100 SEC TION II Immunology   

Immunology—Cellular Components

Differentiation of T cells

Bone marrow Thymus Lymph node Peripheral blood

Cortex Medulla

Secretes Function
IFN-γ, IL-12 Activate macrophages
Th1 IFN-γ, IL-2
IL-4, IL-10 and cytotoxic T cells

CD8+ Cytotoxic
IL-2, IL-4 IL-4, IL-5, IL-6, Activate eosinophils,
Th2 IL-10, IL-13 IgE
IFN-γ
T cell CD4+
precursor CD8+
TGF-β, IL-1, IL-6 IL-17, IL-21, Induce neutrophilic
Th17
IFN-γ, IL-4 IL-22 infiltration
CD4+ Helper

TGF-β, IL-2 TGF-β, IL-10, Prevent autoimmunity

Treg
IL-6 IL-35 (maintain tolerance)
selection selection

Positive selection
Negative selection
Thymic cortex. Double-positive (CD4+/CD8+) T cells expressing TCRs capable of binding self-
MHC on cortical epithelial cells survive.
Thymic medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis or
become regulatory T cells. Tissue-restricted self-antigens are expressed in the thymus due to the
action of autoimmune regulator (AIRE); deficiency leads to autoimmune polyendocrine syndrome-1
(Chronic mucocutaneous candidiasis, Hypoparathyroidism, Adrenal insufficiency, Recurrent
Candida infections). “Without AIRE, your body will CHAR”.

Macrophage- Th1 cells secrete IFN-γ, which enhances the ability of monocytes and macrophages to kill
lymphocyte microbes they ingest. This function is also enhanced by interaction of T cell CD40L with CD40
interaction on macrophages. Macrophages also activate lymphocytes via antigen presentation.

Cytotoxic T cells Kill virus-infected, neoplastic, and donor graft cells by inducing apoptosis.
Release cytotoxic granules containing preformed proteins (eg, perforin, granzyme B).
Cytotoxic T cells have CD8, which binds to MHC I on virus-infected cells.

Regulatory T cells
Help maintain specific immune tolerance by suppressing CD4+ and CD8+ T-cell effector
functions.
Identified by expression of CD3, CD4, CD25, and FOXP3.
Activated regulatory T cells (Tregs) produce anti-inflammatory cytokines (eg, IL-10, TGF-β).
IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome—
genetic deficiency of FOXP3 Ž autoimmunity. Characterized by enteropathy, endocrinopathy,
nail dystrophy, dermatitis, and/or other autoimmune dermatologic conditions. Associated with
diabetes in male infants.

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T- and B-cell activation APCs: B cells, dendritic cells, Langerhans cells, macrophages.
Two signals are required for T-cell activation, B-cell activation, and class switching.
T-cell activation  APC ingests and processes antigen, then Q
Antigen
migrates to the draining lymph node. T cell
MHC II/I R receptor
 T-cell activation (signal 1): exogenous Naïve T cell
antigen is presented on MHC II and Antigen-presenting
recognized by TCR on Th (CD4+) cell. cell CD4/8
Endogenous or cross-presented antigen is
presented on MHC I to Tc (CD8+) cell. CD80/86 S CD28 T
(B7)
 Proliferation and survival (signal 2): Activated
T cell actions
costimulatory signal via interaction of B7
protein (CD80/86) on dendritic cell and
CD28 on naïve T cell.
 Activated Th cell produces cytokines. Tc cell
able to recognize and kill virus-infected cell.
B-cell activation and   Th-cell activation as above. Antigen
R
B cell
class switching  B-cell receptor–mediated endocytosis. receptor
 Exogenous antigen is presented on MHC II T cell S
MHC II
receptor
and recognized by TCR on Th cell. Q
Activated B cell
 CD40 receptor on B cell binds CD40 ligand CD4+ T cell
CD4
(CD40L) on Th cell.
 Th cells secrete cytokines that determine Ig
class switching of B cells. CD40L CD40
T V
 B cells are activated and produce IgM. Activated
They undergo class switching and affinity B cell actions
U
maturation. Cytokines

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 102 SEC TION II Immunology   
Immunology—Immune Responses

IMMUNOLOGY—IMMUNE RESPONSES
` 

Antibody structure Fab fragment consisting of light (L) and heavy (H) chains recognizes antigens. Fc region of
and function IgM and IgG fixes complement. Heavy chain contributes to Fc and Fab regions. Light chain
contributes only to Fab region.
Fab:
ƒ Fragment, antigen binding
Antigen- ƒ Determines idiotype: unique antigen-binding
binding site Fa pocket; only 1 antigenic specificity expressed
b reg Epitope
VH Heavy chain
ion
JHD per B cell
VL Fc (5 C’s):
Hy reg

C H1 Hinge CH1 JL
pe io

ƒ Constant
rva ns

Light chain
CL CL
ria

ƒ Carboxy terminal
ble

SS SS SS
SS
C = Constant ƒ Complement binding
V = Variable Complement ƒ Carbohydrate side chains
L = Light C H2 CH2
binding ƒ Confers (determines) isotype (IgM, IgD, etc)
H = Heavy
SS = Disulfide bond Fc region Macrophage Generation of antibody diversity (antigen
binding independent)
C H3 C H3
1.  Random recombination of VJ (light-chain)
or V(D)J (heavy-chain) genes by RAG1 and
RAG2
Neutralization Opsonization Complement
activation 2.  Random addition of nucleotides to
DNA during recombination by terminal
Membrane
attack complex deoxynucleotidyl transferase (TdT)
(MAC) 3.  Random combination of heavy chains with
light chains
Generation of antibody specificity (antigen
dependent)
4.  Somatic hypermutation and affinity
C3b maturation (variable region)
5.  Isotype switching (constant region)
Antibody prevents Antibody promotes Antibody activates
bacterial adherence phagocytosis complement, enhancing
opsonization and lysis

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Immunoglobulin All isotypes can exist as monomers. Mature, naïve B cells prior to activation express IgM and IgD
isotypes on their surfaces. They may differentiate in germinal centers of lymph nodes by isotype switching
(gene rearrangement; induced by cytokines and CD40L) into plasma cells that secrete IgA, IgG,
or IgE. “For B cells, IgMom and IgDad mature to plasma cells as they AGE.
Affinity refers to the individual antibody-antigen interaction, while avidity describes the cumulative
binding strength of all antibody-antigen interactions in a multivalent molecule.
IgG Main antibody in 2° response to an antigen. Most abundant isotype in serum. Fixes complement,
IgG opsonizes bacteria, neutralizes bacterial toxins and viruses. Only isotype that crosses the placenta
IgG (provides infants with passive immunity that starts to wane after birth). “IgG Greets the Growing
fetus.” Associated with warm autoimmune hemolytic anemia (“warm weather is Great!”).
IgA
IgG
IgA
IgG Prevents attachment of bacteria and viruses to mucous membranes; does not fix complement.
IgA
IgG Monomer (in circulation) or dimer (with J chain when secreted). Crosses epithelial cells by
transcytosis. Produced in GI tract (eg, by Peyer patches) and protects against gut infections (eg,
IgA J chain Giardia). Most produced antibody overall, but has lower serum concentrations. Released into
IgA
IgM J chain secretions (tears, saliva, mucus) and breast milk. Picks up secretory component from epithelial cells,
IgA J chain
IgM
which protects the Fc portion from luminal proteases.
J chain
IgMJJ chain
chain First antibody to be produced during an immune response. Fixes complement. Antigen receptor
IgM J chain on the surface of B cells. Monomer on B cell, pentamer with J chain when secreted. Pentamer
IgM J chain
J chain enables avid binding to antigen while humoral response evolves. Associated with cold autoimmune
IgM
IgD J chain hemolytic anemia.
IgD

IgD
IgD Expressed on the surface of mature, naïve B cells. Normally, low levels are detectable in serum.
IgE
IgD
IgE
IgD

IgE
IgE
IgE
IgE Binds mast cells and basophils; cross-links when exposed to allergen, mediating immediate (type I)
hypersensitivity through release of inflammatory mediators such as histamine. Contributes to
immunity to parasites by activating Eosinophils.

Antigen type and memory

Thymus-independent Antigens lacking a peptide component (eg, lipopolysaccharides from gram ⊝ bacteria); cannot
antigens be presented by MHC to T cells. Weakly immunogenic; vaccines often require boosters and
adjuvants (eg, capsular polysaccharide subunit of Streptococcus pneumoniae PPSV23 vaccine).
Thymus-dependent Antigens containing a protein component (eg, diphtheria toxoid). Class switching and immunologic
antigens memory occur as a result of direct contact of B cells with Th cells.

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Immunology—Immune Responses

Complement System of hepatically synthesized plasma proteins that play a role in innate immunity and
inflammation. Membrane attack complex (MAC) defends against gram ⊝ bacteria. The CH50 test
is used to screen for activation of the classical complement pathway.
ACTIVATION PATHWAYS Classic—IgG or IgM mediated. General Motors makes classic cars.
Alternative—microbe surface molecules.
Lectin—mannose or other sugars on microbe
surface.
FUNCTIONS C3b—opsonization. C3b binds to lipopolysaccharides on bacteria.
C3a, C4a, C5a—anaphylaxis. MAC complex is important for neutralizing
C5a—neutrophil chemotaxis. Neisseria species. Deficiency results in
C5b-9 (MAC)—cytolysis. recurrent infection.
Get “Neis” (nice) Big MACs from 5-9 pm.
Opsonins—C3b and IgG are the two 1° Opsonin (Greek) = to prepare for eating.
opsonins in bacterial defense; enhance
phagocytosis. C3b also helps clear immune
complexes.
Inhibitors—decay-accelerating factor (DAF,
also called CD55) and C1 esterase inhibitor
help prevent complement activation on self
cells (eg, RBCs).

B Bb
C3
Alternative
C3bBb C3bBb3b
C3 C3b
(C3 convertase) (C5 convertase)
Spontaneous and
microbial surfaces
Amplifies generation of C3b
C3a
C5a C6-C9

Lectin Lysis,
C1-like C5 C5b MAC
complex C3b cytotoxicity
Microbial surfaces (C5b-9)
(eg, mannose) C4a

C4 C4b C3a

Classic C4b2b C4b2b3b

C1 C1 (C3 convertase) (C5 convertase)
Antigen-antibody
complexes
C2 *
C2b C3

*
C2a *Historically, the larger fragment of C2
was called C2a but is now called C2b.

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Complement disorders
Complement protein deficiencies
Early complement  risk of severe, recurrent pyogenic sinus and respiratory tract infections. C3b used in clearance of
deficiencies (C1–C4) antigen-antibody complexes Ž  risk of SLE (think SLEarly).
Terminal complement  susceptibility to recurrent Neisseria bacteremia.
deficiencies (C5–C9)
Complement regulatory protein deficiencies
C1 esterase inhibitor Causes hereditary angioedema due to unregulated activation of kallikrein Ž  bradykinin.
deficiency Characterized by  C4 levels. ACE inhibitors are contraindicated (also  bradykinin).
Paroxysmal nocturnal A defect in the PIGA gene prevents the formation of glycosylphosphatidylinositol (GPI) anchors for
hemoglobinuria complement inhibitors, such as decay-accelerating factor (DAF/CD55) and membrane inhibitor of
A reactive lysis (MIRL/CD59). Causes complement-mediated intravascular hemolysis
Ž  haptoglobin, dark urine A .
Can cause atypical venous thrombosis (eg, Budd-Chiari syndrome; portal vein, cerebral, or dermal
thrombosis).

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Important cytokines Acute (IL-1, IL-6, TNF-α), then recruit (IL-8, IL-12).
Secreted by macrophages
Interleukin-1 Causes fever, acute inflammation. Activates “Hot T-bone stEAK”:
endothelium to express adhesion molecules. IL-1: fever (hot).
Induces chemokine secretion to recruit WBCs. IL-2: stimulates T cells.
Also called osteoclast-activating factor. IL-3: stimulates bone marrow.
Interleukin-6 Causes fever and stimulates production of acute- IL-4: stimulates IgE production.
phase proteins. IL-5: stimulates IgA production.
IL-6: stimulates aKute-phase protein
production.
Tumor necrosis Activates endothelium. Causes WBC Causes cachexia in malignancy.
factor-α recruitment, vascular leak. Maintains granulomas in TB.
IL-1, IL-6, TNF-α can mediate fever and sepsis.
Interleukin-8 Major chemotactic factor for neutrophils. “Clean up on aisle 8.” Neutrophils are recruited
by IL-8 to clear infections.
Interleukin-12 Induces differentiation of T cells into Th1 cells. Facilitates granuloma formation in TB.
Activates NK cells.
Secreted by T cells
Interleukin-2 Stimulates growth of helper, cytotoxic, and
regulatory T cells, and NK cells.

Interleukin-3 Supports growth and differentiation of bone

marrow stem cells. Functions like GM-CSF.

From Th1 cells

Interferon-γ Secreted by NK cells and T cells in response to
antigen or IL-12 from macrophages; stimulates
macrophages to kill phagocytosed pathogens.
Inhibits differentiation of Th2 cells.
Induces IgG isotype switching in B cells.
Increases MHC expression and antigen
presentation by all cells.
Activates macrophages to induce granuloma
formation.

From Th2 cells

Interleukin-4 Induces differentiation of T cells into Th Ain’t too proud 2 BEG 4 help.
(helper) 2 cells. Promotes growth of B cells.
Enhances class switching to IgE and IgG.
Interleukin-5 Promotes growth and differentiation of B cells. I have 5 BAEs.
Enhances class switching to IgA. Stimulates
growth and differentiation of Eosinophils.
Interleukin-10 Attenuates inflammatory response. Decreases TGF-β and IL-10 both attenuate the immune
expression of MHC class II and Th1 cytokines. response.
Inhibits activated macrophages and dendritic
cells. Also secreted by regulatory T cells.
Interleukin-13 Promotes IgE production by B cells. Induces Interleukin thirtEEn promotes IgE.
alternative macrophage activation.

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Respiratory burst Also called oxidative burst. Involves the activation of the phagocyte NADPH oxidase complex
(eg, in neutrophils, monocytes), which utilizes O2 as a substrate. Plays an important role in the
immune response Ž rapid release of reactive oxygen species (ROS). NADPH plays a role in both
the creation and neutralization of ROS. Myeloperoxidase contains a blue-green, heme-containing
pigment that gives sputum its color. NO Safe Microbe (NADPH Oxidase Ž Superoxide
dismutase Ž Myeloperoxidase).

Phagolysosome
NADPH oxidase
Q deficiency = chronic
granulomatous disease
O2
NADPH
R Superoxide dismutase Q
NADP+
O2 -∞
S Myeloperoxidase Neutrophil
R cell membrane
Catalase/glutathione
T peroxidase H2O2

U Glutathione reductase H2O + O2 H2O2 H2O

via bacterial Cl –
V Glucose-6-phosphate catalase S T
dehydrogenase G6PD GSH GSSG
∞
HOCl
GSH/ Glutathione reduced/ U
GSSG oxidized NADP+ NADPH
Bacteria from HMP shunt
HOCl ∞ Hypochlorite bleach V
Glucose-6-P 6-phosphogluconolactone
O2- ∞ Superoxide

Phagocytes of patients with CGD can utilize H2O2 generated by invading organisms and convert it
to ROS. Patients are at  risk for infection by catalase ⊕ species (eg, S aureus, Aspergillus) capable
of neutralizing their own H2O2, leaving phagocytes without ROS for fighting infections.
Pyocyanin of P aeruginosa generates ROS to kill competing pathogens. Oxidative burst leads to
release of lysosomal enzymes.

Interferons IFN-α, IFN-β, IFN-γ.

MECHANISM A part of innate host defense, interferons interfere with both RNA and DNA viruses. Cells
infected with a virus synthesize these glycoproteins, which act on local cells, priming them
for viral defense by downregulating protein synthesis to resist potential viral replication and by
upregulating MHC expression to facilitate recognition of infected cells. Also play a major role in
activating antitumor immunity.
CLINICAL USE Chronic HBV, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum, renal cell carcinoma,
malignant melanoma, multiple sclerosis, chronic granulomatous disease.
ADVERSE EFFECTS Flulike symptoms, depression, neutropenia, myopathy, interferon-induced autoimmunity.

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Cell surface proteins

T cells TCR (binds antigen-MHC complex), CD3
(associated with TCR for signal transduction),
CD28 (binds B7 on APC)
Helper T cells CD4, CD40L, CXCR4/CCR5 (coreceptors for
HIV)
Cytotoxic T cells CD8
Regulatory T cells CD4, CD25
B cells Ig (binds antigen), CD19, CD20, CD21
(receptor for Epstein-Barr virus), CD40, Must be 21 to drink at a Barr
MHC II, B7 (CD80/86)
NK cells CD16 (binds Fc of IgG), CD56 (suggestive
marker for NK cells)
Macrophages CD14 (receptor for PAMPs [eg, LPS]), CD40,
CCR5, MHC II, B7, Fc and C3b receptors
(enhanced phagocytosis)
Hematopoietic CD34
stem cells

Anergy State during which a cell cannot become activated by exposure to its antigen. T and B cells
become anergic when exposed to their antigen without costimulatory signal (signal 2). Another
mechanism of self-tolerance.

Passive vs active immunity

Passive Active
MEANS OF ACQUISITION Receiving preformed antibodies Exposure to exogenous antigens
ONSET Rapid Slow
DURATION Short span of antibodies (half-life = 3 weeks) Long-lasting protection (memory)
EXAMPLES IgA in breast milk, maternal IgG crossing Natural infection, vaccines, toxoid
placenta, antitoxin, humanized monoclonal
antibody
NOTES IVIG and other immune globulin preparations Combined passive and active immunizations
can be administered to provide temporary but can be given for hepatitis B or rabies exposure
specific passive immunity to a target pathogen.

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Vaccination Induces an active immune response (humoral and/or cellular) to specific pathogens.
VACCINE TYPE DESCRIPTION PROS/CONS EXAMPLES
Live attenuated Microorganism rendered Pros: induces cellular and Adenovirus (nonattenuated,
vaccine nonpathogenic but retains humoral responses. Induces given to military recruits),
capacity for transient growth strong, often lifelong typhoid (Ty21a, oral),
within inoculated host. MMR immunity. polio (Sabin), varicella
and varicella vaccines can be Cons: may revert to virulent (chickenpox), smallpox,
given to people living with form. Contraindicated in BCG, yellow fever, influenza
HIV without evidence of pregnancy and patients with (intranasal), MMR, rotavirus.
immunity if CD4+ cell count immunodeficiency. “Attention teachers! Please
≥ 200 cells/mm3. vaccinate small, Beautiful
young infants with MMR
routinely!”
Killed or inactivated Pathogen is inactivated by heat Pros: safer than live vaccines. Hepatitis A, Typhoid
vaccine or chemicals. Maintaining Cons: weaker cell-mediated (Vi polysaccharide,
epitope structure on surface immune response; mainly intramuscular), Rabies,
antigens is important for induces a humoral response. Influenza (intramuscular),
immune response. Mainly Booster shots usually needed. Polio (SalK).
induces a humoral response. A TRIP could Kill you.
Subunit, recombinant, All use specific antigens that Pros: targets specific epitopes HBV (antigen = HBsAg),
polysaccharide, and best stimulate the immune of antigen; lower chance of HPV, acellular pertussis
conjugate system. adverse reactions. (aP), Neisseria meningitidis
Cons: expensive; weaker (various strains), Streptococcus
immune response. pneumoniae (PPSV23
polysaccharide primarily
T-cell–independent response;
PCV13, PCV15, and PCV20
polysaccharide produces
T-cell–dependent response),
Haemophilus influenzae type
b, herpes zoster.
Toxoid Denatured bacterial toxin with Pros: protects against the Clostridium tetani,
an intact receptor binding bacterial toxins. Corynebacterium diphtheriae.
site. Stimulates immune Cons: antitoxin levels decrease
system to make antibodies with time, thus booster shots
without potential for causing may be needed.
disease.
mRNA A lipid nanoparticle delivers Pros: high efficacy; induces SARS-CoV-2
mRNA, causing cells to cellular and humoral
synthesize foreign protein (eg, immunity. Safe in pregnancy.
spike protein of SARS-CoV-2). Cons: local and transient
systemic (fatigue, headache,
myalgia) reactions are
common. Rare myocarditis,
pericarditis particularly in
young males.

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Hypersensitivity types Four types (ABCD): Anaphylactic and Atopic (type I), AntiBody-mediated (type II), Immune
Complex (type III), Delayed (cell-mediated, type IV). Types I, II, and III are all antibody-mediated.
Type I Anaphylactic and atopic—two phases: First (type) and Fast (anaphylaxis).
hypersensitivity ƒ Immediate (minutes): antigen crosslinks Test: skin test or blood test (ELISA) for allergen-
Allergen Allergen- preformed IgE on presensitized mast cells specific IgE.
specific IgE
Ž immediate degranulation Ž release of Example:
Fc receptor histamine (a vasoactive amine), tryptase ƒ Anaphylaxis (eg, food, drug, or bee sting
for IgE
(marker of mast cell activation), and allergies)
leukotrienes. ƒ Allergic asthma
ƒ Late (hours): chemokines (attract
inflammatory cells, eg, eosinophils)
and other mediators from mast cells
Degranulation
Ž inflammation and tissue damage.

Type II Antibodies bind to cell-surface antigens or Direct Coombs test—detects antibodies

hypersensitivity extracellular matrix Ž cellular destruction, attached directly to the RBC surface.
inflammation, and cellular dysfunction. Indirect Coombs test—detects presence of
NK cell unbound antibodies in the serum.
Cellular destruction—cell is opsonized (coated) Examples:
by antibodies, leading to either: ƒ Autoimmune hemolytic anemia (including
ƒ Phagocytosis and/or activation of drug-induced form)
complement system. ƒ Immune thrombocytopenia
ƒ NK cell killing (antibody-dependent cellular ƒ Transfusion reactions
Fc receptor
for IgG cytotoxicity). ƒ Hemolytic disease of the newborn
Surface antigen
Inflammation—binding of antibodies to cell Examples:
Abnormal cell surfaces Ž activation of complement system ƒ Goodpasture syndrome
Antibody-dependent and Fc receptor-mediated inflammation. ƒ Rheumatic fever
cellular cytotoxicity ƒ Hyperacute transplant rejection
Cellular dysfunction—antibodies bind to Examples:
cell-surface receptors Ž abnormal blockade or ƒ Myasthenia gravis
activation of downstream process. ƒ Graves disease
ƒ Pemphigus vulgaris

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Hypersensitivity types (continued)
Type III Immune complex—antigen-antibody (mostly
hypersensitivity IgG) complexes activate complement, which
attracts neutrophils; neutrophils release
lysosomal enzymes.
Can be associated with vasculitis and systemic
Neutrophils manifestations.
Enzymes from Serum sickness—the prototypic immune
neutrophils complex disease. Antibodies to foreign proteins
damage
endothelial cells are produced and 1–2 weeks later, antibody-
antigen complexes form and deposit in tissues
Ž complement activation Ž inflammation
and tissue damage ( serum C3, C4).
Arthus reaction—a local subacute immune
complex-mediated hypersensitivity reaction.
Intradermal injection of antigen into a
presensitized (has circulating IgG) individual
leads to immune complex formation in the
skin (eg, enhanced local reaction to a booster
vaccination). Characterized by edema,
fibrinoid necrosis, activation of complement.
Type IV Two mechanisms, each involving T cells:
hypersensitivity 1. Direct cell cytotoxicity: CD8+ cytotoxic T
cells kill targeted cells.
AAntigen-
presenting cell 2. Inflammatory reaction: effector CD4+
T cells recognize antigen and release
inflammation-inducing cytokines (shown
Antigen
in illustration).
Sensitized
Th1 cell
Cytokines
Delayed-type
hypersensitivity
Activated
macrophage
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SEC TION II 111
In type III reaction, imagine an immune
complex as 3 things stuck together: antigen-
antibody-complement.
Examples:
ƒ SLE
ƒ Rheumatoid arthritis
ƒ Reactive arthritis
ƒ Polyarteritis nodosa
ƒ Poststreptococcal glomerulonephritis
ƒ IgA vasculitis
Fever, urticaria, arthralgia, proteinuria,
lymphadenopathy occur 1–2 weeks after
antigen exposure. Serum sickness–like
reactions are associated with some drugs (may
act as haptens, eg, penicillin, monoclonal
antibodies) and infections (eg, hepatitis B).
Response does not involve antibodies (vs types I,
II, and III).
Examples:
ƒ Contact dermatitis (eg, poison ivy, nickel
allergy)
ƒ Drug reaction with eosinophilia and
systemic symptoms (DRESS)
ƒ Graft-versus-host disease
Tests: PPD for TB infection; patch test for
contact dermatitis; Candida skin test for T cell
immune function.
4T’s: T cells, Transplant rejections, TB skin
tests, Touching (contact dermatitis).
Fourth (type) and last (delayed).
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Immunologic blood transfusion reactions

TYPE PATHOGENESIS TIMING CLINICAL PRESENTATION DONOR BLOOD HOST BLOOD
Allergic/ Type I hypersensitivity Within minutes Allergies: urticaria, IgE
(anti-IgA)
anaphylactic reaction against plasma to 2–3 hr (due to pruritus
reaction proteins in transfused release of preformed Anaphylaxis:
blood inflammatory wheezing,
IgA-deficient individuals mediators in hypotension,
should receive blood degranulating mast respiratory arrest,
Donor plasma proteins, Host mast cell
products without IgA cells) shock including IgA

Acute Type II hypersensitivity During transfusion Fever, hypotension,

hemolytic reaction or within 24 hr tachypnea,
transfusion Typically causes (due to preformed tachycardia,
reaction intravascular hemolysis antibodies) flank pain,
(ABO blood group hemoglobinuria Donor RBC with A and/ Host anti-A, anti-B IgG,
or B group antigens IgM
incompatibility) (intravascular),
jaundice
(extravascular)
Febrile Cytokines created by Within 1–6 hr (due Fever, headaches,
nonhemolytic donor WBCs accumulate to preformed chills, flushing
transfusion during storage of blood cytokines) More common in
reaction products children Donor WBC releases Host anti-HLA, anti-
preformed cytokines leukocyte IgG
Reactions prevented by
leukoreduction of blood
products
Transfusion- Two-hit mechanism: Within minutes to Respiratory distress,
related acute ƒ Neutrophils are 6 hr noncardiogenic
lung injury sequestered and pulmonary edema Host
neutrophils
primed in pulmonary
vasculature due to
recipient risk factors Donor antileukocyte
antibody
ƒ Neutrophils are
activated by a product
(eg, antileukocyte
antibodies) in the
transfused blood and
release inflammatory
mediators Ž  capillary
permeability
Ž pulmonary edema
Delayed Anamnestic response to Onset over 24 hr Generally self limited
hemolytic a foreign antigen on Usually presents and clinically silent
transfusion donor RBCs (Rh [D] or within 1–2 wk Mild fever,
reaction other minor blood group (due to slow hyperbilirubinemia
antigens) previously destruction by
encountered by recipient reticuloendothelial
Typically causes system)
extravascular hemolysis

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Autoantibodies AUTOANTIBODY ASSOCIATED DISORDER

Anti-postsynaptic ACh receptor Myasthenia gravis
Anti-presynaptic voltage-gated Ca2+ channel Lambert-Eaton myasthenic syndrome
Anti-β2 glycoprotein I Antiphospholipid syndrome
Antinuclear (ANA) Nonspecific screening antibody, often associated
with SLE
Anticardiolipin, lupus anticoagulant SLE, antiphospholipid syndrome
Anti-dsDNA, anti-Smith SLE
Antihistone Drug-induced lupus
Anti-U1 RNP (ribonucleoprotein) Mixed connective tissue disease
Rheumatoid factor (IgM antibody against IgG Rheumatoid arthritis
Fc region), anti-cyclic citrullinated peptide
(anti-CCP, more specific)
Anti-Ro/SSA, anti-La/SSB Sjögren syndrome
Anti-Scl-70 (anti-DNA topoisomerase I) Scleroderma (diffuse)
Anticentromere Limited scleroderma (CREST syndrome)
Antisynthetase (eg, anti-Jo-1), anti-SRP, anti- Polymyositis, dermatomyositis
helicase (anti-Mi-2)
Antimitochondrial 1° biliary cholangitis
Anti-smooth muscle, anti-liver/kidney Autoimmune hepatitis
microsomal-1
Myeloperoxidase-antineutrophil cytoplasmic Microscopic polyangiitis, eosinophilic
antibody (MPO-ANCA)/perinuclear ANCA granulomatosis with polyangiitis, ulcerative
(p-ANCA) colitis, 1° sclerosing cholangitis
PR3-ANCA/cytoplasmic ANCA (c-ANCA) Granulomatosis with polyangiitis
Anti-phospholipase A2 receptor 1° membranous nephropathy
Anti-hemidesmosome Bullous pemphigoid
Anti-desmoglein (anti-desmosome) Pemphigus vulgaris
Antithyroglobulin, antithyroid peroxidase Hashimoto thyroiditis
(antimicrosomal)
Anti-TSH receptor Graves disease
IgA anti-endomysial, IgA anti-tissue Celiac disease
transglutaminase, IgA and IgG deamidated
gliadin peptide
Anti-glutamic acid decarboxylase, islet cell Type 1 diabetes mellitus
cytoplasmic antibodies
Antiparietal cell, anti-intrinsic factor Pernicious anemia
Anti-glomerular basement membrane Goodpasture syndrome

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 114 SEC TION II Immunology   
Immunology—Immune Responses

Immunodeficiencies
DISEASE DEFECT
B-cell disorders
X-linked (Bruton) Defect in BTK, a tyrosine Recurrent bacterial and
agammaglobulinemia kinase gene Ž no B-cell enteroviral infections after 6
maturation; X-linked recessive months ( maternal IgG)
( in Boys)
Selective IgA Cause unknown
deficiency Most common 1°
immunodeficiency
Common variable Defect in B-cell differentiation. May present in childhood
immunodeficiency Cause unknown in most cases
 risk of autoimmune disease,
T-cell disorders
Thymic aplasia 22q11 microdeletion; failure
to develop 3rd and 4th
pharyngeal pouches Ž absent
thymus and parathyroids
DiGeorge syndrome—thymic,
parathyroid, cardiac defects
Velocardiofacial syndrome—
palate, facial, cardiac defects
IL-12 receptor  Th1 response; autosomal
deficiency recessive
Autosomal dominant Deficiency of Th17 cells due to
hyper-IgE syndrome STAT3 mutation Ž impaired
(Job syndrome) recruitment of neutrophils to
sites of infection
Chronic T-cell dysfunction
mucocutaneous Impaired cell-mediated
candidiasis immunity against Candida sp
Classic form caused by defects
in AIRE
PRESENTATION
Majority Asymptomatic
Can see Airway and GI
infections, Autoimmune
disease, Atopy, Anaphylaxis to
IgA in blood products
but usually diagnosed after
puberty
bronchiectasis, lymphoma,
sinopulmonary infections
CATCH-22: Cardiac defects
(conotruncal abnormalities
[eg, tetralogy of Fallot, truncus
arteriosus]), Abnormal facies,
Thymic hypoplasia Ž T-cell
deficiency (recurrent viral/
fungal infections), Cleft
palate, Hypocalcemia 2° to
parathyroid aplasia Ž tetany
Disseminated mycobacterial
and fungal infections; may
present after administration of Mendelian susceptibility
BCG vaccine
Cold (noninflamed)
staphylococcal Abscesses,
retained Baby teeth, Coarse
facies, Dermatologic problems
(eczema),  IgE, bone
Fractures from minor trauma
Persistent noninvasive Candida Absent in vitro T-cell
albicans infections of skin and proliferation in response to
mucous membranes
FINDINGS
Absent B cells in peripheral
blood,  Ig of all classes.
Absent/scanty lymph nodes
and tonsils (1° follicles
and germinal centers
absent) Ž live vaccines
contraindicated
 IgA with normal IgG, IgM
levels
 susceptibility to giardiasis
Can cause false-negative celiac
disease test and false-positive
serum pregnancy test
 plasma cells,
 immunoglobulins
 T cells,  PTH,  Ca2+
Thymic shadow absent on
CXR
 IFN-γ
Most common cause of
to mycobacterial diseases
(MSMD)
 IgE
 eosinophils
Learn the ABCDEF’s to get a
Job STAT!
Candida antigens
Absent cutaneous reaction to
Candida antigens

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 Immunology   
Immunology—Immune Responses
Immunodeficiencies (continued)
DISEASE DEFECT
B- and T-cell disorders
Severe combined Several types including
immunodeficiency defective IL-2R gamma
chain (most common,
X-linked recessive); adenosine
deaminase deficiency
(autosomal recessive);
RAG mutation Ž VDJ
recombination defect
Ataxia-telangiectasia Defects in ATM gene Ž failure
A to detect DNA damage
Ž failure to halt progression
of cell cycle Ž mutations
accumulate; autosomal
recessive
Hyper-IgM syndrome Most commonly due to
defective CD40L on Th cells
Ž class switching defect;
X-linked recessive
Wiskott-Aldrich Mutation in WAS gene;
syndrome leukocytes and platelets
unable to reorganize actin
cytoskeleton Ž defective
antigen presentation; X-linked  risk of autoimmune disease
recessive
Phagocyte dysfunction
Leukocyte adhesion Defect in LFA-1 integrin
deficiency (type 1) (CD18) protein on
phagocytes; impaired
migration and chemotaxis;
autosomal recessive
Chédiak-Higashi Defect in lysosomal trafficking
syndrome regulator gene (LYST)
B Microtubule dysfunction in
phagosome-lysosome fusion;
autosomal recessive
Chronic Defect of NADPH oxidase
granulomatous Ž  reactive oxygen
disease species (eg, superoxide)
and  respiratory burst in
neutrophils; X-linked form
most common
FAS1_2023_02-Immunology.indd 115
PRESENTATION
Failure to thrive, chronic
diarrhea, thrush
Recurrent viral, bacterial,
fungal, and protozoal
infections
Triad: cerebellar defects
(Ataxia), spider Angiomas
(telangiectasia A ), IgA
deficiency
 sensitivity to radiation (limit
x-ray exposure)
Severe pyogenic infections
early in life; opportunistic
infection with Pneumocystis,
Cryptosporidium, CMV
WATER: Wiskott-Aldrich:
Thrombocytopenia, Eczema,
Recurrent (pyogenic)
infections
and malignancy
Late separation (>30 days) of
umbilical cord, absent pus,
dysfunctional neutrophils
Ž recurrent skin and
mucosal bacterial infections
PLAIN: Progressive
neurodegeneration,
Lymphohistiocytosis,
Albinism (partial), recurrent
pyogenic Infections,
peripheral Neuropathy
 susceptibility to catalase ⊕
organisms
Recurrent infections and
granulomas
SEC TION II 115
FINDINGS
 T-cell receptor excision
circles (TRECs)
Part of newborn screening for
SCID
Absence of thymic shadow
(CXR), germinal centers
(lymph node biopsy), and
T cells (flow cytometry)
 AFP
 IgA, IgG, and IgE
Lymphopenia, cerebellar
atrophy
 risk of lymphoma and
leukemia
Normal or  IgM
 IgG, IgA, IgE
Failure to make germinal
centers
 to normal IgG, IgM
 IgE, IgA
Fewer and smaller platelets
 neutrophils in blood
Absence of neutrophils at
infection sites Ž impaired
wound healing
Giant granules ( B , arrows) in
granulocytes and platelets
Pancytopenia
Mild coagulation defects
Abnormal dihydrorhodamine
(flow cytometry) test ( green
fluorescence)
Nitroblue tetrazolium dye
reduction test (obsolete) fails
to turn blue
11/17/22 7:26 PM
 116 SEC TION II Immunology   
Immunology—Immune Responses

Infections in immunodeficiency
PATHOGEN  T CELLS  B CELLS  GRANULOCYTES  COMPLEMENT
Bacteria Sepsis Encapsulated (Please Some Bacteria Encapsulated
SHINE my SKiS): Produce No species with early
Pseudomonas Serious granules: complement
aeruginosa, Staphylococcus, deficiencies
Streptococcus Burkholderia cepacia, Neisseria with late
pneumoniae, Pseudomonas complement (C5–
Haemophilus aeruginosa, Nocardia, C9) deficiencies
Influenzae type b, Serratia
Neisseria
meningitidis,
Escherichia coli,
Salmonella,
Klebsiella
pneumoniae,
group B
Streptococcus
Viruses CMV, EBV, JC Enteroviral N/A N/A
virus, VZV, chronic encephalitis,
infection with poliovirus
respiratory/GI viruses (live vaccine
contraindicated)
Fungi/parasites Candida (local), PCP, GI giardiasis (no IgA) Candida (systemic), N/A
Cryptococcus Aspergillus, Mucor
Note: B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-cell deficiencies produce more fungal and
viral infections.

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 Immunology   
Immunology—Immune Responses SEC TION II 117

Transplant rejection
TYPE OF REJECTION ONSET PATHOGENESIS FEATURES
Hyperacute Within minutes Pre-existing recipient antibodies Widespread thrombosis of graft vessels
react to donor antigen (type II (arrows within glomerulus A )
hypersensitivity reaction), activate Ž ischemia and fibrinoid necrosis
complement Graft must be removed
Acute Weeks to months Cellular: CD8+ T cells and/or CD4+ Vasculitis of graft vessels with dense
T cells activated against donor MHCs interstitial lymphocytic infiltrate  B
(type IV hypersensitivity reaction) Prevent/reverse with
Humoral: similar to hyperacute, except immunosuppressants
antibodies develop after transplant
(associated with C4d deposition)
Chronic Months to years CD4+ T cells respond to recipient Dominated by arteriosclerosis C
APCs presenting donor peptides, Recipient T cells react and secrete
including allogeneic MHC cytokines Ž proliferation of vascular
Both cellular and humoral components smooth muscle, parenchymal
(type II and IV hypersensitivity atrophy, interstitial fibrosis
reactions) Organ-specific examples:
ƒ Chronic allograft nephropathy
ƒ Bronchiolitis obliterans
ƒ Accelerated atherosclerosis (heart)
ƒ Vanishing bile duct syndrome
Graft-versus-host Varies Grafted immunocompetent Maculopapular rash, jaundice,
disease T cells proliferate in the diarrhea, hepatosplenomegaly
immunocompromised host and reject Usually in bone marrow and liver
host cells with “foreign” proteins Ž transplants (rich in lymphocytes)
severe organ dysfunction Potentially beneficial in bone marrow
HLA mismatches (most importantly transplant for leukemia (graft-versus-
HLA-A, -B, and -DR antigens)  the tumor effect)
risk for GVHD For patients who are
Type IV hypersensitivity reaction immunocompromised, irradiate
blood products prior to transfusion
to prevent GVHD
A B C

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 118 SEC TION II Immunology   
Immunology—Immunosuppressants

IMMUNOLOGY—IMMUNOSUPPRESSANTS
` 

Immunosuppressants Agents that block lymphocyte activation and proliferation. Reduce acute transplant rejection by
suppressing cellular immunity (used as prophylaxis). Frequently combined to achieve greater
efficacy with  toxicity. Chronic suppression  risk of infection and malignancy.

CD4 Basiliximab
–

FKBP +
CD3 Tacrolimus FKBP + Azathioprine
TCR IL-2R
Sirolimus
– (rapamycin)
Cyclophilin + 6–MP
– Mycophenolate
Cyclosporine – Calcineurin

NFAT–P NFAT mTOR –

–
PRPP
IMP amidotransferase
dehydrogenase
Proliferation
Glucocorticoids genes
Purine
T HELPER – – nucleotides
CELL
NF–κB De novo
T Inflammatory purine
NFA
cytokine genes synthesis
DNA replication

DRUG MECHANISM INDICATIONS TOXICITY NOTES

Cyclosporine
Tacrolimus (FK506)
Sirolimus (Rapamycin)
Calcineurin inhibitor; Psoriasis, rheumatoid Nephrotoxicity,
binds cyclophilin arthritis hypertension,
Blocks T-cell activation hyperlipidemia,
by preventing IL-2 neurotoxicity, gingival Both calcineurin
transcription hyperplasia, hirsutism inhibitors are
highly nephrotoxic,
Calcineurin inhibitor; Immunosuppression Similar to cyclosporine, especially in higher
binds FK506 binding after solid organ  risk of diabetes doses or in patients
protein (FKBP) transplant and neurotoxicity; with  renal function
Blocks T-cell activation no gingival
by preventing IL-2 hyperplasia or
transcription hirsutism
mTOR inhibitor; binds “Pansirtopenia” Kidney “sir-vives.”
FKBP (pancytopenia), Synergistic with
Kidney transplant insulin resistance, cyclosporine
Blocks T-cell
rejection prophylaxis hyperlipidemia; Also used in drug-
activation and B-cell
specifically not nephrotoxic eluting stents
differentiation by
preventing response Sir Basil’s kidney
to IL-2 transplant

Basiliximab Monoclonal antibody; Edema, hypertension,

blocks IL-2R tremor

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 Immunology   
Immunology—Immunosuppressants SEC TION II 119

Immunosuppressants (continued)
DRUG MECHANISM INDICATIONS TOXICITY NOTES
Azathioprine Antimetabolite Rheumatoid arthritis, Pancytopenia 6-MP degraded by
precursor of Crohn disease, xanthine oxidase;
6-mercaptopurine glomerulonephritis, toxicity  by
Inhibits lymphocyte other autoimmune allopurinol
proliferation by conditions Pronounce “azathio-
blocking nucleotide purine”
synthesis
Mycophenolate Reversibly inhibits Glucocorticoid-sparing GI upset, Associated with
mofetil IMP dehydrogenase, agent in rheumatic pancytopenia, invasive CMV
preventing purine disease hypertension infection
synthesis of B and T Less nephrotoxic and
cells neurotoxic
Glucocorticoids Inhibit NF-κB Many autoimmune Cushing syndrome, Demargination
Suppress both B- and and inflammatory osteoporosis, of WBCs causes
T-cell function by disorders, adrenal hyperglycemia, artificial leukocytosis
 transcription of insufficiency, asthma, diabetes, amenorrhea, Adrenal insufficiency
many cytokines CLL, non-Hodgkin adrenocortical may develop if drug is
Induce T cell apoptosis lymphoma atrophy, peptic ulcers, stopped abruptly after
psychosis, cataracts, chronic use
avascular necrosis
(femoral head)

Recombinant cytokines and clinical uses

CYTOKINE AGENT CLINICAL USES
Bone marrow stimulation
Erythropoietin Epoetin alfa (EPO analog) Anemias (especially in renal failure)
Associated with  risk of hypertension,
thromboembolic events
Colony stimulating Filgrastim (G-CSF), Sargramostim (GM-CSF) Leukopenia; recovery of granulocyte and
factors monocyte counts
Thrombopoietin Romiplostim (TPO analog), eltrombopag (think Autoimmune thrombocytopenia
“elthrombopag.” TPO receptor agonist) Platelet stimulator
Immunotherapy
Interleukin-2 Aldesleukin Renal cell carcinoma, metastatic melanoma
Interferons IFN-α Chronic hepatitis C (not preferred) and B, renal
cell carcinoma
IFN-β Multiple sclerosis
IFN-γ Chronic granulomatous disease

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