Pathoma Chapter 2C Flashcards
Step 4?Transmigration and Chemotaxis
- Leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis).
Neutrophils are attracted by
bacterial products, IL-8, C5a, and LTB4
Step 5?Phagocytosis
- Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins (IgG and C3a). 2. Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes.
Chediak-Higashi syndrome
is a protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome formation.
Clinical features of Chediak-Higashi syndrome include
Increased risk of pyogenic infections, Neutropenia, Giant granules in leukocytes, Defective primary hemostasia, Albinism, Peripheral neuropathy
Why is there Neutropenia in Chediak Higashi syndrome?
(due to intramedullary death of neutrophils)
In chediak higashi there are Giant granules in leukocytes because?
due to fusion of granules arising from the Golgi apparatus
In chediak higashi Defective primary hemostasia is due to?
abnormal dense granules in platelets
Step 6?Destruction of phagocytosed material
- O2-dependent killing is the most effective mechanism. 2. HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes.
How does O2 dependant killing occur?
O2 is converted to O2. by NADPH oxidase (oxidative burst). O2. is converted to H202, by superoxide dismutase (SOD). H202 is converted to HOCl (bleach) by myeloperoxidase (MPO).
NADPH oxidase
O2 is converted to O2. by (oxidative burst).
SOD
O2. is converted to H202, by superoxide dismutase
MPO
H202 is converted to HOCl (bleach) by myeloperoxidase (MPO).
CGD is characterized by?
poor O2-dependent killing.
CGD is Due to?
NADPH oxidase defect (X-linked or autosomal recessive)
What does CGD lead to?
recurrent infection and granuloma formation with catalase-positive organisms, particularly Staphylococcus aureus, Pseudpmonas cepacia, Serratia marcescens, Nocardia, and Aspergillus
Nitrobiue tetrazolium test
is used to screen for CGD. Leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert 02 to O2. but remains colorless if NADPH oxidase is defective.
MPO deficiency results in?
defective conversion of H202 to HOCl
MPO deficiency symptoms?
Increased risk for Candida infections; however, most patients are asymptomatic.
MPO deficiency and NBT?
normal; respiratory burst O2. to H2O2 is intact.
O2-independent killing
less effective than O2-dependent killing and occurs via enzymes present in leukocyte secondary granules (e.g., lysozyme in macrophages and major basic protein in eosinophils).
Step 7?Resolution
Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus.
Macrophages
Macrophages predominate after neutrophils and peak 2-3 days after inflammation begins.
What are macrophages derived from?
monocytes in blood
How do macrophages arrive in tissue?
via the margination, rolling, adhesion, and transmigration sequence
What do macrophages do?
Ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using enzymes (e.g., lysozyme) in secondary granules (02-independent killing)
What are the outcomes for macrophages managing the next step of the inflammatory process?
Resolution and healing, 2. Continued acute inflammation, Abscess, Chronic inflammation
Macrophages induce Resolution and healing by?
Anti-inflammatory cytokines (1L-10 and TGF-(Beta) are produced by macrophages.
Macrophages induce Continued acute inflammation by?
persistent pus formation; IL-8 from macrophages recruits additional neutrophils.
Macrophages induce Abscess by?
acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines.
Macrophages induce chronic inflammation by?
Macrophages present antigen to activate CD4+ helper T cells, which secrete cytokines that promote chronic inflammation
Chronic inflammation is characterized by?
presence of lymphocytes and plasma cells in tissue, its a delayed response but more specific (adaptive immunity) than acute inflammation
Chronic inflammation stimuli include
(1) persistent infection (most common cause); (2) infection with viruses, mycobacteria, parasites, and fungi; (3) autoimmune disease; (4) foreign material; and (5) some cancers.
T lymphocytes are produced where?
Produced in bone marrow as progenitor T cells
Where are T lymphocytes further developed?
Further develop in the thymus where the T-cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4+ helper T cells or CD8 cytotoxic T cells
T cells use TCR complex for?
(TCR and CD3) for antigen surveillance
What does the TCR complex do?
recognizes antigen presented on MHC molecules i. CD4+ T cells?MHC class II, CD8+ T cells?MHC class I
Activation of T cells requires what?
(1) binding of antigen/MHC complex and (2) an additional 2nd signal.
CD4+ helper T-cell activation
Extracellular antigen (e.g., foreign protein) is phagocytosed, processed, and presented on MHC class II, which is expressed by antigen presenting cells (APCs) - B7 on APC binds CD28 on CD4+ helper T cells providing 2nd activation signal.
Activated CD4+ helper T cells do what?
secrete cytokines that help inflammation and are divided into two subsets.
What are the subsets of activated CD4+?
TH1 and TH2
TH1 subset
secretes IL-2 (T cell growth factor and CD8+ T cell activator) and IFN-gamma (macrophage activator)
TH2 subset
IL-4, IL-5, IL-10
TH2 subset secretes IL-4 which results in?
facilitates B-cell class switching to IgG and IgE
TH2 subset secretes IL-5 which results in?
eosinophil chemotaxis and activation, maturation of B cells to plasma cells, and class switching to IgA
TH2 subset secretes IL-10 which?
inhibits TH1 phenotype
How does CD8+ cytotoxic T-cell activation occur?
Intracellular antigen (derived from proteins in the cytoplasm) is processed and presented on MHC class I, which is expressed by all nucleated cells and platelets.
What provides the 2nd activation signal for CD8+?
IL-2 from CD4+ TH1 cell
Cytotoxic T cells are activated for?
killing
SLE is characterized by
antinudear antibody ANA; sensitive, but not specific and anti dsDNA antibodies (highly specific)
Antihistone antibody is characteristic of?
drug-induced SLE.
What are some common causes of drug induced SLE?
- Hydralazine, procainamide, and isoniazid are common causes 2. Removal of drug usually results in remission.
30% of what cases are associated with SLE?
Antiphospholipid antibody syndrome
Antiphospholipid antibody syndrome is characterized by?
autoantibody against proteins bound to phospholipids. 2.
In antiphospholipid antibody syndrome what are the most common antibodies?
Anticardiolipin and lupus anticoagulant
In antiphospholipid antibody syndrome what tests are disrupted?
Leads to false-positive syphilis test and falsely-elevated PTT lab studies, respectively
What does antiphospholipid antibody syndrome result in?
arterial and venous thrombosis including deep venous thrombosis, hepatic vein thrombosis, placental thrombosis (recurrent pregnancy loss), and stroke
What does antiphospholipid antibody syndrome require?
lifelong anticoagulation
What is sjogren syndrome?
Autoimmune destruction of lacrimal and salivary glands, lymphocyte-mediated damage (type IV hypersensitivity) with fibrosis
How does sjogren syndrome classically present?
as dry eyes (keratoconjunctivitis), dry mouth (xerostomia), and recurrent dental carries in an older woman (50-60 years)?Can’t chew a cracker, dirt in my eyes
