My favorite topic.

1. I M M U N O L O G YI M M U N O L O G Y
A brief survey
Naira Renault (former Naira Roland Matevosyan) MD, PhD, MSJ
Seton Hall Law School. Emory University. CDC
10.01.2017

2. CONTENTSCONTENTS
Anatomy of Defense
- Primary and Secondary Defense Organs
Naȉve and Learned Immunity
Workhorses of Defense
- Myeloid and Lymphoid Lineages
Major Histocompatibility Complexes: MHC- I and MHC-II
Human Leukocyte Antigens (HLA) and Associated Diseases
Immunoglobulins (Ig) and Ig Deficiency Syndromes
T-cells: Regulated and Educated Assassins
T-cell Deficiency Syndromes
Interleukins: High-yield Cytokines
Compliment Systems: The Confusing Cascade
Complement Deficiencies and Associated Disorders
Hypersensitivity Responses: Types 1 - 4
Graft Immunity: High-yield Immunosuppressants
Review Q & A and Court Holdings
4 - 14
15
16
17
18
19 - 21
22
23
24
25
26
27 - 28
29
30 - 31

3. Foreword
I find nothing more gratifying than talking about the human immunology with my
students, although obstetrics-gynecology is my specialty.
An up-to-the-minute institution, immune defense could serve as a model for man-made
military establishments, be that Department of Defense, Artillery, Navy, Air Force,
Coast Guard Reserve, or Cyber-security.
There is much to observe and imprint from: for instance, how the thymic cortex
“educates” (positive selection) T-cells toward distinct certification (killers, helpers,
regulators) and how those who “fail the tests” for being either “paranoid or
hypersensitive ” are blocked from the peripheral mechanisms (negative selection) to
prevent autoimmune conflict.
At the risk of witticism, some resemblance between the military maneuvers and
immune defense tactics are presented below. As you see, when it comes to immune
defense, there is no place for petty guerrilla warfare:
MILITARY MANEUVERS IMMUNE DEFENSE MILITARY MANEUVERS IMMUNE DEFENSE
Reconnaissance patrol
MHC I and MHC II,
thymic cortex, spleen's
white pulp, AIRE, mT
Leapfrogging
Th2, Ig switching,
IL-4, CD4+ T-cells
Hull-down
IL-1, IL-2, IL-3, TNF-α,
CD40 ligand
Center Peel
Complement 5 ,
IL-8, opsonization
Linear Ambush APCs, IL-10, IL-12 Coup de grace
CD8+, C5b-9,
cytokines

4. Anatomy of Defense
PRIMARY LYMPHOID ORGANS (bone marrow and thymus) function as
“boarding schools” for immature progenitor cells to generate, mature, and
educate young lymphocytes in an antigen-independent manner.
– Bone Marrow: A critical primary defense organ, it consists of red
marrow (the bone parenchyma, containing hematopoietic stem-cells
which generate all blood cell lines, including B and T cells), and yellow
marrow (the stroma, a supportive adipose tissue).
– Thymus: The high cellular-density cortex is for positive selection of
immature T-cells, the cortico-medullar junction for negative selection of
T-cells through apoptoric signal, and the low-cellular density medulla for
housing both positively and negatively selected mature thymocites.
SECONDARY LYMPOID ORGANS (peripheral lymph nodes, jugular and
subclavian trunks, parotid nodes or tonsils, occipital, mastoid and
mediastinal nodes, adenoid, appendix, spleen*, mucosa-associated
lymphoid tissue or MALT, etc) are where lymphocytes differentiate and
undergo clonal expansion (quantitative growth) in an antigen-dependent
fashion (i.e. to act only when there is a foreign invader). *See slide 11.
4

5. Thymus
THYMUS is a central, yet temporary organ of immune defense. It bridges
between the innate (naive) and adaptive (learned) immune systems. As a
primary lymphoid organ (along with the bone marrow), it is responsible
for de novo generation of immunocompetent T-cells with a diverse
repertoire of antigen-recognition.
Thymus originates from the ventral wings of the 3rd branchial
(pharyngeal) pouch at 5-6 weeks of gestation, extending laterally and
backward into the surrounding mesoderm and neural crest-derived
mesenchyme (later to be the capsule) in front of the ventral aorta. (The
dorsal wing of the same 3rd branchial pouch gives rise to the inferior pair
of parathyroids and the 9th cranial nerve – glossopharyngeus).
5
Complex thimyc embryology (endoderm, mesoderm)
explains why the phagocytes of thymic medulla
negatively select auto-reactive CD4+ and CD8+
thymocytes and eliminate T-cells bearing
autoreactive T-cell antigen receptors (TCRs), and
why thymic cortex positively selects cadet T-cells.

6. Thymus (continued)
Branches of the
internal thoracic artery
and superior thyroid
artery supply the gland.
Veins fall in the left
brachiocephalic vein
(innominate vein) and
in thyroid veins.
Nerves are exceedingly
minute and derived
from the vagus and
sympathetic n. system.
Branches from the descended hypoglossi and phrenic nerves reach
the investing capsule, but do not penetrate into the substance of the
organ. 6

7. Thymus (concluding)
The two main components of thymus,
lymphoid thymocytes and thymic
epithelial cells, have distinct
embryonic origins. Such a network
forms an adventitia to the blood
vessels.
The medullar reticulum is coarser than
the cortex; lymphoid cells are relatively
fewer and peculiar bodies with the
unknown function (corpuscles of
Hassall) are found, composed of
granular cells encapsulated by
eosinophilic type VI epithelial cells.
Autoimmune regulator gene (AIRE) is
expressed by thymic medulla, to drive
the transcription of organ-specific
genes (insulin receptor genes) to allow
maturing thymocytes be exposed to
more complex set of self-antigens than
that in the cortex. 7

8. Thymic cortex is where positive selection takes
place, ensuring that T-cells have the bare minimum
functionality of binding cell-surface proteins major
histocompatibility complex class I (MHC-I) and II
(MHC-II). Most immature T-cells do not pass this
stage and therefore undergo apoptosis. The ones
that get “certified” for binding with MHC-I are CD8+
T-cells (assassins), those who are assigned to bind
with MHC-II are CD4+ T-cells (helpers).
Corticomedullary junction is where T-cells undergo
negative selection. Positive-selection finalists are
presented with self-antigens. If their specificity is
too high (“paranoid” T-cells), they see body's own
normal antigens as alien invaders) for what they
are destroyed by apoptotic signal. Some highly
autoreactive cells, however, are able to pass the
negative selection, but are eliminated by
peripheral mechanisms (anergy, regulatory T-
cells). If such last-resort mechanisms fail, then
body becomes predisposed to autoimmune
diseases.

9. Lymph Nodes
Secondary lymphoid organs (spleen,
lymphoid nodes, tonsils, adenoids, MALT)
are sites where lymphocytes undergo
differentiation with an antigen-dependent
intelligence.
Lymph nodes are encapsulated and
trabeculated with multiple afferent
vessels and with only one efferent vessel
(many ways in and only one way out!).
Flow through the node: Afferent vessel
→ subcapsular sinus → trabecular sinus
(phagal filtration) → efferent vessels.
9
Each anatomical division of the node has its specific function. Medulla consists of
cords, densely packed lymphocytes, and sinuses (reticular cells, macrophages).
Paracortex contains endothelial venues for the entering B and T-cells and enlarges
during the cellular adaptive response. Cortex has follicles to host the migrating B-
cells. Primary follicles are densely packed and dormant; secondary follicles (after
antigen response activation) are large and contain pane germinal cells.

10. Spleen
Known as a defense
and purifying organ
but not a vital one,
spleen is typical to
nearly all vertebrates,
with an exception of
lampreys and
hagfishes. In a healthy
adult human, spleen is
a shoe-shape,
singleton, obliquely
oriented parenchymal
organ positioned
beneath the T-9th
and
10
T-11th
ribs in the left hypochondriac region, between the gastric fundus and diaphragm,
and separated by costodiaphragmatic recess. The convex (pariental, phrenic) surface looks
at the diaphragm and the concave visceral surface (hilus) faces the porta, pancreatic islet,
left kidney, stomach, and the spleno-omental fold of Morgenstern known as the "criminal
fold." Vessels entering or exiting the hilus form letter "S," if one connects the upper polar,
hilar, and lower polar vessels. Spleen undergoes involution after 60 years.

11. Spleen (continued)
Spleen functions as a secondary
“lymphoid organ.”Yet, thinking of
spleen as the “largest lymphatic
organ” is a confusion* (see slide
4). Spleen can't be a “giant lymph
node” since there is no
connection of splenic lymphatic
net with other lymph vessels.
Rather, spleen is the bulky
component of the
reticuloendothelial complex.
The splenic primordium becomes
detectable during the 5th
gestation weeks as an outgrowth
11
of dorsal mesogastrium. Splenic lobules form around the central arteries in the
13th
-14th
weeks of pregnancy.
Spleen has 3 to 5 vascular segments named S1-S5 (slide 12). Subsequent to its
origin from the celiac trunk, the splenic artery courses leftward and
retroperitoneally under the posterior wall of the omental bursa, along the
posterior-superior edge of the pancreatic islet, with multiple branches into
pancreatic parenchyma.

12. Spleen (circulation)
Splenic aretery is a branch of the celiac trunk, arising
together with common hepatic and left gastric arteries.
Its length (8 - 32 cm) and characteristic tortuous
appearance is easy to identify with angiographic
studies. The artery's termination in the splenic porta is
unpredictable, due to the number of branches to
spleen and neighboring organs (left kidney, stomach,
omentum). Branches of splenic artery include:
12
short gastric arteries,
posterior gastric artery,
left gastroepiploic artery,
dorsal pancreatic artery,
transverse pancreatic
artery, great pancreatic
artery, caudal pancreatic
artery, as well as multiple
collateral and atypical
branches.

13. The only splenic vein joins the superior mesenteric vein to
form the portal vein. Splenic vein originates from several
veins leaving the splenic hilum and joining at variable
distances. These venules closely follow the arterial
distribution.
Spleen weighs 1/4 of lymphoid mass of the body (while
lymph in bone marrow corresponds to the 1% of body's
weight). Spleen is approximately ½ of the weight of liver.
The lymphatic vessels of spleen form the splenic capsule
and some of the larger trabeculae. One of the paradoxal
features is the scarce lymphatic net of the splenic pulp.
Sympathetic -noradrenergic
innervation of spleen (supplied by the
medial and anterior parts of the
celiac plexus) is regional and unique.
Postganglionic nerve fibers enter
spleen with splenic artery, run along
the trabecular plexi, extend into the
white pulp along the central artery
and end in periarterial lymphatic
sheath. Regions of T-cells and plasma
cells (not B-cells) are targeted.

14. Spleen (concluding)
Most of the blood flow passes through the splenic marginal zone and directly via the
white pulp, ensuring an efficient monitor. While the white pulp is mainly for the
adaptive immunity, the marginal zone is involved in both innate and adaptive
responses through specific metallomorphic macrophages and B-cells.
In addition to pattern-recognition receptors (Toll-like receptors) expressed by most
tissue macrophages, marginal-zone metallomorphic macrophages express a C-type
lectin SIGNR1 and type-I scavenger receptor MARCO. SIGNR-1 efficiently binds
polysaccharide antigens (Micobacterium Tuberculosae, Streptococcus Pneumoniae, E-
coli, Staphylococcus aureus).
Marginal-zone macrophages lack the expression of MHC class II molecules and
subsequent activation of marginal-zone-B cells occurs through shedding of pathogen-
degradation products that are opsonized by complement.
When signaling through LT-β receptors (LT-βR) or TNF receptor 1 (TNFR1) is lacking,
levels of homeostatic chemokines CXCL13, CCL19 and CCL21 are reduced in spleen,
resultant in disorganization of the white-pulp. Chemokines CCL19, CCL21 (produced by
the stromal cells of T-cell zone) play a crucial role in regulating T-cell zone integrity.
Splenectomy leads to mild thrombocytosis (spleen can store 1/3 of total body
platelets, so removal allows more circulate in plasma), Howell-Jolly bodies (RBC
remnants), poorer response to vaccines, and higher risk of certain infections:
Haemophilus influenzae, Neisseria meningitidis, Salmonella typhi - “SHiNS”. 14

15. Naive and Learned Immunity
Innate (naive) immune system
is characterized by fast and
non-specific to infection and
lack of immune memory. It
recognizes foreign antigens
that are highly conserved over
time and across pathogenic
species. For example,
lipopolysaccharide (LPS) is a
component of the cell-wall
conserved between gram
15
-negative bacteria. Toll-like receptors are able to recognize LPS and, once bound, activate
the release of inflammatory cytokines. Constituents of innate immunity include:
phagocytes (neutrophils, macrophages, dendritic cells), natural killers (NK), mast cells,
complement system, and epithelial (mucose, epidermal, entothelial) barriers.
Adaptive (learned) immune system is featured with slow initial response to the 1st-
time antigen exposure and more rapid/robust/diverse antigen-specific responses
during subsequent exposures secondary to “immune recollections.” It is divided into
humoral (circulating antibodies) and cell -mediated immunity (antigen-specific CD+ T-
cells, antigen presenting cells (APCs) like B-cells, dendritic calles, macrophages).

16. Workhorses of Defense
All cells of immune system originate from hematopoietic stem-cells of the bone marrow. These
are multipotent cells (are able to form all blood cell lines) and have the capacity of self-renewal.
They further differentiate to form myeloid and lymphoid cell-lines:
MYELOID LINEAGE
➔ Basophil: Mature cell with bilobed nucleus and large blue granules.
➔ Dendritic cell: Have long cytoplasmic arms capable of efficient antigen presentation to
lymphocytes (professional antigen-presenting cells [APCs]).
➔ Eosinophil: Mature cell with bilobed nucleus and large pink granules containing major
basic protein that attacks parasitic and helminthic agents.
➔ Macrophage: Tissue histocyte (differentiated monocyte) capable for phagocytosis, as well
as synthesis and secretion of various cytokines (IL-1, IL-6, IL8, IL-12, TNF-α).
➔ Mast cell: Has small nucleus and large cytoplasmatic granules containing histamine and
other allergic mediators in response to allergies, hives, anaphylaxis.
➔ Monocyte: Circulating phagocytic cell to be further stimulated and differentiated to the
tissue macrophage.
LYMPHOID LINEAGE
➔ B-lymphocytes: Cells that undergo differentiation into either memory B-cells or plasma cells
(that produce antibodies).
➔ T-lymphocytes: Cells that further differentiate to either CD4+ helpers, CD8+ cytotoxic cells,
regulatory T-cells, and memory T-cells.
➔ Natural Killers (NK): CD56+ lymphocytes containing cytoplasmic toxic granules (granzymes)
and are able to kill malignant, virus-infected, and antibody-coated (opsonized) cells. 16

17. Major Histocompatibility Complexes: MHC- 1, MHC-2
MHC system helps us discern ourselves from everything else, as well as detect
when body's own cells are either infected or undergo malignant changes. Two
structurally and functionally distinct classes of MHC are involved:
MHC Class I is present in all nucleated cells of our body and is encoded by
human leukocyte antigen genes HLA-A, HLA-B, HLA-C. MHC is a cell-surface
protein that displays peptide fragments from inside the cell to out. Normally,
the antigen loaded onto MHC-I is an autoreactive antigen and cytotoxic CD8+
T-cells will not react to it. However, if a virus infects a cell, it produces viral
proteins using the host's cellular machinery. These viral proteins too, are
loaded onto MHC-I. This makes cytotixic CD8+ confer immunity to viral
infection, and by recognizing the viral antigen they target to destroy it – if a
costimulatory signal (for anergy) isn't present (discussed in slide 23).
MHC Class II is only present on antigen-coated cells (macrophages, dendritic
cells), is encoded by the HLA genes HLA-DP, HLA-DQ, HLA-DR, and composed
of two α- and β- subunits. After phagocytosing the microbe, the APCs process
and load antigens onto MHC-II. Then, MHC-II is inserted into the cell
membrane to make it recognizable by CD4+ T-cells (helpers) which after
activate B-cells and trigger local inflammation. 17

18. Human Leukocyte Antigens (HLA)
and Associated Diseases
HLA SUBTYPE DISEASES
A3 Hemochromatosis
B8 Graves disease (hyperthyroidism)
B27 PPsoriasis, AAnkylosing spondylitis,
IInflammatory bowel disease, RReactive
arthritis (PAIR)
DR2 Goodpasture disease (glomerulonephrosis)
DR3 Type-1 diabetes mellitus
DR4 Rheumatoid arthritis, type-1 diabetes mellitus
DR5 Hashimoto thyroiditis, Pernicious anemia
18

19. Immunoglobulins
Antibody formation is accomplished by mature plasma B-cells which
synthesize and release immunoglobulins (Ig) after being activated by the
appropriate mechanisms of antigen stimulation. The number of
antigens is unlimited; so too the number of activation mechanisms. This
is called antibody diversity and is built on four main processes:
1) Random recombination of VJ (light chain) or V(D)J (heavy chain) genes
2) Random combination of various heavy chains with light chains
3) Somatic hypermutation in germinal centers (after antigen stimulation)
4) Terminal deoxynucleotidyl transferase (TdT) addition of DNA to the heavy
and light chains.
The common antibody isotypes are IgM and IgG. Isotope switching
occurs after antigen stimulation and activation of B-cells, resulting in
alternative splicing of messenger - mRNA. The resultant post-
translational modification of mRNA dictates the isotype of plasma B-
cells (IgA, IgG, IgE, IgM, etc).
19

20. Ig and Ig Deficiency Syndromes
IgA: Occurs as a monomer in bloodstram and as a diamer when secreted
(epithelial cell component). IgA is secreted onto mucosal surfaces (GI, GUI,
respiratory) to block attachment of pathogens to mucose membranes.
IgD: Found on the surface of mature B-cells. Function is unclear.
IgE: Implicated in allergic response (type-1 hypersensitivity) because it
binds with both mast cells and basophils and undergoes cross-linking after
exposure to appropriate antigen.
IgG: The main antibody in the secondary (slow) antigenic response. Occurs
as a monomer in complement fixing job, cross the placenta to provide
passive immunity to developing fetus, opsonize bacteria, neutralize various
toxins and viruses. IgD does not make multimers and therefore, it does
cross the placenta.
IgM: Found on the surface of mature B-cells. Produced in the primary, fast
antigen response. Occurs as a monomer and commonly as a pentamer for
more efficient trapping and complement fixing. As a pentamer is does not
cross the placenta. 20

21. B-cell Deficiency and Ig Deficiency Syndromes
● COMMON VARIABLE IMMUNODEFICIENCY: Most common form of
primary B-cell deficiency with distinct low levels of IgG and IgA (rarely IgM)
resultant in high rates of lymphomas and gastric cancer.
● HYPER IgM SYNDROME: Normal level of B-cells, with diminished levels
of IgG and IgA and higher levels of IgM. Associated with increased risk for
Pneumocystis infections (fungi). Conditioned with inability of isotype
switching and sequential secondary deficiency in CD40 ligand on Th2 cells.
● SELECTIVE IgA DEFICIENCY: Most common type of Ig deficiency,
associated with increased respiratory, GI, GUI infections, and high risk of
anaphylaxis from blood-product transfusions.
● X-LINKED AGAMMAGOBULINEMIA (Bruton agammaglobulinemia):
Results from a mutation in the receptor tyrosine kinase (BTK). Present
exclusively in males. Children with XLA are usually healthy for the first
months of infancy, as they are protected by the maternal antibodies. After,
they begin to develop recurrent infections, resistant to anti-microbal
treatment. 21

22. T-cells: Regulated and Educated Assassins
As noted before, T-cells originate from the lymphoid lineage of
hematopoietic differentiation. They are “born” in the bone-marrow and
“trained” in the thymus. It is in thumys where they get “certifications” of
helpers (CD4) or assassins (CD8).
CD4+ T Cells: These “helpers” (Th) will undergo further differentiation
after appropriate stimulation by interleukins to become either Th1 or
Th2 with specific functions to help regulate both humoral and cell-
mediated immunity.
- Th1 are involved in regulation of cell-mediated response, and are
activated by APCs and secret interferon-gamma (IFN-γ) which in turn
activates APCs for efficient killing. They also secrete IL-2 which activates
CD8+ to kill virally infected cells.
- Th2 are involved in activating B-cells and enhancing isotype
switching by secreting IL-4, IL-5, and IL-6.
CD8+ T Cells: These cytotoxic cells are responsible for seeking out and
eliminating virus/parasite-infected cells, cancer cells, and other foreign
cells.
22

23. T-cell Deficiency Syndromes
Viral infection has unique activation arrays. When an APC (dendritic cell, macrophage) is
exposed to viral antigen, it will load the latter onto MHC-II for presentation to the CD4+
T-cell. It will also express co-stimulatory signal. The T-cell receptor (TCR) then interacts
with antigen-positive MHC-II on the APC. Yet, a single signal is not enough. Immune
system's checks and balances require a second signal for an appropriate activation. This
B7 costimulatory signal on the APC must interact with CD28 on CD4+ T-cell while the
TCR-MHC II interaction is occurring. If these conditions are met, then CD4+ T-cell will
also release IL-2 to activate CD8+ killers and differentiate CD4+T-cell in autocrine
manner. If TCR, weirdly sees and binds to host antigens (autoreactivity), immune system
tackles with this issue by anergy command, i.e. deactivating self-reactive T-cells. If this
process fails as well, then autoimmune disorders occur.
T-CELL DEFICIENCT SYNROMES:
- Acquired Immunodeficiency Syndrome (AIDS): The final stage of the decremental
quantity and quality of T-cells (CD4+) caused by HIV.
- Ataxia Telangiectasia: A T-cell deficiency along with cerebellar ataxia and increased
risk for various types of cancer (impaired double-strand DNA repair).
- DiGeorge Syndrome: 22q11.2 deletion syndrome resultant in CATCH-22 (Cardiac
defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalciemia).
- Severe Combined Immunodeficiency (SCID): The common form of X-linked disorder
with suspectibility to numerous pathogenic infections with diarrhea, pneumonia, otitis,
sinusitis.
23

24. Interleukins: High-yield Cytokines
IL-1: An acute phase reactant produced by macrophages, inflicting fever,
leukocyte recruitment, adhesion molecule activation, and stimulation of
further chemokines.
IL-2: Secreted by Th cells to enable growth, maturation, and proliferation of
CD4+ and CD8+ T-cells.
IL-3: Stimulates the bone marrow.
IL-4: Secreted by the Th2 it furthers the B-cell development and enhances Ig
isotype switching to IgG.
IL-5: Secreted by the Th2 cells it enhances Ig class switching to IgE and
increases production of eosinophils (allergic response).
IL-6: Like IL-1, this is an acute-phase reactant produced by Th and
macrophages to further an acute inflammatory response and to stimulate
antitel production.
IL-8: The neutrophil chemotactic factor.
IL-10: Secreted by the regulatory T-cells, it suppresses cell-mediated
immunity and stimulates humoral immunity.
IL-12: Secreted by the macrophages, it enhances NK-cells and T-cells. 24

25. Compliment Systems: The Confusing Cascade
Complement is a system of liver-derived serum proteins that - once activated
trigger a cascade of proteolytic cleavage reactions to further the cascade and
convert pro-proteins into functional and active immune constituents.
There are three main initial pathways that activate C5 and initiate the final
response - formation of the membrane attack complex (MAC):
● Classical pathway → antigen → antibody complexes
● Mannan-binding lectin pathway → microbial lectin particles
● Alternative pathway → microbial surfaces like LPS/endotoxin.
Main functions of the complement system include:
1. Opsonization → C3b
2. Neutrophil chemotaxis → C5a
3. Viral neutralization → C1, C2, C3, C4
4. Lysis (membrane attack complex) → C5b-9
5. Anaphylactic reaction → C3a, C5a. 25

26. Complement Deficiency and Associated Conditions
26
C1 esterase inhibitor deficiency: Hereditary angioedema
Decay-accelerating factor (CD55)
deficiency:
Paroxysmal nocturnal
hemoglobinuria
Protectin (CD59) deficiency: Paroxysmal nocturnal
hemoglobinuria
C3 deficiency: Propensity to develop severe
recurrent pyogenic infections of the
sinus and respiratory tract
MAC deficiency: Propensity to develop Neisseria
bacteremia (gonorrhea or meningitis)

27. Hypersensitivity Responses: Types 1, 2
TYPE 1 (Allergy): Occurs when presensitized mast cells or basophils with
antigen-specific IgE are exposed to a particular antigen. The antigen binds
the Fab portion of IgE, cross-linking and immediately releasing performed
vasoactive substances (histamine, for instance). Examples: allergic
rhinitis, atopic dermatitis (eczema), hives (urticaria), asthma, and
anaphylaxis. Anaphylactic reactions occur in same Type-1 fashion but in
fast and widespread vasodilation and subsequent shock (normovolemic
or hypovolemic hypotension).
TYPE 2 (Antibody-dependent Cytotoxicity): Occurs when either IgM
or IgG bind to the cell surface antigen leading to cytotoxic destruction by
various mechanisms, including opsonization (for neutrophils),
complement activation, and interference with cellular functioning.
Examples: autoimmune hemolyitc anemia, idiopathic thrombocytopenic
purpura (ITP), acute transfusion reactions with hemolysis, rheumatic
fever, Goodpasture syndrome, bullous pemphigoid, vulgar pemphigus,
Graves disease, myasthenia gravis. 27

28. Hypersensitivity Responses: Types 3, 4
TYPE 3 (Immune Complex Disease): Occurs when antigen-antibody
(mainly IgG) complexes are formed and deposited in tissues, resulting in
activation of complement systems and recruitment of neutrophils leading
to the tissue injury. Examples: systemic lupus erythematosus (SLE),
rheumatoid arthritis, Arthus reaction, serum sickness, post-streptococcal
glomerulonephritis.
TYPE 4 (Delayed, Antibody-dependent Cytotoxicity): Being not
antibody related, these are the only reactions that are not transferred by
serum. These are slow, cell-mediated reactions occurring when the
learned T-cell interacts with the same antigen, resulting in lymphokine
production and activation of other players (macrophages). Examples:
contact dermatitis, nickel allergy, PPD test,, GVHD test, multiple
sclerosis, Gullian-Barré syndrome.
28

29. Graft Immunity: High-yield Immunosuppressants
TYPES OF TISSUE TRANSPLANTANTS
● Autograft: Transplanting tissue back to the same host but in a different location.
● Allograft: Transplanting tissue/organ/fluid/cell from one human to another.
● Xenograft: Transplanting tissue from animals to a human being.
TYPES OF REJECTION
Hyperacute rejection: Rapid failure resultant from complement activation and
neutrophil migration into the donor organ.
Acute rejection: T-cell-mediation rejection occurring within weeks to months,
reversible with immunusuppressants.
Chronic rejection: Long-lasting failure with progressive loss of function of the
transplant – secondary to vascular fibrosis.
HIGH-YIELD IMMUNOSUPPRESSANTS
Azathioprine: A prodrug converted in vivo to 6-mercaptopurine (6-MP) to inhibit
purine metabolism and proliferation of T and B cells. Used in acute rejection and
autoimmune disorders.
Cyclosporine: Binds to cyclophilin, which inhibits calcineurin and therefore prevents
transcription of IL-2 in T-cells. Used in tissue transplantation only.
Tacrolimus: Binds to FK-binding protein, inhibits calcineurin (and IL-2). Used as
ciclosporine replacement.
Microphenolate mofetil: Inhibits inosine monophosphate dehydrogenase, the rate-
limiting enzyme in guanosine monophosphate (GMP) synthesis. Used in organ
transplantation only.
29

30. Review Q & A
Q1. Which type of immunization a patient with a compliment disorder
involving deficiency of the membrane attack complex (MAC) should
specifically receive?
A1. That patient is at risk for Neisseria infections, therefore is at high
risk for meningococcal infections. S/he should receive meningococcal (MCV-
4) vaccine.
Q2. A teenage African male with sickle-cell anemia presents for a regular
exam. The peripheral smear shows sickle cells together with RBCs and large
numbers of platelets. Your guess.
A2. The peripheral smear with thrombocytosis and Howell-Jolly bodies
suggests that the patient is after splenectomy or autosplenectomy (from the
chronic splenic infections).
Q3: Which cell type in the human body does not express MHC class I?
A3: MHC-I is expressed by all nucleated cells. Therefore, mature RBC
(erythrocytes) no longer express MHC class I on their membranes. 30

31. Kennedy v. Collagen Corp. (1998)1
● PROCEDURAL HISTORY: Plaintiff alleges injuries sustained by defendant
(Collagen Corporation) and its employees for negligently injecting her Zyderm,
a substance made from the skin, tendons, and connective tissue of bovine
animals, for purposes of cosmetically curing her facial wrinkles. The claimed
side-effect is systemic lupus erythematosus (SLE), for what strict liability, breach
of express and implied warranty, battery, and conspiracy are incorporated in
this malpractice claim. Former two summary judgments, entered for defendant,
were based on insufficient expert testimony (a poor cause-effect relationship
affidavit) on part of plaintiff.
● HOLDING: The district court abused its discretion by improperly applying the
Daubert test, as it failed to consider relevant scientific evidence presented by
plaintiff's expert witness.
● JURISPRUDENCE: Daubert v. Merrell Dow Pharmaceuticals (1993) 2
● DISPOSITION: Judgment of the former court is reversed and remanded.
● REASONING: Daubert's court has established that the trial judge, in making
initial assessment as to the admission of evidence, must determine whether
the expert's testimony reflects (1) "scientific knowledge," and (2) will assist the
trier of fact to understand or determine a material fact at issue. This requires a
preliminary assessment of a number of factors.
1) 161 F. 3d 1226 - Court of Appeals, 9th Circuit 1998; 2) 509 US 579 - Supreme Court 1993

32. DISCLAIMERDISCLAIMER
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