Inflammation/Immunology

Question 1

inflammation

Answer 1

Allows inflammatory cells, plasma proteins (e.g., complement), and fluid to exit
blood vessels and enter the interstitial space B Divided into acute and chronic inflammation
.

Question 2

Acute Inflammation

Answer 2

A. Characterized by the presence o f edema and neutrophils in tissue (Fig. 2.lA)
B. Arises in response to infection (to eliminate pathogen) or tissue necrosis (to clear
necrotic debris) C. Immediate response with limited specificity (innate immunity)

Question 3

Mediator of acute inflammation

Answer 3

1. toll like receptors
2. arachidonic acid metabolites
3. mast cells
4. complement
5. hangman factor (XII)

Question 4

Toll-like receptors (TLRs

Answer 4

1. Present on cells o f the innate immune system (e.g., macrophages and dendritic
   cells)
2. Activated by pathogen-associated molecular patterns (PAMPs) that are
   commonly shared by microbes
   i. CD14 (a co-receptor for TLR4) on macrophages recognizes lipopoly-
   saccharide (a PAMP) on the outer membrane of gram-negative bacteria.
3. TLR activation results in upregulation o f NF-κB, a nuclear transcription factor
   that activates immune response genes leading to production o f multiple immune
   mediators.
4. TLRs are also present on cells o f adaptive immunity (e.g., lymphocytes) and,
   hence, play an important role in mediating chronic inflammation.

Question 5

Arachidonic acid metabolites

Answer 5

1. AA is released from the phospholipid cell membrane by phospholipase A2 and
   then acted upon by cyclooxygenase or 5-lipoxygenase.

i. Cyclooxygenase produces prostaglandins (PG).
a. PGI PGD and PGE mediate vasodilation and increased vascular 2, 2, 2
permeability.
b. PGE2 also mediates pain and fever.

ii. 5-lipoxygenase produces leukotrienes (LT).
a. LTB 4 attracts and activates neutrophils. b. LTC 4, LTD 4, and LTE 4 (slow reacting substances o f anaphylaxis) mediate
vasoconstriction, bronchospasm, and increased vascular permeability.

Question 6

Mast cells

Answer 6

1. Widely distributed throughout connective tissue
2. Activated by (1) tissue trauma, (2) complement proteins C3a and C5a, or (3)
   cross-linking o f cell-surface IgE by antigen
   i. Immediate response involves release o f preformed histamine granules, which
   mediate vasodilation o f arterioles and increased vascular permeability. ii. Delayed response involves production o f arachidonic acid metabolites,
   particularly leukotrienes.

Question 7

Complement

Answer 7

1. Proinflammatory serum proteins that “complement” inflammation
2. Circulate as inactive precursors; activation occurs via
   i. Classical p a t h w a y - C 1 binds IgG or IgM that is bound to antigen. ii. Alternative pathway - Microbial products directly activate complement. iii. Mannose-binding lectin (MBL) pathway - MBL binds to mannose on
   microorganisms and activates complement.
3. All pathways result in production of C3 convertase (mediates C3 C3a and
   C3b), which, in turn, produces C5 convertase (mediates C5 C5a and C5b).
   C5b complexes with C6-C9 to form the membrane attack complex (MAC).
   i. C3a and C5a (anaphylatoxins) - trigger mast cell degranulation, resulting in
   histamine-mediated vasodilation and increased vascular permeability ii. C5a - chemotactic for neutrophils iii. C3b - opsonin for phagocytosis iv. MAC - lyses microbes by creating a hole in the cell membrane
   E. Hageman factor (Factor XII)

Question 8

Hageman factor (XII)

Answer 8

1. Inactive proinflammatory protein produced in liver
2. Activated upon exposure to subendothelial or tissue collagen; in turn, activates
   i. Coagulation and fibrinolytic systems ii. Complement iii. Kinin system - Kinin cleaves high-molecular-weight kininogen (HMWK) to
   bradykinin, which mediates vasodilation and increased vascular
   permeability (similar to histamine), as well as pain.

Question 9

Signs of inflammation

Answer 9

A. Redness (rubor) and warmth (calor)
1. Due to vasodilation, which results in increased blood flow 2. Occurs via relaxation of arteriolar smooth muscle; key mediators are histamine,
prostaglandins, and bradykinin.
B. Swelling (tumor)
1. Due to leakage o f fluid from postcapillary venules into the interstitial space
(exudate) 2. Key mediators are (1) histamine, which causes endothelial cell contraction and
(2) tissue damage, resulting in endothelial cell disruption.
C. Pain (dolor)
1. Bradykinin and PGE2 sensitize sensory nerve endings.
D. Fever
1. Pyrogens (e.g., LPS from bacteria) cause macrophages to release IL-1
and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus.
2. Increased PGE2 raises temperature set point.

Question 10

neutrophil arrival and function

Answer 10

A. Step 1 - Margination
1. Vasodilation slows blood flow in postcapillary venules.
2. Cells marginate from center of flow to the periphery.

B. Step 2 - Rolling
1. Selectin “speed bumps” are upregulated on endothelial cells.
i. P-selectin release from Weibel-Palade bodies is mediated by histamine. ii. E-selectin is induced by TNF and IL-1.
2. Selectins bind sialyl Lewis X on leukocytes.
3. Interaction results in rolling of leukocytes along vessel wall.

C. Step 3 - Adhesion
1. Cellular adhesion molecules (ICAM and VCAM) are upregulated on
endothelium by TNF and IL-1. 2. Integrins are upregulated on leukocytes by C5a and LTB4• 3. Interaction between CAMs and integrins results in firm adhesion of leukocytes to
the vessel wall. 4. Leukocyte adhesion deficiency is most commonly due to an autosomal recessive
defect of integrins (CD18 subunit).
i. Clinical features include delayed separation of the umbilical cord, increased
circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes), and recurrent bacterial infections that lack pus formation.

D. Step 4 - Transmigration and Chemotaxis
1. Leukocytes transmigrate across the endothelium of postcapillary venules and
move toward chemical attractants (chemotaxis). 2. Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4.

E. Step 5 - Phagocytosis
1. Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by
opsonins (IgG and C3b). 2. Pseudopods extend from leukocytes to form phagosomes, which are internalized
and merge with lysosomes to produce phagolysosomes. 3. Chediak-Higashi syndrome is a protein trafficking defect (autosomal recessive)
characterized by impaired phagolysosome formation. Clinical features include
i. Increased risk of pyogenic infections
ii. Neutropenia (due to intramedullary death of neutrophils)
iii. Giant granules in leukocytes (due to fusion of granules arising from the Golgi
apparatus) iv. Defective primary hemostasis (due to abnormal dense granules in platelets) v. Albinism vi. Peripheral neuropathy

F. Step 6 - Destruction of phagocytosed material
1. O2-dependent killing is the most effective mechanism.
2. HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed
microbes.
i. O2 is converted to O 2ꜙ by NADPH oxidase (oxidative burst).
ii. O2ꜙ
is converted to H2O2 by superoxide dismutase (SOD). iii. H2O2 is converted to HOCl (bleach) by myeloperoxidase (MPO).
3. Chronic granulomatous disease (CGD) is characterized by poor O2-dependent
killing.
i. Due to NADPH oxidase defect (X-linked or autosomal recessive) ii. Leads to recurrent infection and granuloma formation with catalase-positive
organisms, particularly Staphylococcus aureus, Pseudomonas cepacia,
Serratia marcescens, Nocardia, and Aspergillus
iii. Nitroblue tetrazolium test is used to screen for CGD. Leukocytes are
incubated with NBT dye, which turns blue if NADPH oxidase can convert
O2 to O2ꜙ, but remains colorless if NADPH oxidase is defective.
4. MPO deficiency results in defective conversion of H2O2 to HOCl.
i. Increased risk for Candida infections; however, most patients are
asymptomatic. ii. NBT is normal; respiratory burst (O2 to H2O2) is intact.
5. O2-independent killing is 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).
G. Step 7 - Resolution
1. Neutrophils undergo apoptosis and disappear within 24 hours after resolution of
the inflammatory stimulus.

Question 11

macrophages

Answer 11

A. Macrophages predominate after neutrophils and peak 2-3 days after inflammation
begins.
1. Derived from monocytes in blood
B. Arrive in tissue via the margination, rolling, adhesion, and transmigration sequence C. Ingest organisms via phagocytosis (augmented by opsonins) and destroy
phagocytosed material using enzymes (e.g., lysozyme) in secondary granules ( O 2-
independent killing) D. Manage the next step of the inflammatory process. Outcomes include
1. Resolution and healing - Anti-inflammatory cytokines (e.g., IL-10 and TGF-
β) are produced by macrophages.
2. Continued acute inflammation - marked by persistent pus formation; IL-8
from macrophages recruits additional neutrophils.
3. Abscess - acute inflammation surrounded by fibrosis; macrophages mediate
fibrosis via fibrogenic growth factors and cytokines.
4. Chronic inflammation - Macrophages present antigen to activate CD4+
helper T cells, which secrete cytokines that promote chronic inflammation.

Question 12

chronic inflammation

Answer 12

A. Characterized by the presence of lymphocytes and plasma cells in tissue (Fig. 2.lB)
B. Delayed response, but more specific (adaptive immunity) than acute inflammation
C. 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.

Question 13

t lymphocytes

Answer 13

A. Produced in bone marrow as progenitor T cells

B. 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
1. T cells use TCR complex (TCR and CD3) for antigen surveillance.
2. TCR complex recognizes antigen presented on MHC molecules.
i. CD4+ T cells - MHC class II
ii. CD8+ T cells - MHC class I 3. Activation o f T cells requires (1) binding o f antigen/MHC complex and (2) an additional 2nd signal.

C. CD4 + helper T-cell activation
1. Extracellular antigen (e.g., foreign protein) is phagocytosed, processed, and
presented on MHC class II, which is expressed by antigen presenting cells (APCs).
2. B7 on APC binds CD28 on CD4 + helper T cells providing 2nd activation signal.
3. Activated CD4 + helper T cells secrete cytokines that “help” inflammation and are
divided into two subsets. i. TH1 subset secretes IFN-γ (activates macrophage, promotes B-cell class switching from IgM to IgG, promotes TH1phenotype and inhibits TH2
phenotype). ii. TH2 subset secretes IL-4 (facilitates B-cell class switching to IgE), IL-5
(eosinophil chemotaxis and activation, and class switching to IgA), and IL-13 (function similar to IL-4).

D. CD8+ cytotoxic T-cell activation
1. 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. 2. IL-2 from CD4 + TH1 cell provides 2nd activation signal. 3. Cytotoxic T cells are activated for killing. 4. Killing occurs via
i. Secretion of perforin and granzyme; perforin creates pores that allow
granzyme to enter the target cell, activating apoptosis. ii. Expression of FasL, which binds Fas on target cells, activating apoptosis

Question 14

Lymphocytes

Answer 14

A. Immature B cells are produced in the bone marrow and undergo immunoglobulin
rearrangements to become naïve B cells that express surface IgM and IgD. B. B-cell activation occurs via
1. Antigen binding by surface IgM or IgD; results in maturation to IgM- or IgD-
secreting plasma cells 2. B-cell antigen presentation to CD4+ helper T cells via MHC class IL
i. CD40 receptor on B cell binds CD40L on helper T cell, providing 2nd
activation signal. ii. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching,
hypermutation, and maturation to plasma cells).

Question 15

Granulomatous inflammation

Answer 15

A. Subtype of chronic inflammation
B. Characterized by granuloma, which is a collection of epithelioid histiocytes
(macrophages with abundant pink cytoplasm), usually surrounded by giant cells and a rim of lymphocytes
C. Divided into noncaseating and caseating subtypes
1. Noncaseating granulomas lack central necrosis (Fig. 2.2A). Common etiologies
include reaction to foreign material, sarcoidosis, beryllium exposure, Crohn
disease, and cat scratch disease. 2. Caseating granulomas exhibit central necrosis and are characteristic of
tuberculosis and fungal infections (Fig. 2.2B).
D. Steps involved 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 CD4 + helper T cells to
differentiate into TH1 subtype. 3. TH1cells secrete IFN-γ, which converts macrophages to epithelioid histiocytes
and giant cells.

Question 16

DiGeorge Syndrome

Answer 16

A. Developmental failure o f the third and fourth pharyngeal pouches
1. Due to 22q11 microdeletion

B. Presents with T-cell deficiency (lack of thymus); hypocalcemia (lack o f parathyroids);
and abnormalities o f heart, great vessels, and face

Question 17

Severe combined immunodeficiency (SCID)

Answer 17

A. Defective cell-mediated and humoral immunity

B. Etiologies include
1. Cytokine receptor defects - Cytokine signaling is necessary for proliferation
and maturation o f B and T cells. 2. Adenosine deaminase (ADA) deficiency - ADA is necessary to deaminate
adenosine and deoxyadenosine for excretion as waste products; buildup of
adenosine and deoxyadenosine is toxic to lymphocytes. 3. MHC class II deficiency - MHC class II is necessary for CD4 + helper T cell
activation and cytokine production.

C. Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections,
including opportunistic infections and live vaccines

D. Treatment is sterile isolation (‘bubble baby’) and stem cell transplantation.

Question 18

x-linked agammaglobinemia

Answer 18

A. Complete lack o f immunoglobulin due to disordered B-cell maturation
1. Pre- and pro- B cells cannot mature.

B. Due to mutated Bruton tyrosine kinase; X-linked

C. Presents after 6 months of life with recurrent bacterial, enterovirus (e.g., polio and
coxsackievirus), and Giardia lamblia infections; maternal antibodies present during the first 6 months o f life are protective.

D. Live vaccines (e.g., polio) must be avoided.

Question 19

common variable immunodeficiency (CVID)

Answer 19

A. Low immunoglobulin due to B-cell or helper T-cell defects

B. Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in
late childhood

C. Increased risk for autoimmune disease and lymphoma

Question 20

IgA deficiency

Answer 20

A. Low serum and mucosal IgA; most common immunoglobulin deficiency
B. Increased risk for mucosal infection, especially viral; however, most patients are
asymptomatic.

Question 21

Hyper- IgM Syndrome

Answer 21

A. Characterized by elevated IgM

B. Due to mutated CD40L (on helper T cells) or CD40 receptor (on B cells)
1. Second signal cannot be delivered to helper T cells during B-cell activation.
2. Consequently, cytokines necessary for immunoglobulin class switching are not produced.

C. Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor
opsonization), especially at mucosal sites.

Question 22

Wiskott- Aldrich Syndrome

Answer 22

A. Characterized by thrombocytopenia, eczema, and recurrent infections (defective
humoral and cellular immunity); bleeding is a major cause of death

B. Due to mutation in the WASP gene; X-linked

Question 23

Complement Deficiencies

Answer 23

A. C5-C9 deficiencies-increased risk for Neisseria infection (N gonorrhoeae and N
meningitidis)

B. Cl inhibitor deficiency-results in hereditary angioedema, which is characterized by
edema of the skin (especially periorbital, Fig. 2.3) and mucosal surfaces

Question 24

Autoimmune disorders

Answer 24

A. Characterized by immune-mediated damage of self tissues
1. US prevalence is 1%-2%. B. Involves loss of self-tolerance
1. Self-reactive lymphocytes are regularly generated but develop central (thymus
and bone marrow) or peripheral tolerance. 2. Central tolerance in thymus leads to T-cell (thymocyte) apoptosis or generation
of regulatory T cells.
i. AIRE mutations result in autoimmune polyendocrine syndrome. 3. Central tolerance in bone marrow leads to receptor editing or B-cell apoptosis. 4. Peripheral tolerance leads to anergy or apoptosis of T and B cells.
i. Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS). 5. Regulatory T cells suppress autoimmunity by blocking T-cell activation and
producing anti-inflammatory cytokines (IL-10 and TGF-β ). i. CD25 polymorphisms are associated with autoimmunity (MS and type
1DM).
ii. FOXP3 mutations lead to IPEX syndrome (Immune dysregulation,
Polyendocrinopathy, Enteropathy, X-linked).
C. More common in women; classically affects women of childbearing age
1. Estrogen may reduce apoptosis of self-reactive B cells. D. Etiology is likely an environmental trigger in genetically-susceptible individuals.
1. Increased incidence in twins
2. Association with certain HLA types (e.g., HLA-B27) and PTPN22 polymorphisms 3. Environmental triggers lead to bystander activation or molecular mimicry.
E. Autoimmune disorders are clinically progressive with relapses and remissions and
often show overlapping features; partially explained by epitope spreading

Question 25

systemic lupus erythematous

Answer 25

A. Chronic, systemic autoimmune disease
1. Flares and remissions are common. B. Classically arises in middle-aged females, especially African American and Hispanic
women
1. May also arise in children and older adults (less dramatic gender bias)
C. Antigen-antibody complexes damage multiple tissues (type III HSR).
1. Poorly-cleared apoptotic debris (e.g., from UV damage) activates self-reactive
lymphocytes, which then produce antibodies to host nuclear antigens. 2. Antigen-antibody complexes are generated at low levels and taken up by dendritic
cells. 3. DNA antigens activate TLRs, amplifying immune response (IFN-α ).
4. Antigen-antibody complexes are subsequently generated at higher levels and
deposit in multiple tissues causing disease. 5. Deficiency of early complement proteins (C1q, C4, and C2) is associated with
SLE.

Question 26

SLE findings

Answer 26

1. Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon
2. Malar ‘butterfly’ rash (Fig. 2.4A) or discoid rash (Fig. 2.4B), especially upon
   exposure to sunlight 3. Oral or nasopharyngeal ulcers (usually painless) 4. Arthritis (usually involving ≥ 2 joints) 5. Serositis (pleuritis and pericarditis) 6. Psychosis or seizures 7. Renal damage
   i. Diffuse proliferative glomerulonephritis is the most common and most severe
   form of injury. ii. Other patterns of injury (e.g., membranous glomerulonephritis) also occur.
3. Anemia, thrombocytopenia, or leukopenia (type II HSR) 9. Libman-Sacks endocarditis 10. Antinuclear antibody (ANA; sensitive, but not specific) 11. Anti-dsDNA or anti-Sm antibodies (highly specific)

Question 27

Anitphospholipid antibody

Answer 27

E. Antiphospholipid antibody is associated with SLE (one-third of patients).
1. Autoantibody directed against proteins bound to phospholipids
2. Important antiphospholipid antibodies include anticardiolipin (false-positive
VDRL and RPR syphilis screening tests), anti-β2-glycoprotein I, and lupus
anticoagulant (falsely-elevated PTT).

Question 28

antiphospholipid antibody syndrome

Answer 28

F. Antiphospholipid antibody syndrome is characterized by hypercoagulable state due
to antiphospholipid antibodies (especially lupus anticoagulant).
1. Results in arterial and venous thrombosis including deep venous, hepatic vein,
placental (recurrent pregnancy loss), and cerebral (stroke) thrombosis 2. Requires lifelong anticoagulation 3. Associated with SLE; however, more commonly occurs as a primary disorder
G. Antihistone antibody is characteristic of drug-induced lupus.
1. Procainamide, hydralazine, and isoniazid are common causes.
2. ANA is positive by definition.
3. CNS and renal involvement are rare.
4. Removal of drug usually results in remission. H. First-line treatment includes avoiding exposure to direct sunlight and
glucocorticoids for flares; other immunosuppressive agents are useful in severe or refractory disease.
I. 5-year survival is > 90%; renal failure, infection, and accelerated coronary
atherosclerosis (occurs late) are common causes of death.

Question 29

Sjogren syndrome

Answer 29

A. Autoimmune destruction of lacrimal and salivary glands
1. Lymphocyte-mediated damage (type IV HSR) with fibrosis

B. Classically presents as dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia),
and recurrent dental caries in an older woman (50-60 years)-“Can’t chew a cracker, dirt in my eyes”
1. May progress to ulceration of corneal epithelium and oral mucosa

C. Can be primary (sicca syndrome) or associated with another autoimmune disorder,
especially rheumatoid arthritis
1. Rheumatoid factor is often present even when rheumatoid arthritis is absent.

D. Characterized by ANA and anti-ribonucleoprotein antibodies (anti-SSA/Ro and
anti-SSB/La)
1. Anti-SSA and anti-SSB are associated with extraglandular manifestations (e.g.,
neuropathy). 2. Pregnant women with anti-SSA are at risk for delivering babies with neonatal
lupus and congenital heart block. 3. Anti-SSA and anti-SSB are also seen in a subset of patients with SLE (screen
pregnant patients)
E. Lymphocytic sialadenitis on lip biopsy (minor salivary glands) is an additional
diagnostic criterion (Fig. 2.4C). F. Increased risk for B-cell (marginal zone) lymphoma, which presents as unilateral
enlargement of the parotid gland late in disease course

Question 30

Systemic sclerosis (scleroderma)

Answer 30

A. Autoimmune disorder characterized by sclerosis of skin and visceral organs
1. Classically presents in middle-aged females (30-50 years) B. Fibroblast activation leads to deposition of collagen.
1. Autoimmune damage to mesenchyme is possible initiating event.
2. Endothelial dysfunction leads to inflammation (increased adhesion molecules),
vasoconstriction (increased endothelin and decreased NO), and secretion of growth factors (TGF-β and PDGF).
3. Fibrosis, initially perivascular, progresses and causes organ damage.
C. Limited t y p e - S k i n involvement is limited (hands and face) with late visceral
involvement.
1. Prototype is CREST syndrome: Calcinosis/anti-Centromere antibodies,
Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly (Fig. 2.4D), and
Telangiectasias of the skin.
D. Diffuse t y p e - S k i n involvement is diffuse with early visceral involvement.
1. Any organ can be involved.
2. Commonly involved organs include
i. Vessels (Raynaud phenomenon) ii. GI tract (esophageal dysmotility and reflux) iii. Lungs (interstitial fibrosis and pulmonary hypertension) iv. Kidneys (scleroderma renal crisis)
3. Highly associated with antibodies to DNA topoisomerase I (anti-Scl-70).

Question 31

mixed connective tissue disease

Answer 31

A. Autoimmune-mediated tissue damage with mixed features of SLE, systemic
sclerosis, and polymyositis

B. Characterized by ANA along with serum antibodies to U1 ribonucleoprotein