L8 - Lymphoid Organs & Lymphocyte Trafficking

8/7/2019 L8 - Lymphoid Organs & Lymphocyte Trafficking

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Immunology

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Key Terms

Haemopoiesis Production of haematopoietic stem cells (precursors of immune cells)

Chemokines Cytokines that are involved in the regulation of mobility.

Germinal Centre A transient structure of intense B-cell proliferation

Primary Lymphoid Tissues

Where lymphocytes are developedProduction, maturation, selectionaka central lymphoid tissues

Bone Marrow:

Where most B-cells are developed

The main site is haemopoiesis in an adult is the bone marrow (in an embryo it is the foetal liv er)

Bone marrow is found in the central medullary cavity of bone

The majority of bone marrow is found in our long bones, notably the femur

Precursors are packed in the extracellular spaces (cavities) between sinuses

There are other cells here that interact and help the precursors

A good area to produce these cells, well protected as deep within bone

Thymus:

Where most T-cells are madeFound between lungs, above heart

A bi-lobed organ

Each lobe of the thymus is made up of lobules

Lobules are separated by connective tissue (trabeculae)

Each lobule is made up of an outer cortex and an inner medulla

Sensitive to hormone levels, o hormones = q thymus size

Thymus is largest early in life, this is when most T-cells are produced and stockpiled

Size begins to decrease in puberty and throughout lifeT-cell generation does still continue as an adult

Cortex may disappear entirely, medulla remains

Cortical atrophy (wasting) is related to the production of corticosteroid

There is a big o in corticosteroids during pregnancy and stress


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Immunology

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Cortex (outer)

Tightly packed with cellsImmature, proliferating thymic lymphocytes (thymocytes, T-cells)Site of positive selection

Medulla (inner)

Loosely packed with cellsMore mature thymocytesSite of negative selectionSite of a lot of cell death

Three types of thymic epithelial cells (TECs) are involved in T-cell development

Epithelial nurse cellsCorticalMedullary

Hassalls corpuscle is found in the medulla and might be involved in removing dead cells

High endothelial venules (HEVs) are involved in T-cell exit in the thymus

Found at the corticomedullary junction


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Immunology

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1. Nave T-cells are recirculated between bloodstream / lymph / secondary lymphoid tissues

T-cell enters the lymph node across an HEV (catflap) in the cortex2. A nave T-cell encounters an antigen that is presented by a macrophage or dendritic cell

This occurs in the medullaT-cells will monitor presented antigensIf the T-cell does not encounter a specific antigen it will leave the lymph node

oLeave via the efferent lymph3. If the T-cell encounters a specific antigen, it will proliferate and differentiate

Activation of T-cellsDifferentiationpeffector cells

Afferent = incoming

Efferent = leaving


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Immunology

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T-cells and B-cells need to be encouraged to enter lymphoid tissue

Needs to recognise the epithelial cells of the HEV

This is mediated by adhesion molecules

The primary molecule on B-/T-cells involved with recognition of a lymph node is L-selectin

L-selectin recognised two molecules in particular, found on the surface of HEVs

GlyCAM-1 has a sulphated-sialyl-LewisXgroup (carbohydrate) on its surfaceCD34 also as carbohydrate moieties on its surface

This process is not just recognition, it also slows the cells down

The circulation of blood / lymph moves the B-/T-cells around at

some speed. They need to be slowed if they are going to enter a

lymph node. The binding of

L-selectin to CD34 or GlyCAM-1 starts the rolling interaction.

Chemokines will bind to receptors on the incoming T-cell. If the

concentrations of chemokines are high enough,

LFA-1 (an integrin found on the surface of the T-cell) will be

activated through a conformational change induced by the

chemokine receptor binding to it. LFA-1 will now bind to ICAM-1, a

cell surface receptor on the HEV. There will now be tight binding

between the T-cell and the HEV.

Diapedesis then takes place, the lymphocyte moves from the

blood to the lymph node through gaps between cells.


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Immunology

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T-cells can only encounter an antigen via APCs (antigen presenting cells)

Antigen on an MHC molecule (on an APC)The lymphocytes need to get close to the APCs for an interaction to take placeAlso need to be there long enough for an interaction to take place

Molecules on the surface of the T-cellinteract with molecules of the surface ofdendritic cells:

CD2pLFA-3

LFA-1pICAM-1

LFA-1pICAM-2

ICAM-3pDC-SIGN

A lot of these molecules are only expressed on T-cells or

dendritic cells

The interactions hold the cells together close enough and long

enough for an interaction to occur. These reactions are low

affinity in comparison to that of an Ag and a T-cell receptor.

If the T-cell encounters its specific antigen there will be an interaction between the peptide Ag (presented by

MHC class II) and its Ag-receptor. Binding of the TCR will activate intracellular signalling, which will change

the LFA-1 conformation, resulting in it binding tightly to ICAM-1. The T-cell is now strongly bound to the

dendritic cell. This interaction can now last for many hours. The TCR interaction will cause T -cell proliferation,

daughter cells will also recognise the Ag.

Lymph


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Immunology

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Nodes:

Encapsulated bean-shaped structure

Clustered at junctions of lymphatic vessels

Found in the neck, armpit, groin, gut etc.

Filter and trap antigens from lymph

Lymph nodes consist of:

Cortex (B-cell area)Paracortex (T-cell area)Medulla

Has an afferent vessel (in tube) and an efferent vessel (out tube)

Promote crucial interactions between

APCs (dendritic cells) and T-cellsActivated antigen-specific T- & B-cells

Primary lymphoid follicles can differentiate into germinal centres (important in B-cell activation)

Lymphoid Follicles:

All secondary lymphoid organs have them

Start off as a network of follicular dendritic cells (FDCs) embedded in a B-cell-rich region

FDCs display antigen to B-cells

During an infection, complement binds to pathogen, which is coated in Ag

This is then delivered to the secondary lymphoid organs

FDCs have a lot of complement receptors, so the FDCs will get covered in Ag

The dendrites on the FDCs have a lot of complement receptors

FDCs also have receptors that bind the constant region of antibodies

FDCs can hold antigens for months

FDCs display antigens in a way that can cross-link B-cell receptors

B-cells with receptors cross-linked by Ag coating the FDCs will proliferate to form germinal centres, and will

later differentiate to plasma cells.

FDCs are not DCs (dendritic cells)

B-cells in the germinal centres are fragile and will die without help


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Helped to survive by THcells (helper T-cells) that have been activated in T-cell areas

Activated THcells express high levels of CD40L (ligand) that bind CD40 or B-cell surfaceThis rescues dying B-cells allowing them to proliferateHas to be a THcell that recognises the same antigen as the B-cell

If B-cells and T-cells interact with the same antigen on a FDC they can form a primary follicle

10% T-cells90% B-cells

The primary follicle differentiates into a germinal centre

There is a huge amount of proliferation of B-cells in the germinal centres (dark zone)

B-cells will eventually differentiate, affinity maturation will take place then it will move through the HEV

If B-cells recognise a self antigen, there is a selection process that will remove them to prevent an

autoimmune response.

High Endothelial Venules (HEVs):


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Immunology

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Found in all secondary lymphoid organs other than the spleen

Allow the passage of T-/B-cells between blood and secondary lymphoid organs

There is enough space between the cells in HEVs to allow lymphocytes to pass efficiently

The Spleen:

A fist-sized organ found behind the stomach

Collects antigens from the blood

Disposes of ageing red blood cells

Trabecular artery separates compartments

Red pulp contains many red blood cells

Makes up the majority of the spleen

Site of RBC disposal

Venous sinuses contain resident macrophages, erythrocytes, platelets and some lymphocytes

White pulp contains many white blood cells& lymphoid tissue

Lymphocytes surround a central arteriole forming Periateriolar Lymphoid Sheaths (PALS)

T-cells surround the central arteriole

Primary lymphoid follicles are attached to the PALS

Rich in B-cellsSometimes contain germinal centres

Marginal Zone surrounds the PALS

Contains B-cells, macrophages and dendritic cells

Mucosa-Associated Lymphoid Tissue (MALT):

Trabecular artery


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Immunology

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Protects mucus membranes lining the digestive, respiratory and urogenital systems

These regions are more exposed to pathogens

BALT = Bronchiole Associated

GALT = Gut Associated

Tonsils + appendix

Peyers patches are found within the intestinal lining

They monitor what is happening in the gut

Found near the surface of the gut wall

Epithelial M cells transport antigens into the lymphoid tissue from the

lumen of the small intestine. Membrane ruffles help to pick up antigens

from the gut on microvilli. Endocytosis brings the Ags in. The M cells

are selective in that they can only bring in antigens that bind to

receptors on their cell surface. The subtypes of molecules they bring in

are those that could be pathogen related. Pathogens will generally have

molecules that allow them to bind to host cells anyway, this is what allows them to be infectious.

This way an immune response can be initiated in case the pathogenic material enters the bloodstream.

The Peyers patches have HEVs through which lymphocytes can enter the blood


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Immunology

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Captured antigens are then transferred to lymph nodes.

Peyers patches are not lymph nodes, and are unable to mount an i mmune response

Lymph nodes are placed in strategic positions; skin, gut etc.

Crucial in mounting an immune response

Have some control in determining what type of immune response is mounted

e.g. Peyers patches specialise in turning out THcells making TH2 responses

Also B-cells making IgA (perfect for intestinal invasion)

In terms of lymphocyte trafficking, the movement of nave and activated lymphocytes differs

We want the nave cells to be circulating and the activated cells to go to infection sites

Surface molecules such as L-selectin (found on nave T-cells) will direct their movement

The surface molecules will differ on nave / activated cells

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L8 - Lymphoid Organs & Lymphocyte Trafficking