hyperplasia → increase in tissue mass, increased rate of cell division and cell proliferation
no change in size, only cell number
increase in local production of growth factors and growth factor receptors
Metaplasia → change from one cell type to another
new type better able to tolerate adverse environment
change in:
morphology (size, shape, orientation)
cell number, maturity
may be reversible in early stages
pre-malignant condition
ex. chronic irritation transitioned epithelium to squamous epithelium
Dysplasia → disordered cell morphology, organization and function
all fucked up vibes
PATHOLOGIC PROCESS only
pre-malignant change
may be preset for years prior to development of neoplasm
mild forms may be reversible by removal of pathologic stimuli
ex. cervical epithelium (common site of dysplasia), dysplasia here sometimes progresses to cervical cancer)
connections between neighbouring cells → now gone (paracrine signaling)
Cellular adaptations - molecular level
cells adapt via molecular and morphological remodeling
to tolerate stress and maintain their function
Regulation of:
Transcription → genetics, epigenetics
genetic
direct interaction of transcription factors and co-activators with DNA
epigenetic
chemical modification of histones or methyl groups to facilitate or block access of transcription factors to DNA
Translation
Post-translational
Metabolic (adaptations)
adaptability has a limit → exceeding limit marks transition from DYSFUNCTION → DEATH
What happens when cells succumb to injury? → cell comes apart
Cell swelling
Intracellular accumulations
Calcification (harden)
Enzyme leakage
Cell death: necrosis, apoptosis
Cell death → biochem mechanism
loss of ATP (ex. hypoxia)
membrane changes (losses) → leaky cell af
mitochondria → cell death
lysosomes → disgestion of organelles
cell membrane → loss of cellular content
Increase in intracellular Calcium & oxygen and nitrogen reactive derivatives
cause structures to be fixed and rigid
denaturation of proteins and damage membranes and DNA
Cell integrity → homeostasis
to live: cell must remain physically intact
if there are changes in membrane, the membrane integrity will be lost and leak cell contents
Also: if cell is out of whack, so are its ion concentrations
increasing Ca+ causes disruption
if no ATP (ex. if hypoxia)
sodium potassium pump drives ion gradients and sets membrane potential
ATP dependent → no ATP, pumps, enzymes stop working → cell membrane collapses
cell swells
ATPase, influx of Na Ca H2O (less K) causes swelling of cell
forming reactive oxygen and nitrogen species (ROS)(RNS)
causes widespread damage to cells
more antioxidants human consume the better to combat theses
loss of membrane permeability
mitochondria, lysosomes
Increasing calcium → ER and SarcoR
contraction (stress mechanism), phospholipases (degrade membrane), proteases (rupture protein structures), endonucleases (chromatin mods)
Calcium-dependent processes will start to modify the inside of the cell
Cell-death pathway
severity of stress usually corresponds to type of cell death
autophagy → apoptosis → necrosis
Necrosis (murder)
enzymatic digestion of cell by its own hydrolytic lysosomal enzymes
denaturation and precipitation of proteins
messy affffff
gangrene
induces inflammation, lyses membrane
Apoptosis (MAID)
apoptosis is cell-programmed, normal physiologic process
to eliminate unwanted, abnormal cells
does not induce inflammation
absense of membrane lysis
emission of signals at surface allowing phagocytosis of bodies
key morph changes:
formation of membrane blebs
compaction & nuclear fragmentation
permeabilization of mito membranes
formation of apoptotic bodies
DNA damage → cell will opt for apoptosis
DNA is degraded, cell shrinks and forms apoptotic bodies, phagocytosis
intrinsic pathway → triggered by internal factors
extrinsic pathway → triggered by extracellular signals
clean way of death
Autophagy
induced by nutrient deprivation
cell degrades itsself to provide essential elements for survival
amino acids, nucleic acids
can degrade small molecules or whole organelles
Immune response:
Non-specific
Inflammatory reaction
response to harmful agent
Innate immunity
exists independent of harmful agent
Barrier immunity
physical/chemical barriers to infection
barriers, enzymes, acidity, mechanics, serum molecules → first line of defense!
skin, lysozyme, coughing, sneezing, tears, inflammation
Immune Cells → chemical mediators
Monocyte/macrophages
phagocyte
migrate into tissues where they differentiate into macrophages
form a network of cells that can phagocytose pathogens
may be M1 or M2 phenotype
depending on environment and cytokines present
Neutrophils
phagocyte, granulocyte
quickly go to areas of infection or inflammation
phagocytose and destroy pathogens
release granules, release reactive oxygen species
Eosinophils
granulocyte (sometimes phagocyte)
pass from blood into the tissues
numbers increased from allergy, asthma (pro-inflammatory role)
Basophils
granulocyte
express receptor for IgE, can be activated by allergens
Mast cells
granulocyte
phagocyte → cells capable of ingesting particles larger than 1 micrometer
Natural Killer (NK) cells
activate extrinsic pathway
kill by secretion of granzymes / interferon-gamma tumor or infected cells that no longer express MHC class 1
Chemical Messengers
Cytokines
families of small proteins/lipids
signaling ligands
bind to specific cytokine receptors on target cells
Key functions:
stimulate cell growth, proliferation, differentiation
cell activation promotion
recruit cells (chemotaxis)
destroy target cells
trigger apoptosis
Families:
Interleukins
IL-1
IL-2
IL-6
IL-10
Interferons
interfere with viral replication
Tumor necrosis factors (TNF)
Colony stimulating factors (CSF)
Fibroblast growth factors
Vascular endothelial growth factors (VEGF) → involved in helping blood vessels grow in strength, wound repair (damaged blood vessels), supports tumor growth
Adipokines (released from adipocytes)
Cytokine receptor families:
Ig (immunoglobulin) type
single-pass transmembrane
TNFR type
single-pass transmembrane
trimer
CytokineR type 1
single-pass transmembrane
dimer
CytokineR type 2
single-pass transmembrane
dimer
ChemokineR
7 transmembrane domains
G-protein coupled receptor (GPCR)
set off an enzyme that can stimulate or inhibit things
Danger signal receptors:
alarm receptors that detect the presence of pathogens
PAMPs (pathogen associated molecular patterns)
sensitive to cell damage indicators
DAMPs (damage-associated molecular patterns)
→ have a role in the activation of cells that have encountered a pathogen
→ induce the expression of several genes of innate immune response
Non-specific immune response: COMPLEMENT SYSTEM
series of proteins that work to complement the work of antibodies in destroying bacteria
proteins circulate in an inactive form (C1 to C9)
synthesized in a biologically inactive form → great strategy to build up stockpile of these products to use when needed (simply release enzymes to cleave each protein → become active proteins)
small complement fragments (by products) increase vascular permeability and participate in attracting white blood cells into the inflammation site
attacks and breaks down cell walls, attracts phagocytes, stimulates inflammation
Non-specific immune response: INFLAMMATION
accumulation of fluid in the interstitial space: enlarged/engorged tissues
swelling
caused by transudation (movement out of vessel) of plasma from dilated permeable vessels → volume of fluid in inflamed tissue increased
pain
secondary to irritation of sensory nerve endings at the site of inflammation
redness, heat
caused by dilation of capillaries, slowing of blood flow through vessels
loss of function
Pathological processes: INFLAMMATION
delivery of cytokines and cells to injury
formation of a physical barrier to the spread of the tissue damage or replication of pathogens
would healing and tissue repair
Cells involved
phagocytes → large white blood cells that can engulf and digest foreign invaders
granulocytes → WBC contain granules filled w cytokines
Process of Inflammation:
Tissue trauma → bacteria, fungi, virus, non-pathogenic injury
inflammatory process → nonspecific response to cell injury
physical (heat, cold)
chemical (acid, alkali)
microbiologic (bacteria, virus)
dirty nail punctures skin, bacteria enter and multiply, injured cells release histamine, blood vessels dilate and become permeable releasing inflammatory exudate, blood flow to the damaged site increases, neutrophils move toward bacteria (chemotaxis) and destroy them (phagocytosis)
immediate VASOCONSTRICTION of damaged blood vessels, mediated by release of thromboxane A2 and serotonin
helps control blood loss
hemostasis (clotting) at site of vessel injury begins
Histamine release
histamine → compound produced by mast calls, basophils
binds to cell surface histamine receptors (H1,2,3,4 and GPCR)
major functions:
vasodilation (arterioles)
veins more open → more bloodflow → more inflammation
anti histamines for allergic reactions (swelling can close throat, want to get rid of it)
increased permeability in venules and capillaries
Pyremia → heat & Dilation of arterioles and capillaries
non-injured blood vessels (who supply blood to site of injury) become dilated
increased vol. of blood → produces redness and heat → increased pressure may produce transudation of fluid into the tissue spaces
swelling is transudation of plasma from dilated and permeable vessels into inflamed tissue (increasing the vol. of fluid in the tissue)
Increased capillary permeability
vessels become more permeable to plasma proteins
water drawn out of vessels into tissue cells
think: osmosis and water/plasma moving from an area of high concentration to an area of low concentration
swelling used as a barrier around injury
**Movement of neutrophils in and out of blood vessels → leukocyte adhesion cascade
how do WBCs (leukocytes) know there has been an injury in a tissue?
chemotaxis → the migration of an organism or entity in response to a chemical stimulus (NOT a chemotaxi, the process of chemotaxis)
small proteins or lipids formed when tissues are damaged
histamine, serotonin, prostaglandins, leukotrienes
mediators → derived from cells
mast cells
degranulate in response to: physical injury, chemical agents, immunological process
blood platelets
contain histamine and serotonin
released when platelets adhere to collagen fragments at site of injury
mediators → from proteins in blood plasma in injured area
Bradykinins (kinins) → group of mediators activated during inflam response
Four functions:
arteriolar dilation
increased capillary/venule permeability
increased migration of WBC to site of injury (chemotaxis)
produce pain
Damaged tissue sends out chemical signals (chemokines) to attract WBCs, neutrophils (the WBCin inflammation) needs to get out of blood vessel and reach the site of injury → how?
neutrophils need to bind to receptors on the walls of the blood vessels
neutrophils are tightly packed into the blood vessel along with RBC (decreased velocity = concentration of cells increases)
allows neutrophils to stick to blood vessel wall (endothelium)
Leukocyte Adhesion Cascade
sequence of adhesion and activation events that ends w movement of the leukocyte from blood vessel into interstitial space
Steps:
capture
rolling
slow rolling
firm adhesion
transmigration
not phases of inflammation → all happen in parallel w different leukocytes in the same vessel
VCAM-1
enables leukocytes to stick/bind to endothelium
in LAC, there is increased expression of VCAM-1 in response to cytokines
adhesion results when VLA-4 molecules on surface of neutrophils binds to VCAM-1
Inflammatory exudate
exudate → fluid mixture of protein, leukocytes, debris formed during inflam process
blisters, pus, adhesions, bloody exudate
Wound repair: steps
hemostasis
inflammation
proliferation (repair starts)
remodelling
resolution
dead cellular material and debris removed by phagocytosis, replace dead/injured cells by mitosis
regeneration
new cells (mitosis), rejoining of blood vessels (anastomosis), formation of new blood vessels mediated by VEGF (angiogenesis)
repair
fibroblasts migrate into damaged area
form granulation tissue (connective tissue)
hours to weeks post injury
epithelization
covering of a surface by development of epithelial tissue
covering for the wound
scar tissue formation 6-7 days post injury
wound contraction
pulls sides of wound together
fibroblasts produce collagen → holds healing wound together
eventually a mature scare almost completely of dense collagen is produced
remodelling
strengthen new tissue, return to function
destruction of old collagen, formation of new collagen
Scars:
contracture, hypertrophic, keloid, stretch marks, acne
Harmful effects of inflammation?
inflammation is disease risk factor
More inflammation → more tissue damage → more need for mitosis → possibility of mistakes → cancer
Specific immune response (3rd line of defence)
→ acquired immunity (2 types):
Cell-mediated: T-cells form: T helper cells, cytotoxic cells, memory cells
formation of population of lymphocytes that can attack and destroy foreign material
main defense against pathogens
mechanism by which body rejects transplanted organs and eliminates “bad” cells
Helper T-cells
CD4+ marker on cell surface
activate other immune cells (B cells, T cells)
directs immune response
secrete cytokines that trigger cell proliferation
also to attract neutrophils and enhance the ability of macrophages to engulf and destroy microbes
different cytokines have different roles
each cytokine binds to a cell surface receptor on a target cell and promotes cellular activity in some form
naive T cell → T cell that has never seen a pathogen (virgin)
will need assistance to see the pathogen (assisted by APC antigen presenting cells)
after assistance, can release certain cytokines that will help program other helper cells to target pathogens
programmed helper t cells differentiate into cytokines that all have different roles
Cytotoxic T cells
CD8+ marker on cell surface
destroys cells infected by virus/cancer cells
kills donated cells (from transplants etc)
so in transplants it is important to find CD8 cels with as many markers in common to the recipient as possible
release cytokines, trigger apoptosis
cytokines contained in its granules
SPECIFICALLY binds to its target, releases destructive cytokines
whereas NKC degranulate in response to chemical signals in vicinity of targets (NON SPECIFIC)
Suppressor T cells (Regulatory T cells Treg)
acts to turn off or suppress immune cells
secrete immunosuppressive cytokines
inhibit production of cytotoxic t cells → opposing cell
too much cytotoxic t cells can be a bad thing
Specific memory cells
need a population of memory cells for each one of our cells
already programmed to go after a pathogen
can go through mitosis if pathogen is reintroduced
CD4+, CD8+ memory cells
naive t cell → effector t cell → effector memory t cell → central memory t cell
***concept of acquired immunity and vaccines
3 phases:
recognition of foreign antigen
Phase I:
Major histocompatibility complex (MHC)
present processed antigen to human cells
distinguishes foreign cells
carrier for processed foregin antigen fragments on cell surfaces
immune response differs depending on MHC class (I or II)
class I → present on all nucleated cells
class II → restricted to B cells, macrophages, APCs
helps to show immune system the piece of foreign pathogen
results in activated T cell (primed t cell)
antigen presenting cell (APC) required for recognition
during infection with pathogen → macrophages express MHC II receptors that recognize differential carb patterns on foreign cell
Dentritic cells (DC)
phagocytose material
MHC connects to APC, MHC bridges T cell receptor and APC
T cells can only mediate immune responses in the presence of MHC-antigen complexes
CD8+ t cells responds to → MHC class I
CD4+ t cells respond to → MHC class II
Recognition of antigen by CD4+ cells
requires that the antigen be processed and presented to the CD4+ cell by APC with class II MHC
Recognition of antigen by T8 cells
antigen be processed and presented to the CD8+ cell by a cell expressing MHC I
CD8+ T cell
CD8+ cell complexes with infected cell (MHC I binds with TCR)
CD8+ cell releases toxic cytkines
cytokines activate target cell apoptosis
CD4+ T cell
remote detonation via release of cytokines
T cell receptors cannot bind antigens
Humoral: Antibodies, B-cells form: plasma cells, memory cells
associated with production of antibodies that combine with and eliminate foreign material
big players:
T4 cells (CD4+)
alr talked about
B cells
develop in bone marrow
express cell surface Ig receptors that recognize specific antigens
many surface proteins on these cells
CDs (clusters of differentiation)
can use these to identify a b cell vs a t4
don’t produce antibodies
least efficient antigen presenting cells
present antigen to ACTIVATED t-4 helper cells via MHCII
B cells cannot stimulate naive T-4 helper cells
they will be activated by APC macrophage
Activation steps
B cell activation by direct encounter w antigen
T4 cell activation by APC
→ after antigen recognition, B cell ingests whole protein antigen (endocytosis)
Plasma cells
is a b cell
but differentiated
make and secrete antibodies
remain associated with organs
Antibodies (Y)
IgM
pentamer
there is a monomeric form
IgG
small size
major Ig in blood
trigger complement
IgA
circulates as monomer, found as dimer in secretions
IgD
there is a monomeric form
IgE → allergy one
present in small quantities
increased quantity in allergic individuals
binds Fc receptors on basophils and mast cells
triggers mast cell degranulation → release of histamine
→ variable region, ends of the Y
combines with antigen: SPECIFIC to antigen (lock and key)
→ constant region, rest of the Y
identical region of the antibody class
→ Fab region, the top of the Y
antigen binding region
one constant domain, one variable domain
→ Fc region, the bottom of the Y
highly conserved not specialized
proliferation of the lymphocytes programmed to respond to the antigen, forming a large group of clone cells
interleukins → cytokines that send regulatory signals between cells of the immune system
destruction of foreign antigen by the lymphocytes that have responded to the antigen
Roles of antibodies
Agglutination
sticking together insoluble antigens
IgM
Precipitation
antibody binding to sobule antigens
removed by phagocytic cells
Opsonization
coating of bacteria by antibodies
then phagocytosis by macrophages
Neutralization
toxins released by bacteria or virus
try to interact with cell receptors
antibodies bind toxin and prevent interaction with receptors on host cells
Immobilization
antibodies block normal bacteria cillia or flagella movement
immobilized pathogen more easily phagocytosed
Mucosal protection
mainly by IgA, IgG
inhibiting pathogens from gaining attachment to mucosal surfaces
Expulsion of parasites
IgE increased during parasitic infection
trigger basophil and mast cell degranulation
contraction of smooth muscle
diarrhea and expulsion of parasites
Passive immunity
giving immunity to the fetus through transplantal passage of IgG
only class that can cross placenta
Activation of complement
classical pathway
Fc region of IgM and IgG
complement attack complex
target cell lysis, leading to an osmotic death
Vaccination
induce immune response that confers protection against infection and/or disease, if exposed to the pathogen
reduces acquisition/transmission of a pathogen → establishing herd immunity (the most important characteristic of immunization programs)
Herd immunity
95% vaccinated required for HI (high pathogen transmission)
86% for low pathogen transmission
influenza - depends on season
contains antigens → derived from pathogen or synthetic
viral vectors
RNA DNA
virus like particles
inducing immune response
activated through pattern recognition receptors (PRRs)
presentation of peptides of the vaccine protein antigen by MHC molecules on the APC activates T cells through their t cell receptor
B cell activated through b cell receptor
memory cells also produced
Types of vaccine:
live attenuated
weakened form of the germ inserted
killed whole organism
toxoid
subunit (purified protein, recombinant protein, polysaccharide, peptide)
include only the parts of a virus that best stimulate your immune system
ex. covid vaccine contains S(spike) proteins
immune sys recognizes the S proteins, creates antibodies and cell mediated immunity
the antibodies will fight covid if infected
virus-like particle
outer membrane vesicle
protein-polysaccharide conjugate
viral vectored
made when genetic material from a covid 19 virus is inserted into an unrelated harmless virus
when viral vector gets into cells, it delivers the genetic material from the virus and gives your cells instructions for how to make the spike protein found on surface of virus
once the cells add the spike proteins on their surfaces, your immune system creates antibodies to fight
nucleic acid vaccine
mRNA vaccine is made using mRNA for spike protein found on surface of covid 19 virus
after vaccination, immune cells begin making the spike protein and displaying them on cell surfaces
your body then makes antibodies to fight covid
bacterial vectored
APC
Factors affecting success of vaccine:
level of antigens induced by memory B cells
antibody levels after vaccination remain above protective threshold and can provide lifelong immunity
Incubation period
long incubation period needed for a new immune response to develop
between pathogen exposure and onset of symptoms
booster shots → attempt to sustain antibody levels above the threshold
Monovalent vs. Multivalent vaccines
mono → designed to immunize against a single antigen or single microorganism
multi → designed to immunize against 2+ strains of the same microorganism or against 2+ diff microorganism
Flu vaccine
why vaccinate every year?
antigenic drift
Antigenic drift vs. shift?
drift → process of random accumulation of mutations in viral genes recognized by the immune system
shift → process of random accumulation of mutations in viral genes; may allow virus to jump hosts
Vaccine Adverse Event Reporting System (VAERS)
reporting system for any unfavourable/unintented sign
valuable early warning system
cannot be used on its own to figure out if an event following vaccination is common or rare
Factors affecting vaccine protection
→ highest burden of mortality in first 5 yrs of life and older adults
Primary immunodeficiency (genetic) → genetic condition may lead to insufficient b t cell, phagocyte production
Secondary immunodeficiency → HIV/AIDS, therapeutic drugs
Immunocompromised → immune system impaired, could be due to co morbidities, obesity, diabetes
Neonates show significant immune variation at birth
mRNA vaccines potential targets:
cancer, heart disease, autoimmune disease, neurodegen disease, rare genetic, allergic disease
Cytokines → therapies
IL-2 boost immune systems ability to detect and destroy cancer cells
enhances proliferation of t cells and NK cells (crucial in anti tumor immunity)
INF-alpha
enhances anti cancer immune functions
suppresses development of blood vessels (anti-angiogenic)
promotes cancer cell death
downregulation of IL-8 and VEGF gene expression
HLA matching
organ transplants can be more compatible when made within the same ethnic groups
HLA matching is better with related people
unrelated HLA match is uncommon
Immune system related tissue injury
Hypersensitivity reactions
altered reactivity to bacterial products or foreign material during acquired immune response
increased immune response → undesirable
associated tissue damage during response
ALLERGY
Types:
Immediate hypersensitivity
→ antibody-mediated
Allergy: localized reaction
allergy-prone: atopic person
allergic manifestations localized to tissues exposed to allergens
IgE, Mast cells, Basophils (mast and baso found throughout the body, allergy systems can affect diff parts of the body)
cells with Fc receptors
follows contact with foreign antigens that induce formation of specific IgE antibodies in person
activation of B cells, T4 helper cells → differentiation of B cells → plasma cells → IgE production
IgE attaches to the Fc receptors of mast cells and basophils
mast cells and basophils are triggered to release granules filled w histamine, leukotrinenes, prostaglandins
histamine H1 and H4 receptors
binding of histamine to receptors means → inflammation, gene expression, proliferation/chemotaxis
symptoms explained by: vasodilation, increased vascular permeability (mucus, swelling), bronchoconstriction (wheezing), nerve endings activated (itching)
anti histamine drugs
block histamine receptors
allergen immunotherapy (allergy shots)
induces formation of anti allergen (IgA, IgG)
Ig’s combine w allergen, prevent allergen interaction with basophil/mast IgE
asthma
recurrent episodes
chronic airway hyper-reactivity
Anaphylaxis: widespread systemic reaction
exposure to antigen triggers systemic circulations of antigen
triggering of IgE release from mast cells and basophils
Cytotoxic hypersensitivity reactions
→ antibody-mediated
antibody formed against cell or tissue antigen binds to the surface of the target cell
mediated by IgM or IgG
inflammatory cells are attracted and contribute to tissue inury
antibody-antigen complex triggers complement
activation or products of complement destroy antigen
Can be activated in 3 ways:
→ classical pathway
triggered by antigen-antibody interactions
→ lectin pathway
triggered by specific pathogens (PAMP)
→ alternative pathway
by bacterial cell wall material or by products generated during the inflam reaction
Immune complex disease
→ antibody-mediated
IMMUNE COMPLEXES
antigen-antibody clumps within circulation that are deposited in the tissues (physical obstruction)
activate complement and secondary tissue damage
damage to kidneys, lungs, skin, joints, blood vessels
Delayed (cell-mediated hypersensitivity)
→ cell-mediated
T-cells (instead of antibodies) are responsible for tissue damage
initial antigen contact sensitizes affected person, generating T4 cells
sensitized T4 cells accumulate at site of antigen material → secrete variety of cytokines that attract macrophages and activate T8 cells
tissue damage via inflammation, cytotoxic T8 cell destruction of target cell (apoptosis)
sensitization phase and effector phase
Autoimmune diseases
→ immune system targetted toward host
associated with formation of cell-mediated immunity against own body
Features:
multiple cells, cytokines, mediators working together
spontaneous remission
combinations of multiple AD are common
process is dynamic
variable!!
Cause:
polymorphisms in many genes result in a defective immune regulation, also environmental factors trigger activation of self-reactive lymphocytes
genetic susceptibility
environmental triggers
antigen mimicry → regions of similarity between auto-antigens and pathogen antigens (antibodies recognize both pathogen and host cell antigen)
gut microbiome
defective immune regulation
Treg (suppressor t cells) normally function to suppress autoreactive t cells, but defects in development/stability/function may make cells dysfunctional (unable to control autoreactivity)
AIRE gene → encodes for autoimmune regulator gene
makes sure mTEC cells express tissue-restricted antigens
acts as a trap: if a t cell responds to tissue-restricted antigens it fails quality control test
t cell will be killed
negative selection is part of regulation/quality control
mutations here associated with AD
Autoimmune disease trajectory:
Initiation
genetic predisposition
environmental triggers
→ no or minor symptoms
Propagation
cytokine prod
self perpetuating inflammation and tissue damage
epitope spreading
disrupted Teff/Treg balance
very important to a healthy body is this balance
Resolution
resolve with the activation of cell-intrinsic (inhibitory pathways) and cell-extrinsic (Treg) mechanisms to restore TeffTreg balance
here patient often suffer from relapsing and remitting disease, hard to keep balance
Diseases:
rheumatic fever
rheumatoid arthritis
systemic lupus
vitiligo
Infectious Diseases:
AIDS → attacks and destroys T helper cells
making affectd people susceptible to many unusual infections and malignant tumors
end stage of Human Immunodeficiency Virus (HIV)
HIV-1 → predominant type
HIV-2 → less common (mostly west africa)
RNA virus (retovirus)
viral RNA and reverse transcriptase are enclosed within a protein coat (capsid) that form core of virus
core surrounded by envelope composed of a double layer of lipids
interact with specific receptors on host cell, to use host’s transcription machinery to replicate virus components to make baby viruses
How does virus gain entry into the cells?
glycoprotein molecules on HIV virus surface
gp 41 (stem) and gp 120 (cap)
inside: 3 viral enzymes who enter along with RNA
reverse transcriptase
integrase
protease
receptor for cell entry:
CD4 proteins (receptors) on cell membranes of: (HIV likes attacking)
Helper T cell
monocytes/macrophages and macrophage-like cells
→ virus attaches to CD4 via gp120 protein → docking stabilized by CCR5/CXCR4
binds to cell, virus envelope fuses with cell membrane, virus enters cell
binding
fusion
reverse transcription
take viral RNA and make viral DNA
integration (integrase)
inserting transcribed viral DNA into our own DNA
replication
assembly
budding
→ helper t cells are damaged and many are killed
monocytes are more resistant and survive
virus replicates inside the monocytes and are able to spread the virus throughout the body (into NS and brain)
→ monocytes act as vehicle (virus festers in there and spreads to other cells)
What happens to immune cells after infection?
depletion of CD4+ t helper cells
below threshold of needed t cells → immune depleted
for activated against HIV cd4 t helper cells (actively involved in the immune response)
HIV induces apoptosis for them (only 5%)
for those cd4 not actively involved in immune response
die of pyroptosis (95%) → pro inflammatory cell death
responsible for slow and progressive death during chronic phase
diff from apoptosis: caspase-1, cell swelling, lysis of cell membrane, production of inflammatory cytokines
bystander (non immune) cell death
major mechanisms:
upregulation of Fas-L
inhibition of Bcl-2 (anti-apoptotic protein)
activates pro-apoptotic procaspase 8
chronic inflammation
Trajectory of disease:
Early
large amts of virus detected in blood and body
large amts of virus infected cells in lymph nodes, lymphoid tissue
body forms anti HIV antibodies and generates cytotoxic t cells
Once acute phase subsides
amt of virus in blood and body decreases
but virus is not eliminated
instead, virus enters the chronic phase → no dormant phase
virus particles produced continuously, infect and destroy cd4
with meds, some may reach asymptomatic holding phase
presence of anti HIV antibodies can be a useful test if a person is infected or infectious
Body’s response to destruction of cd4 cells
produce more cd4 to replace the killed ones
cytotoxic cd8 directed against virus infected cells
newly formed t cells cannot keep up w killed ones
immune system fails
Factors affecting disease progression:
genetic mutations in CCR5 or CXCr4 genes
HAART (highly active antiretroviral therapy)
AIDS (late HIV)
most people develop manifestations of immune deficiency
opportunistic infection
ex. Candida, pneumocytsis (pneumonia), tuberculosis,
neoplasms (HIV associated cancers)
kaposi sarcoma (gay cancer), B cell non hodgkin lymphoma, cervical cancer
diagnosis of these cancer confirms AIDS status of HIV
tumors with aids patients are all related to immune system failure
CNS damage
confusion, forgetfulness, headaches, mood disorders, HIV asociated neurocognitive disorders (demntia)
→ causes CNS disease in 2 ways:
primary HIV CNS diseases → virus is both necessary and sufficient
HIV does not directly infect neurons
gp120 interacts with host receptors to change glutamate pathway signaling, indue cytokine production
HIV infection of CNS cells → pro inflammatory cytokines → alters permeability of blood brain barrier → more HIV invasion
secondary CNS disease require opportunistic pathogen, takes advantage of imune deficiency
** side effects from HAART will also cause CNS disturbances
Only 40% of people who need treatment get it
Subsaharan africa is most affected
more women affected here
more men still die though → women tend to be affected earlier and survive longer
Many cases go undiagnosed
AIDS stigma exists
PrEP → pre exposure prevention
PEP → post exposure prevention
PMTCT → prevention of mother to child transmission
Respiratory Health Issues
obstructive lung disease
asthma, emphysema, chronic bronchitis, environmental irritants
restrictive lung disease
fibrosis, ARDS, pleural effusion, pneumothorax
neoplastic disease
non-small cell lung carcinoma, small cell lung carcinoma
vascular lung disease
embolism, PAH
infectious disease
coronavirus, influenza, resp tract infections, pneumonia, TB
Obstructive lung disease
Asthma
contraction of smooth muscle in walls of bronchi and bronchioles
bronchoconstriction
lower airway inflammation
increased secretions by the bronchial mucous glands
mast cell activation in the lungs
pathogenesis
infectious
hypersensitivity
Bronchitis
inflammatory condition of the bronchi
chronic bronchitis → risks
virus, bacteria
bronch damage by: smoking, environmental contaminants, GERD
coughing, shortness of breath, wheezing, fatigue
CHRONIC BRONCHITIS + EMPHYSEMA → COPD
Emphysema
commonly associated with chronic bronchitis
smoking, environmental contaminant
shortness of breath
damage to alveoli
inhaled matter (smoke) trapped by hairs in bronchi, unable to be exhaled
localized inflammatory response (bronchitis)
during inflammatory response, chemicals released (trypsin, elastase…), begin to break down the walls of alveoli (elastin breakdown)
walls between lungs air sacs become weakened and collapse
enlarged air sacs, collapse, filled with excess mucus
way to maintain adequate oxygen levels: hyperventilation
COPD (Chronic Obstructive Pulmonary Disease)
difficult to find pure cases of emphysema or chronic bronchitis as they come as a package deal under the name of COPD
damage permenant and irreversible
Environmental irritants
→ Air pollutants
particulate matter (PM2.5, PM10)
NO2
SO2
O3
volatile organic compounds
SMOKING
secondhand, thirdhand (contributes to particulate matter)
→ Effects on resp. system
inflammation of airways
exacerbation like asthma, bronchitis, COPD
→ Long term exposure risks
reduced lung function
increased risk of lung infections
lung cancer
pulmonary fibrosis
Wildfires → air pollution
ozone
methane
SO2
NO2
CO
VOC
FPM
PAHs (polycyclic aromatic hydrocarbons)
Restrictive lunch disease
loss of airway compliance, causing incomplete lung expansion (via increased lung stifness)
manifests in reduced total lung capacity, inspiratory capacity and vital capacity
→ FIbrosis
formation or development of excess fibrous connective tissue in an organ or tissue as a reparative or reactive process
Cystic Fibrosis
caused by malfunctioning chloride channels encoded by CFTR gene
CFTR gene contains instructions to make cystic fibrosis transmembrane conductance regulator (CFTR PROTEIN)
protein functions as a chloride channel → maintains the right balance of fluid in the airways
without the membrane protein → too much fluid (mucus) in the airways
→ less transport of Cl (sodium gradient is reversed), means less water in the airways, means mucus layer is very thick and sticky
Sticky mucus cannot be moved easily to clear stuff from the lungs, AND traps bacteria and causes more lung infections
Pulmonary Fibrosis
lung tissue becomes damaged and scarred
thickened due to fibroblast infiltration
end stage result of some chronic lung diseases
Pleural Effusion
fluid buildup in the pleural space
restricts lung expansion → hard to breathe
Causes:
congestive heart failure
infections
cancer
pulmonary embolism
Pneumothorax
→ medical emergency cause by accumulation or air and gas in the pleural cavity, leads to a collapsed lung
penetrating chest wound
ARDS
increased capillary permeability → accumulation f protein rich fluid inside the alveoli → damages alveoli
release of pro inflam cytokines
neutrophils recruited to lungs by cytokines
release toxic mediators, reactive oxygen species, proteases
inflammation
proliferation of type II alveolar cells, fibroblasts, myofibroblasts
pulmonary hypertension
death → multisystem organ failure
Vaping (ENDS) → electronic nicotine delivery systems
aerosols → toxic substances inhaled
can lead to lung damage, cardiovasular problems
Neoplastic disease
respiratory tumor → cancerous or non cancerous masses in lungs or lung parenchyma
masses of tissue within the lung, generally malignant
common cause: tobacco smoke
Vascular lung disease
conditions that affect the pulmonary capillary vasculature
alterations in the vasculature manifest in a general inability to exchange blood gases (O2 and CO2) around the vascular damage (in the area of)
ex. pulmonary embolism, hypertension
Pulmonary embolism
blood clot (thrombus) forms in deep veins of legs
clot travels throughout circulatory system until it gets stick
ischemic (no oxygen) tissue damage
stroke, myocardial infarction, pulmonary embolism
Pulmonary Arterial Hypertension (PAH)
affects only arteries in lunchs
caused by vasoconstriction (increases resistance) of smallest arteries and capillaries caused by scar tissue
resistance increased, raises pressure within pulmonary arteries and the right ventricle
Infectious respiratory disease
→ upper resp.
nose, throat, pharynx, larynx
→ lower resp.
trachea, bronchi, lungs
pneumonia, bronchitis
Common cold
rhinoviruses, coronaviruses, parainfluenza, adenoviruses, respiratory syncytial virus
→ viruses frequently mutate
Respiratory syncytial virus (RSV)
common respiratory virus, usually causes mild cold like symptoms
RNA virus
infants, older ppl more likely to develop severe RSV
vaccines to help
Pneumonia
infection in one or both lungs
caused by bacteria viruses and fungi
characterized by alveoli inflammation and accumulation of fluid
HIV related opportunistic infections: TB
caused by Mycobacterium tuberculosis
TB → lungs
can be inactive (latent) or active (TB disease)
HIV/TB coinfection
latent is more likely to advance to TB in people w HIV
TB disease might also cause HIV to worsen
COVID 19 (influenza)
→ respiratory infection, infectious disease
Influenza
types A and B
responsible for seasonal flu epidemics
fever, aching muscles, headache, cough
W shaped age specific mortality pattern
H5N1
cytokine production is 10x higher with H5N1 than normal human flu disease
hyper-release of cytokines and chemokines
Influenza pregnancy risk
oxygen consumption increases in pregnancy, as the uterus pushes diaphragm upward, decreasing total lung capacity
Greatest source of pandemics:
ANTIGENIC SHIFTS
MERS COV
SARS COV2
SARS COV
→ mers has different spike protein than sars, all 3 have same cofactor enzymes → TMPRSS2 (helps interaction between virus and host)
SARS CoV 1
Spike proteins on outside of virus have interactions with ACE2 receptor on host cell, with help from TMPRSS2
ACE2 has role in blood pressure → explains non respiratory effects
Virus invades host cell to produce viral proteins
U122 protein
induces apoptosis
S protein
activate AP-1 protein, that induces apoptosis
AP-1 → transcription factor activates IL-8
N proteins
induces pathways: MAPK (pro apoptotis) and Akt (anti apoptotic)
MERS
camels, human-human poor
Receptor → DPP4
SARS CoV2
RNA
S protein → binds to host, M protein (membrane protein region of genome), N protein (nucleocapsid protein region)
COVID-19
phase 1 → infection of epithelial cells
phase 2 → acute inflammation
phase 3 → severe disease or resolution
cytokine storm emphasized!!!
chemokines attract more inflammatory cells to migrate from blood vessels , cells release more cytokines/chemokines
Genetic diseases:
Monogenic diseases → single gene
medelian disorders
ex. cystic fibrosis, sickle cell
Sickle Cell
mutation of HBB gene → abnormal hemoglobin
autosomal recessive
advantage against malaria
Complex diseases → multifactorial
mendelian trait - single locus
multifactorial trait → controlled by several genes + environment
Autism
gene-environment interactions
distrupted fetal brain development
older dads increase risk
90% ASD kids → feeding related concern
Mitochondrial diseases
basis of mitochondrial dysfunction
Leigh syndrome
auto rec
mutations in LRPPRC gene, 2p21
mutations disrupt mictochondrial energy production (ETC!!)
developmental delay
common in Quebec
Chromosomal aberrations
occur as accident in egg or sperm
before conception → in all cells
after conception → some cells affected (mosaic)
monosomy → missing chromosome from pair
trisomy → missing more than 2 chromomes
aneuploidy → change in number of chromosomes
structural abnormalities → deletion, insertion, duplications, translocations
Trisomy 21 (downs syndrome)
extra 21st chromosome
maternal age risk (after 35 its a MUCH bigger risk)
Trisomy 18 (edwards syndrome)
half die in utero
Turner syndrome
short stature
sterile
only one X
Klinefelters Syndrome
small testes
XXY
Fragile X syndrome
syndrome of X linked cognitive impairments
Amniocentesis
Congenital diseases can be caused by genetic and or environmental factors
maternal disease, teratogenic factors, age, epigenetic factors, genetic factors
all contribute
Congenital Anomalies
Cryptochidism
one or both testes fail to descend from abdomen into scrotum
Hypospadias
opening of urethra is on underside of penis instead of the tip
Developmental anomaly
Fetal alcohol syndrome
growth deficiency in the fetus and newborn in all parameters
heart defects
STBBI and Baby
conjunctivitis infections (chlamydia and gonnorrhea) for baby
need for prenatal testing
herpes given to baby
Zika virus
single stranded RNA
zika in pregnancy can cause severe brain defects and
Microencephaly
birth defect → babys head is smaller than expected
Neural tube defects
birth defects of brain and spinal cord
neural tube (future brain, spine), fails to close properly
prenatal vitamens (folic acid supplementation) greatly reduced incidence