Download Immunologic Concepts -Overview of Phagocytic, Cell Mediated

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Proceeding of the NAVC
North American Veterinary Conference
Jan. 8-12, 2005, Orlando, Florida
Reprinted in the IVIS website with the permission of the NAVC
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Published in IVIS with the permission of the NAVC
Small Animal - Immunology
IMMUNOLOGIC CONCEPTS - OVERVIEW OF
PHAGOCYTIC, CELL MEDIATED & HUMORAL
IMMUNITY
Leah A. Cohn, DVM, PhD, DACVIM
College of Veterinary Medicine
University of Missouri, Columbia, MO
INTRODUCTION
Because the immune system must ward off or kill a wide
variety of pathogens, and yet manage to recognize and avoid
attacking the host’s own tissues, it requires complex,
redundant, and overlapping systems of effectors and
regulators. Our understanding of these systems has grown
exponentially in recent years. A basic understanding of these
systems is important for veterinarians as they recognize and
treat a myriad of infectious and immunologically mediated
diseases.
Protection from infection is not entirely immunologic.
Crucial physical defense systems provide the initial barrier to
infection. In addition to physical barriers (e.g., skin, epithelial
surfaces), physical defenses include directional movement
(e.g., respiratory mucociliary escalator, cough, sneeze,
flushing action of urination), chemical properties (e.g., acidic
gastric pH, concentrated urine, secreted antimicrobial
molecules), and more. When these systems malfunction,
infection follows. Immunity is integrally tied to inflammation,
although the two aren’t quite the same thing. Inflammation is
a cyclic, complex series of events initiated when tissue is
injured (by pathogens, trauma, chemicals, or nearly anything)
designed to destroy, dilute, and wall off the injurious agents.
It utilizes both soluble mediators (e.g., cytokines, histamine,
serotonin, eicosanoids, kinins, complement, coagulation
factors) and cells (e.g., monocytes, neutrophils (PMN), mast
cells, platelets, basophils, eosinophils) to accomplish these
goals. Many of these same mediators and cells are integrally
involved in immune responsiveness. Inflammation presents
the injurious agent to the immune system, which attempts to
eliminate the agent. If successful, inflammation resolves.
Immunity itself is often categorized as innate and adaptive.
Innate immunity is “ready to go”, and requires no previous
exposure to a pathogen. Adaptive immunity “learns” from
prior exposure. After initial exposure to a pathogen, memory
forms of that specific pathogen allowing a more rapid,
precise, and effective immune response on subsequent
exposure. Both forms of immunity are necessary for health.
An alternative way to classify immunity is into three systems
described as phagocytic immunity (PI), cell mediated
immunity (CMI), and humoral immunity (HI).
PHAGOCYTIC IMMUNITY
Phagocytic immunity is fundamental to innate immunity,
and is carried out by effector cells that literally devour
pathogens or other foreign material. Animals with defective
PI are particularly prone to bacterial and fungal infections.
The two major cell types involved in PI are the PMN and the
monocyte, which develops into a mature macrophage (MØ).
The PMN and MØ share many similarities, but there are key
differences as well. Both cells are derived from myeloid
precursors in the marrow, then released into peripheral
circulation. Both leave circulation to enter tissues under the
influence of chemotaxins, which are chemical signals that
attract phagocytes much the way a hound follows the scent
of its prey. Both use cell surface receptors and ligands,
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including integrins and cell adhesion molecules, to receive
signals and then to carry out actions. Both PMN and MØ are
capable of engulfing many types of particulates (including
pathogens) without prior exposure, but they do so much more
avidly when the target has been opsonized by antibodies or
complement (c’). Both cell types are equipped with a large
arsenal of weapons such as preformed chemical poisons and
newly synthesized oxygen radicals to kill ingested microbes.
There are crucial differences between PMN and M∅ too.
The PMN is a single purpose cell that engulfs the pathogen,
kills it, then itself dies. The M∅ assumes multiple functions
including killing pathogens, but also including roles in tissue
remodeling and repair, inflammation, clean up of debris, and
regulation of immunity.
The M∅ does not die after
completing phagocytosis, but assumes a vital role which ties
innate to acquired immunity. Both the M∅ and closely
related dendritic cells can digest a pathogen into many
individual antigens (recognizable small bits), and then
present those antigens to T-lymphocytes in a recognizable
form, allowing the lymphocytes to orchestrate an adaptive
immune response. Large, inert substances such as metal or
ceramic implants which cannot be digested into small bits by
the M∅ and dendritic cells therefore cannot elicit adaptive
immunologic rejection. Using the military as an analogy for
immunity, the dendritic cells and M∅ provide intelligence
based on which the “brass” can make decisions regarding the
optimum form of attack. Attack can only follow recognition of
the enemy.
CELL MEDIATED IMMUNITY
Cell mediated immunity, carried out by T-lymphocytes, is
quite complex. There are different types of T-lymphocytes,
each with different functions. The most basic distinction is
between the T helper cells (Th, a.k.a., CD4 cells) and the
T-cytotoxic cells (Tc, a.k.a., CD8 cells). The term “CD”
stands for cluster designation, and is simply a numerically
ordered naming system for recognizable molecules on the
surface of cells. The number provides no direct information
on cell type or function of the molecule, and often these CD
numbers also have alternative, descriptive names (e.g., CD4
is the same thing as the MHC II receptor).
Continuing the military analogy, the Tc cells are soldiers
that carry out CMI, while the Th cells are the commanders
who stay back from the front lines and direct the military-like
immune response to the pathogen. Neither the Th cells nor
the Tc cells are capable of recognizing antigen unless it is
presented in a specific fashion. The key to presentation of
antigen is that it must be displayed to the lymphocytes in the
context of a genetically encoded major histocompatibility
complex molecule (MHC) on the surface of a cell. There are
two major types of MHC molecules used to present antigen.
Nearly every cell of the body carries MHC I molecules on its
surface; these molecules can be thought of as identification
badges. The “foot soldiers” of CMI, the Tc cells, examine the
ID badge of the cells they encounter throughout the body.
If the ID badge is recognized as belonging to the host, the
cell is allowed to pass. If the ID badge has been tampered
with, as when there is an intracellular infection or in
transplanted tissue, the soldier kills the cell on sight. On the
other hand, the commanding Th cells need more detailed
information to organize an all out attack; the question of
whether they should mount a cell mediated or humoral
response is somewhat like deciding whether air strikes or a
ground attack is more appropriate and then calling in the air
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The North American Veterinary Conference – 2005 Proceedings
force or army. The commander Th cells only respond to
information gathered by specialized intelligence units, or
antigen presenting cells. These cells, including M∅, dendritic
cells, and even B-lymphocytes, gather information about the
pathogen and present it to the Th cells in the context of
surface MHC II molecules.
Once the Th cells have been presented with information
from the antigen presenting cells, they consider all the
circumstances and choose the most appropriate course of
action. They decide if they should ignore the threat, or if they
should mount an attack using CMI or HI. The type of attack
is directed in large measure by the secretion of chemical
cytokine signals from the Th cell. The Th cells develop into
one of two mutually inhibitory types – T helper 1 or T helper 2
cells. These cell types don’t differ in structure, but rather in
the type of cytokines they secrete. The Th1 cells promote
CMI to defend from intracellular pathogens, activate M∅ and
resist bacterial infection, and promote delayed type
hypersensitivity. The Th2 cells provide antibody mediated
responses including protection from parasites as well as
mediation of allergic responses. The two responses are
antagonistic, meaning that stimulation of Th1 inhibits Th2
response and vice versa. This means that animals with a
chronic parasite burden, for instance, may be less capable of
effectively dealing with viral, bacterial, or fungal infection. It
also means that therapy for allergic disease might involve
“tricking” the immune system into turning away from a Th2
response and towards a Th1 response.
HUMORAL IMMUNITY
Humoral immunity is mediated by B lymphocytes, but
requires significant “help” from T-lymphocytes, and
particularly from Th cells. The B cells have 2 basic jobs; to
serve as an alternative type of antigen presenting cell and to
cause the secretion of antibodies. Antibodies come in a
variety of isotypes (IgG, IgM, IgA, IgE, IgD), each of which is
particularly well suited for specific jobs in a specific
environment. The jobs of the antibodies include opsonizing
pathogens so that they are more readily phagocytized,
triggering c’ activation, promoting cytotoxic reactions to kill
cells or pathogens, preventing attachment and penetration of
pathogens into tissues, neutralizing some toxins, and
providing maternal immunity. Each antibody is a bifunctional
molecule. The aforementioned functions are triggered by the
base (Fc portion) of the molecule. The opposite end of the
molecule (Fab portion) provides specificity to the reactions
carried out by the antibody. The ends of the Fab portion are
configured in such a way that they bind to only a very limited
number of structures, or antigen epitopes.
Specificity is key to adaptive immunity. Both CMI and HI
are restricted by very specific reaction to very specific pieces
of an antigen called epitopes. Any one pathogen, even the
smallest virus, can have hundreds of different epitopes. Only
a very few lymphocytes (T and B) will react with any one
epitope on first encounter. Once an encounter has occurred,
these same few lymphocytes can be stimulated to replicate at
an amazing rate. The specificity of the reaction between the
lymphocytes and the epitope is conferred by receptors for the
epitope on the lymphocyte. In the case of the T cells, it is the
T cell receptor (TCR) that provides specificity. In the case of
the B cell, it is the B cell receptor (BCR). It turns out that the
BCR is an antibody molecule, but instead of a secreted
antibody molecule, it is an antibody attached by its base to
the surface of the B cell. Any single B cell (or T cell) has only
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a single type of BCR (or TCR), but it has hundreds of them.
When the BCR (or TCR) binds to the epitope that fits the
receptor, and the lymphocyte receives the needed costimulatory signals, then that lucky lymphocyte is stimulated
to proliferate.
In the case of HI, stimulated B cells go on to develop into
plasma cells and memory cells. Plasma cells produce and
secrete large quantities of antibody to fight the immediate
threat. Once the threat is gone, proliferation and stimulation
of the lymphocytes ceases and the immune response
becomes inactive. The memory cells, however, persist.
These cells allow a second meeting with the same pathogen
to trigger a more rapid response. This is one of the key ways
in which active vaccination works. An injected epitope (either
from an inactivated intact pathogen, a killed pathogen, or just
a piece of a pathogen) stimulates memory cells that can then
recognize the same epitope from a real infection later on, and
triggers a rapid response to the pathogen.
IMMUNOLOGIC TOLERANCE
Immune responsiveness must be regulated in both quality
and quantity to avoid damaging the host tissue. Regulation
begins with immune tolerance, or the ability to tolerate or
ignore given antigens. Since nearly any cell can serve as an
antigen, the host must learn to ignore their own cells, and to
ignore antigens that will not cause harm (e.g., food antigens,
pollens, commensal bacteria). Just as there are many ways
to stimulate immunity, there are many ways to induce
tolerance. Central tolerance begins in utero, in the thymus
for T-lymphocytes and in the marrow for B lymphocytes.
Although both cell types can be made tolerant, it is more
important to render T cells tolerant since they provide needed
help for both CMI and HI. In the thymus, T cells are first
positively selected to recognize self MHC. Those that do
recognize self MHC proliferate. Next, T cells undergo
negative selection. Self antigens from most of the body
reach the thymic tissue in utero. Those T cells that bind to
self antigens are caused to die via apoptosis (as opposed to
necrosis), and they simply disappear. This “clonal deletion”
means that progenitors of self-reactive T cells are simply
wiped out before birth. Because not all self reactive clones
will be eliminated, there are mechanisms of peripheral
tolerance as well, including sequestration of antigens,
deletion of self-reactive cells in the periphery, rendering selfreactive cells non-reactive through lack of co-stimulation, and
deviation of the immune response. Failure of immunologic
tolerance can lead to autoimmunity. Failure of immune
regulation can lead to hypersensitivity related diseases,
whether autoimmune in nature or not. Hay fever and atopy
are examples of immune mediated but not autoimmune
diseases that result from faulty immune regulation.
Previously presented at the 22nd Annual ACVIM Forum,
Minneapolis, MN, June 2004.
REFERENCES
1. Roitt I, Brostoff J, Male D. Immunology. 6th edition.
Mosby, Harcourt Publishers Lmtd. London, 2001.
2. Tizard IR, Schubot RM. Veterinary Immunology: An
Introduction. WB Saunders Co, Philadelphia, 7th edition,
2004.
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