Molecular Medicine Block 3 Flashcards
Essential dietary requirements
Amino acids, fats, vitamins, minerals
Excess fuel stored as
Carbohydrate (glycogen) and fat (triglycerides)
Process of anabolism
Animals don’t store protein for use in fasted state
Waste
Compounds generated by metabolism, foreign compounds taken in as food and drink that aren’t useful as fuel
Body has a echo sim to dispose of them
ATP
Chemical unit of energy used by cells for fuel
Dietary and stored fuel is oxidized to produce energy in the form of heat and ATP
2 mechanism to produce ATP
Substrate level phosphorylation
Oxidative phosphorylation
3 fuels oxidized to produce ATP
Carbohydrates fats and proteins
Process of catabolism
Branched metabolic pathways common
Different fuels from many sources enter similar metabolic pathways
Fates of metabolites are determined by an organisms energy status
Common substrate produced
Acetyl coA
Can be metabolized (completely when oxidized to CO2 and H2O
can be stored as fatty acids and triglycerides
Common substrates may produce different storage fuels such as
Glucose converted to glycogen and fat
Other metabolites can only become fat
Major dietary carbs
Starch (polysaccharide)
Simple sugars : glucose and fructose
Disaccharides lactose and sucrose
Dietary proteins
Polymeric chain of amino acids linked by peptide bonds
Digestion breaks them into amino acids and dipeptides for absorption
Dietary lipids (fat)
Triglyceride fats oils
Dietary alcohol
Ethanol
Energy content of food
1 kcal = 4.128 kj
Carbs and proteins 4 kcal/g
Fat 9 kcal/g
Alcohol 7kcal/g
Body stores fuel how
Fat - triglycerides stored in droplets in adipose tissue(85% of stored fuel, very efficient)
Carbohydrate - glycogen stored in cytosolic granules in liver and muscle cells (limited)
Protein - function as structural component of enzymes, can be used as fuel but may result in loss of function
ATP transfers phosphate to what in muscle
Creatine
Creatine phosphate generated by Creatine kinase from atp and Creatine to store atp equivalent
Daily energy expenditure
Basal metabolic rate (BMR) + physical activity + set induced thermogenesis + wound repair and growth
Measurements of body composition
Body fat %
BMI 704x(weight/height^2)
Effective weight loss
Calorie intake less than calorie expenditure
Change eating habits increase fiber and grains decrease fat
Increase exercise specifically low impact aerobic
Essential fatty acids
Linolenic acid - seeds, green leafy vegetables
Linoleic acid - vegetable oils
Eicosapentanoic acid (EPA) - cold water fatty fish, milk, yogurt
Docosahexaenoic acid (DHA) - cold water fatty fish, full fat milk, yogurt
Essential amino acids
PVT TIM HALL
phenylalanine, valine, threonine tryptophan, isoleucine, methionine, histidine, arginine lysine, leucine
Nitrogen balance - amino acids required for protein synthesis, excess proteins ingested not stored they’re removed as waste and carbon skeleton stored as fat or glycogen
Nitrogen balance
Positive - growing child, pregnant woman, body builders
Balanced - adult
Negative - illness, injury, stress
Kwashiorkor : protein deficit but not calorie deficit
Marasmus : protein and calorie deficit
Anorexia nervosa : eating disorder
Long term starvation leads to what illness
Kwashimiorkor and marasmus
Anabolic pathways
Synthesize molecules for fuel (glycogen, triglyceride, glucose)
Synthesize molecules for function (dna/rna, proteins, amino acids acids, membranes and extra cellular matrix)
Catabolic pathways
Breakdown of fuel molecules (digestion, glycolysis, amino acid metabolism)
Breakdown of functional molecules (nitrogen disposal, detoxification, endocytosis, apoptosis)
Physiological status controls metabolism how
Fed - body can use excess dietary intake to add to metabolic food stores
Fasted - body utilizes stored fuels during time of need, during starvation other fuels are produced or spare glucose is used
Glucose homeostatic levels
80-100 mg/dl
Hormone signals
Insulin = fed
Glucagon = fasting
Cortisol = fasting, trauma, infection, chronic stress
Epinephrine= fight or flight
Biomolecules regulating metabolism
Pancreatic hormones = insulin and glucagon
Glucocorticoids = cortisol
Catecholamines = epinephrine and norepinephrine
ATP aerobic vs anaerobic
Oxidative phosphorylation requires oxygen
Substrate level phosphorylation doesn’t require oxygen
Carb digestion
Hydrolyzed to 2 monoacylglycerols and free fatty acids in small intestine
Absorbed and resynthesized into standard triacylglycerols for secretion
Liver in fed state
Glucagon freely enters and leaves, excess glucose stored as glycogen and converted to fat, amino acids absorbed from proteins or converted to glucose and fat
Brain
Always use glucose and metabolize it completely to CO2 and water
Red blood cells
Use glucose only, metabolize it only to lactose or pyruvate
Insulin dependent absorption of glucose happens where
Muscle
Adipose tissue
No insulin effect on glucose transport happens where
Brain, red blood cells, liver
Muscle in fed state
Glucose absorbed when insulin permits its entry
Active aerobic = glucose to CO2
Active anaerobic = glucose to lactate
Inactive = glucose to glycogen
Adipose in fed state
Dietary fat delivered to chylomicra, fatty acids and glucose absorbed, insulin stimulates glucose uptake and triglyceride assembly
Adipose in fasted state
Hydrolyze triglycerides for fuel to free fatty acids and glycerol
Liver in early fasted state
Generate glucose by breaking down glycogen
Produces ketone bodies
Muscle in fasted state
Uses fatty acids and ketone bodies as fuel
As starvation progresses what happens
Body becomes more dependent on fat as fuel,produce more ketone bodies, brain uses ketones for fuel
Liver in starvation
Some gluconeogenesis
Adipose in starvation
Hydrolyze triacylglycerols to free fatty acids and glycerol
Muscle in starvation
Use fatty acids and ketones as fuel
Brain in starvation
Uses ketones for fuel
Metabolism of toxic waste
Nitrogenous waste disposed as water soluble metabolites
Liver plays important role in metabolism of waste
What happens to urea in starvation
Production decreases as starvation proceeds
Bacteria classifications
Eukaryotes - animals, plants, parasites, fungi, archaebacteria
Prokaryotes - eubacteria, cyanobacteria
Eubacteria classification
Family, genus, species
Classification scheme
Numerical taxonomy, nuclei acid homology
Traditional - gram and acid fast stains, cell morphology and arrangement, growth conditions biochemical reactions
General properties of bacteria
No nucleus, rigid cell wall, cell envelope, 70s ribosome, polycistronic mRNA (no introns)
Virulence
Relative capacity of a pathogen to overcome body defenses
Increases ability to cause infection
May be spread via mobile genetic elements
May be structural component, enzymes, or toxins released from the cell
Capsule or slime layer
Widespread occurrence, dispensable for growth, hydrated gel
Function - to protect from external environment, protect cell from uptake by phagocytosis, attachment
Biofilms
Important sources of infection
Form on or within indwelling devices
Bacteria and yeast have been identified as components of biofilms
Once bacteria reach a suitable surface they colonize, reach a significant level then cell detachment and emboli occur
Antimicrobial resistance effectively spreads
Duration of indwelling devices correlates with infection risk
Pili or fimbrae
Short thin
Only on gram negative
2 types somatic and sex
Flagella
Long thin wave appendage, H antigen, basal body, hook, filament ( rotates using 256 H per turn)
Chemotaxis - counter clockwise is swimming, clockwise is twiddle
Prokaryotic cell wall
Responsible for cell shape and structural rigidity
Composition - peptidoglycan polysaccharide backbone, repeating disaccharides, cross linked by tetrapeptide bridge composition and linkages vary among organisms
Gram positive cell wall
Thick peptidoglyan, lipoteichoic acids, teichoic acids
Gram negative cell structure
Surface protein layer, outer membrane, periplasmic space, peptioglycan thinner and less cross linked, cytoplasmic inner membrane
Outer membrane composition of gram negative bacteria
Lipopolysachrides (LPS), phospholipids, proteins
LPS structure of gram negative bacteria
Lipid A endotoxin, core region, polysaccharide side chains (O antigen)
Function is to protect the cell
Periplasmic space of gram negative bacteria
Gel like solution of proteins and binding proteins, degradative enzymes, detoxifying enzymes, peptidoglycan cell wall
Cytoplasmic membrane of gram negative bacteria
Similar in gram negative and positive, 30% phospholipids 70% proteins, small amount of carbs, no sterols, osmotically fragile, enzymatically active, osmotic barrier
Endospores
Resistant to killing, cryptobiotic, means of survival
Triggered by exhaustion of C/N source, accumulates a large amount of calcium and dipicolinic acid, very stable
Endospores structure
Core, spore wall, cortex, spore coat, exosporium
Endospores activation
Spontaneous
Endospores germination
(Water, amino acid, or simple sugars)
Cortex swells, hydrolysis begins, water uptake, loss of heat resistance, excretion of calcium and dipicolinic acid
Spore germination
Core enlarges, mRNA synthesis, protein synthesis, energy by simple glycolysis, spore wall thickens, spore coat ruptures, cell emerges
Bacterial growth
Binary fusion, 4 stages (lag, exponential and logarithmic growth, stationary, death)
Analog to infectious disease
During incubation what happens
Increase nucleosides, amino acids, trnas
Bacterial growth requirements
Energy source, carbon source, nitrogen source, essential minerals, other metabolites
Types of bacterial energy and carbon sources
Photoautotrophs (requires light and carbon dioxide)
Photoheterotrophs (light and organic compounds)
Chemoautotrophs (inorganic chemicals and carbon dioxide)
Chemoheterotrophs (organic compounds and carbon)
Types of bacterial growth required minerals
Nitrogen, sulfur, phosphorus, trace elements (magnesium, potassium, iron, zinc, copper, cobalt, molybdenum, selenium)
Bacterial growth factors
Any ,metabolite bacteria can’t make for themselves
Environmental factors for bacterial growth
Temperature, salt concentration, pH, water, osmotic conditions, oxygen requirements
Obligate anaerobes
Oxygen is toxic
Aerotolerant anaerobes
Only grow in anaerobic conditions but not killed by oxygen
Facultative
Grow in aerobic and anaerobic conditions
Obligate aerobes
Require oxygen
Microaerophiles
Grow best under low oxygen tension
Capnophile
Grow best in the presence of increased carbon dioxide
What happens to toxic oxygen (superoxide) during metabolism
Detoxified by superoxide dismutase, catalase, and peroxidase
Bacteria cell division
Cell division and dna replication tightly coordinated, cell mass determines initiation of replication, rapidly growing bacteria have multiple replication forks
Energy yielding degradative catabolic pathways
Fermentation (partial oxidation of organic compounds)
Respiration (complete oxidation of organic compounds)
ATP and glucose (central to fermentation, respiration, and bio synthetic processes)
Anabolic pathways
Energy consuming, biosynthetic
Amphibolic processes
Involves both degradative and biosynthetic processes
Fermentation
Partial oxidation of organic compounds
2 phases : oxidation of glucose (2 ATP) and reductive (reoxidation of NADH2 and NADPH2)
Phases of fermentation
Embden meyerhof - 2 ATP from substrate level phosphorylation (NAD reduced, PEP to pyruvate)
Reductive phase - maintain oxidation reduction balance
End products - lactic acid, alcohol, mixed acid, butanediol, butyric acid, propionic acid
Propagation methods
Solid media
Liquid media (defined or complex)
Hemolysis on blood ager
Differential media, identification based on phenotype, color difference most common
Selective media
Selects for growth of 1 type of bacteria and inhibits another
MacConkeys agar
Promotes gram negative growth
Bile salts inhibit gram positive growth
Used for wounds, cervix, sputum, urine, stool
CNA agar
Promotes gram positive growth
Colistn and nalidixic acid inhibit gram negative growth
Used for blood, genital, urine
3 main bacterial tests
Microbial identification by isolation and culture
Identification by specific microbial genes or products
Detection of pathogen specific antibodies or pathogen specific antigens
Common lab test
Catalase, coagulase, oxidase, quelling reaction, antibiotics (optochin, novobiocin, bacitracin)
Bacteria identified by
Simple characteristics, biochemical properties
Bacterial antibiotic susceptibility test
Qualitative, quantitative, with images
Common stains
Gram, giemsa, periodical acid schiff, Ziehl neelsen, India ink, silver
Agglutination
Specific antibodies coated onto latex beads, useful when patient has received antibiotics
Immunofluorescence
Specific antibodies bind to immunifluorescent tag and will react with organisms to allow visualization
ELISA
Enzymes linked immunosorbent assay
Detects pathogens, antigens, or host antibodies against pathogens
Direct - presence of antigen analyzed
Indirect - antigen bound by primary antibody which is detected and labeled with a second antibody
PCR
detects a single gene target
normal flora is associated with what
skin and mucous membranes
most normal flora are what
commensals
what happens at birth in regards to normal flora
born sterile then will colonize
benefits of normal flora
antagonism - prevent colonization of pathogens
immunologic imprinting - primes host to response quickly to pathogens
maintin GI peristalsis and intestinal integrity
convert dietary carcinogens and precarcinogens to noncarcinogens
synthesis of vitamin k and b complexes
detrimental effects of normal flora
opportunistic infections - all normal flora has the potential to cause disease
ecological disruption leading to overgrowht by indogenous bacteria
convert noncarcinogens to carcinogens
general maladies caused by normal flora
dental caries, periodontal disease, abcesses, endocarditis
true resident flora
relatively fixed, in particular anatomical sites, if removed come back
transient flora
nonindoginous, do not establish as permanent members of normal flora, may colonize skin and mucous membranes for hours days or months
skin normal flora has more organisms where
sites with partial occlusion (axilla, perineum, toe webs)
what is the most common infectious agent
viruses
what are the severity rankings of viruses
subclinical, mild disease, moderately sever, life threatening, chronic disease, cancer
virus properties
small, obligate intracellular parasite, highly organized, uses host biosynthetic machinery, key enzymes for genome replication virally encoded
virus classification
RNA or DNA then family genus species
virus structure
genome - ssRNA, dsRNA, ssDNA, dsDNA
capsid
nucleocapsid (capside and genome together)
envelope (around nucleocapsid of some)
virion (infectious particles)
virus DNA genomes
linear, circular, size varies, all genomes single molecule
virus RNA genomes
70% viruses, high mutation rate, minimal RNA viruses linear, can be several RNA fragments, ssRNA classified based on polarity (act as mRNA = +, must be transcribed = -)
capsid structure
protein shell, infectious particle in viruses that dont have envelope, protomers are viral structural protein that form the capsid (bind w noncovalent bonds)
types of capsid structure
helical - cylindrical, protomer is single protein
icosahedran - crystalline, an icosahedron
complex - symmetry hasnt been resolved
envelope structure
surrounds capsid of some viruses, derived from modified portion of cellular membrane, viruses with and envelope sensitive to lipid solvents
viral pathogensis
process that produces disease (entry, replication, cytopathology, spread, interaction with host system, overall outcome of infection)
virus entry
direct inocculation, respiratory tract, gastrointestinal tract, genitourinary tract, conjunctiva
primar infrection
location of initial virus infection prior to systemic spread, some visuses only produce primary infection
prodrome
early symptoms before main disease presentation
cell and organ tropism
influenced by host and viral factors
virus spread
local - only replicates at site of inocculation
subepithelium invasion and lymphatic spread
viremia - most efficient, primary = low virion in blood, secondary = high virion in blood
cell injury
oucome of virus infection stems from fate of infected cell
macromolecular synthesis inhibited, damage to organelles, general cell necrosis
host immune response
positive effects
increase pathogenesis of virus
overall outcome of virus
subclinical, acute infection, persistent infection, slow viral diseases, transformation (tumors)
virus lifecycle
attachment, penetration, uncoating, biochemical replication, assembly, release
mykoses
disease caused by fungus
fungus
eukaryotic, most aerobes, derive nutrients via absorption
saprobes
live on dead or decaying material
commensals
live with another deriving benefits from its host, host may or may not benefit but not harmed
parasites
benefits from host without contributing to relationship, pathogenic if it harms the host
fungal structure
membrane bound organelles and cytoskeleton, plasmalemma (phospholipids and sterols), cell wall, capsule
imidiazole
antidungal, inhibit synthesis of ergosterol
polyene antifungals
bing more tightly to ergosterols than cholesterol
fungal cell wall
antigenic, multilayered (polysacharrides and proteins), polysacharrides = chitin, glucan, mannan
fungal capsule
polysacharide, only in some fungi, antiphagocytic and a virulence factor
yeast
unicellular, reproduce with nuclear fission and budding
mold
molticellular, hyphae
spores
conidia, asexual reproduction
dimorphic
can grow in mold or yeast form under different conditions (mold in cold, yeast in beast)
spores
function in reproduction of fungi, sexual and asexual reproduction
labratory diagnosis of fungi
direct microscopic examination, culture, morphology or PCR, serology, molecular techniques
dermatophycosis
infection of skin, hair, nails
sporotrichosis
chronic infection of cutaneous, subcutaneous, lymph tissue (acquired through cutaneous inoculation)
endemic mycoses
natural habitat restricted to specific geographic regions
systemic mycoses
infection of healthy and immunosuppressed
parasitic relationship
host is harmed
bacteria or fungi
parasitic disease
caused by protozoa, helminths, ectoparasites
host types
definitive - harbors adult stages of parasite
intermediate - harbors larval stages of parasite
paratenic - parasite infective to definitive host but doesnt undergo development
many stages in parasite lifecycle
tropozoite, cyst, cercaria (free swimming larval stage), metacaria (infective larvae), miracidium (ciliated nonfeeding larva)
appendages
proglottid, scolex
antiparasitic agents
amphotericin B, chloroquine, metronidazole, mebendazole, praziquantes
ectoparasites
live outside host
endoparasites
live inside host
most deadly animals
mosquitos, freshwater snails, assassin bugs, tsetse fly
types of hosts
resevoire - natural habitat of infectious agent
vector - living carrier that transports infectious agent (mostly arthropods)
carrier - host harbors pathogen without symptoms
classification of endoparasites
protozoa - single cell eukaryotes with movement (flagellates, sporozoans, microsporidians, ciliates
amebas - lumen dwelling, 2 stage lifecycle (trophozoite and cyst stages), use pseudopoda and protoplasmic flow to move
sporozoa - complex lifecycle, altrnate sexual and asexual reproduction
helminths
parasitic worms, large multicellular parasites
nematoda
roundworms
cestodes
tapeworms
termatodes
flukes and blood flukes
ascaris
transmitted by consumption of fertilized eggs (roundworms) worms in stoolsch
istosomiasis
blood flukes
cysticercosis
tapeworms, parasitic tissue infection, must swallow eggs found in feces
polio
acute systemic viral infection leading to wide range manifestations, transmitted by fecal oral route, small single stranded encapsulated RNA
3 stereotypes of polio
1 (most infected), 2 (vaccine infection), 3 (wild type)
poliomyelitis
due to polio, GI first then moves to lymph nodes then to spinal cord and brain stem, primary target is motor neurons
post polio syndrome
polio survivors have progressive muscle weakness and disability (1/3 - 1/2 survivors)
acute flaccid myelitis
acute motor weakness, nonpolio enterovirus infection (ventral spinal cord dies)
public health when considering infections (especially polio)
test persons of interest, wastewater surveillance, vaccination rates, vaccine derived polio possible
duke trial on polio
use polio to treat glioblastomas, in phase 2
ATP created by
fuel oxidation, can be used for mechanical transport and biochemical work
energy provided by atp how
hydrolysis to adp
atp high energy bonds
2 phosphoanhydride bonds (between phosphate groups)
exergonic reaction
substrates have higher energy than products, release energy, -G
endergonic reactions
products have more energy than substrates, absorb energy, +G
thermodynamically favorable reactions
negative delta G, paired with unfavorable
unfavorable reactions proceed if
substrate raised to high enough level, product concentration very low
biochemical work of glycogen synthesis
2 energy harvesting reactions
2 energy harvesting reactions
phosphoryl transfer reaction - phosphte from atp transferred
active intermediates - cleavage of intermediate provides energy (ATP, UTP, GTP, CTP)
thermogenesis
energy expended for generating heat
shivering - increase ATP utilization and release heat
nonshivering - more fuel oxidized to ATP producing heat in brown fat
fuel oxidation
energy transformed to reduction state of coenzymes which transfer elctrons to oxygen in ETC where the electrochemical gradient makes ATP
oxidation reduction reactions
fuel donates electrons, NAD and FAD accept
oxidized in 3 ways - transfer of electrons as H or H-, direct addition of oxygen, direct donation electrons
transfer as H or H-
nad accepts 2 electrons as hydride to form NADH and proton H
FAD accepts 2 electrons as 2 Hs donated separately to become FADH2
oxidases
transfer electrons from substrate to oxygen which is reduced to water or hydrogen peroxide, not used in ATP generation
glycolysis
central pathway producing ATP
aerobic and anaerobic
glucose converted to pyruvate generating ATP from substrate level phosphorylation
aerobic glycolysis
pyruvate oxidized to CO2 in TCA cycle and ATP generated from electron transport chainto oxygen in oxidative phosphorylation
anaerobic glycolysis
pyruvate and NADH converted to lactate and ATP generated via substrate level phosphorylation
preparative phase of glycolysis
1 glucose to 2 G3P using 2 ATP
ATP generating phase
2 G3P to 2 pyruvate
generates 2 NADH, 4 ATP
G3P oxidized by NAD and phosphorylated using inoganic phosphate
phosphates transfered to ATP (substate level phosphorylation)
conversion of glucose to G6P
done by hexokinase
irreversible, commited to metabolism not necessarily glycolysis
conversion G6P to fructose 6 phosphate
by phosphoglucose isomerase
F6P to fructose 1,6-bisphosphate
by phosphofructokinast-1 (PFK-1)
first commited step of glycolysis
conversion F1,6bisP to G3P
by aldolase creating 2 triose phosphates then triose phosphate isomerase creates G3P
G3P to 1,3 biphosphoglycerate
by glyceraldehyde 3-P dehydrogenase
oxidizes G3P transfers electrons to NAD, forms high energy intermediate
phosphoglycerate kinase
transfers phosphate of 1,3 biphosphoglycerate to ATP leaving 3 phosphoglycerate which is converted to 2 phosphoglycerate by phosphomutase and enolase removes water creating PEP
pyruvate kinase
removes phosphate from PEP to ATP generating pyruvate
oxidative fate of NADH
aerobic - shuttles transfer reducing equivalents across mitochondrial membrane to ETC and oxygen
anaerobic - reoxidized in cytosol by lactate dehydrogegnase
oxidative fate of pyruvate
aerobic - shuttles, oxidized to acetyl coA and enter TCA cycle for complete oxidation
anaerobic - reduced to lactate by lactate dehydrogenase
in aerobic glycolysis 2 shuttles regenerate NAD
glycerol 3 phosphate shuttle
malate aspartate shuttle
regulation of glycolysis
by hexokinase
phosphofructokinase 1 (rate limiting)
pyruvate kinase in liver
pyruvate dehydrogenase in mitochondria
2 paths of pluripotent stem cells
lymphoid prgenitor cells
myeloid progenitor cells
cell mediators of immune system derived from
common stem cell
hematopoietic
stem cells can
differentiate into other cell types
hemaotpoeisis
formation and development of redand white blood cells
cells involved in adaptive immune response
antigen specific lymphoctes, specialized accessory cells that participate in lymphocyte activation
effector cells that function to eliminate antigens
lymphocytes
circulate continuously in blood and lymph
capable of migrating into tissue spaces and lymph organs
T and B cell (differentiate based on CD markers)
Natural killer cells (NK)
t cell marker
CD4/8
B cell marker
CD19
b lymphocytes
bone marrow site of maturation, activation cause naive b cells to differentiate into effector (plasma) cells that secrete antibody and into memory b cells
they are membrane bound antibody as antigen receptor
t lymphocytes
thymus maturation
only recognize antigen bound to major histocompatability complex (MHC) used for antigen presentation
t helper cells are CD4
t cytotoxic cells are CD8
natural killer cells
large granular lymphocytes that are cytotoxic
part of innate immunity
lack antigen specific receptors
monocytes and macrophages
activated by phagocytosed antigen and stimular, cells secrete cytokines inhancing activation
monocytes ciculate in blood
macrophages resident in tissues
granulocytic cells
neutrophils, eosinophils, basophils
neutrophils
50-70% circulating white blood cells
multilobed nucleus and granulated cytoplasm and polymorphonucleated
phagocytic (increase with acute bacteria infection)
eosinophils
bilobed nucleus and granulated cytoplasm
phagocytic (parasitic infection and allergies)
basophils
lobed nucelus and havily granulated cytoplasm
secreted substances play major role in certain allergic responses
mast cells
release histamine necause allergen
dendritic cells
antigen capture and presentation
primary lymph organs
thymus, bone marrow
secondary lymph organs
lymph nodes, spleen, mucosal associated lymphoid tissue, (adaptive immune response initiated)
MALT
mucosal lining, tonsils, peyers patches, appendix
lymph nodes
sites where immune response to lymph borne protein anitgens initiated
spleen
response to blood borne antigens
parts of lymph node
outer cortex with follicles, inner medulla and medullary sinus, hilum, efferent lymph vessels
outer cortex
B cell area
paracortex
tcell area
inner medulla
has macrophages
immune system
cells and molecules responsible for immunity
immune response
coordinated response to intro of foreign substances
antigen
antibody generating substance
immunogen
immune response generating substance
to be antigen
must be recognized as foreign, must have certain degree of clinical complexity, must have molecular weight of at least 5000-10000 kD
innate immunity
less specific, early response
stimulated by structures common to groups of related microbes, epithelia, phagocytic cells (neutrophils, macrophages), NK cells, cytokines and blood proteins
adaptive response
activated in antigen specific fashion to provide for elimination of antigen and lasting protection (memory)
adaptive immunity
later response, specificity to remember and respond more vigorously to repeated exposure, generates diversity
lymphocytes in adaptive immunity
stimulated by antigens which are specific pieces of foreign substances
2 types of adaptive immunity
humoral - mediated by molecules in the blood (antibodies produced by B lymphoctes), antibodies recognize microbial antigens, neutralize infectivity, target microbes for elimination
cell mediated - mediated by T lymphocytes (specificity, diversity, memory, clonal expansion, specialization, contraction, homeostasis, nonreactivity to self
generate receptor diversity
millions of idiotypes (variable portion of antibody), accomplished by set of rearrangements of DNA segments during maturation of lymphoid cells (3 gene segments VDJ)
epitope (antigeneic determinant of immunogen)
portion of molecule with 3D complimentary idiotype
hapten - only 1 epitome, cant produce immune response
drug allergies
drug itself works as hapten, becomes conjugated to body proteins and hapten carrier conjugate serves as imunnogen for ensuing allergic response
innate immunity
bacteria breaches skin barrieer and activates innate response
phagocytosis (pseudopodia to engulf and trap, fuse phagosome to lysosome to form phagolysosome for digestion and exocytosis of digested contents)
opsonization - macrophages and neutrophils have membrane receptors for antibody and complementary components, antigen coated with these phagocytosed more
innate and adaptive link
macrophage ingest antigens and present to t cell
innate immunity major functions
physical and chemical barriers, recruit WBC to site of infection and inflammation using cytokines, identify and remove pathogens and debris using WBC, activate adaptive immune system, clear dead tissue and initiate repair
when pathogen breaches barrier
sensors detect pathogen and initiate response mechanism
sensor receptors - pattern recognition receptors (PRRs) or toll like receptors (TLRs)
patterns on pathogen - pathogen associated molecule patterns (PAMPs)
DAMPs
damage associated molecular patterns
endogenous danger molecules released from damaged or dying cells
activate innate immune response by interacting and promoting inflammation process
intracellular killing
in phagocytosis respiratory (oxidative) burst
activates membrane bound oxidase that generates oxygen metabolites that are toxic to ingested microorganisms
2 oxygen dependent intracellular digestion mechanisms activated
- NAPDH oxidase - reduces oxygen to superoxide which leads to hydroxyl and hyrdrogen peroxide
- myeloperoxidase - in lysosome it acts on hydrogen peroxide and chloride to produce hypochlorite
lysosome contents of phagocytes have oxygen independent degradative materials
lysosome, defensins, lactoferrin, hydrolytic enzymes
neutrophils
early in innate response
macrophages
later in innate response
macrophages
coordinate other cells and tissues to clear infections, produce cytokines
cytokines
soluble proteins tat mediate immune and inflammatory reaction
communicate with interleukins
pyrogens induce fever
accute inflammatory response
- activate vascular endothelium in breached epithelial layer
- cytokines released induce selectin type adhesion molecules
- neutrophils bind and extravasaate into tissues (peak within 6 hours)
- monocytes, macrophages, eosinophils arrive (5-6 hours later)
leukocyte extravasation
migration of leukocytes from blood to sites of infection, stimulated by cytokines
endothelial activation, rolling, integrin activation of chemokines, stable adhesion, migration through endothelium
neutrophils release chemoattractive factors that call in other neutrophils
IL8, C5a
complement
proteins made by liver, coat surface of bacteria and extracellular virus particles
IL2
survival, proliferation, differentiation of effector and regulatory T cells
IL 4
b cell switching to IgE
IL5
activation of eosinophils
interferon gamma
activation macrophages
TGF beta
inhibit t cell activation, differentiation of regulatory T cells
initiation of T cell response requires multiple receptors on t cell recognition ligands on APCs
- TCR recognizes MHC associated peptide antigens, coreceptors recognize MHC molecules
- adhesion molecules strenthen binding of T cells to APCs
- receptors for costimulates recognize and send signals provided by APCs
integrins
enhance T cell response
initially bind weakly before antigen recognition
if APC displays antigen T cell recognizes, the antigen recognition increases binding strength
becoming effector cells
1st signal - antigen binding to antigen receptor and ensures specificity of subsequential immune response
2nd signal - provided by costimulators : B7-1 (CD80) binds CD28 and stimulates, B7-2 (CD86) binds CTLA4 and inhibits
t cells secrete IL2 why
to keep up with rapidly dividing microbes
CD4 T cells that have differentiated express
CD40L and secrete cytokines
differentiating into effector cells
CD8 t cells - functional CTLs with ability to kill target cells that express MHC these T cells recognize
cells killing by CTLs is antigen specific and contact dependent
pecificity of CTL effector function ensures normal cells not lysed by CTLs secreting against microbes
CD4 cells differentiate into TH1 and TH2 cells
subsets defined by ability to produce different cytokines
TH1 produces TNF alpha and gamma
TH2 produce IL4 and 5
TH17 produce IL17 and 22 (extracellular bacteria and fungus)
humoral immunity
antibodies neutralize and eliminate antigens that induced their formation
primary humoral immunity
first isotype of immunoglobin is IgM (peentamer)
most effective at sponging up antigen, low affinity, high avidity
secondary humoral resposne
next isotype is IgG
activates complemetn and transported across placenta (protects fetus)
IgA
produced in submucosa
IgE
mast cells, Fe receptors, allergies
antibody responses
T dependent (protein antigens)
T independent (non protein antigen)
peptide antigens from microbes bound by MHC molecule of antigen presenting cell
dendritic cell most effective
t cells tcr recognize peptide antigen this way
MHC aka HLA
class 1 presents to CD8 (expressed on all nucleated cells)
class 2 presented to CD4 (expressed mainly on antigen presenting cells)
b cell receptors
antibodies (membrane bound or secreted)
t cell receptors
only 1 specificity
IgA - mucosal immunity
IgD - naive B cell antigen receptor
IgE - mast cell activation, defense for helminth parasites
IgG - opsonization, antigen specific cytotoxicity
IgM - naive B cell antigen receptor, complement activation
cells that fail to express useful receptors
die by apoptosis
thymus each MHC product loaded with normal self peptides and presented to developing lymphocyte
failut=re of positive selection means t cell wont mature
must not bind too strongly
oxidative phosphoryaltion
ATP formed as a result of transfer of electrons from NADH or FADH2 to O2 by electron carriers
requires electron donor, acceptor, inact inner mitochondrial membrane, components of ETC, ATP synthase
proton motive force
energy that pushes protons to reenter matrix to equilibriate
complex 1
NADH and CoQ oxoreductase - NADH carries binding proteins (FMN accept 2 e from NADH and FE S center transsfers e to Co Q
complex 2
succinate dehydrogenase - transfer e to coq (no proton pumping)
coQ
accepts electrons, pumps protons, shuttles electrons, generate toxis ROS
complex 3
cytochrome bc1
complex 4
cytochrome a a3 bound Cu facilitate collection of oxygen and electrons to reduce to water
congenital lactic acidosis
increase in lactate and pyruvate bc inhibition of ETC
uncoupling
DNP carry protons across membrane
RAACCO
rotenone/amytal
antimycin C
CO and CN
oligomycin
UDP glucose
glycosyl transferase rxns
oxidized to form UDP glucuronate which forms glucuranide derivatives
glycotransferases
transfer sugar component of nucleotide sugar donor to acceptor
glucuronides
increased solubility, more exretion
degredation product of heme
bilirubin
lactose synthesis
convert glucose to galactose (epimerization)
lactose synthesis from galactose (lactose synthase)
enzyme that makes UDP glucose into UDP galactose
UDP glucose 4 epimerase
I cell
deficiency UDP N acetylglucoseamine
complex carbs and fatty substances accumulate
Tay sachs
hexosaminidase A deficiency
GM2 ganglioside accumulation
TCA cycle
pyruvate via acetyl coA through cycle of reactions
in mitochondria
produce coenzymes
energy production and biosynthese
acetyl coa to citrate by what
citrate synthase - regulated
citrate to isocitrate by
aconitase
isocitrate to alpha ketoglutarate by what
isocitrate dehydrogenase (produce NADH) - regulated
alpha ketoglutarate to succinyl coa by
alpha ketoglutarate dehydrogenase (produce NADH) - regulated
succinyl coa to succinate by
succinate thiokinase (make GTP)
succinate to fumarate
succinate dehydrogenase (NADH)
fumarate to malate
fumarase
malate to OAA
malate dehydrogenase (NADH) - regulated
alphaketoglutarate dehydrogenase complex
thiamine pyrophosphate
lipoate
FAD
pyruvate converted to acetyl coa how
pyruvate dehydrogenase complex (IMPORTANT bc convert ketone bodies to energy)
phosphorylation inactivates
dephosphorylation activates
reactive oxygen species
highly reactive free radical or rapidly converted into oxygen free radicals
haber weiss rxn
oxygen and hydrogen peroxide to oxygen, water, hydroxyl
fenten rxn
waater to hydroxyl and hydroxide using iron
hydrogen peroxide is a precursor to what
hypochlorous acid in phagocytic cells
what is a major source of free radicals
cytochrome P450
ionizing radiation does what
split water into hydroxyl radicals and hydrogen
chain reactions do what
form lipid free radicals and lipid peroxides, major contribution to ROS induced injury
blood and urine indicator of ROS
malondialdehyde
what terminate chain reactions
lipid soluble antioxidants
what is the major cellular defense against ROS
glutathione
DNA damage by free radicals
break backbone
convert guanine to 8 hydroxyguanine
nitric oxide
synthesized from arginine and nitric oxide synthase
attack ETC complex 3 and hemoglobin
phagocytic cells form free radicals how
NADPH oxidase - e from NADPH forming superoxide
superoxide dismutase - forms hydrogen peroxide
myeloperoxidase - heme containing, forms hypochlorous acid
cellular defense against oxygen toxicity
antioxidant scavenging enzymes - superoxidase dismutase, catalase, glutathione peroxidase, gluthione reductase
dietary antioxidants - vit E, asorbic acid, carotenoids, free radical scavengers, flavonoids
endogenous antioxidants - uric acid, melatonin
gluconeogenesis differences
glucose 6 phosphatase - glucose from G6P
fructose 1,6 biphosphatase - fructose 1,6 biphosphate to fructose 6 phosphate
PEP carboxylase and pyruvate carboxylase - pyruvate to PEP
substrates for gluconeogenesis
lactate, glycerol, amino acids
what is converted into pyruvate
alanine (alanine aminotransferase)
lactate (lactate dehydrogenase)
glycogen phosphorylase is what when phosphorylated
activated (degrades)
glycogen synthase is what when dephosphorylated
activated (makes)
pyruvate to PEP in liver
pyruvate in mitochondria converted to OAA and given to malate aspartate shuttle
OAA reformed in cytoplasm
PEPCK convert OAA to PEP
glycogenolysis break glycogen)
glycogen to G1P to G6P to glycolysis in blood or to glucose in liver
glycogen synthesis
glucose to G6P to G1P to glycogen
glycogen synthase and branching enzyme regulated step
pentose phosphate pathway
generate ribose 5 phosphate and NADPH from G6P in oxidative and nonoxidative step
nonoxidative
reversible, produce 2 fructose 6P and 1 G3P
G6PD deficiency
hemolysis
galactose ingested primarily as what
lactose which is converted to galactose then glucose
galactosemia
deficiency in GALT which leads to acumulation of G1P
essential fructosuria
fructokinase deficiency
hereditary frustose intolerance
deficiency of fructose 1 P cleavage by aldolase B (rae limiting enzyme)
insulin
uptake of glucose and storage of glycogen
glucagon
release glycogen, make glucose
somatostatin
secreted by pancrease, CNS, gastroduodenal cells
inhibit insulin, growth hormone, TSH
growth hormone path
GHRH stimulate release GH
epinephrine
increase metabolism of fuels
glucocorticoids
cortisol
protect against insulin induced hypoglycemia
cortisol secretion
CRH stimulates ACTH, stimulates cortisol release
thyroid hormone
basal metabolic rate
TRH stimulates TRH releases T3/4
ethanol metabolized how
alcohol dehydrogenase and acetaldehyde dehydrogenase
microsomal ethanol oxidizing system
ADH and ALDH
ADH oxidize ethanol to acetaldehyde with reduction of NAD to NADH in cytosol and ALDH oxidize aldehyde to acetate in mitochondria
ALDH2 in liver
microsomal ethanol oxidizing system
CYP2E1
increased expression with increased consumption
aldehyde can be produced faster than its metabolized injuring liver
effects of ethanol metabolism
decreased NAD impairs flux of glucose in glycolysis
increase lactate production bc increased NADH
alcohol induced liver disease forms
fibrosis
sclerosis
cirrhosis
acetaldehyde adduct formation does what
decrease hypatic protein synthesis, decrease protection agains hydrogen peroxide and lipid peroxidation, portal hypertension, lipid reoxidation, decreased fatty acid oxidation
