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The immune system is composed of many interdependent cell types that
collectively protect the body from bacterial, parasitic, fungal, viral
infections and from the growth of tumor cells. Many of these cell types have
specialized functions. The cells of the immune system can engulf bacteria, kill
parasites or tumor cells, or kill viral-infected cells. Often, these cells
depend on the T helper subset for activation signals in the form of secretions
formally known as cytokines, lymphokines, or more specifically interleukins. The
purpose of this article is to review the organs, cell types and interactions
between cells of the immune system as a commentary on their importance and
interdependence on the T helper subset. Such an understanding may help
comprehend the root of immune deficiencies, and perceive potential avenues that
the immune system can be modulated in the case of specific diseases.
The
Organs of the Immune System
Bone Marrow -- All the cells of the immune
system are initially derived from the bone marrow. They form through a process
called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells
differentiate into either mature cells of the immune system or into precursors
of cells that migrate out of the bone marrow to continue their maturation
elsewhere. The bone marrow produces B cells, natural killer cells, granulocytes
and immature thymocytes, in addition to red blood cells and platelets.
Thymus -- The function of the thymus is to produce mature T cells.
Immature thymocytes, also known as prothymocytes, leave the bone marrow and
migrate into the thymus. Through a remarkable maturation process sometimes
referred to as thymic education, T cells that are beneficial to the immune
system are spared, while those T cells that might evoke a detrimental autoimmune
response are eliminated. The mature T cells are then released into the
bloodstream.
Spleen -- The spleen is an immunologic filter of the blood.
It is made up of B cells, T cells, macrophages, dendritic cells, natural killer
cells and red blood cells. In addition to capturing foreign materials (antigens)
from the blood that passes through the spleen, migratory macrophages and
dendritic cells bring antigens to the spleen via the bloodstream. An immune
response is initiated when the macrophage or dendritic cells present the antigen
to the appropriate B or T cells. This organ can be thought of as an
immunological conference center. In the spleen, B cells become activated and
produce large amounts of antibody. Also, old red blood cells are destroyed in
the spleen.
Lymph Nodes -- The lymph nodes function as an immunologic
filter for the bodily fluid known as lymph. Lymph nodes are found throughout the
body. Composed mostly of T cells, B cells, dendritic cells and macrophages, the
nodes drain fluid from most of our tissues. Antigens are filtered out of the
lymph in the lymph node before returning the lymph to the circulation. In a
similar fashion as the spleen, the macrophages and dendritic cells that capture
antigens present these foreign materials to T and B cells, consequently
initiating an immune response.
The Cells of the Immune System
T-Cells --
T lymphocytes are usually divided into two major subsets that are functionally
and phenotypically (identifiably) different. The T helper subset, also called
the CD4+ T cell, is a pertinent coordinator of immune regulation. The main
function of the T helper cell is to augment or potentiate immune responses by
the secretion of specialized factors that activate other white blood cells to
fight off infection.
Another important type of T cell is called the T
killer/suppressor subset or CD8+ T cell. These cells are important in directly
killing certain tumor cells, viral-infected cells and sometimes parasites. The
CD8+ T cells are also important in down-regulation of immune responses. Both
types of T cells can be found throughout the body. They often depend on the
secondary lymphoid organs (the lymph nodes and spleen) as sites where activation
occurs, but they are also found in other tissues of the body, most conspicuously
the liver, lung, blood, and intestinal and reproductive tracts.
Natural
Killer Cells -- Natural killer cells, often referred to as NK cells, are similar
to the killer T cell subset (CD8+ T cells). They function as effector cells that
directly kill certain tumors such as melanomas, lymphomas and viral-infected
cells, most notably herpes and cytomegalovirus-infected cells. NK cells, unlike
the CD8+ (killer) T cells, kill their targets without a prior "conference" in
the lymphoid organs. However, NK cells that have been activated by secretions
from CD4+ T cells will kill their tumor or viral-infected targets more
effectively.
B Cells -- The major function of B lymphocytes is the
production of antibodies in response to foreign proteins of bacteria, viruses,
and tumor cells. Antibodies are specialized proteins that specifically recognize
and bind to one particular protein that specifically recognize and bind to one
particular protein. Antibody production and binding to a foreign substance or
antigen, often is critical as a means of signaling other cells to engulf, kill
or remove that substance from the body.
Granulocytes or
Polymorphonuclear (PMN) Leukocytes -- Another group of white blood cells is
collectively referred to as granulocytes or polymorphonuclear leukocytes (PMNs).
Granulocytes are composed of three cell types identified as neutrophils,
eosinophils and basophils, based on their staining characteristics with certain
dyes. These cells are predominantly important in the removal of bacteria and
parasites from the body. They engulf these foreign bodies and degrade them using
their powerful enzymes.
Macrophages -- Macrophages are important in the
regulation of immune responses. They are often referred to as scavengers or
antigen-presenting cells (APC) because they pick up and ingest foreign materials
and present these antigens to other cells of the immune system such as T cells
and B cells. This is one of the important first steps in the initiation of an
immune response. Stimulated macrophages exhibit increased levels of phagocytosis
and are also secretory.
Dendritic Cells -- Another cell type, addressed
only recently, is the dendritic cell. Dendritic cells, which also originate in
the bone marrow, function as antigen presenting cells (APC). In fact, the
dendritic cells are more efficient apcs than macrophages. These cells are
usually found in the structural compartment of the lymphoid organs such as the
thymus, lymph nodes and spleen. However, they are also found in the bloodstream
and other tissues of the body. It is believed that they capture antigen or bring
it to the lymphoid organs where an immune response is initiated. Unfortunately,
one reason we know so little about dendritic cells is that they are extremely
hard to isolate, which is often a prerequisite for the study of the functional
qualities of specific cell types. Of particular issue here is the recent finding
that dendritic cells bind high amount of HIV, and may be a reservoir of virus
that is transmitted to CD4+ T cells during an activation event.
The Immune
Response
An immune response to foreign antigen requires the presence of an
antigen-presenting cell (APC), (usually either a macrophage or dendritic cell)
in combination with a B cell or T cell. When an APC presents an antigen on its
cell surface to a B cell, the B cell is signalled to proliferate and produce
antibodies that specifically bind to that antigen. If the antibodies bind to
antigens on bacteria or parasites it acts as a signal for pmns or macrophages to
engulf (phagocytose) and kill them. Another important function of antibodies is
to initiate the "complement destruction cascade." When antibodies bind to cells
or bacteria, serum proteins called complement bind to the immobilized antibodies
and destroy the bacteria by creating holes in them. Antibodies can also signal
natural killer cells and macrophages to kill viral or bacterial-infected cells.
If the APC presents the antigen to T cells, the T cells become
activated. Activated T cells proliferate and become secretory in the case of
CD4+ T cells, or, if they are CD8+ T cells, they become activated to kill target
cells that specifically express the antigen presented by the APC. The production
of antibodies and the activity of CD8+ killer T cells are highly regulated by
the CD4+ helper T cell subset. The CD4+ T cells provide growth factors or
signals to these cells that signal them to proliferate and function more
efficiently. This multitude of interleukins or cytokines that are produced and
secreted by CD4+ T cells are often crucial to ensure the activation of natural
killer cells, macrophages, CD8+ T cells, and PMNs is listed in the chart below.
One possible line of therapy is to reintroduce some of these cytokines
to people who have severe immune deficiencies. This approach can be tricky
because large amounts of any particular cytokine can have serious side effects.
Furthermore, their half-life in the body is usually relatively short. Another
short-coming of "replacement" therapy is that many cytokines will activate the
CD4+ T cells or macrophages harboring HIV, and this could lead to faster rates
of HIV production by those cells. Theoretically, this could lead to progression
of HIV rather than prophylaxis against opportunistic infections. However, recent
progress in this area warrants attention and further study. Lack of
interleukin-2 (IL-2) is believed to be one of the major causes of immune
deficiency in AIDS. In recent studies where low dose IL-2 was administered to
people with HIV, CD4 T cell counts rose, as did anti-viral specific immunity,
and natural killer cell cytotoxic activity. Administration of IL-3 to people
with HIV is currently under investigation as a treatment for HIV associated
cytopenia (low production of cells from the bone marrow). IL-4, a cytokine that
activates B cells and also has inhibitory effects on the production of TNF, is
currently under investigation for the treatment of Kaposi's sarcoma. GM-CSF
(granulocyte macrophage-colony stimulating factor), another growth factor
produced by CD4+ T cells, is under investigation for the treatment of decreased
white blood cell production for people on ganciclovir therapy.
Additionally, IFN-gamma (gamma interferon) is under investigation as a
treatment for people with PCP. Hopefully, these studies will lead to cures for
certain opportunistic infections, or for use in inhibiting HIV production and
ultimately saving lives.
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