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Immunology
Innate immunity- most primitive- cytokines, phagocytes, and
complement; barriers to infection (skin, mucous membranes,
pH, temp), inflammation (acute phase proteins, complement,
phagocytic cells)
Adaptive immunity- LYMPHOCYTES, phagocytes,
cytokines, Ab, and complement
Active- convalescence and vaccine
Passive- transplacental and serum therapy
Humoral- Ab and complement
Cellular- lymphocytes, cytokines and
phagocytes
Memory response- if exposed again much greater immune
response- controlled by lymphocytes
3 phases of Adaptive immunity
Cognitive phase- recognition
Activation phase- proliferation and
differentiation of lymphocytes
Effector phase- memory, elimination of Ag
(phagocytes and complement)
Acute phase proteins- induced by stress for inflammation and
healing (C-reactive protein, serum amyloid)
Complement- activation by immune complexes for immune
regulation (over 20 proteins)
Cytokines- all cells in the body to regulate immune and other
responses (interleukins and interferons, TNF
Ab- produced by B cells and plasma cells IgM,A,G,E,D
Clonal selection- lymphocytes, but not all T and B cells
respond to the same Ag, each clone responds to only one Ag
determinant
Clones against self are deleted or
suppressed for the most part
Get autoimmunity if those cells are not
suppressed
Get quicker response when re-exposed by
activation of the clonal cells
Hematopoiesis
Stem cells- blood cells are short lived and
continuously renewed from pluripotent stem
cells found in the bone marrow;
Memory lasts for a long time but a given
lymphocyte does not last for yrs and yrs
progeny are generated
Under influence of cytokines progenitor cells
become a megakaryocyte or granulocyte of
some kind
IL-7 important in B cell development
Megakaryocyte makes platelets
Colony forming units can produce- rbcs,
basophils, eosinophils, neutrophils, or
monocytes
T lymphocytes
TCR- T cell receptor- binds Ag to T cell
o TCRa/b receptor- blood, spleen, lymph
nodes, CD4, CD8,
o TCR g/d receptor- mucosal surfaces, CD8
Subtypes and surface markers:
o Th- CD4
o Tc- CD8
o Ts- CD4 and CD8
o NK- CD16 (no TCR)
Surface markers- proteins functioning as
receptors/ligands
o Common to all T cells- CD3, TCR, CD2,
CD28, CD5, and CD7
CD4 has an affinity for MHCII
CD8 has an affinity for MHCI
B lymphocyte-
Surface markers- surface immunoglobulin,
complement receptors, and Fc receptors
Plasma cells- mature B cells, make bulk of Ab and
secretes them into blood (lives for about 1 week)
Markers: HLA-D, CD22, CD19, CD20, Igb, Iga,
sIg, CD40, CR1, CR2, CD72, CD5, Fc_RII,
Mononuclear phagocytes- large cells, amoeboid, granular,
endosomes, and kidney shaped nuclei
Involved in innate immunity (phagocytosis and
wound healing) and active immunity (Ag
presentation, regulatory cytokines)
Markers: MHCII, Fc receptors (Fc_RI, Fc_RII,
Fc_RIII), complement receptors (CR1, CR3)
Releases many enzymes and prostaglandins
Granulocytes- neutrophils, eosinophils, basophils,
Blood is 70% neutrophils, 5% eosinophils, and 1%
basophils
Antigen presenting cells- express MHCII
ALL nucleated cells express MHCI
Only APC present MHCII
Langerhans cells in skin, interdigitating cells in
thyroid, follicular dendritic cells in neurons, B cells
in blood, macrophages in blood
Lymphoid organs
Primary organ- thymus, bone marrow- foster
maturation of stem cells; cells mature to T or B cells
Secondary organ- lymph node, spleen; contain
mature cells and foster immune response
Thymus- cortex and medulla; macrophages and dendritic
cells present self-Ag to differentiating T cells leading to
positive and negative selection
Positive selection- selecting cells that
respond to non-self
Negative selection- selecting cells that
respond to self (at corticomedullary
junction)
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Bone marrow- contains all cells and cytokines necessary for
B cell development
Spleen- filters Ag out of blood and promotes immune
response
No spleen- more susceptible to blood-borne
infections- esp. Strep. pneumo
Composed of capsule and reticular fiber and cellular
framework
Lymphocytes, macrophages, interdigitating cells,
follicular dendritic cells, and reticular cells
Red pulp surrounds white pulp which surrounds the
central artery and contains the PALS w/ T cells and
B cell zones (T cells surround the germinal centers
of B cells)
Lymph node- filters Ag from lymph;
Capsule, medulla, cortex; contains lymphocytes and
other cells
Cortex- outer region B cells inner region T cells
Medulla- plasma cells
Structure of Ag and Ab
Hapten- small moiety such as DNP that induces immunity
only when attached to carrier such as bovine serum albumin
(BSA)
B cells recognize hapten
T cells recognize carrier protein
Proteins are best immunogens.
Epitope- chemical group that confers Ag specificity- proteins
have more than 1 to engage a variety of clones to increase
chance of stimulation of immune response
Need an APC to present non-peptide to T cells
Do not need APC to present non-peptide to B cell
Lipopolysaccharides:
Lipid A- endotoxin- binds to serum proteins and
ligates to CD14 which stimulates B cells
O antigen- binds to B cell receptors- if receptor is
clone w/ affinity for O Ag
Core polysaccharide
B cells get several signals from a single molecule of
LPS- enough to have it develop into plasma cell-
independent of T cells
Ig Basic structure: 2 Light and 2 Heavy chains both with
variable and constant regions
Ig Properties
4 IgG subclasses- different heavy chains
sIgA- secretory IgA
IgG- most common
3 subclasses of IgA
Isotype- gene product that every member of a species has
Allotype- gene products that vary among individuals
Idiotype- unique gene products for each individual
H chain- 3 C regions and 1 V region
L chain- 1 C and 1 V region
Ag binds to V region- 2 binding sites (bivalent)
Fab- Ag binding region (V regions of H and L chains)
Fc- terminal piece (most glycosylation sites)
J chain- helps link 5 subunits of IgM together to form
pentamer
IgM can bind 10 Ag.
Only 1 IgM pentamer is needed to activate complement since
2 Fc receptors are close to each other.
IgA also has a J chain
Secretory piece- helps protect IgA from proteolytic digestion
in secretion
COMPLEMENT:
Complement is involved in cytolysis, Opsonization, and
inflammation, enhancement of humoral response, and
clearance
Inappropriate firing of complement system can lead to shock
like state.
Insufficiency of complement can cause more susceptibility to
bacteria and have immune complexes that are not cleared.
Classical system- starts with Ab/Ag complex
C3b critical to both classical and alternative
pathways
C5 splitting- entering MAC complex (C5b, C6, C7,
C8, C9)- cascading is now creating small holes in
bacterial cell walls to cause cell lysis
See pg 69 bottom slide
C3a, C4a, and C5a
o Smooth muscle contraction
o Increased vascular permeability
o C3a and C5a- degranulation of eosinophils,
and platelet aggregation
When there is a classical pathways deficiency (C1q,
C1r, C1s, C4, C2) cant have cell lysis and also have
problems clearing immune complexes leading to
autoimmunity, vasculitis, etc
Short lasting for fine control
Receptors : CR1, CR2, CR3, CR4
Specific factors- regulatory factors that have very
specific actions in limiting the complement system
o CCP and DAF inhibit C3 convertase
o MCP- regulated C4b
Missing MAC complex cant undergo Opsonization
but can have inflammatory cells brought in
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Alternative system- no Ab needed
C3b can start alternative system on bacterial cells
C3b can enter the self-amplification loop
Tickover- C3 hydrolyzed into C3a and C3b
Complement Deficiencies:
Early components- absent
o Immune complex disease - increased
incidence
o Pyogenic infections when missing C1, C4,
C2 increased incidence-
Late components
o Neisseria- chronic infections
Regulatory factors missing
o C1H- most common autosomal problem
(controls C1)
! HANE- hereditary angioneurotic
edema when deficiency in C1H-
complement system always firing
leading to inflammation
Complement receptors
o LAD- leukocyte adhesion deficiency-
inflammatory cells do not enter area since
they are missing complement receptor
Ag/Ab Interactions and Functions:
CDR- complementary determining region- has many
substitutions- diff aa sequences in CDR determine Ag
specificity
Overall affinity for Ag is higher after proliferation of Ab
Each clone has a different specificity for each Ag.
Carboxy end motifs of Ig to activate complement:
3 aa in 2
nd
region of IgG found to activate C1q
3 aa in 3
rd
region of IgM activates C1q
IgE Fc_RI- can bind between 2
nd
and 3
rd
region for
immune complex removal
IgD- helps B cell respond to Ag (w/ IgM)
Fc receptors are involved in binding Fc regions of Ab and
leading to phagocytosis of the Ab/Ag complex, also for
degranulation and allergy response
Transport of IgA- Ab produced on abluminal surface of
mucosa and are transported to luminal surface by poly Ig
receptor
Ab-based lab testing:
Primary interaction- bivalent Ab and univalent Ag
Secondary interaction- multivalent Ag- lattice formation
Tertiary- involves secondary interaction leading to activation
of 3
rd
component such as complement
Ab tests- ppt, aggultination, complement fixation, EIA, RIA,
ELISA, flow cytometry
Cant measure Ag/Ab union kinetically- must measure at
equilibrium
Primary union- direct and indirect
Secondary union- ppt- reaches max then decreases (Ab>Ag,
Ab=Ag, Ab<Ag)
Immunodiffusion- secondary union- where lattice formation
occurs size of ring formation is proportional to [Ag]
Agglutination- secondary union- add Ab and see if
agglutination takes place (blood typing)
Tertiary union- complement fixation-
Ag + Ab and just Ag
Add complement to both
Add rbc to both
If complement still active then get lysis of rbc
Sandwich ELISA:
Coat plate w/ Ab
Add specimen containing Ag
Add enzyme linked Ab
Add substrate
Measure color change
Flow cytometry- used to analyze cells in suspension
Generation of Ab diversity and Ig genes:
Clonal selection- individual lymphocyte express membrane
receptors specific for distinct Ag. Receptor specificity
determined prior to Ag exposure.
Somatic mutation- method by which point mutations are
elicited; responsible for affinity maturation
L chain- kappa and lambda genes- constant regions plus V
and J regions
V chain- V, D, and J regions and a number of different
constant regions
RSS- sequence that allows for cutting and recombining
sequences
RAG1 and 2- important in enhancing or making recombinase
enzymes
Class switching-
Occurs only in heavy chains
Changes effector function of Ig
Cannot reverse switching
Cytokines can control
Does not change specificity
Removes introns rather than exons
Accompanied by somatic mutations in Ig
hypervariable region caused by point mutation in
DNA
Seeing Ag again can lead to switching from IgM to
other Ig via Th cell cytokines
Hyper IgM immunodeficiency- cant switch from
IgM to IgG- X-linked; susceptible to infection; treat
with IV IgG
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T Cell Receptors and MHC
MHC- in humans found on short arm of chromosome 6; HLA
Class I-
Co-dominant inheritance
ALL nucleated cells
2 chains (alpha and beta) that are not covalently
linked; Ag binds to looped domains alpha1 and
alpha2. Beta chain does not bind Ag
recognize self vs. non self (transplants,
autoimmunity)
recognize self + foreign Ag (viral infections,
malignancies)
CD8
Class II- found on APC- alpha and beta chains coded for by
D gene regions
binding zone made by alpha 1 and beta 1
recognize processed Ag in context of self
CD4
TCR
Near CD3
Binds Ag and CD3 sends signal
CD8 recognizes alpha 3 domain on class I
CD4 recognizes alpha 2 domain of class II
T cell activation
Most Ag are monomeric
Capping of B cells leads to their activation.
IL-2 induces the release of other cytokines.
ANTIGENS ARE PROCESSED BEFORE THEY ARE
PRESENTED TO T CELLS!!!!
Class I- endogenous protein processing
Class II- exogenous protein processing
TAP- transporter necessary for moving peptides into RER for
MHC I.
Invariant chain- MHCII binding domain that prevents the
binding of endogenous peptides.
Co-stimulation reaction between B7 on APC and CD28 on T
cell that leads to T cell activation for proliferation.
Binding proteins:
T cell- LFA-1, CD4, CD3(zeta chain), TCR, CD2,
CD28
APC- ICAM-1, MHCII, LFA-3, B7
APC make IL-1 which causes Th cells to make IL-2 receptor
and APC cells to make more MHCII receptors.
IL-2 helps Tc cells in killing target cells- does not require co-
stimulatory event.
APC cytokines- IL-1, IL-6, TNFa, IL-12, IL-15
T cell cytokines- IFNg, GMCSF, IL-4, TNFb
Redundancy in cytokines so if one not made proper course
still occurs.
CYTOKINES:
Cytokines are soluble mediators involved in many cellular
processes.
Generalities:
Low molecular weight
Glycosylated protein
Surface receptor
Mode of action- autocrine, paracrine, endocrine
Function and Properties:
Lots of overlap in function and tasks
Produced in novo
Made when contact with Ag is made
Non-specific mediators of immunity
Regulatory of lymphocyte activation, growth, and
differentiation
Activators of nonspecific cells
Stimulators of immature leukocytes
Major cytokines of inflammation: IFN, TNF, IL-1, IL-6
TNFa leads to necrosis and inflammation- why cancer pts
with bacterial infections do better.
TNF can also result in shock and death
Can make Ab to cytokines.
TNF more problematic at higher concentrations.
IL-1: Co-stimulator of inflammation and T cell function;
produced by macro, epithelial, and endothelial cells;
increases cAMP, nuclear factors, other cytokines, and
prostaglandins, can slow cells down with adhesive properties
(low concentrations)
High concentrations- fever, APR, cachexia, but NO
TISSUE DAMAGE OR NO TUMOR NECROSIS
LPS causes increases in TNF, IL1 and IL6
Interferon- (alpha [mac] and beta [fibroblasts])- inhibits viral
replication, increases MHC class I, decreases MHCII,
activates NK cells
Chemokines- small cytokines
Produced by leukocytes, endothelial cells, and
fibroblasts
Stimulate neutrophils, basophils, eosinophils, and
lymphocytes
Interferon (Type II (gamma))- produced by T cells
Function- MAF, increased class I expression,
activates T and B cells, neutrophils, NK cells etc
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IL-2
Produced by T cells (CD4)
Major autocrine growth factor for T cells
Leads to synthesis of other cytokines
Acts on B, T, and NK cells
Can live w/out IL-2
IL-4: produced by T cells (CD4) and acts on B cells
IL-10: Produced by T cells, decreases IFNg, increases B
cells
Hematopoiesis:
CSF- colony stimulating factor
IL-3- early progenitor
GM-CSF: granulocyte/monocytes colony
stimulating factor
M-CSF, G-CSF
Can be used by chemo pts and bone marrow
transplant patients
B CELL ACTIVATION
Major APC:
Interdigitating dendritic cells- induces T cell
proliferation most effectively
Macrophages- produce proliferation of T cells and
helper functions
B cells- most effective APC when Ag conc. is low-
high affinity receptor on cell surface
IgM binds complement the best
Ab mediation is very important need B cell control.
Plasma cells are terminally differentiated. Memory B cells
have a long _ life
Cross-linking is important w/ monomeric Ag and receptors
on B cells.
C3d- degradation product of C3b, binds CR2 on B cells to
lower B cell activation threshold.
CD40- important for B cell activation and class switching.
No CD40 ligand on T cell when hyper IgM immunodeficient.
CELL MEDIATED IMMUNITY:
Innate CMI;
Chemotaxis- activate macrophages or PMN directly
or through C5a
Phagocytosis- enhanced by C3b deposition on
microbes and binding to complement receptors on
phagocytes.
Acute phase cytokines- binding and uptake of
microbes by phagocytes also induces them to
synthesize and release cytokines.
Inflammatory mediators: His, 5-HT, PAF, NCF, IL-8
(chemokines), C3a, C5a, bradykinin, fibropeptides, PG, LT,
(mast cells and macrophages produce many of these)
TNF causes PMN to be more adhesive.
Macrophages release IL-12, and TNFa
NK- IFNgamma
Adhesion and Migration
ICAM- intracellular adhesion molecule- allows cell
to move through endothelium
CD15
E selectin- slows movement of phagocytic cells in
blood
ADCC- Ab dependent cellular cytotoxicity- killer cell w/ Fc_
receptor (IgG) becomes active if it senses an immune
complex to kill target cell
Th0- makes IL12, IFN gamma, and IL4; proliferate into Th1
and Th2
Th1- controls classical side of immunity- activates
macrophages- secretes IFNgamma, TNFa, and IL2
Th2- controls allergy side of immunity- activates mast cells,
B cells and eosinophils (makes Ab)- produces IL4,5,6,10
MHC restricted- as T cells develop recognize self from non-
self
Perforin- in cytoplasmic granules Tc and NK cells induces
lysis by making channels in target cell surfaces
Tc and NK lytic mechanisms- lytic granules store and release
perforin and granzymes- to form pores and induce apoptosis
(respectively)
When natural DNA repair is inhibited by TNF and granzyme
can lead to apoptosis.
Macrophages- phagocytize and present Ag to T cells and
activate immune cytokines to release more cytokines, kill
microbes and tumors
Macrophage products-
Inflammation and fever- IL-1, IL-6, and PG
Lymphocyte activation- processed Ag and IL-1
Tissue rebuild- angiogenesis factor, collagenase
Microbicidal- reactive O2 and NO, lysozyme
Tissue damage- H2O2 and TNF
VACCINES:
Vaccination- infection w/ agent (Ag) that induces an immune
response- doesnt protect against infection, just the disease
Passive immunity- immediate but transient; administration of
preformed Ab; can result in serum sickness
Adoptive immunity- T cells transferred into animal to impart
immunity
Active immunity- delayed but more permanent (vaccines)
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Types of Vaccines:
Killed organism- inactivated or killed vaccine
Ag part of disease causing organism
Attenuated or weakened preparation
Toxoid vaccines- toxins treated w/ or absorbed w/
aluminum salts; usually must add adjuvant to
increase immunogenicity
Organisms similar to virulent organisms but that
does not cause human disease
Subunit vaccines- utilizes techniques of genetic
engineering
DNA plasmid vaccines- circular DNA plasmids
expressing specific proteins are injected w/
presentation of the protein to the immune system
Ways to give vaccines:
Subcutaneous
Intramuscular
Intradermal
Oral
Live attenuated vaccines: Polio, measles, mumps, rubella,
yellow fever, varicella zoster, hep A, TB
Killed vaccines: polio, rabies, typhoid, cholera, influenza,
plague, and pertussis
Toxin Based Vaccines: Clostridium tetani (inactivated toxin),
Corynebacterium diptheria (inactivated toxin), vibrio
cholerae (toxin B subunit), Clostridium perfringes
(inactivated toxin)
Vaccines based on subcellular microbial fragments: Nisseria
meningitis, Strep pneumoniae, H. influenzae B, hep B virus
Safety problems with vaccines:
Attenuated vaccines- reversion to wild type, severe
disease in immunocompromised
Killed vaccines- vaccines not killed, yeast, animal
viruses, or endotoxin contaminant
Organisms that have no vaccine: HIV, staphylococcus,
Candida, malaria, schistomlasis
Adjunvants: inorganic salts, delivery systems, bacterial
products, natural products
DNA plasmid based vaccines- live attenuated vaccines, make
Ab and cellular immunity but risk infection; DNA seen as
endogenous Ag
REGULATION AND TOLERANCE:
Regulation by antigens
Proteins are best
Too much or too little can lead to immune
unresponsiveness or tolerance
Subcutaneous or intradermal induce immunity
Adjuvant augments immunity
Th1- not susceptible to IFN gamma
CR2- augment immune response by binding to complement
receptor
Anti-Ids- produced to either non-antigen binding idiotyopes
or to Ag binding idiotyopes
Anti-Ids can either increase or decrease immune response
Changes in the alpha chains can lead to changes in the
binding cleft of MHCI and II.
Polymorphism of MHC allows us to respond to some
idiotopes and not others can respond to only a certain set of
Ag due to genetic coding
IMMUNITY TO TUMORS
Tumors- breakdown of normal growth regulatory
mechanisms; changes that occur in surface Ag of malignant
cells can sometimes be recognized by the immune system
Often a number of subclinical tumors.
Tumor specific antigens- unique to cancerous cells and are
not found on normal counterparts
Tumor associated antigens- expression is greatly increased on
tumors

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