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6
Dr. heba kalbouneh
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Refer to figures in the PowerPoint presentation The connective tissue is composed of:
Cells-1 2-Extracellular matrix (ground substance and fibers). The ground substance: the medium where fibers and cells are embedded.
Fibers are proteins polymerize to form the fibers
The different proportions of these components give different types of the
connective tissue.
Cells of the connective tissue either are fixed or transient.
Transient cells: they are involved in inflammation (immune response) so that
what makes connective tissue involved in the immune response. These cells
leave blood by migrating between the endothelial cells to enter connective
tissue (this is called diapedesis)
Mast cells:
- under EM its cytoplasm appears filled with secretory vesicles, some thought
it was a phagocytic material or ingested food from the outer environment
so they called it Mast cells (The word "mast" refers to food)
- Large cells.
- Cytoplasm is full with secretory granules.
- Nucleus is rounded and euchromatic because they’re active cells.
- Derived from precursors produced by hematopoiesis
Explanation: Blood has two main types of cells: Red blood cells: carrying o2
White blood cells: immune system (protection against invading
microorganisms)
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Both types of cells originate from the bone marrow in a process called
Hematopoiesis.
Hematopoiesis: Production of blood cells. Mast cells also originate from the
bone marrow
- Mast cells are “alarm cells” scattered within C.T, any slight disturbance of
the tissue makes them release their content in order to recruit the
inflammatory cells and trigger the Process of inflammation, such as:
- Histamine: (important in allergic reactions), it increases blood flow which
means increasing diameter of blood vessel and the permeability.
- Heparin: anticoagulant at the site of inflammation
- Leukotriene.
- Eosinophil chemotactic factor: Eosinophil is white blood cell that increases
at parasite infection.
- Neutrophil chemotactic factor: which are phagocytic cells
- Neutrophils and eosinophils are white blood cells and part of immune
system
- They are seen in 2 places (places exposed to antigens):
1. Perivascular mast cells which surround blood vessels.
2. Mucosal mast cells which are in mucous membrane lining the cavities that
open to the outside like in GI tract, respiratory tract…..
- They’re waiting for any disturbance or allergen to secrete their granules;
Allergies are caused (in part) by inappropriate sensitivity of mast cells. The
symptoms are treated with antihistamines, chemicals which interfere with
the action of histamine
- Under LM the nucleus appears rounded and pale (euchromatic) and you
can’t see cytoplasm, because it’s filled with secretory granules which are
called metachromatic granules.
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- Metachromatic granules: able to change the color of the stain (ex: change
the color of toluidine blue from blue to red purple (violet)).
- This property is called Metachromasia refers to the ability of changing the
color of the dye.
Plasma cells: Remember: they are transient cells not fixed. - Origin: All blood cells are produced within bone marrow; blood contains red and white blood cells. Hematopoiesis is the formation of blood cells, hemato refers to blood, poiesis refers to formation of. - Lymphocytes (are small white blood cells with large nucleus, little cytoplasm and can enter and exit C.T easily).
- These lymphocytes are very important weapons in our immune system;
they give 2 types (T, B).
- B lymphocytes give the plasma cells (origin).
- Plasma cells are seen in chronic inflammation areas due to their function
(producing Antibodies “proteins”) how?
- When a certain antigen enters like bacteria, these cells will synthesize
antibodies against them so when dealing with the same antigen again we
don’t need to produce new antibodies. As they synthesize antibodies they
are Protein synthesizing cells.
For describing plasma cells: - Large rounded cells.
- Its Nucleus is Euchromatic and Eccentric (not in the center) it is toward the
periphery (near the plasma membrane of the cell.)
- Cytoplasm is full with organelles (indicating the activity of the cell):
- Prominent RER for the synthesis of proteins= cytoplasm is Basophilic.
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- Prominent Golgi apparatus for packaging of these proteins (-ve Golgi stain;
it appears pale or non-stained because it’s composed of lipids and can’t be
stained with H &E or aqueous stains).
- Nucleolus presence indicates the activity of the cells.
- The heterochromatin of plasma cells is typically clumped in a characteristic
"spoke-wheel" arrangement which also aids plasma cell recognition.
This appearance is called:
Cart wheel appearance (nucleolus at the center and there’s heterochromatin lines
going outside it). Or Clock-face appearance (peripheral regions of
heterochromatin alternating with lighter areas of euchromatin)
Macrophage - Function: phagocytosis, SO we predict the presence of lysosomes in its
cytoplasm
- Origin: (Monocytes from bone marrow)
Stem cells in bone marrow give Monocytes which are released into blood (circulating cells), once they enter C.T they become Macrophages (fixed cells in C.T), when an antigen enters c.t, macrophages become activated.
- Always in C.T you’ll find scattered number of macrophages (fixed) waiting
for any antigen, when the C.T is exposed to an antigen (infection), it will
cause recruitment of other macrophages from blood circulation (more
differentiation of monocytes into macrophages) so it is considered also
transient cell
Describing Macrophages: - Large cells with many cell membrane projections to phagocytose
(pseudopodia).
- Eccentric nucleus, indented (kidney shaped) or oval shaped.
- Macrophages are usually difficult to distinguish under the light microscope.
One way to visualize them is to inject an animal with carbon particles.
Macrophages which come into contact with the circulating particles will
phagocytose some of them. These particles will be visible as dark black
accumulations in the cytoplasm of the macrophages
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- In very active macrophages which have accumulated indigestible material,
the lysosomes (residual bodies) may be visible by light microscopy as dark
brown granules also. The primary lysosome fuses with the phagosome that
contains the engulfed material and becomes secondary lysosome. The
undigested material accumulates in the cytoplasm giving a brown color
(residual bodies)
Remember: - Primary lysosome fuses with phagosome (ingested material) to become
secondary lysosome. After digestion, it will become residual body (the
remaining undigested material). Accumulation of Residual bodies inside
certain cells gives what so called the age pigment “lipofuscin pigment”
which you’ll see it in long lived cells that have undergone long processes of
digestion (a lot of Residual bodies in their cytoplasm).
- Same concept in Macrophages: when they have been very active in digestion
they accumulate large amount of residual bodies in their cytoplasm so they
appear pigmented.
FOR EX: lung alveoli are lined with simple squamous epithelium with thin layer of C.T, lung macrophages (dust cells) are in direct contact with inhaled air. In the lung, macrophages "patrol" the respiratory surfaces and ingest airborne particles which settle there. They can be identified by the accumulations of fine particles in their cytoplasm.
- They are part of MPS “mononuclear phagocytic system”:
MPS is a system of phagocytic cells in different locations in our body with different names and it is part of the immune system.
- In lungs: dust cells
- In liver: kupffer cells
- In central nervous system: microglial cells
- In skin: langerhans cells
- In bone: osteoclasts
All these cells are characterized by phagocytic activity
Some are macrophages and some look like them and have same
function
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- They used to name this system as Reticulo-endothelial System but it is no
longer used, why:
Reticulo-endothelial System is a system composed of certain organs (liver, spleen, lymph nodes) composed of blood filled channels (lined with endothelium) supported by reticular fibers, so when injecting the animal with carbon material they’ve seen the endothelium of these organs also colored with pigments SO they said that endothelial cells are the origin of macrophages or the same cells. But
later on, they’ve discovered that this is wrong and these endothelial cells only Shuttle the ingested material to the underlying C.T by endocytosis and exocytosis
- Macrophages were also named Histiocytes
- Also, macrophages can aggregate in case of injuries to form giant cells
(huge cells)
Extracellular matrix (ground substance+ fibers):
The Ground Substance: - The ground substance is mainly water (remember that the connective
tissue acts as a transport medium for gases, certain molecules and waste
products between blood vessels and epithelium for example).
- It’s not only water because according to gravity, this water will pool in the
lower part of the body so in fact it’s a gel-like structure.
- The ground substance is mainly water, but this water is stabilized by
macromolecules (called stabilizing macromolecules), it functions like a jello,
it transforms water from liquid state to viscous state. For example, in
blood, the ground substance lacks stabilizing macromolecules and lacks
fibers, so the extracellular matrix is fluid
- With different types of C.T we’ll see different components of ECM (like in
blood its ECM is fluid but in bone it’s solid because it has high amount of Ca
ions), but here we are talking about ORDANIRY C.T which is located directly
under epithelium (for example) not about special types of C.T.
- 3 types of ground substances (macromolecules):
1. Glycosaminoglycan(GAGs)
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2. Proteoglycans
3. Glycoproteins
1. GAGs:
Long chains of repeating units of disaccharides (2 sugars), unbranched
2 types:
- Sulfated: contain sulfate group such as (keratin sulfate, chondroitin sulfate,
dermatan sulfate, and heparin sulfate (heparin).
- Non-sulfated: No sulfate group, the only example is: (hyaluronic acid is a long
molecule with very high molecular weight).
2- proteoglycans: consist of proteins (~5%) and polysaccharide chains (~95%). The polysaccharide chains belong to glycosaminoglycan (a protein core attaches to many GAGs). 3-glycoproteins: consist of proteins (~95%) and polysaccharide chains (~5%). The sugar chains are branched short polysaccharides (oligosacchardies, oligo= few).
- The hyaluronic acid acts as a backbone where the other glycosaminoglycan
are going to attach through a protein core, so simply the hyaluronic acid
interacts with proteoglycans
- Ground substance consists largely of proteoglycans and hyaluronic acid.
Proteoglycans are very large macromolecules, consisting of a core protein
to which many glycosaminoglycan (GAG) molecules are attached. GAGs are
long-chained polysaccharides made up of repeating disaccharide units.
GAGs are highly negatively charged (polyanions). The high density of
negative charges attracts water, forming a hydrated gel. This gel permits
the rapid diffusion of water-soluble molecules but inhibits the movement of
large molecules and bacteria.
- The large structure formed by hyaluronic acid and proteoglycans makes a
spherical space; this space is called a domain. So, bacteria need to pass
between these domains in order to pass through the connective tissue, so
that is why we say that the ground substance has filtering effect and
prevents the spread of the bacteria. The pathogenicity of a bacterium is
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indeed to some extent determined by its ability to find its way through the
mesh, and some of the more invasive types produce the enzyme
hyaluronidase, this enzyme is able to destruct hyaluronic acid which will
destruct this domain so they are able to invade the connective tissue
- Each domain looks like a Bottle Brush: the handle is hyaluronic acid and the
bristles are the proteoglycans
- Functions of Proteoglycans
Resistance of compression. - They are stabilizing macromolecules
(little amount of it gives water gel state).
Retardation of movement of microorganisms.
Act as a filter
Adhesive glycoproteins: Laminin: connects the integrins of the hemidesmosomes with the other components "other proteins" of extracellular matrix. Chondronectin: it is found in cartilage. "chondro= غضروف “, "nectin means connection". The connection (adhesion) is between the cells of cartilage and ECM Osteonectin: "osteo means it is in the bone". Fibronectin: it is found in in basal lamina, connection between cells and ECM.
Fibers of connective tissue: 1- Collagen fibers: the main function is to give strength. 2- Elastic fibers: give elasticity "elasticity means, the ability to restore the original shape after distortion". 3- Reticular: give a network.
- In any connective tissue, we can find the 3 types of fibers, but the proportions of these components differ.
- If the tissue is composed mainly of collagen type 1, we call it collagenous connective tissue.
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- If it's mainly composed of elastic fibers, we call it elastic connective tissue. - If it's mainly composed of reticular, we call it reticular connective tissue.
*Collagen fibers: We have many types of collagen fibers, each type has different distribution than other types, we will mainly focus in collagen type one, which is the strongest type of collagen.
- Collagen is a protein, 30% of the proteins in our body is collagen" it is the most common protein in our body"
- they are very strong, to tear them you need hundreds of kilograms per 1
cm2, leather for example consists of Collagenous Fibers - fibers that originate from the skin of large mammals
- Collagen fibers are colorless, but the bulk accumulation of these fibers
appears white (for example the tendon is composed of collagen type 1, grossly the tendon appears whitish). Birefringence
- with hematoxylin and eosin, collagen appears acidophilic (pink)
- If we want to find the connective tissue, we look for eosinophilia, which is
the collagen fibers; because the connective tissue is composed of cells and extracellular matrix (ground substance "in the section appears unstained").
- Remember: in the sections, the lightly stained nuclei are fibroblasts "active
cells", while the darkly stained are fibrocytes.
- We have 28 kinds of collagen; each type has different sequence of amino acids, different chains combinations, different distributions and different modifications
- Collagen type 1: the strongest type of collagen, most common. Found in
skin, tendons, capsule, bone. - Collagen type 3: Reticuloendothelial system, reticular lamina of basement
membrane. - Collagen type 4: basal lamina.
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- Collagen type 7: it connects collage type 3 to 4 in basement membrane.
How the collagen is synthesized? - Fibroblast makes the extracellular matrix; DNA transcription for collagen
mRNA in nucleus------ mRNA is translated in the rough endoplasmic reticulum (a glycosylation step + hydroxylation-the addition of a hydroxyl group-)------Then it gets modified in the Golgi apparatus (addition of sugar-glycosylation-), then it gets exported from the cell by exocytosis, the product is called Procollagen (not the final form of collagen, pro means before).
- procollagen is made up of triple alpha helical chains + nonhelical parts on
the edges
- There is a certain enzyme in the extracellular matrix that cuts these edges,
after cutting the edges it's called Tropocollagen.
- The Tropocollagens align next to each other and above each other to form Collagen Fibril "smaller than the fiber".
- Collagen Fibrils aggregate to form Collagen Fiber.
- Collagen Fibers aggregate to form Collagen Bundle.
- Only collagen type 1 can form collagen bundles, while collagen type 3 forms fibers (thin fibers), collagen type 2 forms fibrils, collagen type 4 in basal lamina forms sheets.
- Note that each molecule of tropocollagen has head and tail, so the arrangement is (head to tail.. head to tail and so on), also there is a regular gap between two tropocollagens, so when looking at a collagen fibril under electron microscope, cross striations will appear; these striations are formed by the regular gaps between tropocollagen molecules because of the accumulation of the stain in these gaps.
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- The longitudinal areas of completely overlapping tropocollagens are called "overlapping areas".
- The longitudinal areas where there is gaps between tropocollagens are called non-overlapping areas.
- Note the non-overlapping areas appear darker and overlapping areas appear lighter (striations)
- In collagen type one each third amino acid is glycine, also each helix is rich
in proline and lysine. - The process of synthesizing collagen is a very long process and has many
steps; any defect in any step will result in defective collagen (result in diseases).
- For example, Hydroxylation step needs Vitamin C. Our body does not synthesis vitamin C, the source of this vitamin is the diet
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