Professional Documents
Culture Documents
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
IMMUNOLOGY—LYMPHOID STRUCTURES
``
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).
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)
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
Sinusoids are long, vascular channels in red complement activation C3b opsonization
pulp (red arrows in A ) with fenestrated “barrel susceptibility to encapsulated organisms.
hoop” basement membrane. Postsplenectomy blood findings:
T cells are found in the periarteriolar Howell-Jolly bodies (nuclear remnants)
lymphatic sheath (PALS) within the white Target cells
pulp (white arrows in A ). Thrombocytosis (loss of sequestration and
B cells are found in follicles within the removal)
white pulp. Lymphocytosis (loss of sequestration)
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
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
Differentiation of T cells
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
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.
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 autoimmunity. Characterized by enteropathy, endocrinopathy,
nail dystrophy, dermatitis, and/or other autoimmune dermatologic conditions. Associated with
diabetes in male infants.
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
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:
Fragment, antigen binding
Antigen- 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
Constant
rva ns
Light chain
CL CL
ria
ble
SS SS SS Carboxy terminal
SS
C = Constant Complement binding
V = Variable Complement Carbohydrate side chains
L = Light C H2 CH2
binding 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)
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.
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.
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
*
C2a *Historically, the larger fragment of C2 was
called C2a but is now referred to as C2b.
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 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.
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.
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 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
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.
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.
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.
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 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
immediate degranulation release of Example:
Fc receptor histamine (a vasoactive amine) and tryptase Anaphylaxis (eg, food, drug, or bee sting
for IgE
(a marker of mast cell activation). allergies)
Late (hours): chemokines (attract
inflammatory cells, eg, eosinophils) and
cytokines (eg, leukotrienes) from mast cells
inflammation and tissue damage.
Degranulation
Delayed-type
hypersensitivity
Activated
macrophage
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 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 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 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.
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 failure Triad: cerebellar defects AFP.
A to detect DNA damage (Ataxia), spider Angiomas IgA, IgG, and IgE.
failure to halt progression (telangiectasia A ), IgA Lymphopenia, cerebellar
of cell cycle 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.
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 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.
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.
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 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 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:
Bronchiolitis obliterans (lung)
Accelerated atherosclerosis
(heart)
Chronic graft nephropathy
(kidney)
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 severe Potentially beneficial in bone
organ dysfunction. Type IV marrow transplant for leukemia
hypersensitivity reaction. (graft-versus-tumor effect).
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).
Immunosuppression targets
CD4 Daclizumab
– Basiliximab
FKBP +
CD3 Tacrolimus FKBP + Azathioprine
TCR IL-2R
Sirolimus
– (rapamycin)
Cyclophilin + 6–MP
– Mycophenolate
Cyclosporine – Calcineurin
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