Samenvatting
Samenvatting Mechanism Of Disease 1
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- Universiteit Leiden (UL)
Samenvatting aan de hand van de leerdoelen
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Samenvatting door Lieke Touwen. Alleen voor individueel gebruik.Leerdoelen MD1
Theme I: The immune system and its opponents
General
Diseases often do not fit into one category. It is an interaction between many factors and causes. The
focus of this module is immunology, pathology and infectious diseases. A disease is an interaction
between these three categories. Pathology comes from the word pathos (suffering) and logos
(study). All diseases are the result of visible cell abnormalities. The study of
mechanisms is really important for the understanding of diseases. Patients
usually are a clinical presentation of a diseases that is related to
mechanisms. The different mechanisms need to be understood for further
therapies and treatment of the patient and disease.
There are 7 basic mechanisms of disease. This module focusses on the
acute and chronic inflammation, disordered immunity and cell tissue injury
and repair.
The most important part of the mechanism is the immune system. It is a defending mechanism
against micro-organisms. It protects the body from pathogens. The immune system should always be
in balance, not too weak but not too strong as well. If the immune system is too strong, an auto-
immune disease or allergy can arise. An auto-immune disorder is a disease where the immune
system responds to certain self-components that are expressed in the body causing an auto-immune
response.
The human body is challenged by many different types of pathogens. They come in all shapes and
have different characteristics. To protect the body from the outsiders, the body needs to have its own
defence mechanism. This is organized in 3 layers. The body is made as a barrier.
The first layer of defence are the physical and chemical barriers. They prevent pathogens to enter the
body. All surface area, for example the skin, respiratory tract, urogenital tract and gastrointestinal
tract, have a form of protection against the pathogens. The intestines have commensal flora, which
are the bacteria that live there that prevent colonization of pathogens. Another form of protection is
the epithelia that form a tough impermeable barrier which lines the outer
surface and inner cavities of the body. The lungs have mucosa and tight
connected cells to prevent pathogens entering the inner cell. The mucus is
produced in the submucosal gland that consists of antimicrobial peptides,
proteins and reactive oxygen. The cilia on top of the cell wipe out the
mucus and bacterial colonisation in the upper layers of the respiratory tract
by coughing.
The mechanical barrier are the epithelial cells joined by tight junctions all over the body. It is also the
longitudinal flow of air or fluid in the skin and gut. For the lungs it is the movement of mucus by cilia
and for the eyes/nose/oral cavity is its nasal cilia and tears.
The chemical barrier are the fatty acids and antimicrobial peptides
in the skin, the low pH and antimicrobial enzymes / peptides in the
gut, the pulmonary surfactant and antimicrobial peptides for the
lungs and the antimicrobial peptides / enzymes in tears and saliva
in the cavities.
The microbiological barrier is normal microbiota.
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The immune system consists of different cell types. All leukocytes
(white blood cells) origin from the hematopoietic stem cell. It
becomes a common lymphoid precursor or a common myeloid
precursor. The common lymphoid precursor differentiates
eventually into a B-cell, T-cell or NK cell. The common myeloid
precursor differentiates further into a granulocyte macrophage
progenitor or erythroid progenitor. The last progenitor
eventually becomes erythrocyte (red blood cells) or platelets. The
granulocyte macrophage progenitor eventually becomes a
monocyte that differentiates into a macrophage or dendritic cell, or a neutrophil, eosinophil,
basophil or mast cell.
All the ‘end’ cells have different characteristics. The red blood cell does not have a nucleus. The
lymphocyte is very small, has a small volume cytoplasm and a big nucleus. The monocyte has a
coffee bean shaped nucleus, has more cytoplasm and is larger. The neutrophil is produced in
bone merrow. The eosinophil has different types of vesicles that contain little enzymes that can
destroy the pathogens. The basophil plays an important role in allergic responses.
Not only are the shapes and functions different, the proportion of
leukocytes in the body is also different. The most common leukocyte is
the neutrophil (40-75%). The least common leukocyte is the basophil
(<1%). The other leukocytes are in between these numbers. From
most common to least common: neutrophil, lymphocyte, monocyte,
eosinophil, basophil.
The second layer of defence is the innate immune system. It consists of barriers, soluble proteins and
cells. Soluble proteins are for example cytokines and the complement system, but also defensins
(antimicrobial peptides -> damage pathogen’s cell membrane), inter/related soluble protein systems
(coagulation system) and lipid inflammatory mediators. Innate immune cells are NK cells, monocytes,
macrophages, dendritic cells, neutrophils, eosinophils, basophils and mest cells. The NK cell is the
only one that origins from the NK/T cell precursor (common lymphoid precursor). All the other cells
origin from the granulocyte macrophage progenitor. The innate immune system is the primitive
immune defence of animals. It is an older system and a-specific that does not specify to a
type of pathogen. It has phylogeny against all multicellular organisms. Not only vertebrae
specimen but also non vertebrae specimen has this type of immune defence. The location is
mainly on body surfaces. It consists of a rapid response (hours), a fixed set of receptors and
recognitions for pathogens, a limited number of specificities and is constant during the
response. Innate immune responses delay pathogenic replication and spread until adaptive
immune cells take over. It has no memory. Lack of this system will become deadly because of
massive replication of pathogens. There is no control in controlling the pathogens or their
replication.
There are 5 stages of innate immune response.
The first one is recognition of infection or damage. The most
important here is to distinguish ‘self’ from ‘non-self’. Pattern
recognition receptors (PRR) on the macrophages are
activated by pathogen-associated molecular patterns
(PAMPs) for example toll-like receptors. This is an important
mediator triggering an inflammatory reaction after an
infection. The macrophage expresses several receptors
specific for bacterial constituents. Thus, it has different receptors for not one antigen, but different
specific antigens.
The second step is recruitment of cells and soluble factors. There needs to be
something done to eliminate the pathogens. Neutrophils and monocytes are
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recruited from the blood to the sited of infection by binding to adhesion
molecules and by chemo/attractants produced in response to the
infection.
The third step is elimination of microbe. This can happen through
phagocytosis or gene transcription.
Phagocytosis is the elimination of an
antigen by ‘eating’ it. The pathogen binds to phagocytic receptors
on macrophages that induces their engulfment and degradation.
Phagocytosis can also be done by neutrophils. The antigen is
phagocytosed and fuses with azurophilic and specific granules. The
pH of the phagosome rises the antimicrobial response is activated
and the antigen is killed. The pH of phagosome decreases and
fusion with lysomes allows acid hydrolases to degrade the antigen
completely. The neutrophil dies by apoptosis and is phagocytosed by a macrophage. The neutrophils
also consist of a special function: catching bacteria by throwing out their DNA content. This DNA
forms extra-cellular traps (netosis).
Gene transcription causes cytokine production. A bacterial component (not whole pathogen!) is
binding that causes signalling receptors on the macrophages to induce the synthesis of inflammatory
cytokines. This happens when the macrophage recognises the pathogen.
The fourth step is resolution of inflammation, repair and return to homeostasis. This will happen
with macrophages, fibroblasts and angiogenesis.
The last step is induction of adaptive immunity if necessary. This happen with a dendrite cell that is
the messenger between the innate and adaptive system. It takes bacterial antigens and brings it to
the lymphatic nodes to present it to the T-cell and set the adaptive system in motion.
Cytokines come in many different types and therefore have many different functions. They all result
in inflammation at a local place. IL-6 induces fat and muscle cells to metabolize, make heat and raise
the temperature in the infected tissue. CXCL8 recruits neutrophils from the blood and guides them to
the infected tissue. IL-12 recruits and activates natural killer (NK) cells that in turn secrete cytokines
that strengthen the macrophages response to infection. IL-1beta and TNF-alfa induce blood vessels to
become more permeable, enabling effector cells and fluid containing soluble effector molecules to
enter the infected tissue.
Cytokines can also have systemic effects on the body. Especially IL-1, IL-6 and TNF-alfa have these
effects. In the liver the cytokines cause acute-phase proteins that leads to activation of complement
and opsonization. In bone marrow and endothelium, it causes neutrophil mobilization (more T and B
cells) that leads to phagocytosis. The hypothalamus will increase the body temperature and
fat/muscle will increase their protein and energy mobilization to
generate an increased body temperature. The increased body
temperature leads to a decreased viral and bacterial replication
and of course a fever.
Thus, the acute inflammatory response is dilatation of the blood
vessels, increase vessel wall permeability and leukocyte emigration
from the blood to the infected tissue. Neutrophils and monocytes
are recruited from the blood to the sites of infection by binding to
adhesion molecules and by chemo-attractants produces in response to the infection. This all leads to
the symptoms redness, heat, swelling and pain (rubor, calor, tumor, dolor).
The third and last layer of defence is the adaptive immune system. Adaptive immune cells are
B-cells, T-cells and after differentiation plasma cells (B-cell) and effector T-cell. Their origin is the
common lymphoid precursor. This system is different from the innate immune system since it only
occurs in vertebrae specimen, is specific, stronger, has a slow response (days to weeks), is variable in
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receptors and recognitions for pathogens, has numerous highly selective specificities and improves
during response. The location for this system is mainly found in lymph nodes and the spleen. Lack of
this system does not lead to dead immediately since the innate system will be able to
control a little bit of the replication. But when the adaptive immune system takes over,
it will end wrong for the patient. The common goal of both systems is the recognitions
and destruction of the pathogens.
Most immune cells are located in the blood, but they can also be found in the tissues.
The most important body part for the adaptive immune cells are the primary and
secondary lymphoid tissues. Major reservoirs of naïve and memory T and B cells can
be found there. Both cells are made in bone marrow. Immature T and B cells are
produced from lymphoid committed progenitors. T-cells have to go further maturation in the thymus
before it actually works. After both cell types are mature, they leave the primary lymphoid tissue
(thymus and bone marrow) and are given to the circulation. They travel to secondary lymphoid
tissues thought lymphoid vessels to end in lymphoid nodes. Most of secondary lymphoid tissue is
localized in the gastro-intestinal tract (GALT), such as the tonsils, adenoids, appendix, mesenteric LN
and Peyer’s patches. The bronchial-associated lymphoid tissue (BALT) consists of all lymphoid nodes
draining respiratory epithelium. The mucosa-associated
lymphoid tissue (MALT) is the remaining more diffusely
organized lymphoid structures at all mucosal surfaces.
Eventually all the cells will enter the blood circulation again
at the ductus thoraticus.
The lymph nodes consist of different parts with different
functions. The lymph flow enters at the afferent lymphatic
vessel at the cortex of the node. The outline of the cortex is the marginal sinus that are subcapsular
sinus lining cells with macrophages that filter pathogens from incoming lymph draining epithelia and
other tissues. The lymph flow goes to the centre in the medulla where the efferent lymphatic vessel
can be found. The node also has blood vessels for oxygen supply.
The T-cell and B-cell live in different compartments as well. The B cell can be found in the lymphoid
follicle close to the germinal centre (B-cell activation). The T-cells have their own area right under
the B-cell follicle. Connected to the medulla is an area where
the B-cell resides and becomes a plasma cell that produces
anti-bodies. It is close to the blood vessels so it can enter the
circulation.
The spleen is not connected to the lymphatic system. The
main function is filtering the blood by looking for pathogens
and presenting them to B-cells. Blood vessels enter the spleen
and are dissipated throughout the spleen. Macrophages in the spleen are specialized in filtering free
pathogens and immune complexes carried by erythrocytes. On a histology picture of the spleen can a
red pulp and white pulp be seen. The red pulp are the macrophages filtering
erythrocytes. The line between the lymphatic system and the red pulp is the
white pulp in a ring. This has the exact same function as the macrophages in
the marginal sinus in the lymph node.
The skin has its own immune cell, named the Langerhans cell in the epidermis.
It is an innate cell (dendrite cell) because it is an antigen-
presenting cell. Immune responses are induced to skin-invading pathogens due to these
antigen-presenting cells. The many dendrites form a tight network in the epidermis. They
are sentinel cells controlling T cell priming. An inflammation would be found instantly by
a dendrite.
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