immunity/inflammation explosion Flashcards
innate resistance/immunity
natural epithelial barrier (first line of defense) \+ inflammatory response (second line of defense)
confer innate resistance and protection to the body
specificity of response in innate immunity vs adaptive immunity
innate immunity responses are broadly specific
vs
adaptive immunity response is very specific towards a particular antigen
compare timing of defense between innate immunity and adaptive immunity
innate immunity:
- first line (barriers): constant
- second line (inflammatory): immediate response
adaptive immunity: delay between first exposure to antigen and max response, but upon subsequent exposure response is immediate
innate immunity: first line defense cells
epithelial
innate immunity: second line defense cells
Mast cells, granuloyctes, monocytes/macrophages, NK cells, platelets, endothelial cells
adaptive immunity: third line defense cells
T and B lymphocytes, macrophages, dendritic cells
innate immunity: first line defense peptides
Defensins, cathelicindins, collectins, lactoferrin, bacterial toxins
innate immunity: second line defense peptides
complement, clotting factors, kinins
adaptive immunity: third line defense peptides
antibodies, complement
innate immunity: first line defense protective mechanisms
anatomic barriers, cells and secretory molecules or cytokines and ciliary activity
innate immunity: second line defense protective mechanisms
vascular responses, cellular components, secretory molecules or cytokines, activation of plasma protein systems
adaptive immunity: third line defense protective mechanisms
activated T and B lymphocytes, cytokines and antibodies
inflammation
result of damage to the epithelial barrier in order to
- limit extent of damage
- protect against infection
- initiate repair of the damaged tissue
non-specific, rapid initiation with no memory cells
can be activated s/t: infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation
plasma protein systems x3
complement system
clotting system
kinin system
function: via sequential activation of components (aka cascade) - help destroy/contain bacteria
complement system
may destroy pathogens directly and can activate/collaborate with every other component of the inflammatory response
3 pathways: classical, lectin, alternative
4 functions: anaphylatoxic activity, chemotaxis, opsonization, cell lyris
most important result: production of fragments during activation of C2, C3, C4, C5
where do the three pathways of the complement system converge?
activation of C3 → C3a + C3b
C3a: increased vascular permeability via stimulation of mast cells to release histamine
C3b: form thioester bonds - bind with pathogen surface → opsonization
effect of C3a upon activation
increased vascular permeability via stimulation of mast cells to release histamine
effect of C3b upon activation
form thioester bonds - bind with pathogen surface → opsonization
complement system: classical pathway
activated by adaptive immune system proteins (antibodies) bound to specific target (antigen)
complement system: lectin pathway
activated by mannose-containing bacterial CHO
- antibody independent!
complement system: alternative pathway
activated by gram negative bacterial and fungal cell wall polysaccharides
anaphylatoxic activity
rapid induction of mast cell degranulation
complement system function
chemotaxis
biochemical substance that attracts leukocytes to the site of inflammation
(complement system function)
opsonization
opsonins are molecules that tag microorganisms for destruction by cells of the inflammatory system
(complement system function)
clotting system end product
fibrin
clotting system pathways x3
intrinsic
extrinsic
common
clotting system functions x4
- prevent spread of infection to adjacent tissues
- trap microorganisms + foreign bodies at site of inflammation
- forms clot to stop bleeding
- provide framework for future repair/healing
kinin system function
augments inflammation with proteins that
- promote vasodilation + increased capillary permeability
- induce pain
how is the kinin system activated?
conversion of prekallikrein → kallikrein (identical to factor XIIa from the clotting system)
primary cells of inflammation x3
mast cell
endothelium
platelets
primary cell of inflammation: mast cell function
degranulation as immediate response to injury, bacterial/viral presence
release histamine →
- temporary/rapid large blood vessel constriction
- dilation of postcapillary venules
both increase blood flow into microcirculation
primary cell of inflammation: endothelium function
- produce NO & prostacyclin (PGI2) → synergistic
- maintain blood flow/pressure
- inhibit platelet activation
- NO maintains vascular tone/continually relaxes vasculature - express receptors to help leukocytes leave circulation
- retracts to allow fluid to pass into tissues
primary cell of inflammation: platelet function
stop bleeding
degranulation
- alpha granules: coagulation proteins, soluble adhesion molecules, growth factors, protease inhibitors, membrane adhesion molecules
- dense granules: small molecules ie ADP, serotonin, Ca, Mg
damage to the endothelium promotes…?
clotting
mast cell
cellular bags of granules located in loose connective tissues close to blood vessels
found in large numbers in areas directly exposed to the environment
ex: skin, linings of GI & respiratory tracts
great number of stimuli causes activation → initiation of inflammatory response
(a primary cell of inflammation)
causes of mast cell degranulation x5
- mechanical injuries
- chemicals
- pathogen activation of TLRs
- allergens binding to IgE on mast cell surface
- activated complement
toll-like receptor (TLR)
expressed on surface of many cells that have direct and early contact with potential pathogenic microorganism
recognize large variety of PAMPs
bridges between innate resistance and adaptive immune response via induction of cytokines that increase response of lymphocytes to foreign antigens on pathogens
pathogen-associated molecular pattern (PAMP)
molecular “patterns” on infectious agents or their products recognized by PRRs
pattern recognition receptors (PRR)
set of receptors that recognize a limited array of specific molecules (ex: PAMPs) on cells involved in innate resistance
mast cell degranulation effects x3
Histamine → vascular effects → dilation and increased permeability→ exudation
Neutrophil chemotactic factor → neutrophils attracted to site → phagocytosis
Eosinophil chemotactic factor of anaphylaxis → eosinophil attracted to site → phagocytosis and inhibition of vascular effects
effect of histamine binding to H1 receptor x2
H1 receptor is pro-inflammatory
bronchi smooth muscle cells → bronchoconstriction
neutrophils → augmentation of chemotaxis
effect of histamine binding to H2 receptor x2
H2 receptor is anti-inflammatory
parietal cells (stomach mucosa) → secretion of gastric acid
suppression of leukocyte function
leukotrienes
product of arachidonic acid from mast cell membranes
similar effects to histamine (smooth muscle contraction, increased vascular permeability)
more important in later stages of inflammation
L is for later!
Prostaglandins (PGE1 and PGE2)
effect similar to leukotrienes (increased vascular permeability)
+ cause neutrophil chemotaxis
+ induce pain via swelling (tissue distention/nociceptor activation)
P is for pain!
platelet-activating factor
effect similar to leukotrienes (increased endothelial retraction → increased vascular permeability)
+ leukocyte adhesion to endothelial cells
+ activate platelets (DUH)
neutrophils
predominate in early inflammatory response - first responders!
phagocytes! ingest bacteria, dead cells, cellular debris
short lived, can’t divide, become part of pus
primary role: debris removal in sterile lesions, phagocytosis of bacteria in non-sterile
monocytes + macrophages
- survive/divide in the inflammatory site
- involved in activating adaptive immune system
- primary cells that infiltrate tissue in wounds
- remove cells/cellular debris
- produce cytokines: suppress further inflammation and initiate healing
activation results in increased: phagocytic activity, size, plasma membrane area, glucose metabolism, number of lysosomes (predominate in late inflammation)
eosinophils
capable of phagocytosis
- provide defense against parasites
- regulate vascular mediators released from mast cells
- help control vascular effects of inflammation
cytokine examples x4
lymphokines, interferon, interleukins, tumor necrosis factor-alpha (TNF-α)
interleukins
CYTOKINE!
- alteration of adhesion molecule expression on many cell types
- induce: leukocyte chemotaxis
- induce: proliferation/ maturation of leukocytes in bone marrow
- enhance adaptive immune response against pathogenic microorganisms + foreign substances
IL-1 and IL-6 = pro-inflammatory
IL-10 = anti-inflammatory
pro-inflammatory interleukins
IL-1 and IL-6
anti-inflammatory interleukins
IL-10
interferons
CYTOKINE!
- primarily: protect against viral infections & modulate inflammatory response
- produced/released by virally infected host cells in response to viral double-stranded RNA
- does not directly kill viruses but prevents them from infecting additional healthy cells
TNF-α
CYTOKINE!
- secreted by macrophages in response to PAMP recognition by TLR
- local and systemic effects
- endogenous pyrogen
- increases liver synthesis of pro-inflammatory proteins
- causes muscle wasting (cachexia) + intravascular thrombosis as consequence of prolonged production d/t severe infection or cancer
- probably responsible for fatalities from shock caused by gram-negative bacterial infections
lymphokines
CYTOKINE!
most likely cause of fatalities from shock d/t gram neg bacteria
TNF-α
local signs of acute inflammation x4
heat, redness - r/t vasodilation/increased blood flow
swelling - exudate accumulation
pain - pressure exerted by exudate; also d/t bradykinin + prostaglandins
biochemical mediators that cause pain during acute inflammation
bradykinin
prostaglandin
systemic signs of acute inflammation x3
fever
leukocytosis
plasma protein synthesis
systemic sign of acute inflammation: fever
- partially induced by specific cytokines released from neutrophils/macrophages = endogenous pyrogens (act directly on the hypothalamus)
- kills microorganisms highly sensitive to temperature changes
- harmful: increases susceptibility to gram neg endotoxins
systemic sign of acute inflammation: leukocytosis
particularly an increase in neutrophils (especially immature, left shift)
systemic sign of acute inflammation: plasma protein synthesis
acute phase reactants
pro- or anti-inflammatory - i.e. fibrinogen, CRP, haptoglobin, amyloid A, α-1 antitrypsin and ceruloplasmin
increase in fibrinogen = increased ESR
fever can be harmful - why?
increases susceptibility to gram neg endotoxins
pediatric self-defense mechanisms
neonates: transiently depressed inflammatory function & deficiencies in complement/collectins
- increased susceptibility to bacterial infections
self-defense mechanism considerations for aging
- at risk for impaired wound healing s/t underlying illness, comorbidities
- slower rate of cell proliferation = increased healing time and areas of hypoxia s/t atrophy of underlying capillaries
- diminished natural ability to ward off infection
immunogen
most but not all antigens - induce immune response resulting in production of antibodies or functional T cells
Haptens
small molecular weight antigens
cannot trigger immune response alone; do when bound to carrier protein
epitope
aka antigenic determinant
precise portion of antigen configured for recognition/binding
antigen-presenting cells (APCs)
during clonal selection, antigen is processed and presented to immune cells by APCs
T-helper cells interact with APCs & immunocompetent B or T cells → differentiation
B cells: active antibody-producing cells (plasma cells)
T cells: effector cells (i.e. T-cytotoxic cells)
clonal diversity
all necessary receptor specificities are produced
generation takes place in primary (central) lymphoid organs: thymus, bone marrow
results: immature/immunocompetent T & B cells with receptors that can recognize virtually any antigenic molecule
these migrate to secondary (peripheral) lymphoid organs and await antigen
primary (central) lymphoid organs
thymus, bone marrow
secondary (peripheral) lymphoid organs
spleen, lymph nodes, adenoids, tonsils, Peyer patches
clonal selection
antigen selects lymphocytes with compatible receptors, expands their population, causes differentiation into antibody-secreting plasma cells or mature T cells
results in mature, specific immune response against antigen
APC + T helper interaction
During clonal selection, antigen processed/presented to immune cells by antigen-presenting cells (APCs)
T-helper cells interact with APCs + immunocompetent B or T cells → differentiation
B cells: active antibody-producing cells (plasma cells)
T cells: effector cells (i.e. T-cytotoxic cells)
Humoral immunity
primary cells: B cells & circulating antibodies
Causes direct inactivation of microorganism or
activation of inflammatory mediators that destroy pathogen
Primarily protects against bacteria & viruses
Humoral immunity primarily protects against
bacteria + viruses
Cell-mediated immunity
Differentiates T cells
Kills targets directly, or stimulates the activity of other leukocytes
Primarily protects against viruses & cancer
Cell-mediated immunity primarily protects against
viruses + cancer
criteria that influence an antigen’s degree of immunogenicity
Degree of FOREIGNESS to a host – most important
Being appropriate SIZE – large molecules are most immunogenic
Having an adequate chemical COMPLEXITY – greater diversity = more immunogenicity
Being present in sufficient QUANTITY – high or low extremes can cause tolerance
MHC class 1 - genes + function
MHC class 1 genes – HLA: A, B and C
present antigens to cytotoxic T cells
found on almost all cells except erythrocytes
MHC class 2 - genes + function
MHC class 2 genes – HLA: DR, DP and DQ
present antigens to helper T cells
usually found on B cells and APCs
Major Histocompatibility Complex aka
Human Leukocyte Antigen
Encoded from different genetic loci on short arm of chromosome 6
stages of pathologic infection x4
colonization
invasion
multiplication
spread
factors that influence infection by a pathogen x7
Mechanism of action Infectivity Pathogenicity Virulence Immunogenicity Toxigenicity Portal of entry
Infectivity
ability of the pathogen to invade and multiply in the host
Pathogenicity
ability of an agent to produce disease - success depends on communicability, infectivity, extent of tissue damage and virulence
virulence
capacity of pathogen to cause severe disease; potency
immunogenicity
ability of a pathogen to produce an immune response
toxigenicity
ability to produce soluble toxins or endotoxins, factors that greatly influence the pathogen’s degree of virulence
portal of entry
route by which pathogenic microorganism infects the host - direct contact, inhalation, ingestion or bites of animals/insects
factors that influence pathogenicity x4
communicability, infectivity, extent of tissue damage, virulence
how do cytokines raise the thermoregulatory set point?
stimulation of prostaglandin synthesis and turnover in thermoregulatory (brain) and non-thermoregulatory (peripheral) tissue
exogenous pyrogens
derived from outside the host, in general arise from external sources involving invading microorganisms
Little evidence they cause fever directly
endogenous pyrogens
ex: IL-1, IL-6, TNF
- in general tend to arise from colonizing flora
- induce central fever
- cytokines raise the thermoregulatory set point
5 steps required for development of successful vaccination
- characterize desired protective immune RESPONSE
- identify appropriate ANTIGEN to induce response
- determine most effective ROUTE
- optimized NUMBER/TIMING of doses to induce protective immunity in large proportion of at-risk population
- most effective yet safe FORM in which to administer vaccine
recombinant vaccination
vaccine produced through recombinant DNA technology. This involves inserting the DNA encoding an antigen (such as a bacterial surface protein) that stimulates an immune response into bacterial or mammalian cells, expressing the antigen in these cells and then purifying it from them.
ex: Hep B, HPV
viral vaccine types x3
attenuated
inactivated
recombinant
bacterial vaccine types x3
- conjugated (to carrier proteins)
- toxoids
- extracted capsular polysaccharides
percentage of population needed to achieve herd immunity
~85%
attenuated vaccine examples x4
MMR
varicella
polio (PO)
rotavirus
inactivated vaccine examples x3
hepatitis A
polio (IM)
influenza
recombinant vaccine examples x2
Hep B, HPV
conjugated vaccine examples x1
HiB
toxoid vaccine example
DTaP, DT
extracted capsular polysaccharide vaccine examples
meningococcal
pneumococcal
most susceptible cells to HIV and why that’s important
Activated T cells more efficiently support HIV replication (HIV = chronic activation of uninfected T cells with HIV-specific TCR)
Does not bode well for vaccine development if the induced and supposedly protective CD4+ cells are also the most susceptible targets for HIV
factors leading to bacterial resistance x4
capacity to INACTIVATE ANTIBIOTICS
MODIFICATION of target molecule (ex: modified abx sensitive binding site on ribosome → resistance to abx that interfere with protein synthesis)
ALTERATION of METABOLIC PATHWAYS that may be sensitive to abx to alternative more abx resistant pathways
mediated by MULTI-DRUG TRANSPORTERS in microorganism membrane (prevent entrance or increase efflux of abx)
how T helpers interact with B and T cells
APC “activates” T-helper cell
helper T goes to immunocompetent B or T cells → differentiation
B cells: active antibody-producing cells (plasma cells)
T cells: effector cells (i.e. T-cytotoxic cells)
what do T cytotoxic cells destroy?
cancer cells or cells infected with virus
what do natural killer cells destroy?
abnormal cells that don’t express MHC I
NK are cytotoxic cells that are not antigen specific
what do T reg cells do?
regulate immune response to avoid attacking self & avoid overactivation of immune response
antibodies protect against invaders how? x4
- Agglutination - insoluble particles clump together
- Precipitation - soluble antigens become insoluble precipitate
- Neutralization - antibodies cover the toxic parts of the antigen
- Lysis - cause rupture of the cellular membrane on the offending agent
these are just beginning steps, complement system needs to come in next
what three molecules needed for opsonization?
Opsonins + antibody + C3b
Hypersensitivity
altered immunologic response to an antigen resuting in disease or damage to host
Allergy
Exaggerated response against an environmental antigen (exogenous)
Autoimmunity
disturbance in immunologic tolerance of self-antigens
autoimmune diseases
Alloimmunity
aka isoimmunity
immune reaction to tissues of another individual
Directed against beneficial foreign tissues (i.e. transfusions, transplants)
allergy vs immunity
allergy: deleterious response to exogenous
immunity: protective response
desensitization
minute qtys of allergen injected in increasing doses over prolonged period; may reduce severity of the allergic reaction in treated pt
associated with risk of systemic anaphylaxis
desensitization associated with increased risk of what
anaphylaxis
immediate vs delayed hypersensitivity
Immediate - occur min - hours
ex: anaphylaxis
Delayed - may take several hours, max intensity days after exposure
ex: TB skin test
type I hypersensiivity
pollens, molds and fungi, foods, animals, cigarette smoke, house dust
ALMOST ANYTHING IN THE ENVIRONMENT
Type II, III, IV hypersensitivities
II & III: rare but may include abx and soluble antigens produced by infectious agents (hep B)
II: usually against allergic haptens that bind to surface of cells and elicit IgG or IgM
IV: plan resins, metals, acetylates, rubber, cosmetics, detergents, topical abx
5 general mechanisms by which type II hypersensitivity can affect cells
- cell destroyed by IgG/IgM or complement-mediated lysis
- cell destroyed via phagocytosis (macrophages)
- neutrophils release granules
- ab-dependent cell mediated cytotoxicity: natural killer cells use Fc to recognize ab on target cell and release toxic substances that destroy target cell
- modulation/blocking normal function of recetors by anti-receptor an
likely causes of autoimmune diseases x4
- sequestered antigen
- complication of ID
- development of neoantigen
- defective peripheral tolerance
neoantigen
likely cause of autoimmune disease: produces allergic reaction that can lead to autoimmunity
- many are haptens which become immunogenic once they bind to self-proteins
likely causes of autoimmune diseases
1. sequestered antigen
self-antigen doesn’t always encounter immune system; barriers hiding them in a tissue are removed leading to antigenic sensitization against that tissue
likely causes of autoimmune diseases
2. complication of ID
antigen from infectious agent resemble self-antigen so ab and T cell produced to protect against it also recognize self-antigen as foreign
likely causes of autoimmune diseases
4. defective peripheral tolerance
defect in regulatory cells allowing expansion of clones of autoreactive cells and development of autoimmune disease
ab against antigens of ABO systems are usually
IgM
where is Rh expressed and what does + express
RBC
expresses D antigen on RhD protein
Immune deficiency
impaired function of T cells, B cells, phagocytes and/or complement
most severe immunodeficiency
severe combined immunodeficiency (T & B cell deficient)
SCID
primary immune deficiency
(congenital) - most result of single gene defect
vertical transmission of HIV
mom to baby
without tx, develop HIV within 6 mo + life expectancy less than 3 years
how soon does HIV ab appear?
within 4-7 weeks of infection
sexual transmission can result in seronegative for 6-14 mo
definition of AIDS
based on labs & clinical symptoms
- seropositive
- CD4 cells less than 200
- atypical/opportunistic infection
HIV pathophys
RNA retrovirus (info stored on RNA instead of dsDNA)
carries reverse transcriptase which translates RNA to DNA bits
carries integrase which adds to host cell DNA
results in:
- major immunologic finding: significant decreased in CD4 T helper cells
- decreased T cells, especially T-memory (seem more susceptible)
- decreased thymic production of new T cells
- damaged secondary lymphoid organs, especially lymph nodes
HIV structure
Gp120 protein (binds CD4 on helper T)
co-receptors:
CXCR4 prefer T cell to form syncytium (fusion of multiple infected cells)
CCR5 prefer macrophages + no syncytium
