3 - Leukocyte Recirculation and Migration into Tissues

Question 1

Immune system cell migration

Answer 1

The major cellular components of the immune system constantly move through the blood, into tissues, and often back into the blood again, in a highly regulated way

Question 2

Acute inflammation

Answer 2

The accumulation of leukocytes, plasma proteins, and fluid derived from the blood at an extravascular tissue site of infection or injury

Question 3

Steps of acute inflammation

Answer 3

1. Begins when tissue is injured
2. PAMPs and DAMPs activate macrophages, dendritic cells, mast cells (sentinel cells)
3. Cytokines and other mediators are produced
4. Vasodilation and increased vascular permeability (fluid and proteins enter tissues)
5. Complement, antibodies, and antimicrobial proteins kill microbes
6. Adhesion molecules and chemokines cause leukocyte migration into tissue
7. Phagocytosis and killing of microbes

Question 4

Homing

Answer 4

Migration of a leukocyte out of the blood and into a particular tissue, or to a site of an infection or injury

Question 5

Lymphocytes recirculation

Answer 5

Recirculate repeatedly to secondary lymphoid organs, reside there transiently,
and return to the blood

Question 6

4 cardinal signs of inflammation

Answer 6

• redness
• swelling
• heat
• pain

Question 7

Basic components of an inflammatory response

Answer 7

• Vasodilation
• Increased vascular permeability
• Emigration of white blood cells

Question 8

Steps of leukocyte recruitment into tissues

Answer 8

1. Rolling
2. Integrin activation by chemokines
3. Stable adhesion
4. Migration through endothelium

Question 9

Integrin activation

Answer 9

• Integrins on blood leukocytes are normally in a
  low-affinity state.(LFA-1)
• If a leukocyte comes close to endothelial cells, (such as when selectin-dependent rolling of leukocytes occurs) then chemokines displayed on the endothelial surface can bind chemokine receptors on the leukocyte.
• Chemokine receptor signaling then occurs, which activates the leukocyte integrins, increasing their affinity for their ligands on the endothelial cells.

Question 10

Selectins

Answer 10

• Plasma membrane carbohydrate binding adhesion molecules that mediate an initial step of low affinity adhesion of circulating leukocytes
• A mechanism by which leukocytes are recruited to sites of inflammation

Question 11

What are the two types of selectins that are expressed on endothelial cells

Answer 11

• P selectin (CD62P)
• E selectin (CD62E)

Question 11

E selectin

Answer 11

• Synthesised and expressed on the endothelial cell surface within 1 to 2 hours in response to cytokines interleukin-1 (IL-1) and tumour necrosis factor (TNF) which are produced by tissue sentinel cells in response to infection
• Microbial products such as LPS also stimulate E selectin expression

Question 12

P selectin

Answer 12

• Stored in cytoplasmic granules of endothelial cells
• Rapidly redistributed to the luminal surface in response to histamine from mast cells
• The major carbohydrate ligand for P-selectin is sialyl Lewis X

Question 13

L selectin (CD62L)

Answer 13

• Expressed on leukocytes not endothelial cells
• Ligands for L selectin are sialomucins, whose expression may be increased by cytokine activation of the cells
• L-selectin on neutrophils promotes the adhesion of the cells to endothelial
  cells at sites of inflammation
• Required for naive T and B lymphocyte homing into lymph nodes through high endothelial venules (HEVs)

Question 14

PNAd

Answer 14

Collective term for the sialomucin ligands on HEVs that bind to L-selectin on naive lymphocytes

Question 15

T lymphocyte recirculation pathway

Answer 15

• Naive T cells leave the blood and enter lymph nodes across the high endothelial venules
• Dendritic cells bearing antigen enter the lymph nodes through afferent lymphatic vessels
• Naive T cells that do not recognize antigen after several hours return to the circulation
• If the T cells recognize antigen, they are activated and generate effector and memory T cells, which leave the lymph node via efferent lymphatic vessel and return to the circulation
• Effector and memory T cells leave the blood and enter peripheral tissues

Question 16

Naive and effector T lymphocyte migration

Answer 16

• Naive T lymphocytes home to lymph nodes as a result of L-selectin binding to peripheral node addressin (PNAd) on HEVs, which are present only in secondary lymphoid organs, and as a result of binding chemokines (CCL19 and CCL21) displayed
  on the surface of the HEV
• Activated T lymphocytes, including effector cells, home to sites of infection in peripheral tissues, and this migration is mediated by E-selectin and P-selectin, integrins, and chemokines that are produced at sites of infection

Question 17

Mechanism of egress of lymphocytes from lymphoid organs

Answer 17

• S1P is present at relatively high concentration in blood and lymph and at lower concentration within lymphoid tissue
• Circulating naive T cells express low levels of S1PR1 because the receptor is internalized after binding S1P in the blood
• Naive T cells entering a lymph node cannot sense the S1P concentration gradient between the T cell zone of the node and the lymph in the medullary sinus and efferent lymphatics, and these T cells cannot exit the node
• After activation of a naive T cell by an antigen, surface expression of S1PR1 is blocked for several days, and the activated cells will not leave the node
• S1PR1 is re-expressed after several minutes to hours for naive T cells, or days for activated and differentiated effector T cells, and these cells can then sense the S1P gradient and exit the node

Question 18

Steps in CD4 + T cell–mediated immune responses.

Answer 18

• CD4 + T cells recognise peptides that are derived from protein antigens and presented by dendritic cells in secondary lymphoid organs
• The T lymphocytes are stimulated to proliferate and differentiate into effector (and memory) cells, which enter the circulation and migrate to sites of infection in peripheral tissues.
• In the tissues, effector T cells recognise the antigen and respond by secreting cytokines that recruit more leukocytes and activate phagocytes

Question 19

Induction and effector phases of CD8 + T cell responses.

Answer 19

• Naive CD8 + T cells recognise antigens presented by dendritic cells in secondary lymphoid organs and are stimulated to proliferate and differentiate into effector cells (cytotoxic T cells) and memory cells
• CTLs migrate to tissues at sites of infection, tumor growth, or graft rejection, where they recognise the antigen and respond by killing the cells where the antigen is produced

Question 20

MIgration of B cells

Answer 20

• Naive B cells enter lymph nodes and mucosal associated lymphoid tissues through high endothelial venules (HEVs), migrate into follicles, become activated
• Activated B cells differentiate into antibody producing cells (some are plasmablasts)
• IgG secreting plasma cells may be generated in any lymphoid tissues
• Other B cells that enter follicles differentiate into memory B cells, some of which enter circulation

Question 21

IgA secreting plasma cells

Answer 21

Produced mainly in mesenteric lymph nodes of mucosa associated lymphoid tissues and home back to mucosal tissue