Pathoma Chapter 2 Flashcards
What is inflammation used for?
Allows inflammatory cells, plasma proteins, and fluid to exit blood vessels and enter the interstitial space
acute and chronic
What is acute inflammation characterized by?
presence of neutrophils and edema. Arise in response to infection of tissue necrosis (not apoptosis)
How do TLRs work?
These are called ‘Toll-Like Receptors’ and are present on cells of the innate immune system (macrophages and dendritic cells) and are activated by PAMPs on binding pathogens.
TLRs are also on the surface of lymphocytes and are thus involved with acquired immunity
What doe activation of TLRs induce?
results in regulation of NF-kB pathway that activates transcription of multiple immune mediators
What do PGI2, PGD2, and PGE2 do?
cause vasodilation and increased vascular permeability
What else does PGE2 do?
mediates pain and fever (PGI2 does as well)
What does LTB4 do?
attracts and activates neutrophils
What do LTC4, LTD4, and LTE4 do?
vasoconstriction, bronchospasm, and increased vascular permeability
What are mast cells activated by?
1) tissue trauma
2) C3a and C5a
3) cross-linking of cell-surface IgE by antigen
What happens when mast cells are activated?
Immediate- preformed histamine granules degranulate, causing vasodilation and increased vascular permeability
Delayed-production of AA metabolites, particularly leukotrienes
What effects does bradykinin have on acute inflammation?
induces vasodilation and increased vascular permeability (similar to histamine) and pain
The redness (erythema) and warmth (heat) associated with acute inflammation are due to what?
vasodilation, resulting in creased blood flow
key mediators are: histamine, prostaglandins, and bradykinin
Swelling associated with acute inflammation is due to what?
Due to leakage of fluid from postcapillary venues into the interstitial space (exudate)
key mediators are: histamine, tissue damage (which causes endothelial lining disruption)
Pain associated with acute inflammation is due to what?
bradykinin and PGE2 sensitize nerve endings
Fever associated with acute inflammation is due to what?
Pyrogens (e.g. LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase cyclooxyrgenase in perivascular cells of the hypothalamus
The increased PGE2 raises temperature set point
What is the first step of how neutrophils leave vasculature and enter inflammed tissue?
1) vasodilation slows blood flow in post capillary venues and cells marginate from center of flow to periphery
What is the second step of how neutrophils leave vasculature and enter inflammed tissue?
2) Upregulation of P and E Selection facilitate ROLLING of leukocytes at the site of inflammation
P-selectin is released from where?
Weibel-Palade bodies (mediated by histamine)
E-selectin up regulation is induced by what?
TNF and IL-1
P and E Selectins bind to what on incoming leukocytes?
sialyl Lewis X molecules (addressins)
What is the third step of how neutrophils leave vasculature and enter inflammed tissue?
cellular adhesion molecules (ICAM and VCAM) are unregulated on endothelium by TNF and IL-1 and attach to integrins on leukocytes
Integrins are unregulated on leukocytes by what?
C5a and LTB4
Leukocyte adhesion deficiency
autosomal recessive defect on LFA-1 on leukocytes causing delayed umbilical detachment, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes and recurrent bacterial infections that lack pus
Neutrophils are attracted by which chemotaxis?
IL-8, C5a, and LTB4
This is the fourth step of how neutrophils leave vasculature and enter inflammed tissue
What happens when a leukocyte encounters a bacterial pathogen?
phagocytosis leading to degradation of pathogen via PRRs. Phagosomes fuse with lysosomes resulting in pathogen uptake, NADPH reaction, etc.
What is Chediak-Higashi syndrome?
protein trafficking defect (autosomal recessive) characterized by impaired phago-lysosome formation
How does Chediak-Higashi syndrome manifest clinically?
increased risk of pyrogenic infections
neutropenia
giant granules in leukocytes (due to fusion of granules from Golgi)
abnormal dense granules in platelets
Albinism
Peripheral neuropathy
How are pathogens killed by phagocytes?
O2 dependent killing is the most effective
fusion of phagosome with lysosome results in oxidative burst resulting in superoxide. Superoxide is converted to hydrogen peroxide by superoxide dismutase. Hydrogen peroxide is converted to bleach by MPO
O2-independant chilien is less effective and occurs via enzymes like lysosyme in macrophages and major basic protein in eosinophils
Chronic granulomatous disease
Due to NADPH oxidase defect (x-linked or AR)
Leads to recurrent infection and granuloma formation with catalase positive organisms, especially Staph. aureus, Pseudomonas coppice, Serrate marcescens, Aspergillus
How is CGD diagnosed?
nitroblue tetrazolium test used to screen. Turns blue is NADPH oxidase is present
MPO deficiency would lead to what?
not able to convert H2O2 to HOCl
How long do neutrophils live for?
about 1 day, neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus
What cells predominate after neutrophils die?
macrophages peak 2-3 days after inflammation begins
What role do macrophages have in acute inflammation?
macrophages are derived from monocytes in blood and arrive in tissue via the same processes as neutrophils and destroy opsonized pathogens via oxygen species and granules (lysosymes)
Macrophages also work to manage the next step in the inflammatory process
Outcomes of acute inflammation:
1) Resolution and healing- anti-inflammatory cytokines (e.g. IL-10 and TGF-B) are produced by macrophages
2) Continued acute inflammation- marked by persistent pus formation; IL-8 recruits additional macrophages
3) Abscess- acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines
4) Chronic inflammation; macrophages present antigen to activated CD4+ T cells which produce cytokines that promote chronic inflammation
Chronic Inflammation
characterized by the presence of lymphocytes and plasma cells in tissue
delayed response but more acquired (specific) than cute inflammation
What cytokines do TH1 helper T cells produce?
IFN-y (activated macrophages, promotes B-cell class switching to IgG1 and IgG3, and promotes Th1 phenotype)
What cytokines do TH2 helper T cells produce?
IL-4 (promotes B-cell class switching to IgE), IL-5 (promotes eosinophil chemotaxis and activation and IgA class switching), and IL-13 (similar to IL-4)
How can CTLs induce cell death?
Fas ligand binds to initiate apoptosis and secretion of perforin and granzyme
What is granulomatous inflammation?
granuloma forming with giant macrophages in interior and TH1 on exterior
subtypes: caseating and non-caseating
What are non-caseating granulomas?
lack central necrosis. caused by foreign material, sarcoidosis, Crohn disease, cat scratch fever, and beryllium exposure
What are caseating granulomas?
exhibit central necrosis and are characteristic of TB and fungal infections
Steps in granuloma formation:
1) Macrophages process and present antigen via MHC class II to CD4 helper T cells
2) Interaction leads macrophages to secrete IL-12, inducing TH1 differentiation
3) TH1 secrete IFn-y, which converts macrophages to epithelioid histiocytes and giant cells
What happens in DiGeorge syndrome?
Developmental failure of 3rd and 4th pharyngeal pouches leading to lack of thymus (T cell), etc.
X-linked Agammaglobulinemia
Complete lack of immunoglobulin due to disordered B cell maturation due to mutation of BTK leading to cell arrest during pre-B cell phase
Clinical presentation of X-linked Agammaglobulinemia
presents after 6 months of life with recurrent bacterial, enterovirus, and Giardia lamblia infections; maternal antibodies present during first 6 months of life are protective
live vaccines must be avoided
What is Hyper IgM syndrome caused by?
defected in CD40L on T cells or CD40 on B-cells. Thus, B cells cannot be activated and cytokine class-switching cannot occur
low IgA, IgE, and IgG result in current pyogenic infections (due to poor opsonization), specially at mucosal sites
A deficiency in the MAC complex (or any of C5-C9) would leave a patient susceptible to what?
Neisseria infection (meningitidis or gonorrhoeae)
Tissues are divided into what three types based on regeneration ability?
Labile, Stable, or Permanent
What are labile tissues?
these possess stem cells that continuously cycle to regenerate the tissue
Examples of labile tissue
small and large bowel, skin, bone marrow, cervix
What is the difference between primary and secondary intention
Primary- wound edges are brought together (e.g. suturing of a surgical incision); leads to minimal scar formation
Secondary- edges are not approximated granulation tissue fills the defect myofibroblasts then contract the wound, forming a scar.
What things would cause a delay in wound healing?
Infection (Staph. aureus)
Vitamin C, copper, or zinc deficiency
presence of foreign body, ischemia, diabetes, or malnutrition
Why would vitamin C be needed for proper wound healing?
vitamin C is an important cofactor in the hydroxylation of proline and lysine pro collagen residues; hydroxylation is needed for eventual collagen cross-linking
Why would copper be needed for proper wound healing?
a cofactor for lysyl oxidase, which cross-links lysine and hydroxylysine to from stable collagen
Why would zinc be needed for proper wound healing?
a cofactor for collagenase which replaces type III collagen or granulation tissue with stronger type I collagen in classic wound healing
What are the steps of wound repair?
1) Replacement of damaged tissue with fibrous scar
2) Formation of granulation tissue consisting of fibroblasts, myofibroblasts, type III collagen, and capillaries
3) Type I replacement of type III collagen via collegians using zinc as a cofactor (stronger)
