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Microbiology/Immunology
L.5
Dr. Ifad Kerim Al-Shibly
2016-2017
CELLS OF THE IMMUNE SYSTEM
The immune system is a complex network of cells and organs that work together to
defend the body against foreign substances (antigens) such as bacteria, viruses or tumor
cells. It is separated into two branches: humoral immunity and cellular immunity. The
immune cells that make up our immune system consist of several different types of
white blood cells or leukocytes that work together to keep us healthy. They circulate
through the body between the organs and nodes via the lymphatic system. Most
however are stored in the lymphoid organs until needed.
Immune Cells Ancestor:
All immune cells begin as immature stem cells in the bone marrow. They respond to
different cytokines and other chemical signals to grow into specific immune cell types.
All cells of the immune system originate from a pluripotent hematopoietic stem cell in
the bone marrow, which gives rise to two major lineages, a myeloid progenitor cell and
a lymphoid progenitor cell. These two progenitors give rise to the myeloid cells
(monocytes, macrophages, dendritic cells, megakaryocytes and granulocytes
(eosinophils, neutrophils, basophils) and lymphoid cells (T cells, B cells and natural
killer (NK) cells), respectively.
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PHAGOCYTES
This is a group of immune cells specialized in finding and
"eating" bacteria, viruses, and dead or injured body cells. There
are three main types, the granulocyte, the macrophage, and the
dendritic cell. Phagocytes are called "professional" or "nonprofessional" depending on how effective they are at
phagocytosis. The professional phagocytes include many types
of white blood cells (such as neutrophils, monocytes,
macrophages, mast cells, and dendritic cells). The main
difference between professional and non-professional
phagocytes is that the professional phagocytes have receptors on
their surfaces that can detect antigens.
Granulocytes
The granulocytes often take the first stand during an infection. They attack any invaders
in large numbers, and "eat" until they die. Granulocytes kill microbes by digesting them
with killer enzymes contained in small units called" lysosomes". Lysosomes are cellular
organelles that contain hydrolytic enzymes that break down waste materials and cellular
debris. They can be described as the stomach of the cell. Lysosomes digest food
particles, and engulfed viruses or bacteria. The membrane around a lysosome allows the
digestive enzymes to work at the pH they require. Lysosomes fuse with autophagic
vacuoles (phagosomes) and dispense their enzymes into the autophagic vacuoles,
digesting their contents. They are frequently nicknamed "suicide bags" or "suicide sacs"
by cell biologists due to their autolysis. The pus in an infected wound consists chiefly of
dead granulocytes.
Neutrophils: are the main white blood cells that circulate in the blood stream. They are
also granulocytes which contain granules filled with potent chemicals that play a key
role in acute inflammatory reactions. When you have a ‟ bacterial infection‟, the levels
of neutrophils are elevated. Like NK cells (see below) they produce toxins that kill the
antigen and then ingest it. However NK cells are autonomous(innate) but neutrophils
are triggered into action by other immune cells(adaptive). They are the predominant
cells in pus, accounting for its whitish/yellowish appearance.
Eosinophils: are another granulocyte which carry receptors for IgE and will destroy IgE
coated antigens. They are small part of the granulocyte community specialized in
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attacking larger ‟ parasites‟ such as worms. Their granules contain large quantities of
peroxidase as well as a highly toxic protein called major basic protein (MBP), which is
toxic for helminthes. These granules are capable of fusion with plasma membrane and
release their contents into inside of the helminthes, which is larger than eosinophils.
This type of phagocytosis is named as membrane –bound phagocytosis and is the only
way by which these cells can kill large targets. Eosinophils secretions also inactivate
and destroy cancer cells.
Basophils/mast cell : Mast cells and basophils are potent effector cells of the innate
immune system, and they have both beneficial and detrimental functions for the host.
They are mainly implicated in pro-inflammatory responses to allergens but can also
contribute to protection against pathogens. They are also filled with granules of toxic
chemicals that can digest microorganisms. Basophils are the least granulocytes in
peripheral blood. Whereas mast cells are found throughout the body in connective
tissues. Both of them are essential for IgE mediated inflammation. Their granule
contents are histamine, heparin, prostaglandins D2, hydrolases, and peptidases. They are
responsible for the symptoms of allergy. Basophils enter tissues only when they are
attracted to the inflamed sites. Capable of phagocytosis, they process and present
antigen using MHC class I or II receptors. LPS can directly induce release of mast cell
mediators. Complement (C3a and C5a) induce mast cells to release mediators.
"A granular" phagocytes
Monocytes, which can ingest dead and damaged cells, leave the blood stream and
migrate into tissues and develop into macrophages.
The macrophages ("big eaters") are slower to respond to invaders than the
granulocytes, but they are larger, live longer, and have far greater capacities.
Macrophages also play a key part in alerting the rest of the immune system of invaders
(thus play a role in both the innate and the adaptive immune response). Macrophages
start out as white blood cells called monocytes. They are residing in organs that directly
interface with the bloodstream or come into contact with the outside world like the liver
and lung. They do circulate in the bloodstream but are stationed at the respective organs.
Macrophages are the body's first line of defense and have many roles. A macrophage
is the first cell to recognize and engulf foreign substances (antigens). Macrophages
break down these substances and present the smaller proteins to the T
lymphocytes. Macrophages also produce substances called cytokines that help to
regulate the activity of lymphocytes. Their function is similar to neutrophils in that they
eat foreign material and worn-out cells and present them to various T cells. Although
they have their own positions to protect however, when a part of the body becomes
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infected they rush to the infected area helping the neutrophils to "phagocytize" the
antigens. In addition to host defense, macrophages have also been proposed to
contribute to the processes of wound healing and immune regulation. Examples of these
effects include phagocytosis of erythrocytes, removal of cellular debris and clearance of
post-apoptotic cells.
Functions of Monocytes/Macrophages System:
1-Professional phagocytic cells: They act as scavenger cells that remove the articulate
antigens.
2-Antigen-presenting cells (APCs): They present antigens to Th-cells by displaying
antigenic fragments bound by MHC-II expressed on their surface.
Phagocytosis: the process of pagocytosis involves the following steps:
1) Formation of pseudopodia towards the insulting organism.
2) Phagosome formation containing the organism inside the phagocyte.
3) Formation of phagolysosome by fusion of phagosome and lysosome.
4) Killing of the engulfed organism by oxidizing agents, such as Reactive Oxygen
Intermediates (ROI) and Reactive Nitrogen Intermediates (RNI), which are
highly toxic to microbes. This results in digestion and breakdown of the
organism.
5) Finally, the contents of the phagolysosme are eliminated by exocytosis.
Macrophages can ingest and degrade particulate
antigens, including bacteria. Scanning electron
micrograph of a macrophage. Note the long
pseudopodia extending toward and making contact
with bacterial cells, an early step in phagocytosis
Dendritic Cells are "eater" cells (phagocytic cell), like the granulocytes and the
macrophages. The dendritic cells are known as the most efficient antigen-presenting cell
type with the ability to interact with T cells and initiate an immune response. And like
the macrophages, the dendritic cells help the activation of the rest of the immune system
(adaptive immune response). They are also capable of filtering body fluids to clear them
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of foreign organisms and particles. Mostly found in the skin and mucosal epithelium,
where they are referred to as Langerhan's cells. Unlike macrophages, dendritic cells can
also recognize viral particles as non-self. In addition, they can present antigens via both
MHC I and MHC II, and can thus activate both CD8 and CD4 T cells, directly.
LYMPHOCYTES
White blood cells or lymphocytes originate in the bone marrow but migrate to parts of
the lymphatic system such as the lymphnodes, spleen, and thymus. There are two main
types of lymphatic cells, T cells and B cells. On the surface of each lymphatic cell are
receptors that enable them to recognize foreign substances. These receptors are very
specialized - each can match only one specific antigen.
Main distinguishing surface markers of T and B cells
Marker
B cells
Tc
Th
CD3, TCR
-
+
+
CD4
-
-
+
CD8
-
+
-
IgM and CD19,20
+
-
-
B lymphocytes
B lymphocytes are critical for normal immune function. They are called B cells because
they mature in the bone marrow. Their main role is to produce antibodies, which
circulate in the blood and lymph. B lymphocytes are each programmed to make one
specific antibody. When a B cell comes across its triggering antigen it gives rise to
many large cells known as plasma cells. Each plasma cell is essentially a factory for
producing antibody. If any antigen escapes the first line of defense, they will be
captured by the B cells. What the B cells does is, they "tag" the antigens with antibodies
which alert other immune cells of danger ahead. This simple action neutralizes the
antigen and renders them harmless. They act as APCs and secrete certain cytokines that
regulate the activation of other immune cells. Activation of B cells occurs via antigen
recognition by BCRs and a required co-stimulatory, secondary activation signal
provided by either helper T cells or the antigen itself. This results in stimulation of B
cell proliferation and the formation of germinal centers where B cells differentiate into
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plasma cells or memory B cells. Importantly, all B cells derived from a specific
progenitor B cell are clones that recognize the same antigenic epitope.
The Plasma cell is specialized in producing an antibody. Plasma cells produce
antibodies at an amazing rate and can release tens of thousands of antibodies per
second. Plasma cells are found in the spleen and lymph nodes and are responsible for
secreting different classes of clonally unique antibodies that are found in the blood.
The Memory Cells are the second cell type produced by the division of B cells. These
cells which express high-affinity surface immunoglobulins (mainly IgG), have a
prolonged life span and can thereby "remember" specific intruders. T cells can also
produce memory cells with an even longer life span than B memory cells. The second
time an intruder tries to invade the body, B and T memory cells help the immune system
to activate much faster. The invaders are wiped out before the infected human feels any
symptoms. The body has achieved immunity against the invader.
T lymphocytes
T cells are produced in the bone marrow and later move to the thymus (the name T cells
is derived from thymus), where they mature. They do not produce antibodies but have
surface receptors related to the Igs. Not all T cells are the same. Some attack infected or
cancerous cells while others look for the antibody tag before attacking a specific
invader. T cells come in two different types, helper cells and killer cells. T cells
differentiation depending primarily on the antigen, the strength of the TCR signal, and
the cytokines present in the surrounding extracellular environment.
Helper T cells (Th) are the major driving force and the main regulators of the immune
defense. T helper cells (also known as CD4 cells) coordinate immune responses. Their
primary task is to activate B cells and killer T cells. However, the helper T cells
themselves must be activated. This happens when a macrophage or dendritic cell, which
has eaten an invader, travels to the nearest lymph node to present information about the
captured pathogen. The phagocyte displays an antigen fragment from the invader on its
own surface, a process called "antigen presentation". When the receptor of a helper T
cell recognizes the antigen, the T cell is activated. Once activated, helper T cells start to
divide and to produce proteins that activate B and T cells as well as other immune cells.
It comprises 70-75 % of the total T cells, carry CD4, and interact with MHC II on
APCs.
Two types of Th cells:
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A-Th1 cells: T helper type 1 (Th1) cells are a lineage of CD4+ effector T cell that
promotes cell-mediated immune responses and is required for host defense against
intracellular viral and bacterial pathogens. Th1 cells secrete IFN-gamma, IL-2, and
TNF-alpha/beta. These cytokines promote macrophage activation, nitric oxide
production, and cytotoxic T lymphocyte proliferation, leading to the phagocytosis and
destruction of microbial pathogens. T helper cells regulate the cell mediated immunity.
B-Th2 cells: T helper type 2 (Th2) cells are a distinct lineage of CD4 + effector T cell
that secretes IL-4, IL-5, IL-6, IL-13, and IL-17E/IL-25 cytokins which act as B-cells
activating factors. These cells are required for humoral immunity and play an important
role in coordinating the immune response to large extracellular pathogens. They
regulate humoral mediated immunity that eliminates the extracellular infections and
toxins, which unlike intracellular pathogens are exposed to Ab in blood and other body
fluids.
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Cytotoxic T cells (CTLs) or killer cells have CD8 and
interact with MHC I expressed on target cells. They
can kill: virus infected cells(cells infected with
intracellular pathogens), allograft, and cancer cells.
Mechanism of cytotoxicity: CTLs produce perforin, a
serine protease that form pores in the plasma
membrane of the target, in a manner similar to that of
MAC of complement. These pores function as means
for granzymes entry, serine proteinases (granzymes
A-G) that can activate caspases in target cells and TNF which kills target cells by
apoptosis. The physiological role of cytotoxic T lymphocytes (Tc) is the elimination of
altered self-cells, typically as a result of viral infection. Resting Tc are incapable of
cytotoxic activity. They acquire cytotoxic activity as a result of MHC-restricted antigen
recognition on altered cells. This is the key signal for activation and leads to a
phenotypic switch which further enables Tc to respond to cytokines derived from Th1,
principally IL-2. This second signal is required for full activation but activation of Tc
can occur to a more limited extent in the absence of Th1 cytokine signalling.
Suppressor or regulatory T cells (Treg ) Suppress activation of the immune system
after recovery of the infection and maintain immune homeostasis. Most of them are
CD4 marker. They tell the B cells to stop producing when there are enough antibodies
and the cytotoxic T cells to retreat.
Natural Killer Cells
Natural Killer cells or NK cells for short, the aggressive T cells have many different
functions, mainly lysis of target cells and production of cytokines (IFN-γ and TNF-α). Act
against intracellular pathogens and protozoa. They are a type of lymphocytes and have the
"innate" ability to detect and attack an intruder on its own, unlike the cytotoxic T cells which
only attack those that covered with MCH. Therefore they primarily deal with controlling
cancer or tumor cells and acute infection. These cells are called natural killer because they
are already specialized to kill target cells without interaction with MHC. They kill virus infected cells, cancer cells. Like Tc cells, it use perforins and granzymes to kill the target
cells. They have CD56 and do not have TCR, CD4, or CD8.
Thank you
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