SGD 21: IMMUNOLOGY 1

1. Speculate why some vaccines would require multiple dosing at a given

schedule? May use Fig. 1-7 of Basic Immunology by Abbas & Lichtman, 4th
edition. ​(Martinez G., Martin)

- How vaccination works

- Vaccines help develop immunity by imitating an infection.
- This type of infection, however, almost never causes illness, but it does
cause the immune system to produce T-lymphocytes and antibodies.
- (​add ons:​ Sometimes, after getting a vaccine, the imitation infection can
cause minor symptoms, such as fever. These are normal and should be
expected as the body builds immunity.)
- Once the imitation infection goes away, the body is left with a supply of
“memory” T-lymphocytes, as well as B-lymphocytes that will remember
how to fight that disease in the future.
- (​Add ons:​ However, it typically takes a few weeks for the body to produce
T-lymphocytes and B-lymphocytes after vaccination. Therefore, it is
possible that a person infected with a disease just before or just after
vaccination could develop symptoms and get a disease, because the
vaccine has not had enough time to provide protection.)
- Source:
https://www.cdc.gov/vaccines/hcp/conversations/downloads/vacsafe-understand-
color-office.pdf
- Apply with the figure
- Reason as to why multiple doses is needed for vaccination:
- An Immunologic Memory must be established for the adaptive
immune system since with repeated exposure, this mounts a larger
and more effective responses to the same antigen.
- primary immune response​ - the response to the first exposure is
initiated by naive lymphocytes that are seeing antigen for the first
time. Initially, naive B cells that have been exposed to the antigen
will produce a only a small amount of antibodies
- But with subsequent encounters with the same antigen as with
multiple doses of a certain vaccine, a ​secondary immune
response​ is produced
- more rapid, larger, and better able to eliminate the antigen
than primary responses.
 - Secondary responses are the result of the activation of
memory lymphocytes, which are long-lived cells that were
induced during the primary immune response.
- Immunologic memory optimizes the ability of the immune
system to combat persistent and recurrent infections,
because each exposure to a microbe generates more
memory cells and activates previously generated memory
cells.
- In terms of the vaccination schedules, there is a need to comply, since
antibody levels decline with time after each immunization. If it’s not
followed then the immunologic memory won’t be established which may
provide the better secondary response against the exposure with an
antigen.
2. Give the physiologic basis of giving both tetanus toxoid and immunoglobulin to
an adult with unrecalled immunization history who sustained multiple lacerations
after a surfing accident. ​(Mariano)

● What is Tetanus Toxoid?

○ Used to prevent tetanus (also known as lockjaw).
■ Tetanus is a serious illness that causes convulsions (seizures) and
severe muscle spasms that can be strong enough to cause bone
fractures of the spine.
■ Tetanus causes death in 30 to 40 percent of cases.
● What is the recommended dosing for Tetanus Toxoid?
○ Immunization against tetanus is recommended for all infants 6 to 8 weeks
of age and older, all children, and all adults.
○ Immunization against tetanus consists first of a series of either 3 or 4
injections, depending on which type of tetanus toxoid you receive.
■ In addition, it is very important that you get a booster injection every
10 years for the rest of your life.
■ Also, if you get a wound that is unclean or hard to clean, you may
need an emergency booster injection if it has been more than 5
years since your last booster.
○ A tetanus infection in the past does not make you immune to tetanus
in the future.
● What does Tetanus Toxoid do in our body?
○ Tetanus toxin (or Tetanospasmin) is taken up into nerve terminals of lower
motor neurons, the nerve cells that activate voluntary muscles.
■ Tetanus toxin is a zinc-dependent metalloproteinase that targets a
protein (synaptobrevin/vesicle-associated membrane
protein—VAMP) that is necessary for the release of
neurotransmitter from nerve endings through fusion of synaptic
vesicles with the neuronal plasma membrane.
○ The initial symptom of local tetanus infection may therefore be flaccid
paralysis, caused by interference with vesicular release of acetylcholine at
the neuromuscular junction, as occurs with botulinum toxin.
○ However, unlike botulinum toxin, tetanus toxin undergoes extensive
retrograde transport in the axons of lower motor neurons and thus
reaches the spinal cord or brainstem​.
■ Here, the toxin is transported across synapses and taken up by
nerve endings of inhibitory GABAergic and/or glycinergic neurons
that control the activity of the lower motor neurons.
 ■ Once inside inhibitory nerve terminals, tetanus toxin cleaves VAMP,
thereby ​inhibiting the release of GABA and glycine.
● The result is a partial, functional denervation of the lower
motor neurons, which leads to their hyperactivity and to
increased muscle activity in the form of rigidity and spasms.
● the effect of tetanus toxin may be both biochemical and
structural.
○ Temporary reduction of GABA terminals.
○ Inhibition of release of inhibitory neurotransmitters
from inhibitory interneurons.
● What is the reason why we give both Tetanus Toxoid and IgG for patients
with unrecalled immunization after laceration wounds?
○ Done to initiate ​BOTH the active and passive immunities in the
individual
○ Tetanus toxoid vaccine is meant to induce the active immunity by having
the injured individual create his/her own antibodies against the tetanus
vaccine. However since this process takes time to accomplish, and may
not be able to respond in time to an infection, it is necessary to also
induce a passive immune response through TIG.
○ Tetanus infection does not induce natural immunity.
■ This is because tetanospasmin is so potent that even a lethal dose
is insufficient to provoke an immune response — by contrast, the
tetanus vaccine contains a much larger amount of inactivated
toxoid which stimulates protective antibody levels.
● This stimulation od protective antibody will take time and will
be potent for at least 5 years.
● Boosters are required every decade and everytime a
suspicious wound is indicated.
○ Wounds that are covered with soil and dirt.
○ The tetanus vaccine contains ​inactivated tetanus toxoid​.
■ This is prepared by treating tetanus toxin chemically (usually by
formaldehyde) to render it nontoxic without losing its immunogenic
properties.
■ The toxoid is then concentrated, purified and absorbed onto a
suitable adjuvant.
○ Immunization with tetanus toxoid stimulates the body to create protective
antibodies to the tetanus toxin.
○ After receiving primary doses of the vaccine, antibody levels greatly
exceed the protective levels of 0.1 IU/mL.
 ■ However, antibodies decrease over time, and the CDC
recommends a booster every 10 years.
■ It is also recommended that anyone who ​receives a wound that is
neither clean nor minor and has not had a booster in more
than five years should receive one​.
○ The vaccine is nearly 100% effective in preventing tetanus and almost all
reported cases of tetanus are in persons who have either never been
vaccinated, or who completed a primary series but have not had a booster
in the preceding 10 years.
○ Administering immunoglobin (TIG - Tetanus Immunoglobulin) to an
individual with unrecalled TT immunization is part of suggested treatment
in avoidance of Tetanus.
○ The passive immunity would last only for the limited lifetime of the
immunoglobin, however it is a rapid means of giving the patient the means
to resist infection till the active immunity can take over.
○ The main action of the TIG in the donated blood, is to neutralize the toxins
that has not yet reached the Central Nervous System
○ If it has reached the CNS, treatment will now focus on avoidance of CNS
clinical manifestations
■ Binding to nerves and neurons are irreversible and it would take
weeks to regrow nerve endings.
■ Anticonvulsants, sedation, neurmuscular blocks and ventilatory
support are a few of the needed treatments.

Sources:
CDC study on Pathophysiology of
Tetanus Infection (2003)
Online Resources from webmd,
mayoclinic and WHO.
Porth’s Pathophysiology
3. An 8-year old boy sustained a dirty (bacteria contaminated) nail puncture wound
on the left knee. Hours later, he developed pain, swelling, and redness at the site
of puncture. Two days later, he developed swollen and tender lymph node on his
left inguinal area. Enumerate the immunologic events that occured from the time
of injury until the enlargement of the inguinal lymph nodes and classify them as
innate or adaptive immune response. ​(Marasigan, Medrano)

● Hemostasis Phase​: In the first phase, platelets – blood cells that are critical in
forming clots – aggregate at the damaged site and initiate clot formation to
prevent blood loss and create a temporary covering that provides protection from
the external environment.

● Following the Hemostasis phase:

The four cardinal signs of inflammation— (redness, swelling, pain, heat)
redness (Latin ​rubor)​ - caused by the dilation of small blood vessels in the area
of injury
swelling (​tumor​) - caused primarily by the accumulation of fluid outside the blood
vessels
pain (​dolor)​ - associated with inflammation results in part from the distortion of
tissues caused by edema, and it also is induced by certain chemical mediators of
inflammation, such as bradykinin, ​serotonin​, and the ​prostaglandins

● heat​(​calor​) - not mentioned in the case

-results from increased blood flow through the area and is experienced only in
peripheral​ parts of the body such as the skin

● Innate immune response​: Cellular receptors are expressed in the different

cellular compartments of epithelial cells, neutrophils and other lymphocytes
where microbes are located for them to be recognized. When the epithelial
barrier of the skin is broken, epithelial cells produce peptide antibiotics that kill
bacteria. Moreover, neutrophils, macrocytes are recruited to fight off the invading
bacteria through the following proteins:
○ Selectin - mediated rolling
○ Integrin - mediated firm adhesion
○ Chemokine - mediated motility

● Dendritic cells also respond to microbes by producing cytokines that recruit

leukocytes and initiate adaptive immune response.
● However in the process, inflammation occurs when lysosomal proteases in the
phagocytes are liberated into the extracellular space, thus causing damage to the
surrounding tissues.

● Later, the ​adaptive immune response occurs when the innate response acts as
a second signal for its initiation. By this time the infection may have spread to
further tissues, thus necessitating the creation of antibodies from the
B-lymphocytes and the activation of T-lymphocytes to mount a more efficient
response and assist in the killing of infected cells.

● T lymphocytes activation:
○ Interferon Gamma produced by NK cells in response to microbes
stimulate dendritic cells and macrophages to produce costimulators and
IL-12 to activate and stimulate the differentiation of naive T cells into the
effector cells of either helper T or cytotoxic T cells.

● Moreover, enlarged lymph nodes, are manifestations of areas wherein

B-lymphocytes are producing antibodies to combat the infection. T-cells as well
as more effector cells are also activated to work at the site of infection to either
assist the phagocytes by releasing cytokines, or inducing cell lysis of infected
cells by secreting cytotoxic substances such as CD8.