Immunology Review Notes
Emma Holliday Ramahi 2009
The innate vs. adaptive immune system
Innate
Components
Macrophages and other phagocytic
cells
NK cells (a type of lymphocyte)
in the blood
complement
associated
barriers such as skin, mucosa,
anatomy
chemicals like lysozyme, interferons
α & β, body temp and pH
specificity
Adaptive
All other lymphocytes besides NK.
T cells (CTL, Th1 and Th2)
B cells (plasma, memory)
antibodies (secreted)
primary lymphoid tissue = bone
marrow and thymus.
secondary lymphoid tissue = spleen,
lymph nodes, MALT
specific antigens of pathogens.
general structures shared by
microbes: toll-like receptors, f-met
memory
none
memory T and B cells
diversity
limited
high (due to recombination)
speed of response
fast. PMNs get to site of tissue
slow. It takes days for specific
infiltration w/in 6 hrs
lymphocytes to become activated
The pluripotent stem cell differentiates to the myeloid stem cell under the influence of GM-CSF
and IL-3. The myeloid stem cell can then become:
granulocyte/monocyte progenitor  neutrophil or monocyte  tissue macrophage
eosinophil (important for paracyte/helminth infections)
basophil  tissue mast cell (important for mediating type I hypersensitivity)
megakaryocyte  platelet (important clotting function)
erythrocyte
(dendritic cell)  tissue Langerhan’s cell (important for antigen capture/presentation)
The pluripotent stem cell differentiates to the lymphoid stem cell under the influence of IL-7.
The lymphoid stem cell can then become:
NK cell (kills virally infected cells or tumor cells)
T-progenitor  thymocyte (in thymus)  TH0 or CTL
B-progenitor  B-lymphocyte  plasma or memory cell.
B and T cell receptors
B-cell receptor
location
cell bound or freely secreted
antigens recognized unprocessed, peptides, lipids,
carbohydrates.
idiotypes
isotypes
antigen binding
sites per molecule
flexibility?
signal transduction
1 per cell
2 (IgM and IgD)
2
T-cell receptor
always cell bound
only peptides and must be processed by APC
and presented as 8-15aa fragments by MHC I
or II
1 per cell
1 (α/β) or (γ/δ)
1
yes b/c of hinge region
Ig-α, Ig-β, CD19, CD21
no
CD3
Receptor Diversity for Antigen:
Millions of idiotypes of antigens are present. There isn’t enough DNA space to give each
receptor its own gene. DNA recombination happens in germline DNA  diversity:
Heavy chain (or β of TCR) rearranges 1st: D  J (RAG1/2 physically lyse out the
segments in the middle, ligase joins the D and J). Then, V  DJ (RAG1/2 and ligase
again). Then DNA is transcribed, RNA is spliced to join C the VDJ. Then mRNA is
transcribed to make the IgM heavy chain. IgM is made 1st b/c Cμ is closest to variable
region. If functional heavy chain is not made (Tdt puts in random bases that make a stop
codon), the other chromosome is attempted.
Light chain (or α of TCR) rearranges 2nd once functional heavy chain is in cytoplasm:
rearranges V  J. Then DNA is transcribed and VJ is spliced to κ light chain. If κ
doesn’t work, the κ from the other chromosome is attempted, then λ from one
chromosome is attempted, if that doesn’t work, the λ from the other chromosome is
attempted.
Allelic exclusion = if a function heavy/light chain is achieved, then the expression of the
same allele on the other chromosome is shut down via apoptosis. This is done to make
sure there aren’t 2 different specificities on the same lymphocyte.
Junctional diversity occurs b/c Tdt randomly inserts bases (called N-nucleotides) at the
junctions of D and J and V and DJ. Tdt works only in heavy chains of B-cell receptors
but in both α and β of T-cell receptors.
Somatic hypermutation occurs only in B-cells and occurs only after B-cell has left
bone marrow and encountered antigen in the periphery.
**Omenn Syndrome: autosomal recessive inherited missense mutation in rag genes  RAG1/2
only have partial activity  NO B-cells detected and there are much fewer T-cells detected.
Kiddo presents early w/ failure to thrive, red generalized rash, diarrhea and severe immune
deficiency.
**Severe Combined Immunodeficiency (SCID): autosomal recessive inherited null mutation
in rag1 or rag2 genes  NO RAG1/2 activity  total lack of B and T cells. Kiddo has total
defect of humoral and cell-mediated immunity. Susceptibility to all kinds of pathogens.
B-cell differentiation
Occurs in Bone Marrow
lymphoid pro-B
pre-B cell
stem cell cell
Tdt +
Tdt+
Occurs in Periphery
immature mature
activated memory plasma cell
B-cell
B-cell
B-cell
B-cell
CD21,
CD21,
CD21,
40+
40+
40+
B-cells are + for MHCII, CD19, and CD20 throughout their life
see
see
see
see
see
cytoplasmic surface
surface
surface
cytoplasmic
μ
IgM
IgM &
IgG, IgA IgG
IgD
or IgE
In the bone marrow: B-cells that have too much affinity for self-antigen are deleted so only
tolerant B-cells are allowed to leave the marrow.
Immature T-cells leave the bone marrow and go to the thymus to differentiate further:
Bone marrow Thymic Cortex
Thymic Medulla
Circulating T-cells
T-cells
Tdt+
Tdt+
based on whether they bind
“single positive”
“double positive” =
MHCI or II w/ higher affinity,
either CD4 or CD8
CD4+ and CD8+
choose either CD8+ or CD4+
express TCR
express TCR
express TCR
express CD2/CD3
express CD2/CD3
express CD2/CD3
Positive Selection: cells that bind MHC are given the signal to divide and mature. If the TCR
doesn’t bind MHC, it is allowed to die by apoptosis.
Negative Selection: cells that bind MHC too strongly are given a negative signal to die by
apoptosis.
Lymph Node Architecture:
2 afferent lymphatic vessels bring antigen in from the tissues.
Cortex contains primary follicles that are B-cell rich. Clones divide in the germinal center
Paracortex contains T-cells (so B and T cells can interact)
Medulla contains mature cells like plasma cells
Memory cells exit via the efferent lymphatic vessel.
Spleen Architecture:
Splenic artery brings in antigen from the blood.
HEVs (high endothelial venules) bring in naïve lymphocytes L-selectins on lymphs bind
to addressins on HEVs.
Periarteriolar lymphoid sheaths (PALS) contain T-cells
White pulp = lymphoid follicles of lymphocytes and macrophages
Red pulp = sinusoids where blood collects before it leaves via the splenic vein.
Antigen = something capable of inducing the formation of an antibody
Immunogen = something capable of generating an immune response. Requires that the molecule
to be recognized as foreign (different from self), be chemically complex, and have a MW of
>5000Kd  b/c B-cells must be crosslinked to be activated (need more than 1 identical epitope)
Hapten = have only 1 epitope, so it can only bind one arm of the B-cell receptor.
**Drug allergies: especially penicillin, streptomycin, aspirin, sulfa-drugs and succinylcholine
can induce an allergic response 7-14 days post-exposure showing mild symptoms.
The next drug exposure  life-threatening anaphylaxis.
This can only happen b/c drugs act as haptens (MW<5000Kd) and bind to body tissues. The
hapten-carrier complex acts as the immunogen for the allergic response.
The Acute Inflammatory Response:
Rolling: E-selectin on the endothelium bind mucin-like adhesion molecules on the
phagocyte. Only brief binding that blood flow can wash away.
Activation by Chemoattractants: IL-8 from macrophages, C5a from complement, Nformyl peptides from bacteria, fibrinopeptides from endothelial damage, and LTB4
from membrane phospholipids induce the expression of integrin molecues in the
phagocyte membrane and increases their affinity.
Arrest and Adhesion: Ig-CAMs on the endothelium bind integrins on the phagocyte to
stabilize adhesion of the phagocyte to the endothelial cell.
Transendothelial migration: phagocyte extends pseudopodia through vessel wall and
extravasates into the tissues.
Phagocytosis: extend pseudopodia to trap material in phagosome.
Opsonization: enhances phagocytosis by 4,000x. IgG and C3b are main opsonins b/c
phagocyte has Fc and C3b receptors that bind.
Oxygen-dependent killing: “respiratory burst” = NADPH oxidase takes O2 to superoxide
 generates OH radical and H2O2  microbicidal. Myeloperoxidase takes H2O2 and
Cl to make hypochlorite (bleach)  microbicidal.
Oxygen-independent killing: lysozyme (digests cell wall of gram + bugs), defensins
(punches holes in bacterial membrane), lactoferrin (chelates Fe so bugs can’t use it to
grow), other hydrolytic enzymes.
**Leukocyte Adhesion Deficiency (LAD): rare autosomal recessive inherited absence of
CD18 (the common β2) chain of several integrin molecules. Usually this is diagnosed when a
kiddo’s umbilical stump gets infected (omphalitis)  more susceptible to bacterial but NOT
viral infections. The kiddos have high WBC counts in their blood, (b/c WBCs are
appropriately released from the marrow when infected), but the WBCs can’t get to the
infection  no pus is formed. Diagnose w/ flow cytometry and treat w/ bone marrow
transplant.
**Chronic Granulomatous Disease: inherited deficiency in one of the NADPH oxidase
subunits. Phagocytes cannot make superoxide, OH radical or H2O2. However,
myeloperoxidase is still in tact, so if the bug is catalase negative  myeloperoxidase can
make bleach from the bug’s own H2O2 biproducts. Kiddos present w/ increased
susceptibility to catalase positive bacteria (staph aureus, klebsiella, and serratia) and
fungus (aspergillus). Diagnose w/ negative (yellow) nitroblue tetrazolium test.
MHC I and II
MHC Class I
HLA-A, B and C
present on all nucleated cells + platelets
MHC Class II
HLC-DP, DQ, DR
present on B-lymphocytes, macrophages and dendritic
cells (+ activated endothelial cells)
recognized by CD8+ cytotoxic T-cells
recognized by CD4+ TH cells
present endogenously synthesized
present exogenously synthesized peptide(12-15aa) made
peptide (8-10aa) made from virus
from bacteria (extracellular or intravacuolar pathogen),
(intracytoplasmic pathogen), broken
MHC II buds off in a vesicle plugged w/ invariant chain,
down in proteosome  enters ER via
meets an acidic phagolysosome containing bug antigen
TAP  meets an MHCI and is
 acid degrades invariant chain, antigen binds MHCII
transported to plasma membrane
and is transported to plasma membrane
expressed codominantly (contrast w/ TCR/BCR which do allelic exclusion), so all nucleated cells
express HLA A, B, and C from both mom and dad (6 total) and all APCs express HLA-DP, DQ,
and DR from both mom and dad (6 total)
made up of α heavy chain w/ 3 α
made up of 1 α and 1 β of equal length (looks like TCR).
domains plus β2-microglobulin to
Antigen binding groove is at the N-terminus of both
support α in the membrane
chains.
1st Signal: the CD4+ T-cell receptor binds to antigen-MHC complex on the APC (antigenspecific part of the response).
2nd Signal: CD4 binds to non-antigen binding site on MHC-II
LFA-1 (integrin) on T-cells binds to ICAM-1 on APCs to promote adherence.
IgCAMs (CD2) on T-cells binds to LFA-3 (integrin) on APCs for adherence.
CD28 on T-cells binds to B7 on APCs and triggers transcription of cytokine genes
rd
3 Signal: antigen binding promotes growth and proliferation of T-cells by stimulating both
secretion of IL-2 from the T-cell and the upregulation of the IL-2 receptor on the SAME Tcell. IL-1, IL-6 and TNFα come from the macrophage to stimulate the T-cell. IFNγ comes
from the T-cell to stimulate and activate the macrophage.
**Superantigens like TSST-1 from staph aureus and pyrogenic exotoxin from strep: activate
many T-cells (as many as 10% of total number) by crosslinking β domain of TCR w/ α
domain of MHC II w/o the need for involvement of the antigen-binding site. This causes
polyclonal activation of T-cells  overproduction of IFNγ  overactivation of macrophages
 overproduction of inflammatory cytokines IL-1, IL-6 and TNF-α  systemic toxicity.
**Bare Lymphocyte Syndrome: rare autosomal recessive inherited deficiency of MHC II.
Kiddos present early w/ symptoms of mild SCID  increased susceptibility to pyogenic and
opportunistic infections. Can distinguish from SCID by treating w/ phytohemagglutinin (nonspecific T-cell mitogen)  bare lymphocyte syndrome will show a response, but SCID won’t
(b/c there are not T-cells to respond). These kiddos are deficient in CD4+ cells b/c they can’t
do positive selection in the thymus. Have hypogammaglobuminemia, but have CD8+ cells
(But less functional b/c there are no Th1 chemokines to support them).
Differentiation of TH0 cells into TH1 or TH2
TH1  supports cell mediate immunity
Induced By:
intracellular pathogens producing a
strong innate immune response
(Listeria, mycobacteria, Leishmania) w/
lots of IL-12 from macrophages and
IFNγ from NK cells.
Inhibited By: IL-4 and IL-10 from TH2 cells
Cytokines
IFNγ – enhances M0, enhances
produced
expression of MHC.
IL-2 – induces proliferation and activity
of T cells.
TNFβ – has cytotoxic effects and
enhances phagocyte’s activity
IL-3 – supports growth and
differentiation of myeloid cells
GM-CSF – induces proliferation of
granulocyte precursors
TH2  supports humoral immunity
extracellular pathogens whose antigen is
present w/o much innate immunity (default
system)
IL-4 produced constituitively  leads to
more IL-4 if no IL-12 around.
IFNγ from TH1 cells
IL-2 – induces proliferation and activity of
T-cells.
IL-3 – supports growth and differentiation
of myeloid cells
IL-4 – costimulates activation of B-cells,
induces class switching to IgG1 and IgE.
IL-5 – stimulates proliferation and induces
class switching to IgA.
IL-6 – stimulates Ab secretion, promotes
terminal differentiation to plasma cells.
IL-10 – suppresses cytokine production by
TH1.
GM-CSF – induces proliferation of
granulocyte precursors.
**Tuberculoid Leprosy: mycobacterium leprae gets the strong TH1 response it needs to get
rid of intracellular pathogen via granuloma formation. There is some skin and peripheral
nerve damage, but the disease progresses slowly and the patient survives.
**Lepromatous Leprosy: mycobacterium leprae gets an inappropriate TH2 response (and
TH1 response is suppressed by reciprocal inhibition). The patient makes AB that don’t work
against the bug and mycobacteria multiply w/in macrophages (1010 bugs per gram of tissue)
 hypergammaglobulinemia and disseminated and disfiguring infection.
Humoral Effector Mechanisms  work against extracellular pathogens (microbes or toxins)
Naïve B-cell is attracted to follicular areas of lymph nodes and spleen
Signal 1: antigen binds and cross-links idiotypes of membrane receptors
Signal 2: if thymus-dependent antigen (most antigens in body)  B-cell phagocytoses
the pathogen  processes it and presents it on MHCII as well as expressing B7  CD+ TH
cell recognizes the MHC II and CD27 on T-cell binds to B7 on B-cell.
CD40L on the T-cell binds to CD40 on the B-cell to give signal 2 for B-cell activation.
Signal 3: cytokines released by TH2 cells (see above) induce class switching so the most
appropriate antibody can be made for the infection.
*Thymus-independent antigens include stuff T-cells cannot respond to: lipids (like LPS from
gram negative cell envelope) and carbohydrate (like polysaccharide capsular antigen).
B cells are directly stimulated or are activated as mitogens regardless of antigenic specificity
to make antibodies (but can ONLY make IgM and cannot produce a memory response).
The first AB type made by a B-cell is IgM (doesn’t need cytokine support from TH2)
IgM = pentamer held together by J-chain. Big, bulky, can’t cross placenta, but has a
valence of 10  so avidity is high. (2 binding sites for each of 5 IgM)  so it can
bind up antigen in tissue to effectively present it to lymphocytes. It is also most
effective at activating complement, but cannot opsonize and cannot mediate ADCC
(antibody dependent cytotoxicity). IgM is used to measure the extend of the primary
immune response (to an acute infection).
Cytokines from TH2 cells are needed to stimulate isotype switching. The idiotype (variable
region) is linked to another constant region downstream from M, and the DNA in the middle is
excised and degraded (ie, that B cell can never make IgM again).
IgG (subclasses 1-4) = monomer than can cross the placental barrier (protects the
fetus during gestation), activate complement, act as an opsonin, and mediate ADCC.
IgA = dimer held together by J-chain and protects the mucosal surfaces of the body
inhibiting toxins or bugs to the digestive, respiratory and urogenital surfaces. It
doesn’t activate compliment or act as an opsinin, but it is in breast milk.
IgE = binds directly to Fe receptors on mast cells and basophils first w/o binding
antigen. It triggers mast cell degranulation when crosslinked and protects against
helminth parasites but also acts acts in allergic responses. (Type I HS).
Somatic hypermutation: happens in germinal centers after the B-cell has encountered its
antigen and started proliferating. Single, point mutations are introduced to see if they can create
better binding btwn antigen and BCR. The best fit wins and is clonally expanded. Affinity
maturation means that even though avidity is decreased (as we switch from IgM to other types),
affinity is increased so the same amount of antigen can be bound.
**X-linked Hyper-IgM Syndrome: x-linked inherited disorder in the gene for CD40-ligand 
TH cells don’t have CD-40L so they can’t give signal 2 to B-cells  B-cells can’t respond
(proliferate or class switch) to thymus-dependent antigens. (Still see normal response to thymusindependent antigens). See high levels of IgM and a deficiency of IgG, IgA and IgE  see
antibodies to neutrophils, platelets and RBCs, see a lack of germinal centers during humoral
immune response  see recurrent infection w/ respiratory bugs  esp Pneumocystis jiroveci.
Complement:
Alternative Pathway  bacterial polysaccharide and LPS on the surface of pathogens
triggers cascade.
Classical Pathway  antigen-antibody complex (IgM or IgG) trigger cascade.
1. C1 is triggered to cleave C4
2. C4b cleaves C2
3. C2a cleaves C3 (C3b binds on cell/particle surface to opsonize)
4. C2a cleaves C5 (C5a is a important for chemoattractant activation)
5. C5b binds to other complement factors to make MAC.
**Complement Abnormalities:
C3b deficiency  immune complexes cannot be effectively cleared from the body.
Hereditary angioedema  uncontrolled complement activation at mucosal surfaces 
edema and pain.
Paroxysmal nocturnal hemoglobinuria  absence of regulatory proteins causes
hemolysis of RBCs (esp at night when blood is relatively acidotic)  hemoglobinuria.
Cell Mediated Effector Mechanisms  rid the body of antigenic stimuli inside the body’s cells
(viruses, intracellular bacteria and some parasites). Th1 cells provide cytokine support to CD8+
T-cells, NK cells (CD16+, CD56+ and CD2+) and macrophages (CD14+).
TH1 cells release IFNγ to activate M0  cause tissue damage  delayed type
hypersensitivity. Can use DHT skin test to measure a person’s ability to mount CMI response.
How CD8+ T-cells kill their target:
Attachment: TCR binds antigen/MCH I complex. CD8 acts as coreceptor. LFA-1 and
integrin facilitate attachment.
Activation: cytoskeleton rearranges to concentrate granules
Exocytosis: CD8+ cell releases perforin (makes holes in the cell membrane) and
granzyme (serine proteases that activate caspases to carry out apoptosis). Cytokines like
IFNγ, TNFα, and TNFβ can also induce apoptosis. Fas-lignad on CD8+ T-cells can also
bind to Fas on the target cell to activate caspases and mediate apoptosis.
Detachment: leaves to find another infected cell.
How NK cells kill their target:
NK cells don’t have TCR or CD3. They are CD16+ and CD56+
If activating receptor binds lectins (common on pathogens)  kill signal
If inhibiting receptor doesn’t bind to MHC I (b/c virus downregulated the expression of
MHC I) absence of no-kill signal (normal cells have normal MHC I  no-kill signal)
Kill by granzymes, perforin and enhances by IFNα, IFNβ and IL-12.
How Antibodies can kill targets (via antibody-dependent cell-mediated cytotoxicity):
NK cells, macrophages, monocytes, neutrophils and eosinophils have a membrane Fc
receptor for the Fc part of IgG.
IgG binds to target cell  cytotoxic cell binds to IgG’s Fc  lysis of target cell.
Involves lytic enzymes, TNF and perforin.
**Cytomegalovirus: CMV downregulates MHC I molecules, but produces a “decoy” MHC-Ilike molecule. The decoy is different enough that is cannot activate CTLs, but similar enough so
it can evade killing from NK cells. However, ADCC can still kill these CMV-infected cells.
Immunologic Memory  B and T memory cells are created when a pathogen is cleared from the
body. Memory cells have increased adhesion molecules and home to inflamed tissue.
Memory B cells are terminally differentiated, but unlike plasma cells (who only live
2wks), when can remain for months or years w/ IgG, IgE or IgA membrane Ig. This means a
faster response if the body ever encounters the antigen again.
Memory T cells are the T-cells that escape inactivation and apoptosis after their
cytokines are no longer necessary (b/c infection is cleared).
Primary Immune Response
response takes 5-10days after introduction
peak response is small
IgM, then IgG later
variable to low affinity
induced by all immunogens
need high dose antigen w/ adjuvant
Secondary Immune Response
takes 1-3 days
large peak
Increasing IgG, IgA or IgE
high affinity (already did affinity maturation)
induced only by protein antigens
can do w/ low dose w/o adjuvant
**Military Vaccine against Adenovirus types 4 and 7: enteric-coated, live, non-attenuated
virus  produces asymptomatic infection in the intestine  generates memory IgA cells 
protected against 2nd adenovirus infection via aresol (would otherwise cause pneumonia).
Types of Immunity and their clinical applications
Natural Passive Immunity
fetus gets maternal IgG from placental transfer
infant gets maternal IgA through colostrum/breast milk
Natural Active Immunity
when you have an infection and recover, your memory B and T cells
keep you from getting the same infection again (HepB)
Artificial Passive Immunity antitoxin given to someone who is very sick from black widow
spider bite, botulism or diphtheria
pooled immunoglobulin against hepA, hepB, measles, rabies or
tetanus.
monoclonal antibodies against RSV
Artificial Active Immunity
traditional immunizations:
Component vaccine  HepB
Toxoid vaccine  diphtheria, tetanus, pertussus
Capsular vaccine  haemophilus, pneumococcus, meningococcus
Live, inactivated  polio
Live, attenuated  measles, mumps and rubella, also varicella.
**Never give a live viral vaccine to an immunocompromised person (AIDS or chemo)
**Never give a live viral vaccine to an infant under 12mo b/c maternal IgG is still present and
will inactivate the vaccine before it can mount a useful immune response in the infant.
**Passive immunotherapy has risks such as generation of IgE antibodies  anaphylaxis,
formation of compliment-activating immune complexes (type III HS), large amounts of
antibodies being given at one time can induce anti-allotype antibodies, and people w/ selective
IgA-deficiency (1 in 700) can get a reaction if given infused IgA.
*Can use killed vaccine for naked capsid viruses but need live vaccine for enveloped virus.
*Adjuvant is a substance added to a vaccine to increase its immunogenicity.
Aluminum potassium sulfate  prolongs antigen’s persistence
Muramyl dipeptide  enhances co-stimulatory signal
Alum  induces granuloma formation
LPS and synthetic polyribonucleotides  induce a non-specific lymphocyte proliferation.
Important Immunodeficiency Diseases
Disease
Defect
Chronic Granulomatous
def of NADPH oxidase (1
Disease
of 4 proteins)  failure to
make superoxide or other
O2 radicals
Chediak-Higashi
granule structural defect
Syndrome
Glucose-6-phosphate
dehydrogenase deficiency
Myeloperoxidase
deficiency
Leukocyte adhesion
deficiency
def enzy in hexose
monophosphate shunt
granule enzyme deficiency
Common variable
hypogammaglobulinemia
unknown MOA
Selective IgA deficiency
deficiency of IgA
X-linked hyper IgM
syndrome
deficiency of CD40-L on
activated T-cells
absence of CD18 
common β chain for
leukocyte integrins
Bruton X-linked
deficiency of tyrosine
hypogammaglobuminemia kinase that blocks B cell
maturation
Transient hypogammadelayed onset of IgG
globuminemia of infancy
synthesis
Clinical Manifestation
recurrent infections w/ catalase
positive organisms (staph, klebsiella,
serratia and aspergillus)
recurrent infection w/ bacteria,
chemotactic and degranulation
defecits, absent NK activity, partial
albanism
same as CGD but also w/ hemolytic
anemia
mild or none (b/c can still do
respiratory burst, just no bleach)
recurrent/chronic infections, can’t
form pus, umbilical stump won’t fall
off.
low IG of all classes, no circulating
B cells (can’t leave marrow),
stopped at pre-B stage. Normal CMI
5th-6th month of life but resolves by
16-30mo. Incr susceptibility to
pyogenic bacteria
onset in late teens/20s, B cells are in
peripheral blood but IG levels
decrease and autoimmunity incr
repeated sinopulmonary and GI
infections
high titers of IgM w/o other isotypes.
Normal B and T cell numbers but
increased susceptibility to
extracellular bugs and opportunists
Deficiency in classic
pathway of complement
Deficiency in alternative
pathway of complement
C3 deficiency
C1q, C1r, C1s, C4 or C2
like factor B or properdin

increased immune complex disease,
increased pyogenic bacteria infection
increased Neisseria infections
bacterial infections and immune
complex disease
C5, C6, C7, C8 deficiency 
recurrent meningococcal and
gonococcal infections
Hereditary angioedema
deficient C1-INH
overuse of C1, C4 and C2  edema
at mucosa surfaces
Paroxysmal nocturnal
deficient complement
RBCs are lysed by complement esp
hemoglobinuria
decay-activating factor
at night when blood is more acidic
DiGeorge Syndrome
3rd and 4th pharyngeal
hypoparathyroidism, cardiac
pouches don’t develop 
malformations, depressed T-cell
get thymic aplasia
numbers and no T-cell response
MHC class I deficiency
TAP can’t transport
deficient in CD8+ but normal CD4+
molecules to ER
T-cells. Get recurrent viral infections
Wiskott-Aldrich
defect in cytoskeletal
can respond to bacterial
Syndrome
glycoprotein (can’t fuse
polysaccharides, depressed IgM, loss
phagosome and lysosome)
of humoral and CMI responses,
thrombocytopenia and eczema.
Ataxia telangietctasia
defect in a kinase involved
Ataxia, telangiectasias (in the eye),
in the cell cycle
deficiency of IgA and IgE.
X-linked SCID
defect in common γ chain of Chronic diarrhea, skin, mouth and
IL-2, IL-4, IL-7, IL-9 and
throat lesions, fungal opportunistic
IL-15 receptors
infections, low levels of circulating
lymphocytes and cells are
autosomal recessive SCID adenosine deaminase
deficiency (toxic byproducts unresponsive to mitogens
accumulate)
defect in signal transduction
from T-cell IL-2 receptors
Bare lymphocyte
MHC class II deficiency
T-cells are present and will respond
syndrome
to mitogens, no GVHD and
deficiency of CD4+ T-cells w/
hypogammaglobulinemia
AIDS: HIV is a D-type retrovirus that attaches to CD4+ cells (TH, macrophages and microglia)
 affects both innate and adapted immunity.
Early: uses CCR5 chemokine co-receptor: prefers macrophages
Late: uses CXCR4 chemokine co-receptor: prefers CD4+ T-cells
Increases viral load by multiplying inside activated lymphocytes and macrophages
Eliminates CMI by exerting a cytopathic effect on lymphs and macrophages (decr CD4 count)
Makes infected cells less susceptible to CMI by Nef gene product downregulating MHCI
Inhibition cytokine synthesis by Tat gene product
gp120 undergoes antigenic drift  evades antibody mediated effector mechanisms and exhausts
immune capacity
gp120 heavy glycosylation  hides epitopes from immune recognition.
Type I Hypersensitivity:
Mediated by IgE antibodies and mast cells  called atopic or allergic response
Manifested w/in minutes upon re-exposure to antigen
1st exposure to antigen  TH2 released IL-4 to tell B-cells to make IgE.
IgE binds Fc-down onto mast cells.
2nd exposure to antigen  allergen cross-links IgE molecules on the mast cells  opens
calcium channels  contents of mast cell granules are released.
Mast cells contain:
Histamine  contracts smooth muscle and incr vascular permeability
Heparin  anticoagulant
Eosinophil chemotactic factor A  attracts eosinophils
PGE2 (from AA via COX)  incr pain and vascular permeability
PGD2 (from AA via COX)  incr smooth muscle contractions and vascular
permeability
LTC4, LTD4. LTE4 (from AA via Lipoxygenase)  same as PGD2
LTB4 (from AA via lipoxygenase)  chemotactic for PMNs.
Eosinophils contain:
Cationic granule proteins  major basic proten  kills parasites
Enzymes like eosinophil peroxidase  tissue remodelin.
Type I HS Disease Allergen
Clinical Finding
Allergic rhinitis
trees, grass, dust, cats,
edema, irritation, mucus in nasal mucosa
dogs, mites
Food allergy
milk, eggs, fish, cereals,
hives and GI problems
grains
Wheal and flare
insect stings, in vivo
local skin edema, reddening and vasodilation
allergy skin testing
of vessels
Asthma
inhaled materials
bronchial and tracheal constriction, edema,
mucus production and massive inflammation
Systemic
insect stings, snake venoms bronchial and tracheal constriction, complete
anaphylaxis
and drug reactions
vasodilation and death!
Type II Hypersensitivity:
Mediated by antibodies (usually IgG) directed directly at the body’s tissues.
Sometimes autoantibodies are produced when they are cross reactive w/ foreign antigen
Auto-AB damage host tissues by: opsonizing host cells and activating complement,
recruiting PMNs and macrophages that cause tissue damage, or binding normal cell
receptors and interfering w/ their function. ADCC can also be triggered (hemolytic dz)
Type II HS Disease Target Antigen Mechanism
Clinical Picture
Autoimmune
RBC membrane RBC is opsonized,
Hemolytic anemia: high
hemolytic anemia
proteins (Rh, I, phagocytosed, and destroyed
indirect bilirubin, jaundice,
Ag)
via complement
if infant  kernicterus
(basal ganglia)
Autoimmune
platelet
Ab-mediated platelet
Bleeding d/o: menorrhagia,
thrombocytopenic
membrane
destruction through
nosebleeds, normal PT and
purpura
proteins
opsonization and complement PTT but increased BT
Goodpasture
syndrome
Noncollagenous
part of
basement
membrane (IV)
in kidney glom
and lung alveoli
Complement and Fc receptor
mediated inflammation
Acute Rheumatic
Fever
**NOT post-strep
glomerulonephritis!!
AB against
Streptococcal
cell wall Ag
cross-reacts w/
myocardial Ag
Ach receptor
inflammation and macrophage
activation
Myasthenia Gravis
Kidney: smooth, linear IgG
fluorescence w/ symptoms
of nephritic syndrome
(hematuria, HTN). Type II
RPGN (crescent disease)
Lung: hemoptysis usually
preceeds kidney problems
Myocarditis and arthritis.
Ab inhibits ACH from binding
 down-regulates receptors
Muscle weakness and
paralysis, see first in
extraoccular muscles, pt
gets diplopia and ptosis
that gets worse late in day.
Graves Disease
TSH receptor
Ab-mediated stimulation of
Hyperthyroidism: heat
TSH receptor on the thyroid
intolerance, incr HR,
weight loss despite incr
appetite. Followed by
hypothyroidism when
burnout occurs.
Type II Diabetes
Insulin
Ab inhibits binding of insulin
hyperglycemia,
Mellitus (some)
Receptor
ketoacidosis
Pernicious Anemia
Intrinsic factor
Neutralization of intrinsic
Megaloblastic anemia w/
of gastric
factor  decreased absorption hyperseg PMNs,
parietal cells
of B12
neurologic symptoms
**Hemolytic disease of the newborn happens when a Rh- mother gives birth to an Rh+ baby
and the mother makes anti-Rh antibodies. If the mother gets pregnant a 2nd time w/ an Rh+
baby, the anti-Rh IgG can cross the placenta and produce hemolytic disease. Mother should
be treated w/ RhoGam = human anti-RhD IgD antibody at 28 wks gestation (with the first
RH+ pregnancy) and then w/ human anti-RhD IgG antibody w/in 72hr of birth. This prevents
the anti-Rh antibodies from being formed.
Type III Hypersensitivity:
Caused by immune complexes involving foreign or self antigens bound to antibodies
being deposited in places like the glomerulus of the kidney, or capillary bed of the skin.
The site of damage does NOT reflect the site of origin  usually causes systemic
damage.
Disease
Antigen
Clinical Picture
Systemic Lupus
dsDNA, Sm, other Need 4 out of 11 criteria: malar rash, discoid rash, ANA,
Erythmatosis
neucleoproteins,
other Ig like dsDNA or Smith, oropharyngeal ulcers,
neurologic d/o, serositis (pleuritis and pericarditis),
hematologic d/o (antiphospholipid), arthritis, renal d/o,
photosensitivity
Rheumatoid
Arthritis
IgM against IgG
Fc region (called
RF)
Post-strep
glomerulonephritis
strep wall Ags
coated w/ Abs
deposited on
glomerular BM
various proteins
any injected
protein
Serum Sickness
Arthus Rxn
Inflammatory d/o affecting synovial joints w/ pannus
formation in MCPs and PIPs but not DIPs. See rheumatoid
nodules, morning stiffness improving w/ use, systemic
symptoms like fever, fatigue, pleuritis. Associated w/ HLADR4
See “lumpy bumpy” Ig deposition on fluorescence,
See subepithelial “humps” on EM.
See enlarged, hypercellular gloms on LM.
Clinically: nephritic syndrome (hematuria, HTN, azotemia)
arthritis, vasculitis, nephritis
local pain and edema.
Type IV Hypersensitivity:
Tissue injury is caused by T-cells (either released cytokines or direct killing)
CD4+ TH1 cells and CD8+ cells release cytokines (IFNγ) that activate macrophages to
release TNF.
The process can be auto-reactive or directed against foreing antigen that happens to be
bound to host tissue.
Disease
T-Cell Specificity
Clinical Picture
Type I Diabetes
Islet-cell antigen, insulin,
Usually kiddo <18, polydipsia, polyuria,
Mellitus
glutamic acid decarboxylase,
polyphagia, ketoacidosis
other antigens
Multiple Sclerosis
Myelin basic protein,
Usually woman (20-40), presents w/ loss of
proteolipid protein
vision (optic neuritis), INO, hemiparesis,
bladder-bowel incontinence, relapsingremittng course.
Contact Dermatitis
Nickel (cheap jewelry), poison vesicular skin lesions (in the area of contact),
ivy/oak, catechols,
pruritis, rash
hapten/carrier
Guillain-Barre’
peripheral nerve myelin or
ascending paralysis, peripheral nerve
syndrome
gangliosides
demyelination, autonomic dysfxn, incr CSF
protein w/ normal cell count, areflexia.
Almost all pts survive
Peripheral neuritis
P2 protein of peripheral nerve
Ascending paralysis
myelin
Hashimoto
Unknown Ag in thyroid (TSH Hypothyroidism: enlarged, non-tender
Thyroiditis
receptor?)
thyroid, lymphocytic infiltrate w/ germinal
centers and Hurthle cells.
Clinically: decreased HR, weight gain, cold
intolerance, constipation, menorrhagia.
**Cyclophosphamide kills T-cells, corticosteroids inhibit their function, and cyclosporine
inhibits their proliferation = strategies for treatment.
HLA types w/ associated diseases.
Rheumatoid Arthritis
Type I Diabetes Mellitus
Multiple Sclerosis
Systemic Lupus Erythematosus
Ankylosing Spondylitis
Celiac Disease
DR4
DR3/DR4
DR2
DR2/DR3
B27
DQ2 or DQ8
Transplants:
Autograft/Autologous graft: tissue moved from one place to another (skin graft for burn
patient or CABG w/ saphenous vein)
Syngeneic graft: transplantation between monozygotic twins
Allogenic graft: transplant between genetic different members of the same species
(kidney, liver, heart, lung).
Xenogeneic graft: transplant between different species (baboon heart into human)
Because of HLA differences: any graft (besides autografts) will be recognized as foreign and
destroyed. As the graft is vascularized, CD4+ and CD8+ cells migrate into the graft and become
exposed to the foreign antigen (different HLAs = foreign antigen).
Rejection Type
Time Course
Cause
Hyperacute
Minutes  hours
preformed anti-donor antibodies and complement
Accelerated
Days
Reactivation of already sensitized T-cells
Acute
Days  weeks
Primary activation of T-cells
Chronic
Months  years
Not clear: probably combo of antibodies, immune
complexes, slow cellular reaction.
**Graft-versus-Host Disease: happens in bone marrow transplantation b/c if bone marrow
contains some mature T-lymphocytes  they can attack the host (who must be
immunocompromised to prevent rejection of the transplant). Symptoms = widespread epithelial
cell death, rash, jaundice, diarrhea and GI hemorrhage.
Before transplantation, can test for tissue compatibility:
ABO blood typing: a person makes IgM against A/B antigens not present on self RBCs.
Similar glycoprotein antigens are also found in intestinal flora. An ABO mismatch causes
a hyperacute rejection reaction b/c IgM is already formed.
HLA matching (tissue typing): the larger the number of matched alleles, the better the
chances for graft survival. Routine testing is not done for heart, liver and lung (b/c
recipients are in critical condition and the tissue won’t last long enough to get the results
back anyway). HLA-A, B and DR are routine typing done b/c they are best predictors of
rejection.
*Class I Microcytotoxicity testing: mix lymphs from donor or recipient w/
different antisera for different antigens. If antisera recognizes a class I HLA  it will bind,
complement will lyse, and a special dye will be able to penetrate the broken cell membrane.
*Class II Mixed Lympocyte reaction: lymphs from a potential donor are irradiated
so they can’t proliferate, but can still present antigen. The recipient’s cells are added to the
culture and labled thymidine is measured to indicate cell proliferation. If the class II antigens
are different  proliferation will occur. No proliferation = good match.
Screening for preformed antibodies: the patients sera is tested against potential donor
cells to test for the presence of preformed antibodies (like from previous pregnancies,
transfusions or transplantations).
Cross-matching: once a potential donor is identified  donor lymphocytes and recipient
sera are mixed to test for potential reaction (of minor histocompatability complexes not
previously tested).
Cancer and the Immune System:
Tumors typically evade the immune system b/c their products are only weakly
immunogenic.
CTLs can recognize some oncoproteins (E6 and E7 proteins from HPV, products of Rb
or p53, alpha-fetoprotein in HCC and some testicular/ovarian cancers). CTLs can become
sensitized if tumor peptides are present in MHCI of an APC that ingested a tumor cell.
Tumors down-regulate MHC I, so NK cells can play a role in killing tumor cells
TH-1 cells activate macrophages which make TNF  induces thrombosis in tumor blood
vessel. If tumor has no blood supply  dies.
Tumor cells can lose their co-stimulatory molecules which promotes immune tolerance
(no signal 2 give to activate T-cells). Tumors can also evolve to express Fas-L which
induces apoptosis in lymphocytes. Tumor cells can also mask their antigens by hiding
them in sialic acid containing mucopolysaccharides.
Immunotherapy can be useful for tumors like vaccination w/ tumor cells/antigens,
administering tumor cells w/ enhanced #s of costimulators, administering anti-tumor
antibodies (that can help kill tumor cells via complement and ADCC), giving cytokines to
stimulate T-cell proliferation and differentiation, administration of tumor-reactive T-cells
and NK cells to help kill the tumor.
Immunology Lab Tests:
Titration of Ag w/ Ab: early in the infection there is more Ag than antibody, late in the
infection there is more Ab than Ag. Window period = when all available Ag is
complexed w/ Ab, aka equivalence. Can’t detect either free antigen or free antibody.
HepB testing is a good example of this.
Agglutination tests: useful when the antigen is a particle that is not soluble (these tests are
available for haemophilus, pneumococcus, meningococcus and cyptococcus in the CSF).
Antibodies to these bugs are attached to latex beads. If bug antigen is present in the CSF,
adding these beads will cause agglutination. Can use RBCs to perform agglutination tests
to identify ABO blood groups, diagnose EBV infection (mono-spot test) and the Coombs
test.
Direct Coombs Test: used to see if antibodies are bound to a RBC sample (ie, look at
baby’s RBCs to see if maternal IgG are coating them in hemolytic dz of the newborn).
Indirect Coombs Test: used to see anti-RBC antibodies are present in a serum sample.
(ie, look at mom’s serum to see if anti-RH+ Abs are present.
Direct Fluorescent Antibody Test: use when you want to see if antigen is present in a
patient’s tissue sample. Treat tissue w/ fluorescent labled antibodies against that
particular antigen. Used to diagnose RSV, HSV1 and 2, and pneumocystis.
Indirect Fluorescent Antibody Test: use when you want to see if antibodies are present in
the patient. Add patients serum to a sample of known antigen. Then add fluorescenct
labled anti-IG antibody. That way, if antibodies are present in the patient serum, they will
bind to the antigen in the fake tissue, and the fluorescence labled anti-AB antibody will
bind to those and show color.
Radioimmunoassay and Enzyme-Linked Immunoabsorbent Assay (ELISA): are very
sensitive and can pick up very small amounts of material. Usually used to test for
hormones, drugs, antibiotics, serum proteins, infectious disease antigens and tumor
markers. *Used as the screening test for HIV w/ p24 capsid antigen on a microtiter plate,
patient serum is added. If anti-HIV p24 antibodies are present in patient’s serum, they
will bind to the plate. Then, anti-human gamma globulin is added w/ an enzyme attached.
This enzyme will change color when the enzyme substrate is added.
Western Blot or Immunoblot: the test used to confirm HIV when the patient had a
positive ELISA (ELISA has a high false positive rate). Virus antigens are blotted onto
nitrocellulose paper then patient serum is added so if antibodies are present they can bind.
Then, antihuman immunoglobulin is added conjugated to enzyme or radioactive labels.
Flow Cytometry is used to analyze cell types in a complex mixture and sort them based
on their binding to different fluorescent dyes. Can analyze relative numbers of cells in
that tissue location. Computerized histiogram spits out w/ one dye on the x axis and
another dye on the y axis. “Double positives” = cells w/ high fluorescence from both dyes
(ie, they carry both markers) will be in the top right quadrant.