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TOX 4000 Study Guide - Final Guide: Hematopoietic Stem Cell, Innate Lymphoid Cell, Innate Immune System


Department
Toxicology
Course Code
TOX 4000
Professor
Craig Bailey
Study Guide
Final

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Medical Toxicology
Immune Toxicology
Lecture 15 & 16 | Immune System Toxicology
Immunotoxicology can be most simply defined as the study of adverse effects on the
immune system resulting from occupational, inadvertent, or therapeutic exposure to drugs,
environmental chemicals, and, in some instances, biological materials.
Understanding the impact of toxic responses on the immune system requires an
appreciation of its role, which may be stated succinctly as the preservation of integrity. It is
a series of delicately balanced, complex, multicellular, and physiological mechanisms that
allow an individual to distinguish foreign material i.e., nonself and self, and to
neutralize, eliminate, and/or coexist with the foreign matter.
Self includes cells, tissues and organs of the body.
Nonself includes opportunistic pathogens (bacteria and viruses) and transformed cells
and tumors.
If the immune system fails to recognize as nonself an infectious entity or neoantigens
expressed by a newly arisen tumour, then the host is in danger of rapidly succumbing to the
unopposed invasion.
This aspect of immune competence is the reason why the immune system is often
synonymous with host defence.
Alternatively, if some integral bodily tissue is not identified as self, then the immune system
is capable of turning its considerable defensive capabilities against that tissue, and an
autoimmune disease may be the end result.
This aspect of immunocompetence emphasizes the tremendous destructive potential that is
associated with the host defense mechanisms of the immune system.
The cost to the host of these mistakes, made in either direction, may be quite high. The fact
that mistakes can occur in either direction is an indication that immunotoxicology should be
considered as a continuum.
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The Immune System
Unlike most organ systems, the immune system has the unique quality of not being confined
to a single site within the body. It comprises numerous lymphoid organs and many different
cellular populations with a variety of functions.
The bone marrow and thymus are referred to as primary lymphoid organs because they
contain the microenvironments capable of supporting the production of mature B and T
cells, respectively.
Innate Immunity
Innate immunity acts as a first line of defense against anything nonself. With respect to
infectious agents, the innate immune system eliminates most potential pathogens before
significant infection occurs.
The innate immune system includes physical and biochemical barriers both inside and
outside the body, as well as immune cells designed for host defense responses:
(1) Externally, the skin provides an effective barrier, as most organisms cannot
penetrate intact skin.
(2) Innate defenses present to combat infection from pathogens entering through the
respiratory system include mucus secreted along the nasopharynx, the presence of
lysozyme in most secretions, and cilia lining the trachea and main bronchi.
(3) Pathogens that enter the body via the digestive tract are met with severe changes in
pH (acidic) within the stomach and a host of microorganisms living in the intestines.
Cellular Components
Several cell types are involved in innate immunity, and in fact, some also provide critical
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signals to initiate adaptive immune responses.
(A) Neutrophils
Neutrophils (also known as polymorphonuclear cells or PMNs) are phagocytic cells that
develop from the myeloid lineage of hematopoietic stem cells (HSCs). Neutrophils are
capable of passing between the endothelial cells of the blood vessels and thereby represent
a primary line of defense against infectious agents.
Neutrophils enter the bloodstream where they circulate for about 10 hours and then enter
the tissues where they perform effector functions for about one to two days. They are
excellent phagocytic cells and can eliminate most microorganisms through the release of
various reactive oxygen species (ROS); they are also important in the induction of an
inflammatory response.
(B) Macrophages
Macrophages are terminally differentiated monocytes, which develop from the myeloid
lineage of HSCs. Upon exiting the bone marrow, monocytes circulate within the bloodstream
for about one day. At that time, they begin to distribute to the various tissues where they
can then differentiate into macrophage subsets:
(i) Kupffer cells (liver
(ii) Alveolar macrophages (lung)
(iii) Microglial cells (CNS)
Macrophages can be classified as classically activated macrophages (M1), which are
proinflammatory and participate in antigen presentation, or alternatively activated
macrophages (M2), which do not present antigen well, but are efficient in apoptotic cell
removal.
This, M1 macrophages are also considered APCs.
In order to elicit an acquired immune response to a particular antigen, that antigen must be
taken up and processed by accessory cells for presentation to lymphocytes. Accessory cells
that perform this function are termed antigen-presenting cells (APCs) and include
macrophages, B cells, and dendritic cells (DCs).
Of these, the most proficient APC is the DC.
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