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Immunology T lymphocytes

• TCR- T cell receptor- binds Ag to T cell


Innate immunity- most primitive- cytokines, phagocytes, and o TCRa/b receptor- blood, spleen, lymph
complement; barriers to infection (skin, mucous membranes, nodes, CD4, CD8,
pH, temp), inflammation (acute phase proteins, complement, o TCR g/d receptor- mucosal surfaces, CD8
phagocytic cells) • Subtypes and surface markers:
o Th- CD4
Adaptive immunity- LYMPHOCYTES, phagocytes, o Tc- CD8
cytokines, Ab, and complement o Ts- CD4 and CD8
• Active- convalescence and vaccine o NK- CD16 (no TCR)
• Passive- transplacental and serum therapy • Surface markers- proteins functioning as
• Humoral- Ab and complement receptors/ligands
• Cellular- lymphocytes, cytokines and o Common to all T cells- CD3, TCR, CD2,
phagocytes CD28, CD5, and CD7
• CD4 has an affinity for MHCII
Memory response- if exposed again much greater immune • CD8 has an affinity for MHCI
response- controlled by lymphocytes
B lymphocyte-
3 phases of Adaptive immunity • Surface markers- surface immunoglobulin,
• Cognitive phase- recognition complement receptors, and Fc receptors
• Activation phase- proliferation and • Plasma cells- mature B cells, make bulk of Ab and
differentiation of lymphocytes secretes them into blood (lives for about 1 week)
• Effector phase- memory, elimination of Ag • Markers: HLA-D, CD22, CD19, CD20, Igb, Iga,
(phagocytes and complement) sIg, CD40, CR1, CR2, CD72, CD5, Fc_RII,

Acute phase proteins- induced by stress for inflammation and Mononuclear phagocytes- large cells, amoeboid, granular,
healing (C-reactive protein, serum amyloid) endosomes, and kidney shaped nuclei
Complement- activation by immune complexes for immune • Involved in innate immunity (phagocytosis and
regulation (over 20 proteins) wound healing) and active immunity (Ag
Cytokines- all cells in the body to regulate immune and other presentation, regulatory cytokines)
responses (interleukins and interferons, TNF • Markers: MHCII, Fc receptors (Fc_RI, Fc_RII,
Ab- produced by B cells and plasma cells IgM,A,G,E,D Fc_RIII), complement receptors (CR1, CR3)
• Releases many enzymes and prostaglandins
Clonal selection- lymphocytes, but not all T and B cells
respond to the same Ag, each clone responds to only one Ag Granulocytes- neutrophils, eosinophils, basophils,
determinant • Blood is 70% neutrophils, 5% eosinophils, and 1%
• Clones against self are deleted or basophils
suppressed for the most part
• Get autoimmunity if those cells are not Antigen presenting cells- express MHCII
suppressed • ALL nucleated cells express MHCI
• Get quicker response when re-exposed by • Only APC present MHCII
activation of the clonal cells • Langerhans cells in skin, interdigitating cells in
thyroid, follicular dendritic cells in neurons, B cells
Hematopoiesis in blood, macrophages in blood
• Stem cells- blood cells are short lived and
continuously renewed from pluripotent stem Lymphoid organs
cells found in the bone marrow; • Primary organ- thymus, bone marrow- foster
• Memory lasts for a long time but a given maturation of stem cells; cells mature to T or B cells
lymphocyte does not last for yrs and yrs – • Secondary organ- lymph node, spleen; contain
progeny are generated mature cells and foster immune response
• Under influence of cytokines progenitor cells
become a megakaryocyte or granulocyte of Thymus- cortex and medulla; macrophages and dendritic
some kind cells present self-Ag to differentiating T cells leading to
• IL-7 important in B cell development positive and negative selection
• Megakaryocyte makes platelets • Positive selection- selecting cells that
• Colony forming units can produce- rbc’s, respond to non-self
basophils, eosinophils, neutrophils, or • Negative selection- selecting cells that
monocytes respond to self (at corticomedullary
junction)

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Bone marrow- contains all cells and cytokines necessary for Isotype- gene product that every member of a species has
B cell development Allotype- gene products that vary among individuals
Idiotype- unique gene products for each individual
Spleen- filters Ag out of blood and promotes immune
response H chain- 3 C regions and 1 V region
• No spleen- more susceptible to blood-borne L chain- 1 C and 1 V region
infections- esp. Strep. pneumo Ag binds to V region- 2 binding sites (bivalent)
• Composed of capsule and reticular fiber and cellular
framework Fab- Ag binding region (V regions of H and L chains)
• Lymphocytes, macrophages, interdigitating cells, Fc- terminal piece (most glycosylation sites)
follicular dendritic cells, and reticular cells
• Red pulp surrounds white pulp which surrounds the J chain- helps link 5 subunits of IgM together to form
central artery and contains the PALS w/ T cells and pentamer
B cell zones (T cells surround the germinal centers IgM can bind 10 Ag.
of B cells) Only 1 IgM pentamer is needed to activate complement since
2 Fc receptors are close to each other.
Lymph node- filters Ag from lymph; IgA also has a J chain
• Capsule, medulla, cortex; contains lymphocytes and Secretory piece- helps protect IgA from proteolytic digestion
other cells in secretion
• Cortex- outer region B cells inner region T cells
• Medulla- plasma cells COMPLEMENT:
Complement is involved in cytolysis, Opsonization, and
Structure of Ag and Ab inflammation, enhancement of humoral response, and
clearance
Hapten- small moiety such as DNP that induces immunity
only when attached to carrier such as bovine serum albumin Inappropriate firing of complement system can lead to shock
(BSA) like state.
• B cells recognize hapten Insufficiency of complement can cause more susceptibility to
• T cells recognize carrier protein bacteria and have immune complexes that are not cleared.

Proteins are best immunogens. Classical system- starts with Ab/Ag complex
• C3b critical to both classical and alternative
Epitope- chemical group that confers Ag specificity- proteins pathways
have more than 1 to engage a variety of clones to increase • C5 splitting- entering MAC complex (C5b, C6, C7,
chance of stimulation of immune response C8, C9)- cascading is now creating small holes in
bacterial cell walls to cause cell lysis
Need an APC to present non-peptide to T cells • See pg 69 bottom slide
Do not need APC to present non-peptide to B cell • C3a, C4a, and C5a
o Smooth muscle contraction
Lipopolysaccharides: o Increased vascular permeability
• Lipid A- endotoxin- binds to serum proteins and o C3a and C5a- degranulation of eosinophils,
ligates to CD14 which stimulates B cells and platelet aggregation
• O antigen- binds to B cell receptors- if receptor is • When there is a classical pathways deficiency (C1q,
clone w/ affinity for O Ag C1r, C1s, C4, C2) can’t have cell lysis and also have
• Core polysaccharide problems clearing immune complexes leading to
• B cells get several signals from a single molecule of autoimmunity, vasculitis, etc
LPS- enough to have it develop into plasma cell- • Short lasting for fine control
independent of T cells • Receptors : CR1, CR2, CR3, CR4
• Specific factors- regulatory factors that have very
Ig Basic structure: 2 Light and 2 Heavy chains both with specific actions in limiting the complement system
variable and constant regions o CCP and DAF inhibit C3 convertase
Ig Properties o MCP- regulated C4b
• 4 IgG subclasses- different heavy chains • Missing MAC complex can’t undergo Opsonization
• sIgA- secretory IgA but can have inflammatory cells brought in
• IgG- most common
• 3 subclasses of IgA

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Alternative system- no Ab needed Primary union- direct and indirect
• C3b can start alternative system on bacterial cells
• C3b can enter the self-amplification loop Secondary union- ppt- reaches max then decreases (Ab>Ag,
• Tickover- C3 hydrolyzed into C3a and C3b Ab=Ag, Ab<Ag)

Complement Deficiencies: Immunodiffusion- secondary union- where lattice formation


• Early components- absent occurs size of ring formation is proportional to [Ag]
o Immune complex disease - increased
incidence Agglutination- secondary union- add Ab and see if
o Pyogenic infections when missing C1, C4, agglutination takes place (blood typing)
C2– increased incidence-
• Late components Tertiary union- complement fixation-
o Neisseria- chronic infections • Ag + Ab and just Ag
• Regulatory factors missing • Add complement to both
o C1H- most common autosomal problem • Add rbc to both
(controls C1) • If complement still active then get lysis of rbc
 HANE- hereditary angioneurotic
edema – when deficiency in C1H- Sandwich ELISA:
complement system always firing • Coat plate w/ Ab
leading to inflammation • Add specimen containing Ag
• Complement receptors • Add enzyme linked Ab
o LAD- leukocyte adhesion deficiency- • Add substrate
inflammatory cells do not enter area since • Measure color change
they are missing complement receptor
Flow cytometry- used to analyze cells in suspension
Ag/Ab Interactions and Functions:
CDR- complementary determining region- has many Generation of Ab diversity and Ig genes:
substitutions- diff aa sequences in CDR determine Ag Clonal selection- individual lymphocyte express membrane
specificity receptors specific for distinct Ag. Receptor specificity
determined prior to Ag exposure.
Overall affinity for Ag is higher after proliferation of Ab
Each clone has a different specificity for each Ag. Somatic mutation- method by which point mutations are
elicited; responsible for affinity maturation
Carboxy end motifs of Ig to activate complement:
• 3 aa in 2nd region of IgG found to activate C1q L chain- kappa and lambda genes- constant regions plus V
• 3 aa in 3rd region of IgM activates C1q and J regions
• IgE Fc_RI- can bind between 2nd and 3rd region for V chain- V, D, and J regions and a number of different
immune complex removal constant regions

IgD- helps B cell respond to Ag (w/ IgM) RSS- sequence that allows for cutting and recombining
sequences
Fc receptors are involved in binding Fc regions of Ab and RAG1 and 2- important in enhancing or making recombinase
leading to phagocytosis of the Ab/Ag complex, also for enzymes
degranulation and allergy response
Class switching-
Transport of IgA- Ab produced on abluminal surface of • Occurs only in heavy chains
mucosa and are transported to luminal surface by poly Ig • Changes effector function of Ig
receptor • Cannot reverse switching
• Cytokines can control
Ab-based lab testing: • Does not change specificity
• Removes introns rather than exons
Primary interaction- bivalent Ab and univalent Ag • Accompanied by somatic mutations in Ig
Secondary interaction- multivalent Ag- lattice formation hypervariable region caused by point mutation in
Tertiary- involves secondary interaction leading to activation DNA
of 3rd component such as complement • Seeing Ag again can lead to switching from IgM to
Ab tests- ppt, aggultination, complement fixation, EIA, RIA, other Ig via Th cell cytokines
ELISA, flow cytometry • Hyper IgM immunodeficiency- can’t switch from
IgM to IgG- X-linked; susceptible to infection; treat
Can’t measure Ag/Ab union kinetically- must measure at with IV IgG
equilibrium

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T Cell Receptors and MHC T cell cytokines- IFNg, GMCSF, IL-4, TNFb
Redundancy in cytokines so if one not made proper course
MHC- in humans found on short arm of chromosome 6; HLA still occurs.

Class I- CYTOKINES:
• Co-dominant inheritance
• ALL nucleated cells Cytokines are soluble mediators involved in many cellular
• 2 chains (alpha and beta) that are not covalently processes.
linked; Ag binds to looped domains alpha1 and
alpha2. Beta chain does not bind Ag Generalities:
• recognize self vs. non self (transplants, • Low molecular weight
autoimmunity) • Glycosylated protein
• recognize self + foreign Ag (viral infections, • Surface receptor
malignancies) • Mode of action- autocrine, paracrine, endocrine
• CD8
Function and Properties:
Class II- found on APC- alpha and beta chains coded for by • Lots of overlap in function and tasks
D gene regions • Produced in novo
• binding zone made by alpha 1 and beta 1 • Made when contact with Ag is made
• recognize processed Ag in context of self • Non-specific mediators of immunity
• CD4 • Regulatory of lymphocyte activation, growth, and
differentiation
TCR • Activators of nonspecific cells
• Near CD3 • Stimulators of immature leukocytes
• Binds Ag and CD3 sends signal
• CD8 recognizes alpha 3 domain on class I Major cytokines of inflammation: IFN, TNF, IL-1, IL-6
• CD4 recognizes alpha 2 domain of class II
TNFa leads to necrosis and inflammation- why cancer pts
T cell activation with bacterial infections do better.
TNF can also result in shock and death
Most Ag are monomeric
Capping of B cells leads to their activation. Can make Ab to cytokines.
IL-2 induces the release of other cytokines.
ANTIGENS ARE PROCESSED BEFORE THEY ARE TNF more problematic at higher concentrations.
PRESENTED TO T CELLS!!!!
Class I- endogenous protein processing IL-1: Co-stimulator of inflammation and T cell function;
Class II- exogenous protein processing produced by macro, epithelial, and endothelial cells;
increases cAMP, nuclear factors, other cytokines, and
TAP- transporter necessary for moving peptides into RER for prostaglandins, can slow cells down with adhesive properties
MHC I. (low concentrations)
• High concentrations- fever, APR, cachexia, but NO
Invariant chain- MHCII binding domain that prevents the TISSUE DAMAGE OR NO TUMOR NECROSIS
binding of endogenous peptides.
LPS causes increases in TNF, IL1 and IL6
Co-stimulation reaction between B7 on APC and CD28 on T
cell that leads to T cell activation for proliferation. Interferon- (alpha [mac] and beta [fibroblasts])- inhibits viral
replication, increases MHC class I, decreases MHCII,
Binding proteins: activates NK cells
• T cell- LFA-1, CD4, CD3(zeta chain), TCR, CD2,
CD28 Chemokines- small cytokines
• APC- ICAM-1, MHCII, LFA-3, B7 • Produced by leukocytes, endothelial cells, and
fibroblasts
APC make IL-1 which causes Th cells to make IL-2 receptor • Stimulate neutrophils, basophils, eosinophils, and
and APC cells to make more MHCII receptors. lymphocytes

IL-2 helps Tc cells in killing target cells- does not require co- Interferon (Type II (gamma))- produced by T cells
stimulatory event. • Function- MAF, increased class I expression,
activates T and B cells, neutrophils, NK cells etc
APC cytokines- IL-1, IL-6, TNFa, IL-12, IL-15

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IL-2 Inflammatory mediators: His, 5-HT, PAF, NCF, IL-8
• Produced by T cells (CD4) (chemokines), C3a, C5a, bradykinin, fibropeptides, PG, LT,
• Major autocrine growth factor for T cells (mast cells and macrophages produce many of these)
• Leads to synthesis of other cytokines
• Acts on B, T, and NK cells TNF causes PMN to be more adhesive.
• Can live w/out IL-2 Macrophages release IL-12, and TNFa
NK- IFNgamma
IL-4: produced by T cells (CD4) and acts on B cells
Adhesion and Migration
IL-10: Produced by T cells, decreases IFNg, increases B • ICAM- intracellular adhesion molecule- allows cell
cells to move through endothelium
• CD15
Hematopoiesis: • E selectin- slows movement of phagocytic cells in
• CSF- colony stimulating factor blood
• IL-3- early progenitor
• GM-CSF: granulocyte/monocytes colony ADCC- Ab dependent cellular cytotoxicity- killer cell w/ Fc_
stimulating factor receptor (IgG) becomes active if it senses an immune
• M-CSF, G-CSF complex to kill target cell
• Can be used by chemo pts and bone marrow Th0- makes IL12, IFN gamma, and IL4; proliferate into Th1
transplant patients and Th2
Th1- controls classical side of immunity- activates
B CELL ACTIVATION macrophages- secretes IFNgamma, TNFa, and IL2
Th2- controls allergy side of immunity- activates mast cells,
Major APC: B cells and eosinophils (makes Ab)- produces IL4,5,6,10
• Interdigitating dendritic cells- induces T cell
proliferation most effectively MHC restricted- as T cells develop recognize self from non-
• Macrophages- produce proliferation of T cells and self
helper functions
• B cells- most effective APC when Ag conc. is low- Perforin- in cytoplasmic granules Tc and NK cells – induces
high affinity receptor on cell surface lysis by making channels in target cell surfaces

IgM binds complement the best Tc and NK lytic mechanisms- lytic granules store and release
perforin and granzymes- to form pores and induce apoptosis
Ab mediation is very important need B cell control. (respectively)

Plasma cells are terminally differentiated. Memory B cells When natural DNA repair is inhibited by TNF and granzyme
have a long _ life can lead to apoptosis.

Cross-linking is important w/ monomeric Ag and receptors Macrophages- phagocytize and present Ag to T cells and
on B cells. activate immune cytokines to release more cytokines, kill
microbes and tumors
C3d- degradation product of C3b, binds CR2 on B cells to
lower B cell activation threshold. Macrophage products-
• Inflammation and fever- IL-1, IL-6, and PG
CD40- important for B cell activation and class switching. • Lymphocyte activation- processed Ag and IL-1
No CD40 ligand on T cell when hyper IgM immunodeficient. • Tissue rebuild- angiogenesis factor, collagenase
• Microbicidal- reactive O2 and NO, lysozyme
CELL MEDIATED IMMUNITY: • Tissue damage- H2O2 and TNF

Innate CMI; VACCINES:


• Chemotaxis- activate macrophages or PMN directly
or through C5a Vaccination- infection w/ agent (Ag) that induces an immune
• Phagocytosis- enhanced by C3b deposition on response- doesn’t protect against infection, just the disease
microbes and binding to complement receptors on
phagocytes. Passive immunity- immediate but transient; administration of
• Acute phase cytokines- binding and uptake of preformed Ab; can result in serum sickness
microbes by phagocytes also induces them to Adoptive immunity- T cells transferred into animal to impart
synthesize and release cytokines. immunity
Active immunity- delayed but more permanent (vaccines)

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Types of Vaccines:
Th1- not susceptible to IFN gamma
• Killed organism- inactivated or killed vaccine
• Ag part of disease causing organism CR2- augment immune response by binding to complement
• Attenuated or weakened preparation receptor
• Toxoid vaccines- toxins treated w/ or absorbed w/
aluminum salts; usually must add adjuvant to Anti-Ids- produced to either non-antigen binding idiotyopes
increase immunogenicity or to Ag binding idiotyopes
• Organisms similar to virulent organisms but that Anti-Ids can either increase or decrease immune response
does not cause human disease
• Subunit vaccines- utilizes techniques of genetic Changes in the alpha chains can lead to changes in the
engineering binding cleft of MHCI and II.
• DNA plasmid vaccines- circular DNA plasmids
expressing specific proteins are injected w/ Polymorphism of MHC allows us to respond to some
presentation of the protein to the immune system idiotopes and not others can respond to only a certain set of
Ag due to genetic coding
Ways to give vaccines:
• Subcutaneous IMMUNITY TO TUMORS
• Intramuscular
• Intradermal Tumors- breakdown of normal growth regulatory
• Oral mechanisms; changes that occur in surface Ag of malignant
cells can sometimes be recognized by the immune system
Live attenuated vaccines: Polio, measles, mumps, rubella,
yellow fever, varicella zoster, hep A, TB Often a number of subclinical tumors.

Killed vaccines: polio, rabies, typhoid, cholera, influenza, Tumor specific antigens- unique to cancerous cells and are
plague, and pertussis not found on normal counterparts
Tumor associated antigens- expression is greatly increased on
Toxin Based Vaccines: Clostridium tetani (inactivated toxin), tumors
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

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