Introductory Immunology
Areas included
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Gross anatomy of the lymphatic system (structure and function)
Histological identification of the lymphoreticular system
Physiology of lymphatic transport
Immunology of host defenses
Biochemistry of immune pathways
Molecular events in host defense
Pathobiology of immune disorders
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Making their way from the uninhabited regions of the worlds rainforests, deadly diseases like
Ebola, Malaria and AIDS have brought much attention to the field of immunology in the past 15
years. Much of what is known about the immune system today has its thanks to massive amounts
of research, driven by the spread of seemingly unstoppable infectious diseases. History has shown
us that every couple of generations or so produces a pandemic (epidemic of global proportions)
which wipes out millions of people. In the early nineteen hundreds it was influenza, and in the
1800's we saw the black plague decimate populations and communities. Lately we have seen the
introduction of the latest weapon nature has in her arsenal, human immunodeficiency virus HIV.
A blood borne pathogen, it is spread by sexual contact or exchange of bodily fluid. Unlike other
deadly visible diseases that spread through a population with alarming speed, HIV sets itself up in
the host for a sustained period of time, utilizing the cells molecular machinery to reproduce copies
of itself. This type of sustained infection cannot be easily seen or tracked by transmission in a
target area thus making it hard to combat effectively. This is just one example of bugs getting the
best of us, there are of course multitudes of pathogens out there that can and will cause disease.
I)
Lymphatic system
The lymphatic system is not unlike the cardiovascular system in design. The duality of this
system lies in its vessels and lymphoid organs. It is a one way circuit having three functions:
i)
Take up excess fluid from interstitial tissue spaces and returning it back to
ii)
the cardiovascular system.
iii)
Absorb fat from the intestinal tract (lacteals).
iv)
Defend the body against disease.
b) Structure
i)
Lymph capillaries
(a) Begin as cul-de-sacs and gradually form largeer vessels, creating a network that
reaches every part of your body.
(b) Wider than blood capillaries and found in most tissues especially in mucous
membranes, serous surfaces and the dermis of skin. Exception is the brain,
eyeball and spinal cord, bone marrow and spleen parenchyma.
ii)
Lymph vessels
(a) Formed by converging lymph capillaries. Lymphatic vessels have valves:
contraction of skeletal muscle propels the lymph (fluid in the lymphatic
system).
(b) It is a one way system.
iii)
Lymph nodes
(a) Drained by vessels,
(b) Grouped according to regions and named.
(c) Reticular fiber framework.
iv)
Lymph ducts
(a) Formed by convergence of lymph vessels
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(b) Lymphatics from lower extremities converge on lymph nodes located anteriorly
and superficially in upper thigh
(c) From inguinal nodes. The main duct from each LE enters the abdomen (now
called lumbar duct). After passing through lumbar nodes, ducts enter cisterna
chyli.
v)
Cisterna chyli
(a) Dilated sac behind right side of aorta and opposite first lumbar vertebrae
(b) Contains some smooth muscle
(c) Receives lumbar lymphatics, para-aortic lymphatics, and the large common
duct from the intestinal tract.
Major lymphatic vessels that drain into the subclavian veins:
Thoracic duct: (Drains lower
extremities and left side of
body). Starts in the abdomen at
the cisterna chyli and empties
into the left subclavian vein.
Receives lymph from both
legs, pelvis, abdomen, and left
thorax. It may drain the left
side of the head and neck as
well as the left arm as the left
subclavian and jugular ducts
may join it at the base of the
neck. The left
bronchomediastinal duct drains
the viscera on the left thorax
Right lymphatic duct:
accessory lymphatic drainage
from right mammary gland,
right arm, and right head and
neck. Empties into right
subclavian.
Terms Edema: localized swelling due to excessive fluid in the tissue spaces.
Clinical correlation. Edema is a big problem in women who have had radical nodal dissection
(lymph node removal). The fluid essentially has no where to go and the areas swell.
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I)
Lymphoid Organs
These organs filter blood and are a major site for immune activation and priming. The major
organs are encapsulated by dense connective tissue:
1) Node: bean shaped and studded along the lymphatic tracks. They are outposts where
white blood cells filter lymph. It has a connective tissue capsule which divides into
lobules. Reticular Fiber framework
2) Spleen: CT capsule with lobules organized into red and white pulp. Functions to
remove old and defunct RBC's and foreign material. Reticular Fiber Framework
3) Thymus: Located anterior to the trachea, behind the sternum in the anterior
mediastinum. Is the site for T cell maturation. Reticuloendothelial framework
4) Bone marrow: Site for all blood cell development.
A-- Organization of lymphoid organs into three levels:
Level 1:
Stem cell compartment
Bone marrow
Pluripotential stem cell
Lymphoid Stem cell
Pre - B
Level 2:
Primary Lymphoid organs
Level 3:
Secondary Lymphoid Organs
Nodes, Nodules, Spleen
MALT, Tonsils...
Seeding to peripheral compartment
Pre - T
Bone Marrow
Thymus
blast transformation
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B-- Thymus - Primary lymphoid organ
1. Function
 Central organ in cell mediated immunity (no direct role in immune reactions)
 T lymphocyte maturation
 Production of growth factors
2. Structure
 Derived from the third and fourth branchial pouch during sixth week of
embryogenesis (first organ to produce lymphocytes).
 Divided into lobes and lobules by a dense connective tissue capsule.
 Each lobule contains a cortex and medulla
 Stroma of epithelioreticular cells (endodermally derived)
- attach to each other via desmosomes
- form a reticulum or meshwork
- provides the microenvironment for T cell maturation and self recognition
- produce thymic growth factors.
 Hassall's corpuscles- concentric layers of epithelial cells (unknown function)
3. Involutes with age.
4. Circulation
 Cortex = Blood thymic barrier, as a function of its capillaries, providing necessary
isolation from circulating Ag. This is important for pre-T cell development.
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Medulla = Mature Naive T cells enter circulation through special High Endothelial
Venules (HEV) found only in the medulla.
C-- Peripheral lymphoid organs
1. General considerations
1. Function
 Provide optimum environment for antigen encounter
 Drains major route of antigen entry
 Collects antigen specific lymphocytes
2. Structure
 Reticular cells form reticular fiber stroma (mesoderm derivation)
 They have very distinct regions of B and T cells
 Blood vessels = HEV are a general feature. They have homing receptors that target
or recognize specific classes of lymphocytes thus enabling their migration from the
blood circulation
 Lymph vessels = only lymph nodes have afferent vessels. All other PLO have
efferent vessels.
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3. Lymphoid nodule or follicle
 A general feature of all lymphoid organs
 The primary nodules has no germinal centers
 The secondary nodule has germinal centers that are divided into zones.
 Germinal centers are areas of B-cell activation, proliferation, and differentiation.
 Plasma cells precursors migrate to medulla terminally differentiate and release Ab.
2. Diffuse Peripheral lymphatic tissue
1. Appendix
2. Peyers Patches in ileum
3. BALT bronchus associated Lymphoid tissue
4. SALT Skin associated Lymphoid tissue
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II)
Immunity: Nonspecific or Specific
Innate (Nonspecific)
Barrier to entry
a) Skin
b) Respiratory Tract-- cilia sweeps out
c) Stomach-- pH acid
A. Mononuclear phagocytic system (RE system old): a system of phagocytic cells that
line tissue spaces and function to filter microorganisms from the blood stream and lymph
channels in the absence of an adaptive immune response.
1. These include: blood -monocytes; Tissue, lymph nodes- Macrophages of
spleen, skin, liver, lungs, bone marrow, also microglial cells, dendritic cells and
possibly fibroblast and reticular cells.
B. Complement (3 pathways) Proteins that enhance the function of the innate and adaptive
immune response.
1. Classical: Immune complex activated (IgG, IgM) cascade of C1qrs, 4 and 2
through C3b, C5 to MAC
2. MBL: Activator membranes containing mannose activating serine proteases
MASP1-2 activating cascade same of above. C3 convertase (C4b, C2a) to C5 and
MAC.
3. Alternative: The presence of bacterial products and surfaces activates the
cascade independent of C1, 4 and 2 through C3b, C5 and ultimately the MAC.
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[Factors]: Other features which upregulate immune response include
opsonization, lysis of bacteria, anaphylotoxin C5a, C4a, C3a
C. Phagocytosis: Bugs that enter blood, lung, BM or lymph are engulfed.
1. Function of circulating phagocytes includes migration, chemotaxis, ingestion
and intracellular killing.
2. Types of cells: Granulocytes, Macrophages, Monocytes
a) [Factors of phagocytosis]: better in the presence of Ab (opsonins)
coating the surface of bugs.
(1) Opsonins
(a) Ab alone (heat stable)
(b) Ab-Ag activation of classic complement pathway (heat
stable)
(c) Alternative complement pathway (heat labile system)
(2) Effects on cells~ (DEGRANULATION)
Legionaries disease:
Legionella pneumphila
inhibits this pathway to
survive intracellularly.
(a) O2 incr. with incr. O2- and incr. release of H2O2
(b) Glycolysis incr. via HMP shunt
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(c) Phagolysosome; fusion with release of hydrolytic
enzymes.
b) Granulocytes (PMN’s): Function to destroy bacteria intracellularly as
described above. You may read more on the specific mechanisms by which
this is done at your leisure
c) Macrophages: When activates produce proinflammatory cytokines IL1, TNFprostaglandins, Leukotrienes. Intracellualr killing same as above.
D. Inflammation (Lit; Burning): A response to tissue injury. Defined clinically as redness,
heat, swelling and pain or rubor, calor, tumor and dolor (Latin). Produces by anything, i.e.,
trauma, chemical, bugs.
1. Activated cells release proinflamatory cytokines IL-1, TNFa causing
vasodialation of capillaries and arterioles facilitating edema (Plasma and
PMNS). Fibrin deposit clot of lymph channel to stop escaping bugs.
2. Selectins and integrins facilitate attachment of Leukocytes to Endothelial cells
allowing extravasation toward stimules.
3. Chemotaxis is induced by activated macrophages, endo’s and fibro’s secrete
chemokines (IL-8) recruiting more neutrophils.
4. The bug battle is on with Mand PMN’s releasing lot of hydrolytic enzymes.
PH of tissue goes acid and pops the Polys releasing mre junk into the area.
More Mac’s show up to clean the leukocytic debris and kill a few more bugs.
5. Endothelial cells- release bradykinins: triggers pain reflex in neurons, and
histamine release. Also dilates blood vessels.
E. FEVER: IS A CLINICAL MANIFESTATION OF INFLAMMATION AND
CARDINAL SIGN OF INFECTION!
1. Body temperature is controlled at the hypothalamus and can be effected by any
number of substances PYROGENS. WBC’s are triggered to release pyrogens by
toxins, bugs, LPS, Ag-Ab, etc.
a) LPS, IL-1 are great pyrogens
2. Fever is GOOD, hears why;
a) WBC’s function better at slightly higher temps
b) Bacterial metabolism slows
F. Other cells involved in the innate response:
1. NK cells; aid in tumor surveillance, kill viral infected cells, role in cellular
cytotoxicity. (become LAK cells)
2. Kcells function in ADCC
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G. Cytokines: Cytokines are low molecular weight proteins that stimulate immune and
inflammatory responses (fig 1)
1. Interleukin-1 (IL-1)
a) Produced by activated macrophages mainly, but other cells also
b) Stimulates the production of other cytokines
c) Stimulates the formation of TH lymphocytes
d) Is involved in inflammatory rxn's via inducing other inflammatory
metabolites like prostaglandin's, collagenase, and phospholipase A2.
2. Interferon Gamma
a) Production in activated T cells (fig 2)
b) Various roles…activates Macrophages, immunomodulatory effects,
promotion of T/B cell differentiation.
c) Stimulates macrophages to degrade myelin (fig 3).
3. Tumor Necrosis Factor alpha and beta (TNF /)
a) Production in macrophages and T lymphocytes
b) Active in inflammation
c) Enhances vascular permeability of endothelial cells.
4. Transforming Growth Factor Beta (TGF )
a) Produced by almost all cell types
b) Play roles in inhibiting many cell types (epithelial, endothelial,
lymphoid)
c) Promotes angiogenesis (blood vessel growth)
d) Chemotactic factor for macrophages
e) Inhibits immune and inflammatory responses by inhibiting the
production of cytokines.
Specific Immunity
1. Cells: B (bone) Lymphocytes and T(thymus) Lymphocytes
2. Antibodies: called immunoglobulins, five types IgG1-4, IgA1-2, IgM, IgD, IgE
Ab quaternary structure – (Multiple myeloma, Bence-Jones proteins)
a) Four-chain structure/ major subunit (H2L2) – bilateral symmetry
i) H (heavy)-chains: are derived from two genes: VH and CH
 CH region defines Ig class; class dictates effector functions (what functions Abs
have in addition to their recognition function). Five basic amino acid sequences
account for the five different regions of the molecule: 
(2) VH region defines part of the recognition function but is highly variable.
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(3) VH and CH are closely linked on the same chromosome; switch recombination is
used to yield gene sets VHC, VHC, VHC, VHC, but not for C
ii) L (light)-chains: also derived form two genes: VL and CL
(1) Two types of light chains; lambda and Kappa
(2) V lambda and Clambda variations are closely linked on one chromosome
(3) V kappa and Ckappa variations are closely linked but on different chromosomes.
(4) The are no kappa/lambda combinations (or vice versa)
(5) CL binds covalently and non-covalently to CH region, binding the heavy and light
chains
VL region defines the other part of the antigen recognition function of the molecule and
interacts with the VH domain non-covalently.
3. Humoral Response
Involves the production of
antibody (Ab) proteins via
activated B cells called Plasma
cells. In response to a foreign
antigen (anything that triggers an
immune response), B cells are
stimulated to divide and produce
Ab's, clonal expansion theory,
which stick to the cell surface of
the bacterium or cancer cell.
Activated
complement
or
cytotoxic T cells can then destroy
the cell (right).
4. Cell Mediated
T lymphocytes have many
varieties. The most important of
which is the helper and cytotoxic
T cell. After initial induction by
antigen producing cell (APC), TH
cells are activated and expand to
release
lymphokines
called
interleukins, protein that activate
other cells. These then in turn
stimulate the TC cell to seek out,
destroy, and stimulate B-cell
proliferation, among other things.
TC does not produce IL-2.
Memory cells arise and give a
long lasting immune memory.
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III.
Immunity is Active or Passive
Active = persons who immune systems recognize Ag and produce Ab against it. Memory cells (B
and T) are major player.
Passive = Ab are passed on to a recipient. E.g., Mothers have IgA that is transferred to the child
through breast milk.
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IV.
Disease States and Immune Disorders
A. Allergies -- Immune systems produces antigens to non-foreign substances
B. Immunologic Injury to nerve cells
1. Autoantibodies to nerve receptors cause disease by stimulation or blocking
receptor function (fig 4).
Clinical Correlation Myasthenia gravis
2. T-cell mediated disease: T helper cells cross the blood brain barrier and react to
single myelin antigens by proliferation, cytotoxicity, and cytokine production
(IFN, TNF ) whereby causing the demyelination of neurons.
Clinical Correlation Multiple Sclerosis (humans)
 Experimental Allergic Encephalomyelitis (Animals)
3. Viral Invasion (Herpes Simplex)
a) Enters the CNS by piggybacking on a lymphocyte or Macrophage.
Follow maxillary division of the trigeminal nerve
Finally, other things that you should know and be comfortable with being able to describe in some
fashion: Signal transduction pathways of cytokine interactions, Immunogentic regulation of Ab/
Glial cell interactions are not well understood or documented.
ST= cell to cell communication via plasma membrane attached protein signaling.
Steps involved in signaling:
1
Control of biosynthesis
2
Release
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Transport of signal to target cells
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Transduction of signal by target cell and amplification
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Alterations in metabolism of cell i.e. mRNA, Transcription, Translation…
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Signal Termination