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HIGH-YIELD PRINCIPLES IN

Immunology

“I hate to disappoint you, but my rubber lips are immune to your charms.” ``Lymphoid Structures 96
—Batman & Robin
``Cellular Components 99
“An apple a day keeps the doctor away.”
—English proverb ``Immune Responses 104

``Immunosuppressants 120
Understand how the many components of the immune system operate
and interact in the normal immune response to infection at both the
clinical and cellular levels. Know the immune mechanisms of responses
to vaccines. Both congenital and acquired immunodeficiencies are very
testable. Cell surface markers are high yield for understanding immune
cell interactions and for laboratory diagnosis. Know the roles and
functions of major cytokines and chemokines.

95

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96 SEC TION II Immunology   
Immunology—Lymphoid Structures

IMMUNOLOGY—LYMPHOID STRUCTURES
``

Immune system 1° organs:


organs ƒƒ Bone marrow—immune cell production, B cell maturation
ƒƒ Thymus—T cell maturation
2° organs:
ƒƒ Spleen, lymph nodes, tonsils, Peyer patches
ƒƒ Allow immune cells to interact with antigen

Lymph node A 2° lymphoid organ that has many afferents, 1 or more efferents. Encapsulated, with trabeculae.
Functions are nonspecific filtration by macrophages, storage of B and T cells, and immune
response activation.
Follicle Site of B-cell localization and
proliferation. In outer cortex. 1° follicles
lymphatic
are dense and dormant. 2° follicles have
pale central germinal centers and are Follicles (B cells) 1º follicle
active. Paracortex 2º follicle
(T cells)
Medulla Consists of medullary cords (closely
Germinal center
packed lymphocytes and plasma cells)
Mantle zone
and medullary sinuses. Medullary Medullary cords
sinuses communicate with efferent Postcapillary
(lymphocytes,
plasma cells)
lymphatics and contain reticular cells venule
Vein
and macrophages.
Capillary Artery
Paracortex Houses T cells. Region of cortex between supply
follicles and medulla. Contains high
endothelial venules through which T lymphatic
and B cells enter from blood. Not well
developed in patients with DiGeorge Trabecula Medullary sinus
syndrome. Capsule
(reticular cells,
macrophages)
Paracortex enlarges in an extreme cellular
immune response (eg, viral infection).

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Immunology   
Immunology—Lymphoid Structures SEC TION II 97

Lymphatic drainage associations

Lymph node cluster Area of body drained Associated pathology


R Upper respiratory tract infection
Cervical Head and neck Infectious mononucleosis
Kawasaki disease
Primary lung cancer
Mediastinal Trachea and esophagus
Granulomatous disease
Hilar Lungs Granulomatous disease

Upper limb, breast, skin above Mastitis


Axillary
umbilicus Metastasis (especially breast cancer)

Liver, stomach, spleen, pancreas,


Celiac
upper duodenum
Mesenteric lymphadenitis
Lower duodenum, jejunum, ileum, Typhoid fever
Superior mesenteric
colon to splenic flexure Ulcerative colitis
Celiac disease
Colon from splenic flexure to
Inferior mesenteric
upper rectum
Para-aortic Testes, ovaries, kidneys, uterus Metastasis
Lower rectum to anal canal (above
Internal iliac pectinate line), bladder, vagina
(middle third), cervix, prostate
Sexually transmitted infections
Anal canal (below pectinate line),
Superficial inguinal skin below umbilicus (except
popliteal area), scrotum, vulva

Popliteal Dorsolateral foot, posterior calf Foot/leg cellulitis

Palpable lymph node Right lymphatic duct drains right side of body above diaphragm into junction of the right subclavian
Non-palpable lymph node and internal jugular vein
Thoracic duct drains everything into junction of left subclavian and internal jugular veins
(Rupture of thoracic duct can cause chylothorax)

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98 SEC TION II Immunology   
Immunology—Lymphoid Structures

Spleen Located in LUQ of abdomen, anterior to left Splenic dysfunction (eg, postsplenectomy
A
kidney, protected by 9th-11th ribs. state in sickle cell disease):  IgM Ž 
Sinusoids are long, vascular channels in red complement activation Ž  C3b opsonization
pulp (red arrows in A ) with fenestrated “barrel Ž  susceptibility to encapsulated organisms.
hoop” basement membrane. Postsplenectomy blood findings:
ƒƒ T cells are found in the periarteriolar ƒƒ Howell-Jolly bodies (nuclear remnants)
lymphatic sheath (PALS) within the white ƒƒ Target cells
pulp (white arrows in A ). ƒƒ Thrombocytosis (loss of sequestration and
ƒƒ B cells are found in follicles within the removal)
white pulp. ƒƒ Lymphocytosis (loss of sequestration)
ƒƒ The marginal zone, in between the red pulp Vaccinate patients undergoing splenectomy
and white pulp, contains macrophages and against encapsulated organisms
specialized B cells, and is where antigen- (pneumococcal, Hib, meningococcal).
presenting cells (APCs) capture blood-borne
antigens for recognition by lymphocytes.
Splenic macrophages remove encapsulated
bacteria.
Capsule
Germinal center Trabecula
Red pulp (RBCs)
Mantle zone Sinusoid
Marginal zone
Reticular fibrous
White pulp (WBCs) framework
Follicle (B cells)
Periarteriolar
lymphoid sheath
(T cells)

Open
circulation
Closed
circulation
Pulp vein

Artery
Vein

Thymus Located in the anterosuperior mediastinum. T cells = Thymus


A Site of T-cell differentiation and maturation. B cells = Bone marrow
Encapsulated. Thymus is derived from the Hypoplastic in DiGeorge syndrome and severe
Third pharyngeal pouch. Lymphocytes of combined immunodeficiency (SCID).
mesenchymal origin. Cortex is dense with
Thymoma—neoplasm of thymus. Associated
immature T cells; medulla is pale with mature
with myasthenia gravis and superior vena cava
T cells and Hassall corpuscles A containing
syndrome.
B epithelial reticular cells.
Normal neonatal thymus “sail-shaped” on
CXR  B , involutes with age.

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Immunology   
Immunology—Cellular Components SEC TION II 99

IMMUNOLOGY—CELLULAR COMPONENTS
``

Innate vs adaptive immunity


Innate immunity Adaptive immunity
COMPONENTS Neutrophils, macrophages, monocytes, T cells, B cells, circulating antibodies
dendritic cells, natural killer (NK) cells
(lymphoid origin), complement, physical
epithelial barriers, secreted enzymes.
MECHANISM Germline encoded Variation through V(D)J recombination during
lymphocyte development
RESISTANCE Resistance persists through generations; does Microbial resistance not heritable
not change within an organism’s lifetime
RESPONSE TO PATHOGENS Nonspecific Highly specific, refined over time
Occurs rapidly (minutes to hours) Develops over long periods; memory response is
No memory response faster and more robust
SECRETED PROTEINS Lysozyme, complement, C-reactive protein Immunoglobulins
(CRP), defensins
KEY FEATURES IN PATHOGEN Toll-like receptors (TLRs): pattern recognition Memory cells: activated B and T cells;
RECOGNITION receptors that recognize pathogen-associated subsequent exposure to a previously
molecular patterns (PAMPs) and lead to encountered antigen Ž stronger, quicker
activation of NF-κB. Examples of PAMPs immune response
include LPS (gram ⊝ bacteria), flagellin
(bacteria), nucleic acids (viruses).

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100 SEC TION II Immunology   
Immunology—Cellular Components

Major MHC encoded by HLA genes. Present antigen fragments to T cells and bind T-cell receptors
histocompatibility (TCRs).
complex I and II
MHC I MHC II
LOCI HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ, HLA-DR
MHC I loci have 1 letter MHC II loci have 2 letters
BINDING TCR and CD8 TCR and CD4
STRUCTURE 1 long chain, 1 short chain 2 equal-length chains (2 α, 2 β)
EXPRESSION All nucleated cells, APCs, platelets APCs
Not on RBCs
FUNCTION Present endogenously synthesized antigens (eg, Present exogenously synthesized antigens (eg,
viral or cytosolic proteins) to CD8+ cytotoxic bacterial proteins) to CD4+ helper T cells
T cells
ANTIGEN LOADING Antigen peptides loaded onto MHC I in RER Antigen loaded following release of invariant
after delivery via TAP (transporter associated chain in an acidified endosome
with antigen processing)
ASSOCIATED PROTEINS β2-microglobulin Invariant chain
STRUCTURE Peptide
Peptide-binding groove

α2 α1 α1 β1

α3 α2 β2
β2−Microglobulin
Extracellular space

Cell membrane

Cytoplasm

HLA subtypes associated with diseases


HLA SUBTYPE DISEASE MNEMONIC
A3 Hemochromatosis
B8 Addison disease, myasthenia gravis, Graves Don’t Be late(8), Dr. Addison, or else you’ll
disease send my patient to the grave.
B27 Psoriatic arthritis, Ankylosing spondylitis, PAIR. Also known as seronegative arthropathies.
IBD-associated arthritis, Reactive arthritis
DQ2/DQ8 Celiac disease I ate (8) too (2) much gluten at Dairy Queen.
DR2 Multiple sclerosis, hay fever, SLE, Multiple hay pastures have dirt.
Goodpasture syndrome
DR3 Diabetes mellitus type 1, SLE, Graves disease, 2-3, S-L-E
Hashimoto thyroiditis, Addison disease
DR4 Rheumatoid arthritis, diabetes mellitus type 1, There are 4 walls in a “rheum” (room).
Addison disease
DR5 Hashimoto thyroiditis Hashimoto is an odd doctor (DR3, DR5).

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Immunology   
Immunology—Cellular Components SEC TION II 101

Natural killer cells Lymphocyte member of innate immune system.


Use perforin and granzymes to induce apoptosis of virally infected cells and tumor cells.
Activity enhanced by IL-2, IL-12, IFN-α, and IFN-β.
Induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence
of MHC I on target cell surface.
Also kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig,
activating the NK cell).

Major functions of B and T cells


B cells Humoral immunity.
Recognize antigen—undergo somatic hypermutation to optimize antigen specificity.
Produce antibody—differentiate into plasma cells to secrete specific immunoglobulins.
Maintain immunologic memory—memory B cells persist and accelerate future response to antigen.
T cells Cell-mediated immunity.
CD4+ T cells help B cells make antibodies and produce cytokines to recruit phagocytes and
activate other leukocytes.
CD8+ T cells directly kill virus-infected cells.
Delayed cell-mediated hypersensitivity (type IV).
Acute and chronic cellular organ rejection.
Rule of 8: MHC II × CD4 = 8; MHC I × CD8 = 8.

Differentiation of T cells

Bone marrow Thymus Lymph node

Th1
CD8+ Cytotoxic
T cell T cell
γ
N-
2 , IF 0
1 1
T cell IL- , IL-
CD4+ CD8+ 4
precursor IL-
T cell Th2
-4
IL-2, IL
Helper IFN-γ
CD4+
T cell T cell
TGF
-β,
IL-6
TG Th17
F-
β

T-cell receptor Cortex Medulla


(binds MHC I (positive (negative
or MHC II) selection) selection)

CD8 Treg
CD4

Positive selection Thymic cortex. T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells
survive.
Negative selection 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.

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102 SEC TION II Immunology   
Immunology—Cellular Components

T cell subsets
Th1 cell Th2 cell Th17 cell Treg
SECRETES IFN-γ IL-4, IL-5, IL-6, IL-10, IL-17, IL-21, IL-22 TGF-ß, IL-10, IL-35
IL-13
FUNCTION Activates macrophages Activate eosinophils Immunity against Prevent autoimmunity
and cytotoxic T cells and promote extracellular by maintaining
to kill phagocytosed production of IgE for microbes, through tolerance to self-
microbes parasite defense induction of antigens
neutrophilic
inflammation
INDUCED BY IFN-γ, IL-12 IL-2, IL-4 TGF-β, IL-1, IL-6 TGF-β, IL-2
INHIBITED BY IL-4, IL-10 (from Th2 IFN-γ (from Th1 cell) IFN-γ, IL-4 IL-6
cell)
IMMUNODEFICIENCY Mendelian Hyper-IgE syndrome IPEX
susceptibility to
mycobacterial disease

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.

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  Dendritic cell (specialized APC) samples Q
antigen, processes antigen, and migrates to
Dendritic cell
the draining lymph node. Q
 T-cell activation (signal 1): antigen is Dendritic cell
presented on MHC II and recognized by
TCR on Th (CD4+) cell. Endogenous or MHC I/II B7 (CD80/86)
cross-presented antigen is presented on MHC R S
I to Tc (CD8+) cell. MHC I/II
Antigen B7 (CD80/86)
 Proliferation and survival (signal 2): TCR
R
CD4/8 CD28
S
costimulatory signal via interaction of B7 Antigen T cell
TCR CD4/8 CD28
protein (CD80/86) on dendritic cell and
CD28 on naïve T cell. T cell
 Th cell activates and produces cytokines. Tc
cell activates and is able to recognize and kill
virus-infected cell.
Th cell
B-cell activation and   Th-cell activation as above.
class switching  B-cell receptor–mediated endocytosis; Th cell
foreign antigen is presented on MHC II and TCR CD4 CD40L
recognized by TCR on Th cell. R S
  CD40 receptor on B cell binds CD40 ligand TCR CD4 CD40L
MHC II CD40 Cytokines
(CD40L) on Th cell. R S
T
 Th cell secretes cytokines that determine
MHC II B cell CD40 Cytokines
Ig class
Ig class switching of B cell. B cell activates Tswitching
and undergoes class switching, affinity
B cell Ig class
maturation, and antibody production. switching

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104 SEC TION II Immunology   
Immunology—Immune Responses

IMMUNOLOGY—IMMUNE RESPONSES
``

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

C H1 Hinge CH1 JL
pe io

ƒƒ Constant
rva ns

Light chain
CL CL
ria
ble

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

Antibody promotes Antibody prevents Antibody activates


phagocytosis bacterial adherence complement, enhancing
opsonization and lysis

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Immunoglobulin All isotypes can exist as monomers. Mature, naive 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, IgE,
or IgG.
IgG Main antibody in 2° response to an antigen. Most abundant isotype in serum. Fixes complement,
opsonizes bacteria, neutralizes bacterial toxins and viruses. Only isotype that crosses the placenta
(provides infants with passive immunity).

IgA Prevents attachment of bacteria and viruses to mucous membranes; does not fix complement.
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,
Giardia). Most produced antibody overall, but has lower serum concentrations. Released into
J chain secretions (tears, saliva, mucus) and breast milk. Picks up secretory component from epithelial cells,
which protects the Fc portion from luminal proteases.
IgM Produced in the 1° (immediate) response to an antigen. Fixes complement. Cannot cross the
J chain
placenta. Antigen receptor on the surface of B cells. Monomer on B cell, pentamer with J chain
when secreted. Pentamer enables avid binding to antigen while humoral response evolves.

IgD Unclear function. Found on surface of many B cells and in serum.

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. Lowest concentration in serum.

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, pneumococcal polysaccharide vaccine).
Thymus-dependent Antigens containing a protein component (eg, diphtheria vaccine). Class switching and
antigens immunologic memory occur as a result of direct contact of B cells with Th cells.

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106 SEC TION II Immunology   
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.
ACTIVATION PATHWAYS Classic—IgG or IgM mediated. GM makes classic cars.
Alternative—microbe surface molecules.
Lectin—mannose or other sugars on microbe
surface.
FUNCTIONS C3b—opsonization. C3b binds bacteria.
C3a, C4a, C5a—anaphylaxis.
C5a—neutrophil chemotaxis.
C5b-9—cytolysis by MAC.
Opsonins—C3b and IgG are the two 1°
opsonins in bacterial defense; enhance
phagocytosis. C3b also helps clear immune
complexes.
Inhibitors—decay-accelerating factor (DAF,
aka CD55) and C1 esterase inhibitor help
prevent complement activation on self cells
(eg, RBCs).
D

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 referred to as C2b.

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Immunology   
Immunology—Immune Responses SEC TION II 107

Complement disorders
Complement protein deficiencies
Early complement Increased risk of severe, recurrent pyogenic sinus and respiratory tract infections. Increased risk of
deficiencies (C1-C4) SLE.
Terminal complement Increased 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.
Paroxysmal nocturnal A defect in the PIGA gene preventing the formation of anchors for complement inhibitors, such as
hemoglobinuria decay-acclerating factor (DAF/CD55) and membrane inhibitor of reactive lysis (MIRL/CD59).
Causes complement-mediated lysis of RBCs.

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108 SEC TION II Immunology   
Immunology—Immune Responses

Important cytokines
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 known as osteoclast-activating factor. IL-3: stimulates bone marrow.
IL-4: stimulates IgE production.
IL-5: stimulates IgA production.
IL-6: stimulates aKute-phase protein
production.
Interleukin-6 Causes fever and stimulates production of acute-
phase proteins.
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.
Activates NK cells.
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.
SECRETED BY ALL 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 Also activates NK cells to kill virus-infected
antigen or IL-12 from macrophages; stimulates cells. Increases MHC expression and antigen
macrophages to kill phagocytosed pathogens. presentation by all cells.
Inhibits differentiation of Th2 cells.
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.
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.

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Respiratory burst Involves the activation of the phagocyte NADPH oxidase complex (eg, in neutrophils, monocytes),
(oxidative burst) 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.

Phagolysosome
NADPH oxidase
(deficiency = chronic
granulomatous disease)
O2
NADPH
Superoxide dismutase
NADP+
Myeloperoxidase O2– ∞
Neutrophil
cell membrane
Glutathione peroxidase
(requires selenium) H2O2

Glutathione reductase H2O + O2 H2O2 H 2O


(requires riboflavin) (via bacterial Cl –
G6PD catalase) GSH GSSG
HClO ∞
GSH/ Glutathione (reduced/
GSSG oxidized) NADP+ NADPH
Bacteria (from HMP shunt)
HClO ∞ Hydroxyl-halide radicals
Glucose-6-P 6-phosphogluconolactone
O2– ∞ Superoxide anion

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 also leads to
K+ influx, which releases lysosomal enzymes from proteoglycans. Lactoferrin is a protein found in
secretory fluids and neutrophils that inhibits microbial growth via iron chelation.

Interferon-α and -β A part of innate host defense against both Interfere with viruses.
RNA and DNA viruses. Interferons are
glycoproteins synthesized by virus-infected
cells that act on local cells, “priming them”
for viral defense by downregulating protein
synthesis to resist potential viral replication
and upregulating MHC expression to facilitate
recognition of infected cells.

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110 SEC TION II Immunology   
Immunology—Immune Responses

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 (co-receptor for
HIV)
Cytotoxic T cells CD8
Regulatory T cells CD4, CD25
B cells Ig (binds antigen)
CD19, CD20, CD21 (receptor for EBV), CD40 You can drink Beer at the Bar when you’re 21:
MHC II, B7 B cells, Epstein-Barr virus, CD21.
Macrophages CD14 (receptor for PAMPs, eg, LPS), CD40
CCR5
MHC II, B7 (CD80/86)
Fc and C3b receptors (enhanced phagocytosis)
NK cells CD16, CD56 (suggestive marker for NK)
Hematopoietic stem CD34
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 foreign 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 After exposure to Tetanus toxin, Botulinum Combined passive and active immunizations
toxin, HBV, Varicella, Rabies virus, or can be given for hepatitis B or rabies exposure
diphtheria toxin, unvaccinated patients are
given preformed antibodies (passive)—“To Be
Healed Very Rapidly”

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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 loses its Pros: induces strong, often Adenovirus (nonattenuated,
vaccine pathogenicity but retains lifelong immunity. given to military recruits),
capacity for transient Cons: may revert to virulent Polio (sabin), Varicella
growth within inoculated form. Often contraindicated (chickenpox), Smallpox,
host. Induces cellular and in pregnancy and BCG, Yellow fever, Influenza
humoral responses. MMR immunodeficiency. (intranasal), MMR, Rotavirus
and varicella vaccines can “Attention! Please Vaccinate
be given to HIV ⊕ patients Small, Beautiful Young
without evidence of immunity Infants with MMR
if CD4 cell count ≥ 200 cells/ Regularly!”
mm3.
Killed or inactivated Pathogen is inactivated by heat Pros: safer than live vaccines. Rabies, Influenza (injection),
vaccine or chemicals. Maintaining Cons: weaker immune Polio (Salk), hepatitis A
epitope structure on surface response; booster shots SalK = Killed
antigens is important for usually required. RIP Always
immune response. Mainly
induces a humoral response.
Subunit Includes only the antigens that Pros: lower chance of adverse HBV (antigen = HBsAg),
best stimulate the immune reactions. HPV (types 6, 11, 16, and
system. Cons: expensive, weaker 18), acellular pertussis
immune response. (aP), Neisseria meningitidis
(various strains), Streptococcus
pneumoniae, Haemophilus
influenzae type b.
Toxoid Denatured bacterial toxin with Pros: protects against the Clostridium tetani,
an intact receptor binding bacterial toxins. Corynebacterium diphtheriae
site. Stimulates the immune Cons: antitoxin levels decrease
system to make antibodies with time, may require a
without potential for causing booster.
disease.

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112 SEC TION II Immunology   
Immunology—Immune Responses

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 ƒƒ 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) and tryptase ƒƒ Anaphylaxis (eg, food, drug, or bee sting
for IgE
(a marker of mast cell activation). allergies)
ƒƒ Late (hours): chemokines (attract
inflammatory cells, eg, eosinophils) and
cytokines (eg, leukotrienes) from mast cells
Ž inflammation and tissue damage.
Degranulation

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


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

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Hypersensitivity types (continued)


Type III Immune complex—antigen-antibody (mostly In type III reaction, imagine an immune
hypersensitivity IgG) complexes activate complement, which complex as 3 things stuck together: antigen-
attracts neutrophils; neutrophils release antibody-complement.
lysosomal enzymes. Examples:
Can be associated with vasculitis and systemic ƒƒ SLE
Neutrophils manifestations. ƒƒ Polyarteritis nodosa
ƒƒ Poststreptococcal glomerulonephritis
Serum sickness—the prototype immune Fever, urticaria, arthralgia, proteinuria,
complex disease. Antibodies to foreign proteins lymphadenopathy occur 1–2 weeks after
are produced and 1–2 weeks later, antibody- antigen exposure. Serum sickness-like
Enzymes from antigen complexes form and deposit in tissues reactions are associated with some drugs (may
neutrophils Ž complement activation Ž inflammation act as haptens, eg, penicillin) and infections
damage
endothelial cells and tissue damage. (eg, hepatitis B).

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. Characterized by edema, necrosis, and
activation of complement.
Type IV Two mechanisms, each involving T cells: Response does not involve antibodies (vs types I,
hypersensitivity II, and III).
1. Direct cell cytotoxicity: CD8+ cytotoxic T Examples: contact dermatitis (eg, poison ivy,
AAntigen
presenting cell cells kill targeted cells. nickel allergy) and graft-versus-host disease.
2. Inflammatory reaction: effector CD4+ Tests (purpose): PPD (tuberculosis infection);
T cells recognize antigen and release patch test (cause of contact dermatitis);
Antigen
inflammation-inducing cytokines (shown Candida extract (T cell immune function).
in illustration). 4T’s: T cells, Transplant rejections, TB skin
Sensitized
Th1 cell tests, Touching (contact dermatitis).
Cytokines
Fourth (type) and last (delayed).

Delayed-type
hypersensitivity
Activated
macrophage

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114 SEC TION II Immunology   
Immunology—Immune Responses

Blood transfusion reactions


TYPE PATHOGENESIS CLINICAL PRESENTATION TIMING
Allergic/anaphylactic Type I hypersensitivity reaction Urticaria, pruritus, fever, Within minutes to 2–3 hours
reaction against plasma proteins wheezing, hypotension,
in transfused blood. IgA- respiratory arrest, shock.
deficient individuals must
receive blood products
without IgA.
Febrile nonhemolytic Two known mechanisms: type Fever, headaches, chills, Within 1–6 hours
transfusion reaction II hypersensitivity reaction flushing.
with host antibodies against
donor HLA and WBCs; and
induced by cytokines that
are created and accumulate
during the storage of blood
products.
Acute hemolytic Type II hypersensitivity Fever, hypotension, tachypnea, Within 1 hour
transfusion reaction reaction. Intravascular tachycardia, flank pain,
hemolysis (ABO blood hemoglobinuria (intravascular
group incompatibility) or hemolysis), jaundice
extravascular hemolysis (host (extravascular).
antibody reaction against
foreign antigen on donor
RBCs).
Transfusion-related Donor anti-leukocyte Respiratory distress and Within 6 hours
acute lung injury antibodies against recipient noncardiogenic pulmonary
neutrophils and pulmonary edema.
endothelial cells.

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Autoantibodies AUTOANTIBODY ASSOCIATED DISORDER


Anti-ACh receptor Myasthenia gravis
Anti-presynaptic voltage-gated calcium channel Lambert-Eaton myasthenic syndrome
Anti-β2 glycoprotein Antiphospholipid syndrome
Antinuclear (ANA) Nonspecific screening antibody, often associated
with SLE
Anticardiolipin, lupus anticoagulant SLE, antiphospholipid syndrome
Anti-dsDNA, anti-Smith SLE
Anti-histone Drug-induced lupus
Anti-U1 RNP (ribonucleoprotein) Mixed connective tissue disease
Rheumatoid factor (IgM antibody against IgG Rheumatoid arthritis
Fc region), 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 cirrhosis 1° biliary cholangitis
Anti-smooth muscle Autoimmune hepatitis type 1
MPO-ANCA/p-ANCA Microscopic polyangiitis, eosinophilic
granulomatosis with polyangiitis (Churg-
Strauss syndrome), ulcerative colitis
PR3-ANCA/c-ANCA Granulomatosis with polyangiitis (Wegener)
Anti-phospholipase A2 receptor 1° membranous nephropathy
Anti-hemidesmosome Bullous pemphigoid
Anti-desmoglein (anti-desmosome) Pemphigus vulgaris
Antimicrosomal, antithyroglobulin, antithyroid Hashimoto thyroiditis
peroxidase
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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116 SEC TION II Immunology   
Immunology—Immune Responses

Immunodeficiencies
DISEASE DEFECT PRESENTATION FINDINGS
B-cell disorders
X-linked (Bruton) Defect in BTK, a tyrosine Recurrent bacterial and Absent B cells in peripheral
agammaglobulinemia kinase gene Ž no B-cell enteroviral infections after 6 blood,  Ig of all classes.
maturation. X-linked recessive months ( maternal IgG). Absent/scanty lymph nodes
( in Boys). and tonsils. Live vaccines
contraindicated.
Selective IgA Unknown. Most common 1° Majority Asymptomatic.  IgA with normal IgG, IgM
deficiency immunodeficiency. Can see Airway and GI levels.  susceptibility to
infections, Autoimmune giardiasis.
disease, Atopy, Anaphylaxis to
IgA-containing products.
Common variable Defect in B-cell differentiation. Usually presents after age 2 and  plasma cells,
immunodeficiency Cause is unknown in most may be considerably delayed;  immunoglobulins.
cases.  risk of autoimmune disease,
bronchiectasis, lymphoma,
sinopulmonary infections.
T-cell disorders
Thymic aplasia 22q11 deletion; failure Tetany (hypocalcemia),  T cells,  PTH,  Ca2+.
(DiGeorge syndrome) to develop 3rd and 4th recurrent viral/fungal Thymic shadow absent on
pharyngeal pouches Ž absent infections (T-cell deficiency), CXR.
thymus and parathyroids. conotruncal abnormalities
(eg, tetralogy of Fallot,
truncus arteriosus).
IL-12 receptor  Th1 response. Autosomal Disseminated mycobacterial  IFN-γ.
deficiency recessive. and fungal infections; may
present after administration of
BCG vaccine.
Autosomal dominant Deficiency of Th17 cells due to FATED: coarse Facies, cold  IgE.
hyper-IgE syndrome STAT3 mutation Ž impaired (noninflamed) staphylococcal  eosinophils.
(Job syndrome) recruitment of neutrophils to Abscesses, retained primary
sites of infection. Teeth,  IgE, Dermatologic
problems (eczema). Bone
fractures from minor trauma.
Chronic T-cell dysfunction. Can result Noninvasive Candida albicans Absent in vitro T-cell
mucocutaneous from congenital genetic infections of skin and mucous proliferation in response to
candidiasis defects in IL-17 or IL-17 membranes. Candida antigens.
receptors. Absent cutaneous reaction to
Candida antigens.

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Immunodeficiencies (continued)
DISEASE DEFECT PRESENTATION FINDINGS
B- and T-cell disorders
Severe combined Several types including Failure to thrive, chronic  T-cell receptor excision
immunodeficiency defective IL-2R gamma diarrhea, thrush. Recurrent circles (TRECs).
chain (most common, viral, bacterial, fungal, and Absence of thymic shadow
X-linked recessive), adenosine protozoal infections. (CXR), germinal centers
deaminase deficiency Treatment: avoid live vaccines, (lymph node biopsy), and
(autosomal recessive). give antimicrobial prophylaxis T cells (flow cytometry).
and IVIG; bone marrow
transplant curative (no
concern for rejection).
Ataxia-telangiectasia Defects in ATM gene Ž failure Triad: cerebellar defects  AFP.
A to detect DNA damage (Ataxia), spider Angiomas  IgA, IgG, and IgE.
Ž failure to halt progression (telangiectasia A ), IgA Lymphopenia, cerebellar
of cell cycle Ž mutations deficiency. atrophy.
accumulate; autosomal  risk of lymphoma and
recessive. leukemia.

Hyper-IgM syndrome Most commonly due to Severe pyogenic infections Normal or  IgM.
defective CD40L on Th cells early in life; opportunistic  IgG, IgA, IgE.
Ž class switching defect; infection with Pneumocystis, Failure to make germinal
X-linked recessive. Cryptosporidium, CMV. centers.
Wiskott-Aldrich Mutation in WASp gene; WATER: Wiskott-Aldrich:  to normal IgG, IgM.
syndrome leukocytes and platelets Thrombocytopenia, Eczema,  IgE, IgA.
unable to reorganize actin Recurrent (pyogenic) Fewer and smaller platelets.
cytoskeleton Ž defective infections.
antigen presentation; X-linked  risk of autoimmune disease
recessive. and malignancy.
Phagocyte dysfunction
Leukocyte adhesion Defect in LFA-1 integrin Recurrent skin and mucosal  neutrophils in blood.
deficiency (type 1) (CD18) protein on bacterial infections, absent Absence of neutrophils at
phagocytes; impaired pus, impaired wound healing, infection sites.
migration and chemotaxis; delayed (> 30 days) separation
autosomal recessive. of umbilical cord.
Chédiak-Higashi Defect in lysosomal trafficking PLAIN: Progressive Giant granules ( B , arrows) in
syndrome regulator gene (LYST). neurodegeneration, granulocytes and platelets.
B
Microtubule dysfunction in Lymphohistiocytosis, Pancytopenia.
phagosome-lysosome fusion; Albinism (partial), recurrent Mild coagulation defects.
autosomal recessive. pyogenic Infections
by staphylococci and
streptococci, peripheral
Neuropathy.

Chronic Defect of NADPH oxidase  susceptibility to catalase ⊕ Abnormal dihydrorhodamine


granulomatous Ž  reactive oxygen organisms. (flow cytometry) test ( green
disease species (eg, superoxide) fluorescence).
and  respiratory burst in Nitroblue tetrazolium dye
neutrophils; X-linked form reduction test (obsolete) fails
most common. to turn blue.

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118 SEC TION II Immunology   
Immunology—Immune Responses

Infections in immunodeficiency
PATHOGEN  T CELLS  B CELLS  GRANULOCYTES  COMPLEMENT
Bacteria Sepsis Encapsulated (Please Staphylococcus, Encapsulated
SHINE my SKiS): Burkholderia cepacia, species with early
Pseudomonas Pseudomonas complement
aeruginosa, aeruginosa, Serratia, deficiencies
Streptococcus Nocardia Neisseria with late
pneumoniae, complement (C5–
Haemophilus C9) deficiencies
Influenzae type b,
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.

Grafts
Autograft From self.
Syngeneic graft From identical twin or clone.
(isograft)
Allograft From nonidentical individual of same species.
Xenograft From different species.

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

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120 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.
DRUG MECHANISM OTHER USE TOXICITY NOTES
Cyclosporine Calcineurin inhibitor; Psoriasis, rheumatoid Nephrotoxicity,
binds cyclophilin. arthritis. hypertension,
Blocks T-cell hyperlipidemia,
activation by neurotoxicity,
preventing IL-2 gingival hyperplasia,
transcription. hirsutism. Both calcineurin
inhibitors are highly
Tacrolimus (FK506) Calcineurin inhibitor; Similar to cyclosporine, nephrotoxic.
binds FK506 binding  risk of diabetes
protein (FKBP). and neurotoxicity;
Blocks T-cell activation no gingival
by preventing IL-2 hyperplasia or
transcription. hirsutism.
Sirolimus (Rapamycin) mTOR inhibitor; binds “PanSirtopenia” Kidney “sir-vives.”
FKBP. (pancytopenia), Synergistic with
Blocks T-cell insulin resistance, cyclosporine.
activation and B-cell Kidney transplant hyperlipidemia; Also used in drug-
differentiation by rejection prophylaxis not nephrotoxic. eluting stents.
preventing response specifically.
to IL-2.
Basiliximab Monoclonal antibody; Edema, hypertension,
blocks IL-2R. tremor.
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 Lupus nephritis. GI upset, Associated with
Mofetil IMP dehydrogenase, pancytopenia, invasive CMV
preventing purine hypertension, infection.
synthesis of B and T hyperglycemia.
cells. Less nephrotoxic and
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).

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Immunosuppression targets
CD4 Daclizumab
– 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

Recombinant cytokines and clinical uses


CYTOKINE AGENT CLINICAL USES
Bone marrow stimulation
Erythropoietin Epoetin alfa (EPO analog) Anemias (especially in renal failure)
Colony stimulating Filgrastim (G-CSF), Sargramostim (GM-CSF) Leukopenia; recovery of granulocyte and
factors monocyte counts
Thrombopoietin Romiplostim (TPO analog), eltrombopag (TPO Autoimmune thrombocytopenia
receptor agonist)
Immunotherapy
Interleukin-2 Aldesleukin Renal cell carcinoma, metastatic melanoma
Interferon 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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122 SEC TION II Immunology   
Immunology—Immunosuppressants

Therapeutic antibodies
AGENT TARGET CLINICAL USE NOTES
Cancer therapy
Alemtuzumab CD52 CLL, MS “Alymtuzumab”—chronic
lymphocytic leukemia
Bevacizumab VEGF Colorectal cancer, renal cell Also used for neovascular age-
carcinoma, non-small cell related macular degeneration,
lung cancer proliferative diabetic
retinopathy, and macular
edema
Cetuximab EGFR Stage IV colorectal cancer,
head and neck cancer
Rituximab CD20 B-cell non-Hodgkin
lymphoma, CLL, rheumatoid
arthritis, ITP, multiple
sclerosis
Trastuzumab HER2 Breast cancer, gastric cancer HER2—“tras2zumab”
Autoimmune disease therapy
Adalimumab, Soluble TNF-α IBD, rheumatoid arthritis, Etanercept is a decoy
certolizumab, ankylosing spondylitis, TNF-α receptor and not a
golimumab, psoriasis monoclonal antibody
infliximab
Daclizumab CD25 (part of IL-2 receptor) Relapsing multiple sclerosis
Eculizumab Complement protein C5 Paroxysmal nocturnal
hemoglobinuria
Natalizumab α4-integrin Multiple sclerosis, Crohn α4-integrin: WBC adhesion
disease Risk of PML in patients with
JC virus
Ustekinumab IL-12/IL-23 Psoriasis, psoriatic arthritis
Other applications
Abciximab Platelet glycoproteins IIb/IIIa Antiplatelet agent for IIb times IIIa equals
prevention of ischemic “absiximab”
complications in patients
undergoing percutaneous
coronary intervention
Denosumab RANKL Osteoporosis; inhibits osteoclast Denosumab affects osteoclasts
maturation (mimics
osteoprotegerin)
Digoxin immune Fab Digoxin Antidote for digoxin toxicity
Omalizumab IgE Refractory allergic asthma;
prevents IgE binding to FcεRI
Palivizumab RSV F protein RSV prophylaxis for high-risk PaliVIzumab—VIrus
infants

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