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1. Variolation
2. Who introduced vaccination?
3. Who is the father of microbiology?
4. Who introduced antiseptic techniques for surgery?
5. When were antibiotics developed?
6. When were antibiotics commercialized?
1. Injection of crusted material from smallpox blisters used to immunize in ~16th century
2. Jenner for smallpox in England, late 1700s
Inoculated cowpox (vaca Latin for cow)
3. Pasteur (1860s)
Showed bacteria could be killed by heat
Developed chicken cholera, anthrax, and rabies vaccines
4. Lister
5. 1920s
6. 1940s
1. Antigen
2. Immunogen
3. Hapten
4. Tolerogen
5. Epitope
1. Chemical foreign to host which induces immune response
Reacts w/antibodies
2. Induces an immune response (does not necessarily react w/antibodies) ex. bovine serum
albumin (BSA)
3. Antigen that alone does NOT induce immune response
Eg penicillin, dinitrophenyl (DNP)
Not immunogenic b/c they cannot activate helper T cells (cant bind to MHC proteins)
They can stimulate a response when covalently bound to a carrier protein (such as BSA)
4. Antigen altered to induce tolerance (no immune response)
5. An antigenic determinant (confers specificity for Ab)
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1. Defensins
2. Acute phase proteins
1. Proteins secreted by phagocytes
Have antimicrobial effects
2. Produced mainly by liver
Similar to defensins
Bind to microbes, making them more susceptible to being destroyed
Ex. C-reactive protein, mannose-binding protein
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What bridges the two arms (cell-mediated and humoral immunity) of acquired immunity?
Macrophages and certain other phagocytic cells such as dendritic cells
o Participate in both the innate and acquired arms
o As part of innate arm ingest and kill microbes
o As part of acquired arm present antigen to helper T cells (essential 1st step in activation of
acquired arm)
Note: neutrophils (which are phagocytes have excellent microbicidal abilities) DO NOT
present antigen to helper T cells and therefore function in innate BUT NOT acquired immunity
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RAG
Recombinase activating gene
Helps in the formation of lymphocyte receptors
Part of a family of genes that evolved allowing adaptive immunity
After these genes evolved, lymphocytes became major player in immunity
Antigen recognition
1. Cognitive (recognition) phase
Lymphocyte recognizes a foreign antigen by means of a receptor
2. Activation phase
Proliferation and differentiation of lymphocytes expression of new genes, acquire new
functions
3. Effector (response) phase
Effector lymphocytes newly functioning, eliminate antigen
Some lymphocytes differentiate into memory cells
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Clonal Selection
1. Antigen selects a B cell endowed w/the preexisting capacity to make the specific antibody
for that antigen
2. Each person has a large pool of B cells
3. Each B cell bears specific receptor (either IgM or IgD) that can react with 1 antigen (or closely
related group of Ags)
4. An antigen interacts w/B cell w/best fit Ig surface receptor
Stimulates B cells to proliferate and form clone of cells
Selected B cells plasma cells Ig specific for Ag
5. Clonal selection also occurs with T cells
Antigen interacts w/specific receptor on a Th or Tc cell
This selects cell expands into clone of cells with the same specificity
Consequences of immune activation
1. Inflammation
Innate immunity, influx of factors and cells, PMNs
2. Phagocytosis
Ingestion of particles by macrophages and neutrophils
3. Neutralization
Ab combines w/antigen and inactivates it
4. Cytotoxic reaction
Killer cells interact w/target cell and kill it
Origin of immune cells
1. In post-natal life, stem cells reside in bone marrow
2. T cells mature into immunocompetent cells in thymus
Stem cells lack antigen receptors CD3, CD4, and CD8
First differentiate to express both CD4 and CD8
If contacts cell w/class II MHC proteins CD4+ cell
If contacts cell w/class I MHC proteins CD8+ cell
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Thymic education
Two processes that occur in thymus
1. CD4+ and CD8+ cells bearing antigen receptors for self proteins are killed (clonal deletion)
by apoptosis
Removal of these self-reactive cells = negative selection
Results in self tolerance (prevents autoimmune rxns)
2. CD4+ and CD8+ cells bearing antigen receptors that do not react w/self MHC proteins are
killed
Results in positive selection for T cells that react well w/self MHC proteins
These 2 processes produce T cells selected for their ability to react both w/foreign antigens and
with self MHC proteins
MHC proteins
Major histocompatibility complex
Perform 2 essential functions in immune response:
o Positive selection of T cells in thymus
o Presentation of antigens to T cells, the initial step required to activate those cells
Most imp antigens recognized in graft rejection process
GALT
gut-associated lymphoid tissue
Up to 40% of T cells develop here rather than thymus
These intraepithelial lymphocytes are thought to provide protection against intestinal pathogens
o Their antigen receptors and surface proteins are different from those of thymus-derived T cells
o Cannot substitute for thymus-derived lymphocytes
Evidence: pts w/DiGeorges syndrome (lack a thymus) are profoundly immunodeficient
Sepsis
The presence of pathogenic organisms, or their toxins, in the blood or tissues
I.e. blood infection that causes disease/symptoms
Ex. may have bacteremia but no symptoms, thus NOT septic
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Hematopoiesis
1. Blood cells are short lived and are thus continuously renewed from pluripotent stem cells in
bone marrow
Pluripotent under influence of cytokines, stem cells become a variety of other cells
Exception: memory cells, progeny of which last for yrs
2. Process is controlled by cytokines
IL-7 imp for B cell development
IL-3 acts on early bone marrow progenitor cells
3. GM-CSF - stimulates cells of granulocytic & macrophage
4. M-CSF (macrophage colony stimulating factor)
5. G-CSF (granulocyte colony stimulating factor)
Used clinically _ speeds up bone marrow recovery
T lymphocytes: Subtypes and Markers
Subtypes:
o TCR a/b or g/d
o Th-1 T helper cell
o Th-2 T helper cell
o Tc T cytotoxic cell
o Ts T suppressor cell
o NK natural killer (large granular lymphocyte)
Surface markers (CD = cluster designation)
o All T cells TCR, CD3 (TCR complex)
o Th cells CD4
o Tc cells CD8
o NK cells receptors for class I MHC, CD16
TCR complex
Formed by 2 portions (TCR + CD3), totaling 7 proteins
o TCR complex: ab-gden
TCR portion, a/b or g/d, binds the antigen
Rest of the proteins is the CD3 portion
o CD3 transfers signal across membrane into T cell
T cells with g/d TCR primarily located in mucosa
o CD8+ (cytotoxic T cells) only
o Limited antigenic repertoire (100 1000 clones)
T cells with a/b TCR are found in the blood
o ~108 different clones
o CD4+, CD8+, or suppressor T cells
o MHC restricted
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1. Th cells
2. Tc cells
3. Ts cells
4. NK cells
1. Two types distinguished by cytokines they secrete:
Th1: produces IL-2 and IFN
o Involved in cell-mediated immunity
Th2: produces IL-4 and IL-10
o Involved in humoral immunity
3. TCR, CD8
Bind to targets and release killer molecules
4. CD4 and CD8
Release suppressor cytokines
5. CD16 (NO TCR)
Ag receptor less defined
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What enzymes are involved in the signal transduced by CD3, CD4, and CD8?
1. CD3
One of its transmembrane proteins the zeta chain is linked to a tyrosine kinase called fyn
2. CD4 and CD8
May signal via tyrosine kinase lck
Function of CD4 lymphocytes
1. Th-2 cells
Help B cells develop into Ab-producing plasma cells by producing IL-4 and IL-5 (influence
humoral immunity)
2. Th-1 cells
Help CD8 T cells to become activated cytotoxic T cells by producing IL-2, activate NK cells
Help macrophages effect delayed hypersensitivity (eg, limit infection by M tuberculosis) by
producing primarily IL-2 and gamma IFN (i.e. activate macrophages)
Also activate NK cells
Thus influence CMI
What is the main thing that regulates the balance between Th-1 and Th-2 cells?
IL-2 levels
o Produced by macrophages
o Increases the number of Th-1 cells
o Thus enhances:
Host defenses against organisms controlled by delayed hypersens response
Cell-mediated immunity
Gamma IFN
o Inhibits production of Th-2 cells
1. Cleaved viral peptides associate w/which MHC class?
2. Which MHC class do all other antigens associate with?
1. Class I
a. Viral peptides associate w/class I MHC protein
b. Complex is transported to surface, where viral antigen is presented to receptor on CD8+ cell
2. Class II
a. Foreign protein is cleaved into peptides that associate w/class II MHC proteins
b. Complex is transported to surface of APC, where antigen, in association w/class II MHC
protein, is presented to receptor on CD4+ helper cell
Remember the rule of eight:
CD4 cells interact w/class II, CD8 cells interact w/class I
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Activation of T cells
1. Requires that they recognize a complex on surface of APCs consisting of both the antigen and
a class II MHC protein
2. 1st step antigen interacts w/TCR specific for that antigen
CD4 on Th cell also interacts w/class II MHC protein
Other proteins also help stabilize contact between T cell & APC (LFA-1 on T cell binds to
ICAM-1 on APCs)
3. For full activation of Th cells, costimulator is required B7 protein on APC must interact
w/CD28 protein on Th cell
If costimulatory signal occurs: IL-2 is made by Th cell Th cell capable of performing all of its
functions
If costimulatory signal does not occur: state of unresponsiveness called anergy ensues
CTLA-4
Protein that appears on the T cell surface after the T cell has been activated
Binds to B7 by displacing CD28
Interaction of B7 with CTLA-4 inhibits T cell activation by blocking IL-2 synthesis
o This restores activated T cell to a quiescent state and thus plays an imp role in T cell
homeostasis
Mutant T cells that lack CTLA-4 participate w/increased frequency in autoimmune rxns
Administration of CTLA-4 reduces the rejection of organ transplants in experimental animals
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Describe the events that occur when the antigen-MHC complex on the APC interacts with the
TCR.
1. Signal is transmitted by CD3 complex thru several pathways that lead to a large influx of Ca+
into the cell
2. Ca+ activates calcineurin, a serine phosphatase
3. Calcineurin activates genes for IL-2 and the IL-2 receptor
4. IL-2 (T cell growth factor) stimulates:
Th to multiply into a clone of antigen-specific Th cells
Most cells of this clone perform effector and regulatory functions, some become memory
cells
Tc cells to produce gamma interferon
IFN gamma _ expression of class II MHC proteins on APCs enhances ability of APCs to
present antigen to T cells & upregulates immune response
Memory T cells
Endow host defenses w/ability to respond rapidly and vigorously for many years after initial
exposure antigen
This memory response to a specific antigen is due to:
o Many memory cells are produced, so that sec-ondary exposure is greater than primary response
o Memory cells live for many years or have the capacity to reproduce themselves
o Memory cells are activated by smaller amounts of antigen and require less costimulation
o Activated memory cells produce greater amounts of interluekins than do nave T cells when
they are first activated
T cell receptor (TCR)
1. Similar to Ig heavy chains in that:
Genes coding for them are rearrangements of DNAs
There are V (variable), D (diversity), J (joining), and C (constant) segments that rearrange to
provide diversity
Genes (RAG-1 and RAG-2) that encode enzymes that catalyze these rearrangements are similar
in T & B cells
2. Each T cell has a unique TCR on its surface
Millions of different T cells exist in each person, and activated T cells (like activated B cells)
clonally expand
3. TCR is different in 2 ways:
It has 2 chains rather than 4
Recognizes Ag only in conjunction w/MHC proteins
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T cell-dependent response
1. Ab production that requires the participation of Th cells
2. Ex. B cells used as APC (macrophages commonly do this):
Ag binds to IgM or IgD & is internalized w/in B cell
Ag fragments return to surface w/class II MHC mol.
These interact w/TCR and, if B7 on B cell interacts w/CD28 on Th cell, Th cell produces IL-2,
IL-4, & IL-5
IL-4 & -5 induce class switching (IgMIgG, IgA, IgE)
B cell divides and differentiate into plasma cells
Interleukins alone are not sufficient to activate B cells:
CD40 ligand must interact w/CD40 on B cell
Other proteins strength interaction between Th and B cell (LFA-1 on T cell w/ICAM-1 on B
cell)
T cell-independent response
1. Antibody production that is not dependent on Th cells
2. Antigens that induce such a response are usually polymerized (multivalent) macromolecules
such as bacterial capsular polysaccharide, DNA, RNA, many lipids
Repeated subunits act as a multivalent antigen that cross-links the IgM antigen receptors on the
B cell and activates it in absence of help from CD4 cells
3. Primarily IgM is made (vs. T cell-ind response where all classes of Ab are made)
This indicates that the lymphokines produced by the Th cell are needed for class switching
4. Does NOT generate memory B cells
B cell functions
1. They differentiate into plasma cells and produce antibodies
2. They are APCs
B cell origin
1. B cell precursosrs first in fetal liver, then migrate to bone marrow where they remain during
adult life
2. Maturation of B cells has 2 phases:
Antigen-independent phase
Consists of stem cells, pre-B cells, and B cells
Antigen-dependent phase
Cells that arise subsequent to interaction with antigen (eg, activated B cells and plasma cells)
3. B cells display surface IgM, the antigen receptor
Surface IgM = monomer (circulating IgM = pentamer)
4. Located in germinal centers of lymph n, white pulp of spleen, GALT
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1. IL-6
2. IL-3
1. Produced by Th cells
Stimulates B cells to differentiate
Induces fever
Induces production of acute-phase proteins in liver
2. Made by Th-2 cells
Mediator of allergic airway disease (asthma)
Shown to cause asthma in animals
Involved in producing airway hyperresponsiveness
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Interferons
1. Block virus replication
Alpha IFN
Produced by leukocytes
Beta interferon
Produced by fibroblasts
2. Act as Lymphokines
Gamma IFN
Produced primarily by Th-1 and Tc cells, NK cells
Potent activator of phagocytic activity of macrophages, NK cells, and neutrophils
Can also _ synthesis of class I and II MHC proteins (thus enhancing antigen presentation)
Tumor necrosis factor (TNF-a)
1. Inflammatory mediator released primarily by macrophages
2. At low concentrations beneficial effect
_ synthesis of adhesion molecules by endothelial cells
Activates respiratory burst w/in neutrophils
_ lymphokine synthesis by Th cells
Stimulates growth of B cells
3. At high concentrations
Mediator of endotoxin-induced septic shock
Cachectin b/c it inhibits lipoprotein lipase in adipose, thereby _ utilization of fatty acids (results
in cachexia)
Causes death and necrosis of certain tumors in animals
Endogenous pyrogen
1. Lymphotoxin/TNF-b
2. Nitric oxide (NO)
3. Macrophage migration inhibitory factor (MIF)
1. Made by activated T cells, same effects as TNF-a
2. Functions:
Mediator made by macrophages in response to endotoxin
Vasodilation (mediator of hypotension in septic shock)
3. Functions:
Mediator made by macrophages in response to endotoxin
Major role in induction of septic shock
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CD Leukocyte Markers
1. CD2 - costimulatory molecule that binds to LFA3 (integrin)
On T and B cells, NKs, macrophages, neutrophils
2. CD3 TCR coreceptor
3. CD11a a costimulatory molecule that binds to ICAMs
On T and B cells, NKs, macrophages, neutrophils
4. CD16 another name for Fc receptor
5. CD19 B cell coreceptor
6. MHC II on APCs (T cells, B cells, macrophages)
Bind to Ag, CD4
7. MHC I on T and B cells, NKs, macrophages, neutrophils
Binds to Ag, CD8
1. Primary lymphoid organs
2. Secondary lymphoid organs
1. Foster the maturation of nave stem cells
Thymus, bone marrow, bursa of Fabricus (in chicken)
2. Contain mature cells and foster immune response
Lymph nodes, spleen, and GALT
Foreign Ag driven (unlike primary lymphoid organs)
Are both composed of lymphocytes, accessory cells (eg, APCs) and epithelial cells
Epithelial cells can secrete factors that help in maturation and development of immune response
o Ex. thymic epithelial cells secrete thymosin, which promotes T cell maturation
Thymus
1. Fosters maturation of T cells
2. Lymphoepithelial
3. Divided into cortex and medulla
4. Contain macrophages and dendritic cells that present self-antigens to differentiating T cells
leading to positive and negative selection
5. Stem cells originally from bone marrow enter cortex positive and negative selection ensues
at corticomedullary junction
6. Positively selected cells go on into medulla and out into body to secondary organs
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Bone marrow
1. Contains all the cells and cytokines necessary for B cell development
2. preB immature B mature B
Spleen
1. Filters antigen out of blood and promotes immune response
2. No spleen more susceptible to blood-borne infections
3. Composed of capsule and reticular and cellular framework
4. Contains lymphocytes, APCs, and RBCs
5. Divided into red pulp surrounding the white pulp
White pulp surrounds central artery
Contains PALS (peri-arteriole lymphatic sheath) which is where most of the T cells are located
B cells clustered in germinal centers
6. Blood flow enters via central branches of trabecular a. white pulp/PALS lymphatic nodule
marginal zone red pulp pulp veins trabecular veins splenic vein
Lymph nodes
1. Filters Ag from the lymph and supports immune response
2. Composed of capsule, cortex and medulla
Outer cortex follicle or B cell zones
Inner cortex T cell zones
Medulla Location of plasma cells
3. Same structure as spleen: B cells surrounded by T cell
4. Artery associates w/ high endothelial venule/HEV this is how components return to lymph
from the blood
5. HEVs are specialized and found only in this area allow WBCs to get out of blood and into
lymph node
Imp if you have an infection in a node, lymphocytes of right clone can be called out of blood
into node
Factors affecting immunogenicity
1. Protein complexes and particulate antigens are better than non-complexed proteins or soluble
antigens (i.e. they engage APCs better better immune response)
2. Route
Subcutaneous injection give best immune response
Intradermal (I.D.) also good
3. Dose
Too little or too much can be inhibitory
4. Adjuvants
Substances that mix w/antigen thus engaging APCs
Vaccines are given w/adjuvant (eg, Freunds adjuvants)
5. Immune response potential (immune responses are variable)
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IgG
1. Consists of 2 L chains and 2 H chains linked by disulfide bonds (divalent)
2. Four subclasses
3. Directed against polysaccharide antigens
4. Important defense against encapsulated bacteria
5. Predominant Ab in secondary response
6. Only antibody to cross placenta most abundant Igs in newborns
7. Opsonizes (ie, enhance phagocytosis)
8. Neutralizes virus or toxin upon binding to it
IgA
1. Main immunoglobulin in secretions (colostrum, saliva, tears, respiratory, intestinal and genital
tract secretions)
2. Prevents attachment of bacteria and viruses to mucous membranes
3. Each molecule consists of two H2L2 units + J chain and secretory component
Secretory component polypeptide made by epithelium
Provides for IgA passage to mucosal surface
Also protects IgA from being degraded in intestinal tract
4. Neutralizes toxin or virus upon binding to them
IgM
1. Two forms created via alternative mRNA splicing:
Secreted: main Ig produced early in primary response
Membrane bound: on surface of B cells where it functions as an antigen-binding receptor
(BCR)
Accessory proteins a/b activate src-family tyrosine kinases
Signals differentiation to plasma & memory cells
2. BCR is a monomer
3. In serum, it is a pentamer (5 H2L2 units + J chain)
4. Has 10 Ag-binding sites (highest avidity) most efficient Ig in agglutination, compement
fixation, & other rxn
5. Imp in defense against bacteria and viruses
IgD
1. Has no known Ab function
2. May function as an antigen receptor since it is present on surface of many B cells
3. Present in small amounts in serum
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IgE
1. Mediates immediate (anaphylactic) hypersensitivity
2. Participates in host defenses against certain parasites (eg, helminths)
3. Its Fc region binds to surface of mast cells and basophils
4. Bound IgE serves as a receptor for antigen (allergy)
This An-Ab complex triggers allergic responses of the immediate (anaphylactic) type thru
release of mediators
5. Present in trace amounts in normal serum
6. Persons w/allergic reactivity have __ amounts
7. May appear in external secretions
Fc Receptors
1. Fcg receptors on phagocytes
Bind immune complexes promote phagocytosis
On Tc and NK cells regulate ADCC
On trophoblast and endothelial cells of placenta transport IgG into fetal circulation
2. Fce receptors on mast cells
Bind IgE triggers degranulation and allergy
3. Fca receptors on basal surface of intestine epithelium
Bind dimeric IgA promote transport of complex thru cell to gut lumen
Portion is cleaved & remains w/IgA as secretory piece
1. How many gene segments code for V region of L chains?
2. How many gene segments code for V region of H chains?
3. What does antibody diversity depend upon?
4. In the synthesis of the H chain, what two segments are expressed first (and are present in the
primary RNA transcript)?
1. 2 gene segments (V + J)
V codes for first 95 residues
J codes for 13 residues
2. 3 gene segments (V + D + J)
3. a) Multiple gene segments for Variable regions
b) their rearrangement into different sequences
c) combining different L and H chains in assembly of Igs
d) mutations (responsible for affinity maturation)
4. Mu (m) and delta (d) (IgM and IgD H chains)
Delta lacks a switch region, thus comes along for the ride with mu
Two H chains produced will either have mu or delta
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Class Switching
1. Initially all B cells carry IgM specific for an antigen
2. Later, gene rearrangement permits elaboration of Abs of same antigenic specificity but of
different Ig classes
3. Occurs ONLY with HEAVY CHAINS
4. Same VH (variable H) gene can associate with different CH (constant H) genes so that Igs
produced later (IgG, IgA or IgE) are specific for same antigen as original IgM
5. A different mechanism is used in switch from IgM to IgD
A single mRNA is transcribed --> IgM & IgD mRNAs
Thus mature B cells can express both IgM and IgD
6. Note: once B cell has switched pass a certain H-chain gene, it can no longer make it b/c
intervening DNA is discarded
1. How are cytokines involved in class switching?
2. Generation of TCR diversity
1. IL-4 increases IgE, IL-5 (from T cells) increases IgA
2. Ag binding portion of TCR is generated by 4 sets of genes: alpha and beta (on majority of T
cells), & gamma and delta (expressed on subpop of T cells)
General arrangement of TCR genes similar to H chains
Diversity is generated by:
Multiple germ-line genes
VJ and VJD recombination
Joining site variation
Multiple D region
N-region diversification (random base inserts)
NO somatic mutations for T cell diversity
Hyper IgM immunodeficiency
1. X-linked trait, CD40 gene mutation
2. Interaction of the CD40 protein on B cell with CD40 ligand protein on the Th cell is a
controller of class switching
3. Failure of this interaction to occur results in an inability of the B cell to switch to production
of either IgG, IgA or IgE
4. Therefore, only IgM is made
5. Patient presents with:
_ IgM, _ IgG
Normal numbers of T cells and B cells
Recurrent pyogenic infections (b/c these require IgG)
6. Treat with passive immunotherapy IV gamma globulin from a pool of donors
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Alternate pathway
1. Spontaneous activation (autolysis) of C3 into C3a and C3b this process is called tickover
2. C3b then binds to the cell membrane by itself
When C3b binds to self cells _ inactivated
When C3b binds to foreign cells _ it sticks
3. Binding of C3b leads to activation of other components
4. Factor B interacts w/C3b _ proteolyzed by factor D to form C3bBb (C3 convertase) (different
from classical path)
5. C3 convertase then activates another C3 to form C3b
6. C3b combines with C3 convertase to form C3bBb3b (C5 convertase) (also different from one
in classical path)
7. C5 convertase then interacts w/C6, 7, 8 and 9 to form MAC
Control of the Classical Pathway
1. Time complement components need to be under fine control, dont want too much firing
leading to constant inflammation (unbound components active for nanosec)
2. Receptors different CRs on different cells
CR1 B cells, PMNs, monocytes, macrophages
CR2 B cells, dendritic cells
CR3 monocytes, macrophages, PMNs, NK cells
CR4 PMNs, monocytes, macrophages
3. Specific factors regulatory factors that have very specific actions in limiting the complement
system
Ex: CCP and DAF inhibit C3 convertase
MCP degrades C4b
What would a deficiency of the following result in:
1. Early complement components (Clq, r, s OR C4 OR C2)
2. Late components
3. Regulatory factors
4. Complement receptors
1. Still can kill microbes via alternative pathway but
Chronic pyogenic infect. (they need to be phagocytized)
Immune complex disease: Failure to clear Ag-Ab complexes _ vasculitis, glomerulonephritis
2. Chronic Neisseria infections
3. C1H (C1 inhibitor) deficiency _ autosomal HANE
Hereditary angioneurotic edema
Overactive system leading to chronic inflammation.
C1 is not inhibited _ decreased levels of C4
4. Leukocyte adhesion deficiency (LAD)
Inflammatory cells cant come since they are missing a CR leading to pyogenic infections
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Pertinent findings: _ T3 and T4, _ TSH, anti-thyroid antibodies _ from first visit
4. Etiology of disease is the production of Abs to thyroid Ags
Immune Regulation
1. Antibody dependent B cell suppresion
Blocking antibody: high doses of Ig block binding of antigenic determinant (epitope) and
membrane Ig on B cells (ex. Rogam)
Receptor cross linking: Low doses of Ab _ antigen cross-links B cells Fc receptors and its
antigen receptors
Tyrosine phosphatase activate _ inhibits cell activation
2. Regulation by immune complexes either augment or inhibit response
Inhibition: Fc receptor of B cell cross links w/Ag receptor by Ag-Ab complex _ signals B cell
to stop antibody production phase
Augmentation: APC-bound Ab _ presentation of Ag to B cells
3. Anti-idiotypes can either suppress or enhance immune response
Produced to either non-antigen binding sites (paratopes) or to antigen binding sites (idiotopes)
4. Immune repertoire MHC and non-MHC genes polymorphisms
Tumor specific antigens (TSAs)
1. Unique to cancer cells
2. Not found on normal counterparts
3. Arise through point mutations
4. Unique to a single neoplasm arise through point mutations in DNA damaged by carcinogenic
chemicals, UV or X radiation, viral infections:
hep B
human T cell leukemia virus
HPV _ cervical cancer
Epstein Barr _ Burketts lymphoma
Tumor associated antigens (TAAs)
1. More often found on tumors rather than TSAs
2. Found on both normal and malignant cells, but their expression is increased on tumor cells
3. Examples
CEA (carcinoembryonic antigen) _ predictor of recurrence of colon cancer (200 ng/ml) (levels
_ when cancer is present and drops when it is removed)
Also used as prognosticator for metastasis
Normal level: ~10ng/ml
AFP (alpha feto protein) _ elevated in liver and testicular cancer (not absolute, can be raised in
cirrhosis and COPD) (very suspicious if >500ng/ml)
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Cancer immunotherapy
1. Anti-Cancer vaccines
Immunization against oncogenic viruses
More difficult to vaccinate against non-viral origins, ex:
BCG (enhances responses against melanoma)
Transfection of genes for B7, IL-2, IL-4, IFN gamma, GM-CSF (_ response of T cells)
Naked DNA constructs (induces Tc cell)
2. In vitro activation of LAK cells & TIL (tumor infiltrating lymphocytes) with IL-2
3. Monoclonal antibodies (Mabs) made w/mice spleens
Problem: HAMA response (human anti-mouse Ab response); Solution: chimeric Mabs
1. Heteroconjugate Mabs
2. Chimeric Mabs
1. Bi-specific Mabs that have 2 Fab regions:
One against CD marker (ex. CD16 _ NK marker)
One against tumor Ag
2. Mabs made up of:
Human constant region
Murine VL and VH regions
Show a decreased HAMA response
Humanised Ab _ advanced chimeric Ab
Herceptin _ humanised Ab in metastatic breast CA
Binds HER-2/neu, growth factor rec.on tumor cells
Only Mab shown to be effective
Cytokine therapy for tumors
1. IFN alpha
Remission in hairy cell leukemia pts
Possible cytostatic effect on tumor
2. IFN gamma
Ineffective systemically, remission of ovarian CA
_ expression of MHC class I, cytostasis
3. IL-2
Remissions in renal cancer and melanoma
T cell activation and proliferation, NK cell activation
4. TNF alpha
Can _ malignant ascites
Macrophage & lymphocyte activation
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Infectious mononucleosis
1. Presents w/malaise, sore throat, fever, headache, red throat, exudative tonsils, tender lymph
nodes
2. Monospot test positive
3. WBCs show lymphocytosis with atypical cells (T cells)
4. Virus infects epithelium of pharynx, producing sore throat
5. B cells then become infected: Epstein-Barr virus docks to CR2 on B cells, fibroblasts, and
epithelial cells
Stimulates B cells to make polyclonal Abs (heterophile Abs), detected by the monospot test
6. So remember:
The monospot response is the B cell response
The atypical lymphocyte is the T cell
1. Passive immunity
2. Active immunity
1. Immediate immunity but transient
Giving person preformed antibody
Ex. hyperimmune Ig after infection or snake bite
Ex. Passive transfer of Ig from mother to child
2. Delayed immunity but more permanent
Ex. natural exposures to antigens in pathogens
Ex. vaccines
Types of vaccines
1. Killed organism (ex Salk polio vaccine)
2. Ag part of disease causing organism (ex H. influenzae)
Called acellular
3. Attenuated or weakened preparation (polio, measles)
4. Toxoid vaccines
Toxins treated w/or absorbed w/aluminum salts
Usually must add an adjuvant to _ immunogenicity
Ex. diptheria & tetanus toxoids combined w/ pertussis (adjuvant)
5. Organism similar to virulent one (Jenner cowpox, BCG for TB)
6. Subunit vaccines (ex hep B)
Genetically engineered
7. DNA plasmid vaccines
Mimics live attenuated vaccine preps
Ways to give vaccines
1. Parenteral route (not po) _ mainly elicits IgG antibodies
SubQ
IM
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ID (intradermal)
2. Oral route _ mainly elicits IgA antibodies due to GALT
1. Live attenuated vaccines
2. Killed vaccines
3. Vaccines based on subcellular microbial fragments
1. Polio, mumps, measles, rubella, yellow fever, varicella zoster, hepatitis A, TB
2.
Very effective: Polio (salk) and rabies
Moderately effective: Typhoid, cholera, influenza
Debatable: Plague
Controversial on basis of toxicity: Pertussis (cellular) acellular pertussis vaccine that is less
toxic is now used
3. Haemophilus influenza, hepatitis B virus
Recommended childhood immunization schedule
1. Birth _ Hep B1
2. 1 4 months _ DTaP (diptheria, tetanus, acellular pertussis), Hep B2, and Polio
3. 6 18 months _ Hep B3, Hib (H. influenza type B), Polio, MMR (measles, mumps, rubella),
Var (V. zoster), HepA
4. 11-2 years _ tetanus (tetanus should be given every 10 yrs)
Adjuvants
1. Agents given with vaccines to enhance their immunogenicity
2. Mechanism:
Depot effect (concentrate Ag in a particular area)
Increase particle size of an antigen
Increase release of cytokines
3. Examples:
Inorganic salts (Aluminum OH, Aluminum PO4)
Delivery systems (liposomes, BCG)
Bacterial products (Freunds adjuvant)
Causes inflammatory granuloma response that increases immunogenicity
Non-specific immunotherapy
1. Microbial
Filtered bacterial cultures: Coleys preparation
BCG: anti-tumor activity
2. Cytokines
IFNgamma: leprosy, leishmaniasis
IL-2: leishmaniasis
GCSF: bone marrow restoration
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IgA deficiency
Common variable immunodeficiency
2. Combined B Cell & T Cell deficiencies
Severe combined immunodeficiency disease (SCID)
Ataxia telangiectasia
Wiskott-Aldrich syndrome
3. T-cell immunodeficiency
Thymic aplasia (DiGeorges syndrome)
Chronic mucocutaneous candidiasis
4. Neutrophil/granulocyte immunodeficiency (rare)
Leukocyte adhesion defect
Chronic granulomatous disease
Chediak-Higashi syndrome
Jobs syndrome (Hyper IgE syndrome)
5. Complement deficiency (rare) early and late deficiencies
What is the pattern of:
1. humoral immunodeficiencies?
2. Cellular (T lymphocyte) immunodeficiencies?
3. Neutrophil/phagocyte/granulocyte immunodeficiency?
4. Complement defects?
1. Recurrent sinopulmonary infections
NOT a cold! sinusitis, pneumonia, otitis media, high grade pathogens
_ occurrence of arthritis, autoimmune disease, viral gastroenteritis
2. Recurrent Opportunistic infections
LOW grade path (pneumocystisis, fungi, multi-dermatomal zoster)
Generally affect kids, but most common in HIV pts
_ incidence of various malignancies, esp lymphomas
3. Soft tissue bacterial infections
Gingivitis, lymphadenitis, osteomyelitis, pulmonary cool abscesses
~ always by 2 yrs, often from birth w/delayed separation of umbilical cord
Typically infected w/low grade pathogens OR catalase + organisms (staph, strep, pseudomonas,
E. coli, candida, aspergillus)
4. Depends on complement (C) component defect:
Early C defects _ respiratory infections, recurrent colds
Late C defects _ gram- infections (recurrent meningitis)
X-linked Hypogammaglobulinemia (Brutons Agammaglobulinemia)
1. Congenital B cell deficiency
2. B cells dont develop, atypical lymph node structure w/o germinal centers or plasma cells
3. Very low serum Igs of all isotypes
4. Most common defect is in Brutons tyrosine kinase/Btk
Required for maturation of pre-B cells to mature B-cells
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2. Wiskott-Aldrich
3. Mucocutaneous candidiasis
1. Aut recessive, mutation in DNA repair genes
Child starts to walk, but then regresses (gets ataxic) @ 14-16 months, end up in wheelchair by
age 7-10
Then develop telangiectasia of lateral aspect of eye
Lymphopenia and IgA deficiency commonly occur
2. X-linked disease of T cell defect
Recurrent pyogenic infections, eczema in weird places
3. Severe form of candida that spreads everywhere
T cell defect where T cells dont see candida
Treatment: antifungals
Survive to adulthood
DiGeorge Syndrome
1. Congenital defect of T cells of variable severity
2. Malformation of 3rd and 4th branchial clefts
3. Manifestations include:
Thymic aplasia w/deficiency of T-cell development
Absent parathyroids w/hypocalcemia
Abnormality of great vessels connected to heart
Facial deformities (wide set eyes, low set ears, funny looking kid/FLK)
4. Associated w/maternal alcohol ingestion, autosomal dominant inheritance, translocation of
chromosome 22
5. May improve w/time, probably due to partial thymic function or substitution of other lymph
tissue for thymus
Chronic granulomatous disease
1. Recurrent soft tissue abscesses
2. Rare disorder affecting 1:1,000,000 (2/3 are X-linked)
3. Recurrent bacterial and fungal infection (often w/organisms that are catalase positive), often
w/formation of granulomas
4. X-linked: defect in production of superoxide b/c of:
Cytochrome b558 defect _ impaired NADPH oxidase
5. Autosomal: defect in other components of NAPDH oxidase
6. Diagnosis: CBC
Nitroblue tetrazolium test or chemiluminescence to assess production of O2 radicals (dye
reduces to dark color by oxidation)
7. Treatment: IFNg
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