Lecture Five; The lymphatic system

Question 1

What is the function of the lymphatic vasculature?

Answer 1

• Primary role is in fluid homeostasis, the draining of fluid (lymph) from interstitial space
• Provides a conduit for the trafficking of immune cells and antigens
• Lipid Transport

Question 2

Describe the lymp is formed.

Answer 2

• Blood pressure causes plasma to leak out of blood capillaries.
• This interstitial fluid is taken up by lymphatic capillaries along with leukocytes, large macromolecules and microbes. Here it is known as lymph

Question 3

Describe lymph drainage;

Answer 3

Lymph drains from capillaries into precollecting vessels and collecting vessels

Specialised valves prevent backflow and ensure unidirectional flow of lymph

Question 4

Describe the structure of lymphatic capillaries

Answer 4

• Unidirectional fluid flow
• Highly permeable vessels
• No smooth muscle or pericytes
• Little or no basement membrane
• Attached to matrix by anchoring filaments

Question 5

Describe how lymph returns to the blood stream;

Answer 5

All lymph flows into one or two lymphatic trunks; The thoracic duct and the right lymphatic duct.

These connect via specialised lymphovenous valves to the left and right subclavian veins respectively

Question 6

What do lymphatic vessels develop from?

Answer 6

Veins

Question 7

Describe lymphatic vessel development;

Answer 7

Vein
- contains lymphatic progenitor cells which express an array of genes importantly VEGFR3 and VEGF-C*(not sure if this isnt or is)

This encodes lymphatic specification

• Lymphatic sprouting
• Lymph sac formation and proliferation
• Lymphatic plexus remodelling and maturation

Question 8

Describe evolutionary conservation of the lymphatics;

Answer 8

• Lymphatic development is highly conserved among vertebrates
• The thoracic duct develops from lymphangioblasts that sprout from cardinal veins
• Lymphangioblasts are lymphatic precursor cells, derived from veins

Question 9

Describe how during lymphatic development receptors are upregulated

Answer 9

As lymphatic cells become specialised in the veins, they upregulate the expression VEGFR3 (receptor).

Question 10

Describe the importance of VEGFr3

Answer 10

Vegfr3 is acitvated by a ligand VEGFC present in the tissues and this causes the lymphatics to become migratory and sprout from the cardinal vein
- Mutations of knockdown of these genes prevent lymphatic development

Question 11

What causes lymphoedema?

Answer 11

Lymphatic dysfunction causes fluid accumulation, particularly in the limbs.

Milroys disease is a type of lymphoedema and is caused by mutations in VEGFr3

Question 12

Describe lymphatic vessel and lymph node interplay;

Answer 12

Lymph nodes are wired into the lymphatic system.

Question 13

Where are there clusters of lymph nodes?

Answer 13

There are clusters of lymph noes in key regions such as;

• Cervical
• Axillary
• Intestinal
• Inguinal
• Popliteal

Question 14

How do lymph nodes collect antigens?

Answer 14

Directly in the lymph or by cells that travel along the afferent lymphatics (DC)

A variety of lymphocytes within the nodes are able to interact with these antigens

Question 15

What is the problem with lymphocytes and circulation?

Answer 15

The number of lymphocyte specificities is large, only a small population of individual cells are able to deal with a particular infection

Therefore, recirculation of cells from blood to secondary lymphoid organs, into lymph and back to blood increases the likelihood that lymphocytes interact with their target antigens

Question 16

Describe how circulating lymphocytes can enter lymph nodes?

Answer 16

Circulating lymphocytes can enter lymph nodes through specialised blood vessels (High Endothelial Vessels)

HEVs are present in all secondary lymphoid tissue

Question 17

What happens to lymphocytes once they enter secondary lymphoid tissues via HEV?

Answer 17

• Can potentially antigens presented by DC in the node

- Majority of lymphocytes do not meet their target antigens and exit via efferent lymphatic vessel

Question 18

Do DC capture antigens in the node?

Answer 18

DC may have captured the antigens in the tissue and migrated to the node via afferent lymphatics or captured the antigen in the node itself

Question 19

How do lymphocytes exit the circulation into tissue when they are needed?

Answer 19

IN a process called extravasation

Question 20

What are the two broad stages of extravasation?

Answer 20

Margination

Diapedesis

Question 21

What is the first step in leukocyte extravasation?

1/4

Answer 21

Infection or trauma causes localised release of inflammatory cytokines

• TNFa, IL1

Question 22

What is the second step in leukocyte extravasation?

2/4

Answer 22

TNFa and IL1 activate local venous endothelial cells

These upregulate expression and activating cell surface proteins such as selectins and intracellular adhesion molecules (ICAMS)

Question 23

What is the third step in leukocyte extravasation?

3/4

Answer 23

Tethering-rolling of leukocytes in the blood is mediated by interactions between activated selectins and cell surface glycoproteins

As these are weak they only slow the leukocytes

Question 24

What is the final step in leukocyte extravasation?

4/4

Answer 24

During rolling, integrins are activated in the leukocyte and the endothelial cells that allow it to bind to ICAMS

These interactions are strong enough to cause arrest and flattening of the leukocyte

The leukocyte then migrates between endothelial cell junctions in the issue (diapedesis)

Question 25

Describe selectin binding:

Answer 25

Selectins- mediate weak binding between cells.

They bind to glycoproteins with sialylated carbohydrate groups

Question 26

Give example 1/2 of selectins;

Answer 26

I.e L-Selectin on leukocytes binds to glycosylation-dependant cellular adhesion molecule 1 (GlyCAM-1) on endothelial cells

Question 27

What is the function of integrins?

Answer 27

Mediate strong binding between cells. Are expressed on leukocytes and endothelial cells. They bind to immunoglobulin superfamily molecules.

Question 28

Give example 1/2 of integrins;

Answer 28

I.e Lymphocyte function-associated antigen 1 (LFA-1) is an integrin that binds to ICAM-1 , ICAM-2, ICAM-3

Question 29

Give example 2/2 of integrins;

Answer 29

I.e Lymphocyte payers patches adhesion molecule 1 (LPAM-1) is an integrin that binds to mucosal addressin cell adhesion molecule 1 (MAdCAM-1) on HEVs

Question 30

Give example 1/2 of selectins

Answer 30

i.e E-Selectin on endothelial cells binds to E-Selectin Ligand One (ESL-1) on neutrophils

Question 31

What is lymphocyte homing?

Answer 31

Different types of lymphocytes display tissue specific recirculation through lymphoid tissues.

Question 32

Describe B lymphocyte homing;

Answer 32

B cells tend to enter mucosa associated lymphoid tissues better than t cells

Question 33

Describe naive t cell homing;

Answer 33

Naive t cells enter into lymph nodes better than effector and memory t cells

Question 34

What does lymphocyte homing do?

Answer 34

Lymphocyte homing ensures that the correct population of lymphocytes are present at various sites in the body.

Question 35

How is homing achieved?

Answer 35

Homing is achieved due to the differential expression of various cell surface molecules on lymphocytes (homing receptors) and on the endothelial cells of HEVs in different lymphoid tissues (vascular adhesion)