Immunology Basics

Introduction to Immunology
1) Levels of Defense
a. Nonspecific, preformed (acts within minutes)
i. First line of defense (Intact skin/epithelium and mucous membranes, stomach
acid)
1. Disease Correlation: Note that taking omeprazole (H+ pump inhibitor)
lowers the infective dose of a bacteria, ie. Salmonella. Salmonella
normally has a high infective dose and shigella has a low infective
dose, and taking proton pump inhibitors will reduce defense against
salmonella. (Saw this in a U-World question!)
ii. Second line of defense (Innate arm of immune system)
1. Humoral (Antibody Mediated) Immunity
a. Complement
2. Cell-Mediated Immunity
a. Neutrophils
i. Do not present antigen to helper T-cells
b. Macrophages and Dendritic Cells (APCs)
i. Act as bridge between Innate and Acquired arms of
immunity by ingesting, killing, and presenting antigen via
MHC II (first step of acquired immunity)
c. Natural Killer Cells
d. Mast Cells (histamine, activate immune response)
b. Specific, requires several days before activation, improves after exposure,
has memory
i. Third line of defense (Acquired Immunity)
1. Humoral (Antibody Mediated) Immunity
a. B-Lymphocytes
b. Antibodies (Made by plasma cells)
i. Neutralize Toxins and Viruses
ii. Opsonize Bacteria (IgG and C3b both opsonize)
2. Cell Mediated (Fungi, Parasites, and Intracellular Bacteria, kill virus
infected cells and tumor cells)
a. Helper T-Cells (CD4)
b. Cytotoxic T-Cells (CD8)

Immune Response to Foreign Antigen: Timeline with

Details

Innate Immunity: Acute Inflammation Basics

(Read before proceeding;

mostly from pathoma)

Basics: General info
1) Acute Inflammation occurs in response to
a. Infection
b. Tissue Necrosis (ie. if patient had MI, neutrophils will , thus white count will
increase in blood)
2) Primary Cell of Acute Inflammation:
a. Neutrophils (do not present antigen)
3) Goal of acute inflammation
a. Infection: Eliminate Pathogen
b. Necrosis: Clear necrotic debri so healing can begin
4) Response
a. Immediate response with limited specificity.
b. In chronic inflammatory response, there will be antibody or t-cell receptor against a
specific antigen.
Basics: Chemicals Mediators of Acute Inflammation (part of innate immune system)
1) Toll Like Receptors (TLRs)
a. Present on cells of the Innate AND acquired immune system (mediates
both acute and chronic inflam)
i. Macrophages
ii. Dendritic Cells
b. TLRs have the ability to recognize PAMPS
i. PAMPs = pathogen associated molecular patterns
1. This is a great way for the innate immune system to respond to a large
variety of invaders without having specificity
ii. Toll-like receptors recognize patterns, letting the body know there is an
invader in the body, and turns on inflammatory response.
c. High yield example
i. CD14 on Macrophages (FA2013, pg. 201)
1. LPS is a PAMP
2. Once CD14 binds LPS, that
will directly (this is
important) stimulate
macrophages
3. IMPORTANT to note that TCells are NOT involved here
(normally macrophages are activated by T-cells)
4. This is the mechanism by which macrophages get activated to release
cytokines and cause septic shock.
d. TLR Activation results in upregulation of NF-kB
i. NF-kB is the molecular switch that turns on acute inflammatory response
ii. This activates immune response genes Production of immune mediators.
Drug Correlation: Synthetic Glucocorticoids (Beclomethasone, Fluticasone)
inactive NF-kB (pg. 563)

NF-kB is a TRANSCRIPTION FACTOR needed for production of numerous

cytokines such as TNF- and IL-2 (but also IL-3, 4, 5, 6, and 8)

Glucocorticoids (ie.
cortisol) inhibits IL-2
production (most
important one, thats
why its mentioned)
via inactivating NF-kB
(pg. 292)
Inhaled synthetic
glucocorticoids are first line
therapy against chronic
asthma
2) Arachadonic Acid
a. Released from phospholipid cell
membrane by Phospholipase A2
(PLA2)
i. Once arachadonic acid is released, it can be acted on by 1 of 2 pathways
1. Cyclooxygenase or 5-Lipoxygenase pathway
b. Cyclooxygenase produces Prostaglandins
i. PGI2, PGD2, and PGE2:
ii. Note: PGE2 = Feeever and Pain
Mediate Vasodilation and increased vascular permeability
c. 5-Lipoxygenase makes Leukotrienes
i. LTB4: Attracts and activates Neutrophils
1. Neutrophils arrive B4 others (pg. 404)
ii. LTC4, LTD4, LTE4
1. Cause Smooth Muscle Contraction
a. #1: Vasoconstriction (Arteriole)
b. #2: Bronchospasm (Bronchus is lined by
smooth muscle)
c. #3: Increased vascular permeability
Leukotrienes C4 D4 and E4
i. Blood vessels are lined by
cause bronchospasm; recall
endothelial cells
ii. Underneath endothelial cells
they are part of the late
are occasionally PERICYTES,
phase of Type I
which are contractile. When
hypersensitivity
they contract, they will pull
Asthma Drug correlation (pg.
apart the endothelial cells,
563)
increasing vascular
permeability.
Montelukast/Zaiflukast:
2. Responsible for late phase of type 1
Block LT Receptors
hypersensitivity

Zileuton: 5-Lipoxygenase
3) Mast Cells
Inhibitor (prevents
a. 3 mechanisms to activate
i. Tissue Trauma
ii. Complement proteins C3a and C5a (This is why they are anaphylatoxins)

iii. Cross linking of cell-surface IgE by antigen

b. Immediate response
i. Release of preformed histamine granules
1. DILATING SMOOTH MUSCLE OF THE ARTERIOLES
2. Increased VASCULAR PERMEABILITY in the POSTCAPILLARY VENULES
c. Delayed Response
i. Arachadonic acid metabolites, particularly leukotrienes
4) Complement (see section after acute inflammation for detail)
a. C3a/C5a = anaphylaxis (cause mast cell degranulation
release histamine)
b. C5a also chemotactic factor
c. C3b is for opsonization
5) Hageman Factor (Factor XII of the coagulation cascade)
a. Inactive pro-inflammatory protein produced in the liver
b. Activated upon exposure to subendothelial or tissue collagen
c. IMPORTANCE:
i. Gram (-) organism activates Hageman factor Causes DIC
1. How? Hageman factor activates
a. Coagulation and Fibrinolytic Systems
b. Complement
c. Kinin System: Cleaves HMWK to bradykinin mediates
vasodilation, increased vascular permeability, and pain

6)

Bra
dyk
inin

a. Responsible for PAIN, Vasodilation (Arterioles), and Permeability

(Venules)
Drug Side effect Correlation: ACE Inhibitors prevent the breakdown of Bradykinin

Normally bradykinin is broken down by ACE

o Inhibition of ACE Potentially results in angioedema
CONTRAINDICATION IF C1 ESTERASE DEFICIENCY (Hereditary Angioedema)

Nonproductive Cough also results from ACE inhibitor use

7) Fever
a. Pyrogens cause macrophages to release IL-1 and TNF
i. These go through blood and go to PERIVASCULAR CELLS of the POSTERIOR
hypothalamus (where temperature regulation is done) [FA2012, pg. 436]
ii. They will increase COX activity Increase PGE2, leading to fEEEver,
increasing the temperature set point.
Drug Correlation: Acetominophen (pg. 405)
iii. MOA: Reversibly inhibits COX, especially in
the CNS (ie. hypothalamus). Inactivated
Peripherally.

Step 1: Innate Immunity (First Response)

Timeline begins with a nail penetrating through the epithelium
(seen to right)

1) Vascular Events in Acute Inflammation____

a) Vasoconstriction of arterioles
i)

Neurogenic reflex that lasts only seconds

b) ARTERIOLES: Vasodilation
i)

Mediated by
(1) Mast Cells Release Histamine (Most important)
(2) Bradykinin Also responsible for PAIN
(a) Sensitizes sensory nerve endings
(3) Other vasodilators
(a) Nitric oxide
(b) PGI2, PGD2, PGE2 (PGE2 also causes fEEEver, and PAIN)

ii)

Relax vascular smooth muscle, causing increased blood flow.

(1) Increased blood flow increases hydrostatic pressure.

Symptom Correlation: Spider Angiomas (a type of TELANGIECTASIA)

(2) The below info is not really high yield except the correlation to conditions causing spider angiomas

(3) NOTE: Spider angiomas are NOT due to inflammation, but just to correlate
vasodilation of the arterioles, they are due to constant vasodilation of the smooth muscles
in the arterioles (recall arterioles are lined with smooth muscles under sympathetic, -1
control). High estrogen levels will cause dilation of the arterioles.
(4) Central red dot = dilated arterioles, red spider legs = small veins carrying away free flowing
blood
(a) They are telangiectasias will BLANCH with momentary pressure (emptied veins will refill from
center)
(5) This is seen in Hepatic Failure (liver normally metabolizes estrogen), ATAXIA-TELANGIECTASIA
(high yield), pregnant women, or hormonal contraception

c) Post Capillary VENULES: Increased Vascular

Permeability
i)

Histamine from mast cells and other mediators contract endothelial cells
producing endothelial gaps.
(1) Tight junctions are simpler in venules than arterioles.

ii)

A transudate (protein and cell-poor fluid) moves into the interstitial tissue.
(1) The venules is where neutrophils, etc enter. This makes sense that they
would enter through the venules because the venules are much thinner,
and the arterioles have a bunch of smooth muscles around, etc.

d) Swelling of tissue (tumor, edema)

i)

Net outflow of fluid surpasses lymphatic ability to remove fluid.

e) Reduced blood flow

i)

Decrease in hydrostatic pressure caused by outflow of fluid into the interstitial tissue

2) Cellular Events in Acute Inflammation (pg 215)

First 24 hours of Acute

Inflammation: Neutrophil
Dominated
Steps in Acute Inflammation:
a) Margination
i)

RBCs aggregate into rouleaux ("stacks of coins")

in venules.

ii) End result of Rouleaux Formation:

(1) Neutrophils are pushed from the central axial column to the periphery (margination) (close to
where they need to go)

Lab Correlation: Erythrocyte Sedimentation Rate (217)

(1) Products of inflammation (e.g. fibrinogen) coats RBCs and causes AGGREGATION
forms Rouleaux
(2) When aggregated, RBCs fall at a faster rate within test tube
(a) ESR: Infections, Inflammation (e.g. Temporal Arteritis), Cancer, Pregnancy,
SLE
(b) ESR: Sickle Cell (Altered shape), Polycythemia (too many RBC), CHF (unknown)

b) Rolling (selectin adhesion molecules)

Neutrophil adhesion is weak and transient causing them to "roll" along the endothelium.

Vasculature/Stroma

Leukocyte

Sialyl Lewisx

E-Selectin
P-Selectin

Adhesion of neutrophils to endothelial cell

ligands via complementary selectin
molecules on these two cells is enhanced by
interleukin-1 (IL-1) and tumor necrosis factor
(TNF).

Adhesion molecules firmly bind

neutrophils to endothelial cells.
c)

Firm adhesion (integrin adhesion molecules)

i)

LEUKOCYTES express LFA-1 (Integrin), aka CD18: a Receptor

(1) These integrins are located on neutrophils and endothelial cells
(serve as ligands).
(2) Neutrophil integrins are activated by C5a and leukotriene
B4 (LTB4).

1) Neutrophils in the peripheral blood

are subdivided into a circulating
pool and a marginating pool
(already attached to endothelial
cells).
2) Normally, 50% of peripheral
blood neutrophils are in the
circulating pool and 50% in the

ii) Endothelial cells express ICAM-1: Intercellular Adhesion Molecule 1 Acts as the LIGAND
(1) Intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) bind to integrins on
the surface of activated neutrophils.
(2) ICAM and VCAM activation to a high energy state is mediated by IL-1 and TNF leading to firm adhesion
of neutrophils to venular endothelial cells.

Endocrinology Correlation: Catecholamines, corticosteroids, and lithium inhibit activation of adhesion

molecules. (pg. 292)
(1) Peripheral blood neutrophil count (neutrophilic leukocytosis (Neutrophils in blood)) is increased.
(2) Normal marginating pool is now part of the circulating pool.
Microbiology Correlation: Endotoxins enhance activation of adhesion molecules.
(1) Peripheral blood neutrophil count (neutropenia) (Neutrophils in Blood) is decreased.
(2) Normal circulating pool is now part of the marginating pool.
PID Correlation: Leukocyte adhesion deficiency (LAD) Type 1 (Phagocyte Dysfunction)

Autosomal recessive disorder

Etiology

LAD type 1 is a deficiency of LFA-1 Integrin (CD18) on Phagocytes

LAD type 2 is a deficiency of a selectin that binds neutrophils.

Clinical findings
o

Delayed separation of the umbilical cord (HIGH YIELD!!!) (1 month)

Neutrophil enzymes are important in cord separation.

When a baby is born, umbilical cord, which normally had blood going through it, is now
sealed. The next step is umbilical cord will undergo necrosis b/c no blood going through

Next step after necrosis is ACUTE INFLAMMATION (neutrophils destroy tissue

umbilical cord will separate)

But LFA-1 deficiency (lack of CD18) neutrophils cant arrive.

Recurrent Bacterial Infections

Absent Pus Formation: Pus is dead neutrophils sitting in fluid

Severe gingivitis, poor wound healing

Lab Finding
o

d)

If the patient cant get neutrophils into the tissue, you wont get pus, so youll get
recurrent infections without pus.

NEUTROPHILIA (peripheral blood neutrophilic

leukocytosis due to loss of marginating pool)

Transmigration (Diapedesis) EXUDATE

i)

Neutrophils dissolve the basement membrane and enter

interstitial tissue
(1) Neutrophils travel BETWEEN endothelial cells and exits
blood vessel
(2) Vasculature and Leukocyte will both express PECAM-1

ii)

Exudate: Fluid rich in

proteins and cells (i.e.,
exudate) accumulates in
interstitial tissue.

Vasculature/Stroma

Leukocyte

PECAM-1

(1) Due to the increased

permeability of the endothelium now
(a) V
(2) General Info on Exudate (pg 216)
(a) Cellular, Protein rich, specific gravity >1.020.
(b) Due to lymphatic obstruction or inflammation
(3) Functions of exudate
(a) Dilutes bacterial toxins

PECAM-1

(b) Provides opsonins (IgG, C3b) to assist in phagocytosis

Examples of Exudate Disease Correlation: (occurs with any disease involving inflammation, not
comprehensive list, but everything that said exudate using find function in FA2012 along with anything I could think
of where exudate is directly related to damage by deposition of exudate, and possibly inability to clear the exudate
leading to fibrosis). See outcomes of acute inflammation to make sense of this

Small Vessel Disease

o (ie. in eye: angiogenesis damage of small vessels leads to exudate Retinopathy)
Dermatologic: Crust:
o Dried exudate from vesicle, bulla, or pustule (as seen in Impetigo)
Respiratory:
o Pharyngitis (Grayish oropharyngeal exudate Pseudomembranes (May obstruct airway) in
C.Diptheriae
o Pneumonia:
Lobar: Intra-alveolar exudate Consolidation may involve entire lung
Bronchopneumonia
Interstitial Pneumonia
o Pleural Effusion (can be Transudate, Exudate, or Lymphatic)
Malignancy, pneumonia, collagen vascular disease, trauma
o Acute Respiratory Distress Syndrome (ARDS): exudate directly
contributes to damage
Diffuse alveolar damage (due to neutrophilic substances toxic to
alveolar wall, activation of coagulation cascade, and O2 derived free
radicals) alveolar capillary permeability protein-rich leakage
(EXUDATE) into alveoli formation of intra-alveolar HYALINE MEMBRANE
diffusion distance for gasses
Renal:
o Rapidly Progressive Glomerulonephritis
Damage to the Glomerular Basement Membrane Leak of protein rich
INFLAMMATORY DEBRI (EXUDATE Proteins: FIBRIN (last part of
common coagulation cascade makes FIBRIN CLOT, dont confuse w/
fibrosis) and plasma proteins like c3b, Cells: Monocytes and

MACROPHAGES) into the glomerular tuft CRESCENT FORMATION

(blocks filtration acutely)

Cardio
o Fibrinous Pericarditis 1-3 days following MI Friction Rub (pg 271)
o Restrictive Cardiomyopathy (pg. 272)????
GU: Ulcerated genital lesion
o Painful ulcer w/ exudate: CHANCROID = H.Ducreyi
GI: Pseudomembranous Colitis, inflammatory bowel diseases

(Transudate vs. Exudate)

e)

Migration/Chemotaxis (directed
migration of neutrophils)
i)

Neutrophils follow chemical gradients

that lead to the infection site.

ii)

Chemotactic mediators bind to neutrophil

receptors.
(1) 4 chemotactic factors for Neutrophils:
CILK (pg. 215)
(a) C5a
(i) Recall it also is involved with
C3a in anaphylaxis
(b)

IL-8: Cleanup on Aisle 8: Major Chemotactic Factor

(i)

Produced by resident tissue macrophages that sense the antigen and secrete IL-8 to recruit neutrophils

(c) LTB4
(i) Neutrophils arrive B4 others (pg. 404)
(d) Kallikrein (Bacterial Products)

iii) Binding causes the release of calcium, which increases neutrophil motility

PID Correlation: Jobs Syndrome (Hyper IgE Syndrome) (pg. 206)

T-Cell Disorder
(1) Autosomal recessive disorder of neutrophils, characterized by abnormal chemotaxis
(a) Defect = Th1 cells fail to produce IFN-
(i) (Because macrophages are activated by IFN- and they make IL-8 (to attract neutrophils))
(ii) Inability of neutrophils to respond to chemotactic stimuli
(2) Leads to "cold" soft tissue abscesses due to Staphylococcus aureus.

(3) Clinical/Lab Findings: FATED

(a) Facies (Leonine Face)
(i) Recall that lionine facies is classically seen in Pagets Disease
of Bone and Leprosy
(b) Cold (noninflamed) Staphylococcal Abscesses
(c) Retained primary Teeth
(i) Patients fail to lose primary teeth and have two sets of teeth simultaneously (FYI: seen in
autosomal dominant form)
(d) Increased IgE (hyperimmune E syndrome).
(i) The main immunologic defect is a failure to produce gamma interferon by helper T cells, which reduces the
ability of macrophages to kill bacteria. (normally IFN- also suppresses TH-2 production)
(ii) This leads to an increase in Th-2 cells and, as a consequence, a high IgE level. The increased IgE causes
histamine release, which blocks certain aspects of the inflammatory response, hence the "cold" abscesses.
Histamine also inhibits neutrophil chemotaxis, another feature of this syndrome. Treatment consists of
antimicrobial drugs.
(e) Dermatologic Problems (Eczema)

f)

Phagocytosis (Multistep process, consisting of three steps): Opsonization, Ingestion, Killing

i)

Opsonization
(1) Opsonins attach to bacteria (or foreign bodies).
(a) Opsonins include IgG, C3b fragment of complement, and other proteins (e.g., C-reactive protein).
(b) Neutrophils have membrane receptors for IgG and C3b.
(2) Opsonization enhances neutrophil recognition and attachment to bacteria.
PID Correlation: X-Linked Bruton's Agammaglobulinemia (XLA) (206) (Phagocyte Dysfunction)
(a) X-linked Recessive (in boys)
(b) Etiology:
(i) Defect in BTK, a tyrosine kinase
gene blocks pro-B cells from
forming pre-B cells (blocks Bcelll maturation)
(ii) Is considered an opsonization
defect because no mature Bcells around to make antibodies.
(c) Clinical Findings
(i) Results in recurrent bacterial infections after 6 months (after maternal IgG) as a result of lack of
opsonization
(d) Lab Findings
(i) Normal pro-B
(ii) Maturation
(iii) # of B-cells
(iv) immunoglobulins of all classes

ii) Ingestion
(1) Neutrophils engulf (phagocytose) and then trap bacteria in phagocytic vacuoles.
(2) Primary lysosomes empty hydrolytic enzymes into phagocytic vacuoles producing phagolysosomes.
PID Correlation Chdiak-Higashi syndrome (pg 207) (Phagocyte Dysfunction)
(a) Etiology: Autosomal Recessive defect in Lysosomal Trafficking Regulator Gene (LYST)
(i) Results in microtubule function prevents phagolysosome formation.

(b) Clinical Findings

(i) Recurrent Pyogenic infections by staphylococci and streptococci
1. Because phagosome is created, but it cannot merge with lysosome (there are
no tracks)
(ii) Partial Albinism
1. Pigmenting of the skin occurs by melanocytes. Within keratinocytes, there is 1 melanocyte
producing pigment for 25 different keratinocytes. Normally, pigment is produced and handed
off to adjacent cells, using microtubule system. This system is failed now albinism.
(iii) Peripheral Neuropathy
1. Nerve at very periphery (ie. of toe); the nerve of toe is far above at spinal cord; may be 2
feet.
2. If nucleus is all the way in the vertebrae, microtubule defect means they cant keep the
peripheral nerves alive peripheral neuropathy.
(iv) Defective primary hemostasis: 1 hemostasis is dependent on platelets, and platelets contain
granules (dense core granules), if they are not properly distrib/functional, defect in 1 hemostasis
(c) Lab Findings
(i) Neutropenia: Neutrophils w/in bone marrow when dividing into two, you need to separate the cell,
move some cellular components one way and another.
1. if a cell cant move things around properly; theres a defect in bone
marrow o
2. f neutrophils neutropenia
(ii) Giant Granules in Neutrophils
1. These are produced by the Golgi Apparatus. If granules are produced, they wont be able to
sent out to the periphery; instead the granules will pile up next to the golgi.

iii) Bacterial killing

(1) Respiratory Burst (O2-dependent myeloperoxidase (MPO) system) (Fig. 2-4)
Most effective way to kill bacteria
(a) Only present in neutrophils and monocytes (not macrophages)
(i) Macrophages kill by fusing lysosome with phagosome
(b) Production of superoxide free radicals (O2 )

(i) Reduced nicotinamide adenine

dinucleotide phosphate (NADPH)
oxidase converts molecular O2 to O2 ,
which releases energy called the
respiratory, or oxidative, burst.
(c) Production of peroxide (H2O2)
(i) Superoxide dismutase converts O2 to
H2O2, which is neutralized by
glutathione peroxidase.
(d) Some peroxide is converted to hydroxyl
free radicals by iron.
(e) Production of bleach (HOCl)
(i) MPO combines H2O2with
chloride (Cl-) to form
hypochlorous free radicals
(HOCl), which kill bacteria.

Figure 2-4 Oxygen-dependent myeloperoxidase

system.
A series of biochemical reactions occurs in the
phagolysosome, resulting in the production of

(f) PID Correlation: Chronic granulomatous disease (207) (Phagocyte Dysfunction)

(i) Etiology: Lack of NADPH oxidase; defect in the O2-dependent MPO system.
1. Results in ROS (ie. superoxide) and absent respiratory burst in neutrophils
2. Clinical Findings
a. Susceptibility to Catalase-Positive Organisms
i.

S.Aureus

ii.

E.Coli

iii. Aspergillus
iv. Pseudomonas cepacia
v.

S.marcesens

vi. Nocardia
3. Lab Findings
a. Abnormal Dihydrorhodamine (DHR) flow cytometry test
b. Nitroblue tetrazolium dye reduction test no longer preferred
i.

Can we turn oxygen to superoxide? if yes, color turns blue.

(ii) Related Diseases:

1. MPO deficiency

2. Deficiency of NADPH (e.g., glucose-6-phosphate dehydrogenase deficiency) produces a

microbicidal defect.
i. MPO deficiency: normal respiratory burst
ii. NADPH: microbicidal defect
iii. NBT test is normal

(2) O2-independent system

(a) Less Effective
(b) Refers to bacterial killing from substances located in leukocyte granules
(c) Examples
(i) Lactoferrin (binds iron necessary for bacterial reproduction)
(ii) Major basic protein (eosinophil product that is
cytotoxic to helminths)
(iii) Lysozyme

2-7th day of Acute Inflammation:

Macrophage Dominated
1) Macrophage # peaks 2-3 days after
inflammationbegins
2) DERIVED FROM MONOCYTES IN BLOOD
a. Monocytes come into the tissue the exact
same way that neutrophils do
i. Margination, Rolling, Adhesion, Transmigration
3) ONCE THE MACROPHAGES GET INTO THE TISSUES
a. They Ingest via PHAGOCYTOSIS
b. For the most part, macrophages do NOT do respiratory burst.
c. Instead, their killing mechanism is destruction via phagocytosed material using
enzymes in SECONDARY GRANULES LYSOZYMES

Macrophages will manage the next step

of acute inflammatory process
Complete resolution and Healing Restoration of normal function
a) Occurs with mild injury to cells that have the capacity to enter the cell
cycle
i)

Robbins: This is because with mild injury, we have the capability

to CLEAR all the fibrin and exudate

ii) Review of cell types: (Cell cycle: pg 74, pg 214)

(1) Stable (Quiescent/Resting) Cells: Usually in G0, Enter G1 from G0 when stimulated
(a) Hepatocytes, Lymphocytes, Astrocytes, Smooth Muscle Cells

(GH, etc)

(b) May undergo both hyperplasia or hypertrophy as adaptation to cell injury

(2) Labile Cells: Always in G1, rapidly dividing, Never go to G0. G1 is short.
(a) Bone Marrow, Gut Epithelium, Skin, Hair Follicles
(b) May undergo HYPERPLASIA as adaptation to cell injury (note that hyperplasia also has a risk for
increasing into dysplasia and cancer, as in Endometrial Hyperplasia with hyper estrogen and lack of prog.)

Immunology perspective: MACROPHAGES sense that the damage is not severe

Shut down inflammatory process with
IL-10
TGF-
These are the same cytokines that are secreted by Regulatory T-cells to shut down inflammation (pg.
197)
b) Examples-first-degree burn, bee sting
2) Tissue destruction and scar formation Reduced tissue function
a) Occurs with
i)

Extensive injury

ii)

Damage to Permanent cells (Always in G0, cells unable to enter cell cycle, remain in G0, cannot divide)
(1) Neurons, Skeletal and Cardiac Muscle, RBCs
(2) Note these cells can only undergo HYPERTROPHY (only muscle), never hyperplasia

b) Extensive fibrinous exudates (due to increased vascular permeability) may not be

completely absorbed and are organized by ingrowth of connective tissue, with

resultant fibrosis.
c) Example-third-degree burns

3) Continued Acute Inflammation

Immunology Perspective: MACROPHAGES sense that the neutrophils need help

IL-8 is the interleukin by which macrophages call in neutrophils

That will result in continued acute inflammation
(a) Although acute inflammation peaks at 1 day, its NOT defined by time, its defined by RESPONSE
(b) A person could have acute inflammation for 6 weeks!! this is because macrophages could
keep secreting IL-8 to call in more neutrophils
(i) The hallmarks of neutrophil inflammation, particularly formation of pus tells us there is
continued acute inflammatory response.
(c) To illustrate: a person has had a process going for 8 weeks, but is still coughing up pus; it is STILL
acute inflammation even 8 weeks into infection because neutrophil response
(i) Neutrophils are what DEFINE acute inflammation

2) Formation of abscesses Leads to healing and fibrosis eventually Reduced tissue function
a) Abscesses may form in
i)

The setting of extensive neutrophilic infiltrates (see later)

ii)

In certain bacterial or fungal infections (these organisms are then said to be pyogenic,
or "pus forming").

b) Because of the underlying tissue destruction (including damage to the ECM), the usual

outcome of abscess formation is scarring

c) Example-lung abscess in bronchopneumonia

Immunology perspective: Macrophage comes in and senses that the organism needs to be
walled off to protect the host. They will create an abscess around the infection: so infection
gets trapped w/in that space. It is a WALLED OFF AREA of ACUTE INFLAMMATION, and
NEUTROPHILS will be managing the formation of the abscess.

4) Progression to chronic inflammation Leads to healing and fibrosis eventually Reduced tissue function
a) Inflammation of prolonged duration (weeks to years) that most often results from persistence of an injury-causing
agent

Immunology perspective: Macrophage senses that the neutrophils cant handle it

Causes of Chronic Inflammation

(a) Viral Infections
(b) Chronic Infections
(c) Persistent Injury
(d) Autoimmune Disease
Macrophages will then call in chronic inflammation will ingest viral particles,
express on MHC II, and present to Helper T-Cells to start CHRONIC INFLAMMATION

Types of Acute Inflammation (Not high yield, but understanding this helps a lot with tying it all
together)
1) Purulent (suppurative) inflammation
a) Localized proliferation of pus-forming organisms, such as Staphylococcus aureus (e.g., skin abscess; Fig. 2-6)
b) S. aureus contains coagulase, which cleaves fibrinogen into fibrin and traps bacteria and neutrophils.
(a) S. aureus : most common cause of a skin abscess
2) Fibrinous inflammation
a) Due to increased vessel permeability, with deposition of a fibrin-rich exudate
b) Often occurs on the serosal lining of the pericardium, peritoneum, or pleura
i)

Danger of adhesions

c) Example-fibrinous pericarditis (Fig. 2-7)

Robbins: Fibrinous inflammation occurs as a consequence of more severe injuries, resulting in
greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial
barrier. Histologically, the accumulated extravascular fibrin appears as an eosinophilic meshwork of
threads or sometimes as an amorphous coagulum (Fig. 2-11). A fibrinous exudate is characteristic of
inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura.

3) Such exudates may be degraded by fibrinolysis, and the accumulated debris may be removed by
macrophages and lymphatic circulation, resulting in restoration of the normal tissue structure
(resolution).
4) However, failure to completely remove the fibrin results in the ingrowth of fibroblasts and blood
vessels (organization), leading ultimately to scarring (fibrosis) that may have significant clinical
consequences.
5) For example, organization of a fibrinous pericardial exudate forms dense fibrous scar tissue that
bridges or obliterates the pericardial space and restricts myocardial function.
6) Serous inflammation
a) Thin, watery exudate
i)

Insufficient amount of fibrinogen to produce fibrin

b) Examples-blister in second-degree burns, viral pleuritis

7) Pseudomembranous inflammation
i)

Pseudomembranous inflammation: diphtheria, Clostridium difficile; noninvasive bacteria

b) Bacterial toxin-induced damage of the mucosal lining, producing a shaggy membrane composed of necrotic
tissue
c) Example-pseudomembranes associated with Clostridium difficile in pseudomembranous colitis (Fig. 2-8)
i)

Corynebacterium diphtheriae produces a toxin causing pseudomembrane formation in the pharynx and
trachea.

Innate Immunity: Complement Cascade (#2), (pg 199)

1) Overview
a) Synthesized in the
liver
b) Augment natural
host immune
defense
i)

Acute phase
reactant (refer
to Chapter 2)

c) Circulate as inactive
proteins
i)

(1) Activated by IgM, IgG-antigen complexes, endotoxin

ii)

(2) Only complement cleavage products are functional.

d) Functions complement cleavage products

i)

C3a, C5a (anaphylatoxins)

(1) Why anaphylatoxins? Stimulate mast cell release of histamine

ii)

C3b
(1) Opsonization

iii) C5a
(1) Activation of neutrophil adhesion molecules
(2) Neutrophil chemotaxis
iv) C5b-C9 (membrane attack complex, MAC) Cell Lysis
2) Complement pathways (Fig. 3-5)
a) Classic pathway
i)

Activation: C1 binds to IgG or IgM that is bound to antigen

(1) GM Makes Classic Cars

ii)

Contains complement components C1, C4, C2

iii) C1 esterase inhibitor

(1) Inactivates the protease activity of C1
(a) Protease normally cleaves C2 and C4 to produce C4b2b complex (C3 convertase)

(2) Inhibitor is deficient in hereditary angioedema

b) Alternative pathway
i)

Activation: Microbial products directly activate complement

ii)

Contains complement components factor B, properdin, factor D

c) Mannose Binding Lectin Pathway

i)

MBL (acute phase reaction) binds mannose on microorganisms, and activates complement

ALL 3 PATHWAYS have a common result

o C3 Convertase is generated
Converts C3 to C3a and C3b
and C3b joins into produce C5 convertase
Then C5 convertase turns C5 into C5a and C5b
o C5b complexes with C6-9 to make the MAC attack complex
d) Decay accelerating factor (DAF)
i)

Present on cell membranes

ii)

Enhances degradation of C3 convertase and C5 convertase

iii) Protects the cell against MAC destruction

iv) Deficient in paroxysmal nocturnal hemoglobinuria (PNH) (refer to Chapter 11)
v)
3) Testing of the complement system
a) Total hemolytic complement assay (CH50)
i)

Tests functional ability of both complement systems

b) Tests indicating activation of classic system

(a) Classical pathway activation: decreased C4, C3; normal factor B
ii)

(1) Decreased C4, C3

iii) (2) Normal factor B

c) Tests indicating activation of alternative system
(a) Alternative pathway activation: decreased factor B, C3; normal C4
ii)

(1) Decreased factor B, C3

iii) (2) Normal C4

d) Tests indicating activation of both systems
i)

Decreased C4, factor B, C3

Complement Disorders
1) Complement Disorders causing Immunodeficiency Disorders
a) C1 Esterase Inhibitor Deficiency (HEREDITARY ANGIOEDEMA)
i) Autosomal dominant disorder with deficiency of C1 esterase inhibitor
ii) Continued C1 activation decreases C2 and C4 and increases their cleavage
products, which have anaphylatoxic activity
iii) Normal C3
iv) Swelling of face and oropharynx
b) C3 Deficiency
i) Severe recurrent pyogenic sinus and respiratory tract infections
ii) Susceptibility to type 3 hypersensitivity reactions (HIGH YIELD TO UNDERSTAND THIS!!!!)
(1) Why? Normally C3 helps to CLEAR IMMUNE COMPLEXES
(a) Note that in Type 3 hypersensitivity diseases where immune complexes are
involved in the disease process, C3 levels FALL!!!
c) C5-C9 Deficiencies
i) Increased susceptibility to disseminated Neisseria gonorrhoeae or N. meningitidis infections

d) DAF (GPI Anchored Enzyme) Deficiency Paroxysmal Nocturnal Hemoglobinuria (pg. 356)
i) Acquired stem cell disease
ii) Defect in molecule anchoring decay accelerating factor
(DAF), which normally degrades C3 and C5
iii) convertase on hematopoietic cell membranes
iv) Complement-mediated intravascular lysis of red blood cells
(hemoglobinuria), platelets, and neutrophils

2) Renal
a) Nephrotic Syndrome (proteinuria >3.5, etc, edema, etc)
i) Membranoproliferative Glomerulonephritis: Type II
(1) ICs Deposition of immune complexes within the

BASEMENT MEMBRANE
(2) Associated with the C3 nephritic factor (C3NeF) in their blood, an
autoantibody that binds to and stabilizes C3 convertase (C3bBb);
(a) Prevents degradation of C3 convertase causing sustained activation of C3,
resulting in overactivation of complement Inflammation
ii) Review of Complement:
(1) C3 gets turned into C3a + C3b, catalyzed by C3 convertase
(2) C3 convertase is destroyed quickly because we dont want to
overactivate complement. The antibody C3 nephritic factor prevents
breakdown of C3 Convertase.
b) Resulting in very low C3 levels
Bottom line: C3 Nephritic Factor Autoantibody prevent breakdown of
C3 Convertase C3a +C3b Overactivated complement
inflammatory damage within the glomerulus
i)

IL-6
#3: Acute Phase Response (Induced mainly by IL-6)

1) Endogenous
Pyrogen
2) Secreted by TH2
Cells
3) Causes fever and
stimulates
production of acute-

1) The liver synthesizes various Acute Phase Reactants in response to

IL-6 (pg 200), which is made by macrophages after exposure to
microorganisms
a) Important Acute Phase Reactants to know for the step 1 include
i) Mannose Binding Lectin (MBL) (pg. 199). It is a pattern
recognition receptor; part of innate immunity
(1) Starts the lectin binding pathway of complement (activates C1-like complex)
ii) C-Reactive Protein (CRP)
(1) Sensitive indicator of necrosis associated
with acute inflammation
(a) CRP is increased in inflammatory (disrupted)
atherosclerotic plaques and bacterial infections.
(2) Excellent monitor of disease activity (e.g., rheumatoid
arthritis)

iii) Serum Amyloid-Associated (SAA) Protein

May cause AMYLOIDOSIS (pg. 217)
(1) Seen in Chronic Inflammatory Disease (RA, IBD,
Spondyloarthropathy, Chronic Infections)
(2) Fibrils composed to serum Amyloid A.
(3) Often multisystem like AL amyloidosis
iv) Hepcidin Part of Anemia of Chronic Disease
(pg. 355)
(1) Hepcidin is released by the liver and
(a) Binds FERROPORTIN (exports iron from inside of cell to outside) on intestinal
mucosal cells (prevents absorption of iron from GI)
(b) Binds FERROPORTIN on macrophages (prevents iron moving from macrophage
into blood release of iron from macrophages)
(2) Anemia
(a) Lab Findings:
(i) Serum Iron,
(ii) TIBC (body produces less transferrin, which is the blood carrier of iron),
(iii)Ferritin (body produces more ferritin to store iron away in the tissues)
(b) Starts out as Normocytic Anemia (Nonhemolytic)
(i) Eventually becomes Microcytic, Hypochromic over time
(3) In AOCD, the idea is to sequester iron away from pathogenic microbes that need
iron.
v) Fibrinogen (217) [Part of common coagulation cascade, pg. 348]
(1) Causes RBC to aggregate (form rouleaux) pushes neutrophils to periphery
margination of neutrophils
(2) RBCs fall at fast rate within test tube
vi) Haptoglobin (pg 354)
(1) Binds free Hb in the blood and then goes to the spleen (reticuloendothelial system)
to get removed
(a) Therefore, Haptoglobin falls in intravascular hemolysis (Normocytic,
Normochromic anemia intravascular hemolysis)
(i) Intravascular Hemolysis: G6PD Deficiency (can be I/E), and Paroxysmal
Nocturnal Hemoglobinuria (I)
vii) Complement (C3)

#4: Natural Killer Cells (pg. 194)

CD56 (unique marker for NK), CD16 (binds Fc of IgG. Recall CD16 decreases in blood with left
shift)
Only lymphocyte member of innate immune system.
Induced to kill when
1) Exposed to non-specific
activation signal on target cell
2) Absence of MHC I on
target cell surface (ie. tumor
cells that downregulated MHC I
to escape immune detection)

Activity enhanced by
1) IL-2, IL-12, IFN-, IFN-
a. IL-12 activates NK cells,
but it also induces
nave T-cells to turn
into TH1 (recall IL-12
deficiency causes T-cell
dysfunction)
Kills with
1) Perforin and Granzymes to induce apoptosis of virally infected cells and tumor cells

Step 2: Antigen Presenting Cells (specifically, DENDRITIC

CELLS) **Act as the bridge between Innate and Adaptive

Immunity.
IMPORTANT: APCs will definitely phagocytize and present antigen if acute
inflammation via neutrophils failed to clear the infection, and will present to
CD4+ Nave T-Helper to induce CHRONIC INFLAMMATION, where
macrophages and lymphocytes will fight for weeks to years. However, if
neutrophils were able to completely clear the infection quickly, causing
resolution, the antigen may not get presented (this is implied by pathoma
guy)
Detail on Antigen Presenting Cells (APC): (pg 346)
1) 3 Types
a) Dendritic Cells (called Langerhans Cells in the skin)
i) Highly phagocytic APC.
ii) Act as the link between innate and adaptive immune system (After dendritic cell detects offending antigen
and phagocytosis it, it displays it on the surface via MHCII, and presents it to nave T-cell in the lymph node)
iii) Express MHC II and Fc receptor on surface
Neoplasia Correlation: Langerhans Cell Histiocytosis (LCH) (pg 366)
(1) Proliferative disorder of dendritic cells from monocyte lineage.
(a) Langerhans cells are a specialized type of dendritic cell mostly in the skin
(2) Pathogenesis
(a) Cells are FUNCTIONALLY IMMATURE, and do NOT efficiently stimulate Tlymphocytes via antigen presentation
(3) Clinical Presentation: Pediatric Disorder
(a) Child with lytic bone lesions and skin rash
(4) Laboratory
(a) Cells express S-100 (neural crest origin) and SD1a
(b) Birbeck Granules (Tennis Rackets on EM are
characteristic

b)

B-Lymphocyte (B-cells are APCs because thats how they get

activated)
i) Development:
(1) Arises from stem cells in bone marrow.
(2) Matures in bone marrow

(3) Nave but mature B-cell migrates to peripheral

lymphoid tissue (follicles of lymph nodes, white
pulp of spleen, unencapsulated lymphoid tissue)
(4) Differentiates into plasma cells that produce
antibodies and memory cells when antigen is
encountered.
ii) Cell Markers: CD19 and CD20
iii) Expresses MHC II presentation of antigen is part
of how it gets activated
c)

Macrophages
i)
ii)
iii)

iv)
v)
vi)

Located in the tissues (long life in tissues)

Development: Differentiate from circulating blood
monocytes
Function
(1) Phagocytoses bacteria, cell debri, and
senescent RBCs, and scavenges damaged cells
and tissues.
Is activated by IFN-
Functions as APC via MHCII
Cell marker: CD14

Review of MHC I and II (pg. 194)

1) MHC I (HLA-A, HLA-B, HLA-C)

a. Expressed on all NUCLEATED

cells in the body (so, not
present on platelets or RBCs)
b. ANTIGEN PRESENTATION:
i. Loaded in RER with
mostly intracellular
peptides
ii. MHCI pairs with 2
microglobulin (aids in
transport to cell
surface)
c. If expressing a foreign
antigen; CD8+ Cytotoxic T cell
will kill the cell
i. MHCI = Kill me now,
Im infected!
2) MHC II (HLA-DR, HLA-DP, HLADQ)
a. Expressed on Antigen
presenting cells only
i. Dendritic Cells
ii. Macrophages
iii. B-Cells
b. ANTIGEN PRESENTATION:
i. Loaded following
release of invariant
chain in acidified
endosome
c. If expressing a foreign
antigen, APC will go to Nave CD4+ T Helper Cell and activate it (costimulation with
B7/C28, and MHCII with TCR) [see next page]

HLA subtypes associated with disease (pg. 194)

Certain HLA subtypes are associated with disease because they are more likely to present self
antigens and induce autoimmune disease.

Step 3 Beginning of CHRONIC INFLAMMATION

1) Etiologies of Chronic inflammation: Any etiology of neutrophils FAILING to clear the
infection, so APCs will have a chance to pick up the antigen and then go present to the
Nave Helper T-Cell in the paracortex of the Lymph Node
a. Persistent Infection (Most Common)
b. Infection with VIRUSES, Mycobacteria, Parasites, and Fungi
c. Autoimmune Disease
d. Foreign Material
e. Some Cancers (Chronic inflammatory state is the major way our body fights cancer)

Activation of Nave T-Cells in the Paracortex of the Lymph Node

1)

Nave T-Cell Activation in Paracortex of Lymph Node (Houses TCells)

a) APC goes to the PARACORTEX of the lymph node activates Nave
T-Cell via Costimulation
b) Costimulation = 2 signals
i) MHC2AntigenTCR
ii) B7CD28
c) Note that CD3 is involved in TCR signaling Drug target

Mnemonic: Remember that B-cells are also APCs, and that B-7 is on
APCs. Therefore, you know B-7 has to be on the APC.

Microbiology Correlation: Superantigens (pg 125, pg 201)

i) Staph aureus and Strep. Pyogenes both create toxins that crosslink
region of MHCII on APC and TCR nonspecific activation of ~83%
of t-cells in body (wiki) overwhelming release of cytokines,
including IFN- (activates macrophages to release TNF-, and NO,
inducing shock: pg. 125) and IL-2
(1) Toxic Shock syndrome (Staph.Aureus and Strep.Pyogenes): Fever, rash, shock

Drug Correlation: Muromonab-CD3 (pg. 209)

i) Binds to CD3 on surface of T-cells and blocks TCell signal transduction (CD3 needed for TCR
transduction)

Upon Activation, T-Cell secretes IL-2 to activate self (HIGH YIELD!!!!!!!!!!)

d) IL-2 is secreted by T-cells to stimulate the growth of helper, cytotoxic, and regulatory T-Cells
PID Correlation: Severe Combined Immunodeficiency (207)
1) Deficiency in BOTH T-cells and B-Cells
2)

3)

4)

5)

6)

Etiology:
a) X-linked deficiency in IL-2 (most common; remember its Bubble
Boy)
b) Adenosine Deamniase Deficiency
i) ADA deaminates adenosine and deoxyadenosine
(1) (although not the most common etiology, it ties in biochem
so it is high yield)
ii) Buildup of these two w/ in lymphocytes would be toxic. So, you
can get severe immunodeficiency.
c) MHC Class II Deficiency
i) CD4+ t-cell cant activate B-cells, T-cells
Clinical Presentation
a) Similar to AIDs patient, but worse
b) Failure to Thrive, Chronic diarrhea, thrush
c) Recurrent viral, bacterial, fungal, and protozoal infections
Lab
a) Absence of thymic shadow, germinal centers (lymph node biopsy), B-cells (peripheral blood smear), and T-cells (flow
cytometry)
b) T-cell rebomcinant excision circles (TRECs)
Treatment:
a) Sterile Isolation
b) Bone marrow transplant (no allograft rejection)
i) Hematopoetic stem cells will be able to generate normal B and T Cells
c) CANNOT GIVE LIVE ATTENUATED VACCINES!!!
In a patient with SCID, innate immunity is intact, but acquired immunity is not proves innate immunity is
insufficient to survive.

Drug Correlation IL-2: Cyclosporine, Tacrolimus and Sirolimus (pg 209); used in immunosuppression for organ
tsplnt or certain autoimmune disorders
1)

All 3 of these drugs will interfere with IL-2 in different ways; look in FA for details (pg. 209)
a. Cyclosporine: Inhibits calcineurin: Production of IL-2 and receptor
b. Tacrolimus (FK-506) Inhibits Calcineuron: Production of IL-2 and receptor
c. Sirolimus (Rapamycin): Inhibits mTOR: inhibits T-cell proliferation response to IL-2

Drug Correlation IL-2: Aldesleukin (Recombinant IL-2), (pg. 210)

1) Used to treat Renal Cell Carcinoma and Metastatic Melanoma (maybe boost immune system to fight?)
Endocrinology Correlation: Cortisol IL-2, via blocking NF-kB transcription factor (master switch for many of the
cytokines)

2) Nave Helper T becomes a T-Helper 1 Cell or T-Helper 2 Cell (CD4)

specific to antigen
a) IL-12 induces Nave TH to become TH-1
PID correlation: IL-12 Receptor Deficiency (pg 206)
T-cell Disorder
(1) TH-1 Response
(2) Clinical Presentation: Disseminated MYCObacterial infections
(3) Findings: IFN- (because no T-cells to make IFN-)
(a) Because IGN-, released by T-cells is so critical to maintain the Tcell macrophage interaction, granulomas fail Mycobacterium
infections
b) IL-4 induces Nave TH to become TH-2
i) Promotes growth of B-Cells
ii) Enhances class switching to IgG and IgE (Risk of Type 1 hypersensitivity: Atopic Disease)

3) Following costimulation (activation), CD4+ TCells do 3 major things:

a) #1: Activation of B-Cells by CD4+, TH2 (pg 196)
i)

(Image, #1, 2) B-Cell uses antigen-specific surface IgM

(1) Performs receptor-mediated endocytosis of antigen
(2) Presents antigen on MHC II
ii) (Image, #3) TH2 cell specific to antigen (from step #1) comes and
activates the B-Cell
(1) Costimulation occurs, using CD40/CD40L
(2) TH2 secretes
(a) IL-4, IL-5, IL10 (pg 200)
(i) IL-4: Promotes growth of B-Cells. Enhances class switching
to IgE and IgG. Inhibits TH1 cells (196)
(ii) IL-5: Promotes differentiation of B-Cells. Enhances class
switching to IgA.
(iii) IL-10: Inhibits actions of activated T-cells and TH1 (recall
macrophages do resolution of acute inflammatory response by secreting IL-10)
(3) B-Cell migrates to Germinal Center
(a) Class switching Affinity maturation
(b) Antibody production (Type I-III Hypersensitivites are all antibody mediated , pg 203)

b) IMPORTANT: B-cell can also simply bind Antigen on Surface IgM or IgD Becomes IgM

Secreting Plasma Cell

PID Correlation: Hyper-IgM Syndrome (pg. 207). B and T-cell disorder

1) Etiology: Most commonly, defective CD40L on helper T-cells

a. As a result, B-Cells cannot class switch.
b. However, B-cells can also internalize an antigen and become an
IgM (non class switched) plasma cell
2) Presentation: Pediatric
a. Severe pyogenic infections early in life
3) Laboratory:
a. IgM (because the ability of B-cell to internalize antigen and
just become IgM secreting plasma cell is intact
b. IgG, IgA, and IgE

c) #2: Activation of Cytotoxic CD8+ T-Cells by CD4+, TH1;

pg 410 of ROMMAI
i) (Step 3 of the picture to the right. Note the picture includes
step 1, which is presentation of antigen using the
macrophage)
ii) Note that IL-2 activates the CD8 cell
iii) CD8+ cell goes to kill the Virus infected cell that presented
the antigen
(1) 2 Mechanisms to kill
(a) Secretion of PERFORINS
and GRANZYME
induce APOPTOSIS of
the target Cell (via
CASPACES)
(b) Expression of FasL binds
Fas on target cell
Activates Apoptosis

d) #3: Activation of Macrophages by CD4+, TH1 (Type IV Delayed Type Hypersensitivity)

i) If APC is a macrophage, and TH is TH1 Macrophage-lymphocyte interaction (pg. 196): The T-cell and
macrophage activate each other
(1) Activated T-Helper 1 cell releases IFN- Activates
Macrophage
(a) MHCI and II expression (pg 201),antigen expression
(b) Inhibits TH2 (pg 196)
(c) Treat chronic granulomatous disease with IFN- (2012;
241)
(i) Recall that CGD is loss of NADPH Oxidase (neutrophils
and monocytes cannot do respiratory burst w/o HOOH
from bacteria)
(2) Macrophages releases IL-1 and TNF-
(a) (Macrophage-lymphocyte interaction is important for GRANULOMA formation and maintainance)
(b) IL-1 (pg. 200)
(i) IL-1 is intensely produced by tissue macrophages, monocytes, fibroblasts, and dendritic cells, but
is also expressed by B lymphocytes, NK cells and epithelial cells
(ii) An endogenous pyrogen.
(iii) Causes fever, acute inflammation.
1. Activates endothelium to express adhesion molecules (I-CAM)
2. Induces chemokine secretion to recruit leukocytes
Delayed hypersensitivity is a function of T lymphocytes, not antibody (Figure 654). It can be transferred by
immunologically committed (sensitized) T cells, not by serum. The response is "delayed"; i.e., it starts hours
(or days) after contact with the antigen and often lasts for days.

Hypersensitivities (pg. 203)

Type I (immediate) hypersensitivity(IgE activation of mast cells)

1) IgE antibody production (sensitization)
a) Allergens (e.g., pollen, drugs) are first processed by APCs (macrophages or dendritic cells).
b) APCs interact with CD4 TH2 cells, causing interleukins (ILs) to stimulate B-cell maturation.
c) IL-4 causes plasma cells to switch from IgM to IgE synthesis.
d) IL-5 stimulates the production and activation of eosinophils.
2) Mast cell activation (re-exposure)
i)

Mast cell activation: allergens cross-link allergen-specific antibodies

b) Allergen-specific IgE antibodies are bound to mast cells.

c) Allergens cross-link IgE antibodies specific for the allergen on mast cell membranes.
d) IgE triggering causes mast cell release of preformed mediators.
i)

(1) Early phase reaction with release of histamine, chemotactic factors for eosinophils, proteases

ii)

(2) Produces tissue swelling and bronchoconstriction

e) Late phase reaction

i)

(1) Mast cells synthesize and release prostaglandins and leukotrienes.

1. Mast cells: early and late phase reactions

ii)

(2) Enhances and prolongs acute inflammatory reaction

3) Tests used to evaluate type I hypersensitivity

a) Scratch test (best overall sensitivity)
i)

Positive response is a histamine-mediated wheal-and-flare reaction after introduction of an allergen into the
skin.

b) Radioimmunosorbent test
(a) Anaphylactic shock: potentially fatal type I hypersensitivity reaction
ii)

Detects specific IgE antibodies in serum that are against specific allergens

4) Treatment
a) Desensitization therapy involves repeated injections of increasingly greater amounts of allergen, resulting in
production of IgG antibodies that attach to allergens and prevent them from binding to mast cells.
Clinical examples of type I hypersensitivity (Table 3-2)

a) Atopic/Allergic disorders:

i) Hay fever (Allergic Rhinitis)

ii) Eczema
iii) Hives
iv) Asthma
v) Reaction to bee sting
b) Drug hypersensitivity
i) Penicillin rash
ii) Anaphylaxis

Type II (cytotoxic; cy-2-toxic) hypersensitivity

1) Complement-dependent reactions
a) Lysis (IgM-mediated)
i)

Antibody (IgM) directed against antigen on the cell membrane activates the complement system, leading to
lysis of the cell by the membrane attack complex.

ii)

Example-IgM types of cold immune hemolytic anemias (refer to Chapter 13)

iii) Example-transfusion of group A blood (contains anti-B-IgM antibodies) into a group B individual (refer
to Chapter 15)
b) Lysis (IgG-mediated)
i)

IgG attaches to basement membrane/matrix activates complement system C5a is produced

(chemotactic factor) recruitment of neutrophils/monocytes to the activation site release of enzymes,
reactive oxygen species damage to tissue

ii)

Example-Goodpasture's syndrome with IgG antibodies directed against pulmonary and glomerular capillary
basement membranes (refer to Chapter 19)
(1) Damage to

iii) Example-acute rheumatic fever with IgG antibodies directed against antigens in heart, skin, brain,
subcutaneous tissue, joints (refer to Chapter 10)
c) Phagocytosis
i)

Fixed macrophages (e.g., in spleen) phagocytose hematopoietic cells (e.g., RBCs) coated by IgG antibodies
or complement (C3b).

ii)

Example-warm (IgG) immune hemolytic anemia (refer to Chapter 13)

iii) Example-ABO hemolytic disease of the newborn (refer to Chapter 15)

(1) Group O mother has anti-A,B-IgG antibodies that cross the placenta and attach to fetal blood group A or B
red blood cells.
2) Complement-independent reactions
a) Antibody (IgG)-dependent cell-mediated cytotoxicity
i)

Cells are coated by IgG leukocytes (neutrophils, monocyte, NK cells) bind to IgG activated cells release
inflammatory mediators causing lysis of the cells

ii)

Example-killing virus-infected cells or tumor cells

b) Antibody (IgE)-dependent cell-mediated cytotoxicity

i)

Helminth in tissue is coated by IgE antibodies eosinophil IgE receptors attach to the IgE eosinophils
release major basic protein, which kills the helminth
1. Myasthenia gravis, Graves' disease: antibodies against receptors; type II HSR

c) IgG autoantibodies directed against cell surface receptors impair function of the receptor (e.g., antiacetylcholine receptor antibodies in myasthenia gravis) or stimulate function (e.g., anti-thyroid-stimulating
hormone receptor antibodies in Graves' disease)
3) Tests used to evaluate type II hypersensitivity
a) Direct Coombs' test detects IgG and C3b attached to RBCs.
b) Indirect Coombs' test detects antibodies (e.g., anti-D) in serum.
Clinical examples of type II hypersensitivity (see Table 3-2)
a) Complement-dependent reactions
i) Lysis (IgM mediated): ABO mismatch, cold immune hemolytic anemia
ii) Lysis (IgG mediated): Goodpasture's syndrome, PA
(1)
iii) Phagocytosis: warm (IgG) autoimmune hemolytic anemia, ABO and Rh hemolytic disease of newborn, ITP
b) Complement-independent reactions
i) Antibody (IgG)-dependent cell-mediated cytotoxicity: natural killer cell destruction of neoplastic and virusinfected cells
ii) Antibody (IgE)-dependent cell-mediated cytotoxicity: eosinophil destruction of helminths
iii) Antibodies directed against cell surface receptors: myasthenia gravis, Graves' disease

Type III (immunocomplex; antigen-antibody-complement)

hypersensitivity
Activation of the complement system by circulating antigen-antibody complexes (e.g., DNA-anti-DNA complexes)First
exposure to antigen
1) First exposure to antigen
a) Synthesis of antibodies
2) Second exposure to antigen
a) Deposition of antigen-antibody complexes
b) Complement activation, producing C5a, which attracts neutrophils that damage tissue
3) Test used to evaluate type III hypersensitivity
a) Immunofluorescent staining of tissue biopsies (detects IMMUNE COMPLEXES)
b) Example-glomeruli in glomerulonephritis

Clinical examples of type III hypersensitivity (see Table 3-2)

a) Systemic lupus erythematosus (DNA-anti-DNA)

b) Serum sickness (ie. horse antithymocyte globulin-antibody)
i) Antibodies to the foreign proteins are produced (takes 5 days)
ii) Immune complexes form and are deposited in membranes where they fix
complement (leads to tissue damage)

iii) More common than arthus reaction

(1) Most serum sickness is now caused by DRUGS (not serum) acting as
HAPTENS

iv) Clinical Findings

(1) Fever, urticarial, arthralgias, proteinuria, lymphadenopathy 5-10 days after antigen exposure
c) Poststreptococcal glomerulonephritis

i) Nephritogenic strep has M protein virulence factor our bodies make

antibody against it and the immune complexes deposits in
the nephrons
(1)The immune complexes deposit sub-endothelial but slowly
work their way up through the trilayer, and pile up subepithelial, and the deposit will dissipate past the podocytes
and eventually disappear, thats why it usually spontaneously
resolves.
ii) Most commonly seen in CHILDREN
(1)Characteristic finding = Periorbital Edema (sodium retention),
and Spontaneously Resolve

d) Arthus reaction

i)

Localized subacute immunocomplex reaction

(1) Intradermal injection of antigen induces antibodies, which forms antigen-antibody complexes in skin
(2) Characterized by Edema, Necrosis, and Activation of Complement

ii)

Example-Farmer's lung from exposure to thermophilic actinomycetes, or antigens, in air

Type IV (delayed; cell Mediated) hypersensitivity

Antibody-independent T cell-mediated reactions (cellular-mediated immunity, CMI)
1) Functions of CMI
a) Control of infections caused by viruses, fungi, helminths, mycobacteria, intracellular bacterial pathogens
b) Graft rejection
c) Tumor surveillance
2) Types of reactions
a) Delayed reaction hypersensitivity (DRH)
i) CD4 cells interact with macrophages (APCs with MHC class II antigens), resulting in cytokine injury to tissue
(refer to Chapter 2).
ii) Includes Tuberculous Granuloma
b) Cell-mediated cytotoxicity
i) CD8 T cells interact with altered MHC class I antigens on neoplastic, virus-infected, or donor graft cells,
causing cell lysis.
ii) CD8 T cell mediated: altered class I antigens; contact dermatitis
c) Contact dermatitis (pg. 424, FA2012)
i) Activated CD4 and CD8 T cells damage antigens in skin (e.g., poison ivy, nickel).
(1) Contact dermatitis: activated CD4 (primary mediator) + CD8 cells
3) Test used to evaluate type IV hypersensitivity
a) Patch test to confirm contact dermatitis
i) Example-suspected allergen (e.g., nickel) placed on an adhesive patch is applied to the skin to see if a skin
reaction occurs.
b) Skin reaction to Candida
c) Quantitative count of T cells
d) Various mitogenic assays

Clinical examples of type IV hypersensitivity

a) Delayed type:
i) Granuloma

ii)

(1) The key cell that defines a granuloma is the EPITHELOID HISTIOCYTE (macrophages with
abundant pink cytoplasm)
(a) Macrophages normally have foamy cytoplasm (clear), when macrophages get activated, they develop
abundant pink cytoplasm epithelioid, and aggregate of those would cause granuloma.
(2) Giant cells are usually also seen with granuloma, but is not defining
(3) Rim of lymphoid cells is sometimes also seen, but not defining
(4) Types of Granuloma
(a) Non-Caseating
(i) Lacks central Necrosis
(ii) These arise in reaction to foreign material. If a patient has history of breast cancer; breast is
removed and gets implants in the breast as part of reconrstuction, its possible the implants would
leak and release foreign material into lymphatics and cause enlarged lymph nodes in the axilla.
1. What if patient feels lymph nodes in axilla; theres a ddx; could be recurrence of breast
cancer, or it could be reaction to foreign material from the implant. If biopsy was taken and it
was cancer, would be very diff from noncaseating granuloma.
(iii) Etiology
1. Reaction to foreign material
2. Sarcoidosis: noncaseating granulomas in multiple tissues, esp. lung.
3. Beryllium Exposure
4. Crohns Disease
5. Cat Scratch Disease
(b) Caseating
(i) Characteristic of TB and fungal infections
(5) Steps in granuloma formation
(a) Macrophages present antigen via MHCII to CD4+
(b) Macrophages secrete IL-12 to induce CD4+ helper cells to become TH1 subtype
(c) TH1 cells secret IFN- which converts macrophages to epitheloid histiocytes and giant cells.
PPD reaction

iii) MS
b) Cell-mediated cytotoxicity:
i) Killing of tumor cells and virus-infected cells;
ii) contact dermatitis (e.g., poison ivy, nickel)

Fibrinoid Necrosis

Necrosis of VESSELS associated

with Immune Diseases

Fibrinoid necrosis: necrosis of immune-mediated disease
1. Fibrinoid necrosis
a. Limited to small muscular arteries, arterioles, venules, and glomerular capillaries
b. Mechanism

c.

Deposition of pink-staining proteinaceous material in damaged vessel walls due to damaged

basement membranes

Associated conditions

Immune vasculitis (e.g., Henoch-Schnlein purpura), malignant hypertension

ie. Rheumatoid nodules have fibrinoid necrosis in rheumatoid arthritis

Note however, that malignant hypertension also causes fibrinoid necrosis.

Development of Lymphocytes
Lymphocyte receptors (B and T) undergo V(D)J recombination during development, responsible
for HEAVY CHAIN. (pg 197, 193)D

T-Cell

Growth and Maturation (pg. 195)

1) Origin: Stem cells in Bone Marrow

2) Maturation (Differentiation): Thymus (pg. 193)
a) Thymus is Encapsulated
b) Development: Thymus is formed from epithelium of 3rd branchial pouches
Disease Correlation: Digeorge Syndrome (pg. 206, 511)
(1) Etiology:
(a) 22q11 Deletion Failure to Develop 3rd and 4th
pharyngeal pouches
(i) 22q11 deletion CATCH-22 (pg. 89)
(ii) Other 22q11 deletion syndrome = Velocardiofacial
Syndrome
(b) Leads to thymic aplasia and hypocalcemia (Failure of
Parathyroid development)]
(2)Clinical Presentation
(a)Hypoparathyroidism due to parathyroid aplasia
Hypocalcemia Tetany
(b) Recurrent viral/fungal infections (due to T-cell deficiency)
(c) Congenital heart and great vessel defects
(3)Lab findings
(a) Poorly developed paracortex of lymph nodes
(b) Thymus and parathyroid fail to develop T cells
(c) PTH
(d) Ca2+
(e) Absent Thymic shadow on CXR
c) Positive Selection
i) Location: Thymic Cortex
(1)Cortex: is dense with immature T-Cells

ii) T-cells expressing TCRs

capable of binding
surface self MHC
molecules survive
d) Negative Selection
i) Location: Thymic
Medulla
(1) Medulla is pale with
mature T-cells and
epithelial reticular
cells containing
Hassalls
corpuscles
ii) T-cells expressing
TCRs with high affinity
for self antigens
undergo apoptosis.

B-Cell Development
(also has to do with
antibody
development): Created
in bone marrow, MATURE
in bone marrow
Dont need to know too much.
What development occurs in
the bone marrow?

Pro-B Cell (Has no

antibody)
o will now undergo V(D)J for heavy chain rearrangement
Pre-B Cell (Has only Heavy Chain)
o will now undergo VJ for light chain rearrangement
o Need BTK to go to immature B-cell
Deficiency = XLA
Immature B-Cell (IgM on surface)
o (Has both heavy and light
chain rearranged)
o No IgD on surface yet

What development occurs in

Lymphoid tissue

Mature (But Nave) B-Cell

(probably most high yield point
here)
o IgM is now on surface, and
o IgD is now on the surface

Expression of both of these is a marker of MATURE B-lymphocyte.

2 ways to activate B-Cell

1) Antigen Binds Surface IgM or IgD Becomes IgM Secreting Plasma Cell
2) B-Cell presents antigen to CD4+ T-cell via MHCII and CD40 with CD40L on TH2 Class
switching
a. TH2 secretes IL-4 and IL-5, switching, hypermutation, and maturation
Upon B-CELL ACTIVATION (goes to GERMINAL CENTER)
o
o
o

Isotype Switching
Defect here: cant make IgA Selective IgA Deficiency
Somatic Hypermutation
Cancer
Becomes Plasma Cell
Defect here = CVID

Disease Correlations (206)

1) XLA (X-linked Brutons Agammaglobulinemia) [Already covered in opsonization section;
repeat]
a. Etiology: X-linked recessive (in Boys). Defect in BTK, a tyrosine kinase gene B-Cell
cannot become plasma cell

b. Clinical Presentation
i. Recurrent bacterial infections after 6 months
1. Maternal IgG) as a result of opsonization defect
ii. Recurrent Bacterial, Enterovirus, and Giardia Infections
1. Enterovirus is a virus affecting mucosal surface of GI tract, and IgA
protects against mucosa of GI, and wont have this. Giardia is the
same thing; GI infection.
iii. Do not give them live vaccines (e.g. polio). MUST BE AVOIDED.
c. Findings
i. Normal Pro-B, Maturation (Nave B-cells cannot mature to plasma cells)
1. COMPLETE LACK OF IMMUNOGLOBULIN S
ii. . # of B-Cells.
iii. Why: BTK lets you rearrange your light chain: so you can make a preb-cell, but you cant make immature (immature has reorganized light
chain)
iv. Defect in OPSONIZATION
2) Selective IgA Defiency
a. MOST COMMON 1 IMMUNODEFICIENCY!
b. Etiology: Unknown, but patient is unable to produce IgA
i. Recall that IL-5 promotes class switching to IgA (and stimulates growth and
differentiation of eosinophils. However, Selective IgA deficiency is not due to IL-5
deficiency.

c. Clinical Presentation
i. Majority ASYMPTOMATIC
ii. May see sinopulmonary infections (especially viral), GI infections,
Autoimmune Disease
iii. ANAPHYLAXIS to IgA containing blood products (MOST HIGH YIELD
FACT)
1. People getting blood products with this deficiency must avoid
blood with IgA!!!! Im guessing because this is b/c patient
never exposed to IgA, so immune system sees it as foreign.
d. Lab Findings
i. IgA <7 mg/dL with normal IgG, IgM, and IgG vaccine titers
ii. False-positive -HCG tests due to presence of heterophile antibody

3)

Common Variable Immunodeficiency (CVID)

a. Etiology:
i. Defect in B-Cell Maturation (many causes)
ii. or Defect In Helper T-Cell
b. Clinical Presentation: Young Adult (20s-30s) (high yield b/c most of these
present early)
i. Often asymptomatic and present late in adult hood
ii. Risk of autoimmune disease
iii. Risk of Lymphoma
iv. Risk of sinopulmonary infections (Bacterial, Enterovirus, and Giardia)
c. Lab Findings
i. Normal # of B-cells
ii. Plasma Cells and Immunoglobulin (G, A, and/or M) (Hypoglobuninemia)
(also T-Cells)

Antibody

(pg. 197)

Antibody has Fab (antigen binding fragment) and Fc (constant region; carboxy terminal,
complement binding: IgG and IgM only)
Antibody types (198)
1) IgG: Can bind complement. Can cross placenta (can immunize mom to provide antibodies
for kid)
a. Preformed antibodies (IgG) used in To Be Healed Rapidly, pg 202
i. Tetanus toxin, Botulinum Toxin, HBV, or Rabies Virus
2) IgA
3) IgM: Can bind complement. Is a pentamer (most effective at trapping free antigens out of
tissue in humoral response)
4) IgD
5) IgE
Disease Correlations: Light/Heavy Chain

Ig Light chain AL protein (Bence Jones Protein) in Multiple Myeloma (AMYLOIDOSIS)

o Creates casts in the renal tubules
Ig Heavy chain: on chromosome 14; is always on. Therefore if a oncogene gets switched
with heavy chain, it will be always on Lymphoma

Disease Correlations: Autoantibodies (205)

1) Antiphospholipid antibody
a. Lupus Anticoagulant (high yield!! my friends mom who has lupus also has this!)
i. Lab: Increased PTT (anticoagulant) without increasing any other bleeding
values
ii. In Vitro: PRO-Coagulant Strokes, etc
iii. Note: not everyone who has lupus will have lupus anticoagulant
2) Rheumatoid Factor
a. It is defined as IgM against the Fc portion of IgG

Types of Antigens and Memory (pg 198)

Types of Antigens
Thymus Independent Antigens
1) Antigens lacking peptide
component
a. (ie. LPS from cell enveleope of
Gram - Bacteria, and
Polysaccharide Capsular
Antigen)
b. T-Cells can ONLY recognize
peptides, ROMMAI pg 414
These antigens CANNOT be
presented by MHC to T-Cells
2) Results: Stimulates release of
antibodies (because B-Cells can
recognize) and does not result in immunologic memory

Thymus Dependent Antigens

a. Antigens containing protein component
i. Examples: Vaccines, Diptheria Toxin, Viral Hemagglutinin
b. Result: Class switching and immunologic memory occur as a result of direct
contact of B-Cells with Th cells (CD40-CD40L Interaction)

Vaccines (pg. 202)

1) Live attenuated
a. MOA:
i. Microorganism loses pathogenicity, but retains capacity for transient growth
within inoculated host.
ii. Mainly induces cellular response
b. Pro: Often life-long immunity: In an attenuated vaccine, live virus particles with very low
virulence are administered.
i. They will reproduce, but very slowly. (Wikipedia)
ii. Since they do reproduce and continue to present antigen beyond the initial
vaccination, boosters are required less often.
iii. These vaccines are produced by growing the virus in tissue cultures that will select for less
virulent strains, or by mutagenesis or targeted deletions in genes required for virulence.
c. Con: There is a small risk of reversion to virulence; this risk is smaller in vaccines with deletions.
Attenuated vaccines also cannot be used byimmunocompromised individuals.
d. Examples:
i. Measles, Mumps, Rubella (MMR)
ii. Polio (Sabin)
iii. Varicella
iv. Yellow Fever

2) Inactivated/Killed
a. MOA:
i. Microorganism is inactivated by heat or chemicals; however they maintain
epitope structure on surface antigens
ii. Humoral Immunity induced
b. Pro: Stable and safer than live vaccines
c. Con: Weaker Immune Response, Need booster shots:
i. Since the properly produced vaccine does not reproduce, booster shots are required periodically
to reinforce the immune response.

d. Examples
i. Cholera
ii. Hepatitis A
iii. Polio (Salk)
iv. Rabies
v. Pertussis (TdAP)
vi.

Other Primary Immunodeficiencies

PIDs not covered

B&T Cells

o Wiskott-Aldrich Syndrome
Etiology: X-Linked Mutation in WASP Gene
T-cells cannot reorganize ACTIN CYTOSKELETON
Clinical Presentation: Triad = TIE
Thrombocytopenia (petechiae in skin and mucosal membrane)
Recurrent Infections (Defective humoral and cellular immunity)
Eczema (Skin Rash)
Labs:
IgE, IgA
IgM

o Ataxia-Telangiectasia
T-Cells
o Mucocutaneous Candidiasis

Lymph Node (pg

192)
Lymph Node Zones
1) Follicle: Site of B-Cell localization and
proliferation
a. 1 Follicle: Dense and dormant
b. 2 Follicle: Contain pale,
ACTIVE central germinal centers
Wikipedia: When a lymphocyte
recognizes an antigen, B cells
become activated and migrate to germinal centers (by definition, a "secondary nodule" has a germinal
center, while a "primary nodule" does not)

Follicle (pg. 362)

1. Diffuse Large B-Cell Lymphoma (Most common adult NHL)
a. bad prognosis; makes
sense because lymphocytes
are normally small round
cells, and now the cells are
large (anaplastic)
2. Small Lymphocytic Lymphoma
(SLL) Lymphoma version of CLL.
a. good prognosis because the
cells are still somewhat like
what they are supposed to
be like
3. Follicular Lymphoma: t(14;18)
a. Chromosome 14 has
Immunoglobulin Heavy
Chain (IgH)
b. Chromosome 18 has BCL-2
c. BCL-2 replaces the IgH and is constituitively ON
i. BCL-2 stabilizes the mitochondrial membrane, preventing
apoptosis
ii. Over-expressed BCL-2 prevents apoptosis of B-cells within
the follicles even as they undergo somatic hypermutation
results in accumulation of B-Cells
4. Burkitts Lymphoma t(8;14)
a. Chromosome 14 has IgH
b. Chromosome 8 has c-Myc, which is the most important
transcription factor (nuclear regulator) causing upregulation of
genes needed for growth
ii. Mantle Zone: This is where Nave B-cells rest after they are created and go to
the lymph node, but do not meet an antigen
1. Mantle Cell Lymphoma t(11;14). CD5+
a. Chromosome 14 has IgH
b. Chromosome 11 has Cyclin D1, which is part of the CDK4-CyclinD1
complex that kicks E2F off of Rb (tumor suppressor gene). Once

E2F is kicked off, it goes to the DNA to allow the cell to go from
G1S
c. Marginal Zone (not normally present)
i. Chronic inflammation generate germinal centers within the gastric wall. You will generate post
germinal center B-cells; that is a special zone within inflammatory infiltrate called the MARGINAL
zone.
ii. Follicle with germinal center, then outside
that is mantle, then outside that is marginal
zone.
1. Marginal zone only forms when there
is a chronic inflammatory state that
necessitates the need for postgerminal center B-cell
a. Also found in Sjogrens
Syndrome (Chronic
Inflammation) and
Hashimotos Thyroiditis
iii. So in this case, we have chronic
inflammation, results in post-germinal center
B-cells, creates a marginal zone, which
results in MALT lymphoma (A B-Cell
lymphoma that is located in the wall of the
stomach)

2) Medulla: Consists of medullary cords and sinuses

3) Paracortex: Houses T-Cells
a. Adult T-Cell Lymphoma
i. HTLV-1 virus; Japan, West Africa, Carribean
ii. Adults present with cutaneous lesions
b. Mycosis Fungoides/Sezary Syndrome
i. Adults present with cutaneous patches/nodules
4) Outside
a. Plasma Cell
i. Multiple Myeloma
ii. MGUS

Lymphadenopathy
(Pathoma)
Pain?
1) Painful LAD is seen with acute
infection
2) Painless LAD is seen with
chronic inflammation,
metastatic carcinoma, or
lymphoma.
BENIGN Reactive hyperplasia of
lymph node regions depends on
etiology
1) Folliclar Hyperplasia
a) Rheumatoid Arthritis
b) Early HIV (Infects CD4+ TCells. Follicular dendritic cells
in the follicles are also CD4+, however)

2) Paracortical Hyperplasia (Where T-Cells live)

a) Viral infection causes t-cells to grow
b) Infectious mononucleosis (EBV infection) results in enlargement of the lymph nodes, thats
due to paracortical enlargement of the lymph node.
c) The T-cells are atypical
3) Sinus Histiocytes Expansion
a) Lymph nodes draining a tissue of cancer.
b) Cancer has not yet metastasized to the lymph node, but antigens from it are draining to
the lymph node, causing lymphadenopathy
Notable lymphadenopathy connections (My notes)
1) Respiratory
a. Hilar Lymphadenopathy
i. Ghon Complex (1 TB Infection)
b. Bilateral Hilar Lymphadenopathy
i. Sarcoidosis
2) Neoplastic
a. Mediastinal Lymphadenopathy
i. Hodgkins Lymphoma
3) Infectious
a. EBV Infection especially causes the posterior cervical nodes to get enlarged

Cytokine Specifics
Cytokine Details: TNF- (Produced by MACROPHAGES)
1. TNF- is an inflammatory mediator released primarily by macrophages. It has many important effects
that differ depending on the concentration. At low concentrations, it increases the synthesis of adhesion
molecules by endothelial cells, which allows neutrophils to adhere to blood vessel walls at the site of
infection. It also activates the respiratory burst within neutrophils, thereby enhancing the killing power
of these phagocytes. It increases lymphokine synthesis by helper T cells and stimulates the growth of B
cells. At high concentrations, it is an important mediator of endotoxin-induced septic shock; antibody
to TNF- prevents the action of endotoxin. (The action of endotoxin is described in Chapter 7.)
TNF- is also known as cachectin because it inhibits lipoprotein lipase in adipose tissue, thereby
reducing the utilization of fatty acids. This results in cachexia.
TNF-, as its name implies, causes the death and necrosis of certain tumors in experimental animals.
It may do this by promoting intravascular coagulation that causes infarction of the tumor tissue. Note the
similarity of this intravascular coagulation with the DIC of septic shock, both of which are caused by
TNF-
ICAM proteins on the endothelium are increased by inflammatory mediators, such as IL-1 and TNF (see
Chapter 58), which are produced by macrophages in response to the presence of bacteria. The increase
in the level of ICAM proteins ensures that PMNs selectively adhere to the site of infection. Increased
permeability of capillaries as a result of histamine, kinins, and prostaglandins2 allows PMNs to migrate
through the capillary wall to reach the bacteria. This migration is called diapedesis and takes several
minutes to occur.

2. Nitric oxide (NO) is an important mediator made by macrophages in response to the presence of
endotoxin, a lipopolysaccharide found in the cell wall of gram-negative bacteria. NO causes
vasodilation, which contributes to the hypotension seen in septic shock. Inhibitors of NO synthase, the
enzyme that catalyzes the synthesis of NO from arginine, can prevent the hypotension associated with
septic shock.
3. Macrophage migration inhibitory factor (MIF) is another important mediator made by macrophages
in response to endotoxin. The function of MIF is to retain the macrophages at the site of infection.
Recent studies have shown that MIF plays a major role in the induction of septic shock. Antibody
against MIF can prevent septic shock in animals genetically incapable of producing TNF. The
mechanism of action of MIF in septic shock is unclear at this time.

Cytokine Details: Interferons

Interferons are glycoproteins that block virus replication and exert many immunomodulating functions. Alpha
interferon (from leukocytes) and beta interferon (from fibroblasts) are induced by viruses (or double-stranded
RNA) and have antiviral activity (see Chapter 33).

Gamma interferon (IFN-) is a lymphokine produced primarily by the Th-1 subset of helper T cells. It is one
of the most potent activators of the phagocytic activity of macrophages, NK cells, and neutrophils, thereby
enhancing their ability to kill microorganisms and tumor cells. For example, it greatly increases the killing of
intracellular bacteria, such as M. tuberculosis, by macrophages. It also increases the synthesis of class I and II
MHC proteins in a variety of cell types. This enhances antigen presentation by these cells.

Cytokine Details: Interleukins (Affects Lymphocytes)

1. IL-1 is a protein produced mainly by macrophages. It activates a wide variety of target cells, e.g., T and
B lymphocytes, neutrophils, and endothelial cells. It is a proinflammatory cytokine, i.e., plays an
important role, along with tumor necrosis factor (TNF), in inducing inflammation. In addition, IL-1 is
endogenous pyrogen, which acts on the hypothalamus to cause the fever associated with infections and
other inflammatory reactions. (Exogenous pyrogen is endotoxin, a lipopolysaccharide found in the cell
wall of gram-negative bacteria [see Chapter 7].)
2. IL-2 is a protein produced mainly by helper T cells that stimulates both helper and cytotoxic T cells to
grow. IL-2 is T-cell growth factor. Resting T cells are stimulated by antigen (or other stimulators) both
to produce IL-2 and to form IL-2 receptors on their surface, thereby acquiring the capacity to respond to
IL-2. Interaction of IL-2 with its receptor stimulates DNA synthesis.
3. IL-4 is a protein produced by the Th-2 class of helper T cells that induces class switching to IgE. IL-4 is
the most characteristic cytokine produced by Th-2 cells (Figure 583).
4. IL-5 is a protein produced by the Th-2 class of helper T cells that induces class switching to IgA and
activates eosinophils. Eosinophils are an important host defense against many helminths (worms), e.g.,
Strongyloides (see Chapter 56), and are increased in immediate hypersensitivity (allergic) reactions (see
Chapter 65).
5. IL-6 is produced by helper T cells and macrophages. It stimulates B cells to differentiate, induces fever
by affecting the hypothalamus, and induces the production of acute-phase proteins by the liver. Acutephase proteins are described in Innate Immunity.
6. IL-10 and IL-12 regulate the production of Th-1 cells, the cells that mediate delayed hypersensitivity
(Figure 583). IL-12 is produced by macrophages and promotes the development of Th-1 cells, whereas
IL-10 is produced by Th-2 cells and inhibits the development of Th-1 cells by limiting gamma interferon
production. (Gamma interferon is described below.) The relative amounts of IL-4, IL-10, and IL-12
drive the differentiation of Th-1 and Th-2 cells and therefore enhance either cell-mediated or humoral
immunity, respectively. This is likely to have important medical consequences because the main host
defense against certain infections is either cell-mediated or humoral immunity. For example, Leishmania
infections in mice are lethal if a humoral response predominates but are controlled if a vigorous cellmediated response occurs.
The IL-12gamma interferon axis is very important in the ability of our host defenses to control
infections by intracellular pathogens, such as M. tuberculosis and L. monocytogenes. IL-12 increases the
number of Th-1 cells, and Th-1 cells produce the gamma interferon that activates the macrophages that
phagocytose and kill the intracellular bacterial pathogens mentioned above.

7. IL-13 is implicated as the mediator of allergic airway disease (asthma). IL-13 is made by Th-2 cells and
binds to a receptor that shares a chain with the IL-4 receptor. In animals, IL-13 was shown to be
necessary and sufficient to cause asthma. IL-13 is involved in producing the airway hyperresponsiveness
seen in asthma but not in increasing the amount of IgE.
8. The main function of transforming growth factor-

(TGF-

) is to inhibit the growth and

activities of T cells. It is viewed as an "anti-cytokine" because, in addition to its action on T cells, it can
inhibit many functions of macrophages, B cells, neutrophils, and natural killer cells by counteracting the
action of other activating factors. Although it is a "negative regulator" of the immune response, it
stimulates wound healing by enhancing the synthesis of collagen. It is produced by many types of cells,
including T cells, B cells, and macrophages. In summary, the role of TGF-

is to dampen or

suppress the immune response when it is no longer needed after an infection and to promote the healing
process.