Leukocyte Migration and Inflammation: Test 3

Localized inflammatory response: Chemokines cause PMNs to extravasate (........... hours). -PMNs engulf invading microbes - Secrete factors contributing to inflammation - MΦ inflammatory proteins 1α and 1β (MIP-1α, MIP-1β), MΦ specific chemokines. MΦ extravasate (........... hours). They are activated upon entering the site of inflammation. This activation increases phagocytic activity. It also allows for secretion of cytokines that contributes to the inflammatory response.

1-2 5-6

C REACTIVE PROTEIN does what?

- Binds broad spectrum of microbes and activates complement. - Cleaves C3, deposits C3b on microbe surface. - Promotes phagocytosis by PMNs and MΦ.

HOMING (TRAFFICKING) requires two factors to occur, and both are involved in generation of heterogeneity of lymphocyte circulation patterns. These 2 factors are:

- Specialized adhesion molecules - Chemokines (interact with receptors on lymphocytes, and trigger the events required for extravasation)

Central Roles of IL-1, TNF-α, and IL-6:

- Triggers production of acute phase proteins by the liver. - Signals pituitary gland to secrete ACTH - hormone. - Causes bone marrow to produce CSF, which allows generation of more immune effector cells.

Four major classes of CAMs mediate attachment of leukocytes to vascular endothelial (skin) cells. These are:

- selectins - mucins - integrins - ICAMs

HEV have a high affinity for lymphocytes due to various..........................

CAMs * CAMs may vary from tissue to tissue, which mediates extravasation of specific lymphocyte populations.

There are two classes of chemokine, and both have four conserved cysteines. The classes are:

CC CHEMOKINES (conserved cysteines adjacent to each other) CXC CHEMOKINE (cysteines are separated by any amino acid)

Chemokines mediate extravasation and chemotaxis by interaction with specific receptors:...............or................ Chemokine/receptor interaction causes dramatic changes in multiple signal transduction pathways.

CCR or CXCR

Homing is mediated by L-selectin on the Naïve lymphocyte, and by two mucins on HEV at lymphoid tissues, called..........................and.............................. This allows repeated recirculation of naïve lymphocytes through lymphoid tissue.

CD34 and GlyCAM-1.

Several diseases are due to chronic inflammation (diabetes, rheumatoid arthritis).The hallmarks of vascular endothelial cells at sites of disease are: - They strongly resemble HEVs normally found only near tertiary lymphoid tissues. - Facilitate entry of immune effector cells to inappropriate sites. - IFN-γ and TNF-α are often found at the sites of disease. Treatment may require control of development of...........like regions.

HEV

Naïve Lymphocyte Extravasation is similar to extravasation of PMNs.L-selectin interacts with mucin on HEV surface, which is a weak interaction. This ensues rolling, which is less pronounced, as the rate of blood flow is slower. ........................... activates the receptor on the lymphocyte. Thus Induces rearrangement of................. so that it has a high affinity for ICAM-1, which allows tight attachment and entry into lymph nodes.

HEV associated chemokine LFA-1 integrin

Normal venule epithelial cells exhibit a flat shape, but cells at the site of extravasation are very thick! They are said to have cube or "high" shape, and to have affinity for lymphocytes. Regions containing these cells are called:

HIGH ENDOTHELIAL VENULES (HEV)

Specific lymphocytes extravasate into specific tissues in a process referred to as...............................

HOMING or TRAFFICKING

An acute phase response is due to production of:

IL-1, TNF-α, and IL-6.

What does ICAMs stand for, and what are they expressed on?

IntraCellular Adhesion Molecules, expressed on both leukocytes and endothelial cells

Both effector and memory lymphocytes down regulate expression of......................... This prevents homing to secondary lymphoid tissues.

L-selectin

There are tree types of selectins: L-, E-, and P-selectin. .................express L-selectin, and.................... express E- and P-selectin.

Leukocytes vascular endothelial cells

Naïve Lymphocytes Home to:

Lymphoid Tissue! * Naïve lymphocytes cannot be activated in circulation. They must encounter an antigen in a controlled microenvironment. Lymphoid tissue provides a suitable microenvironment for activation, and thats why Naïve lymphocytes specifically home to lymphoid tissue.

When are CAMs expressed?

May be expressed constitutively or may only be expressed in response to cytokine stimulation.

Different chemokine receptors allow activation for different stimuli. Immune cells are activated by specific challenges due to differential production of chemokine receptors! PMNs express...................... receptors basophils express........................ receptors eosinophils express........................... receptors monocytes express........................... receptors

PMNs express CXCR1, 2, 4 basophils express CCR1, 2, 3 eosinophils express CCR1 and 3 monocytes express CCR1, 2, 4, and CXCR4

What chemokine receptors do T-cells express?

T-cells only express CXCR4 before activation! Activation results in production of multiple receptors.

What is Lymphocyte Recirculation?

The process of movement of lymphocytes throughout an organism. There are many destinations once released into circulation: - May move to spleen then reenter the circulatory system. - May enter lymph nodes and return to circulation. - May enter tertiary lymphoid tissue (MALT) and return to circulation via lymph nodes.

MUCINS are also expressed on both vasuclar epithelial cells and leukocytes! They are heavily glycosylated, meaning they have many sugars attached. How do they mediate attachment?

They present sugar to selectins.

Selectins posses a lectin like domain. Lectins bind specific..................... molecules.

carbohydrate (sugar)

Role of thrombin

cleaves fibrinogen to form FIBRIN clot, which contains infection at the site of trauma, and prevents bleeding due to damage.

Leukocyte L-selectin attaches to mucins on........................, and endothelial E- and P-selectin attach to mucins on..............................

endothelial cells lymphocytes

Activation results in a strong interaction between the leukocyte and endothelial cells. This interaction is sufficiently strong to prevent further rolling. Immobilization allows transendothelial migration, which is.......................................................

entry into tissue!!!

Role of kinins

increase vascular permeability, induces vasodilation, induces pain, activates C5.

Effector and memory lymphocytes home to specific tissues. Effector cells home to sites of............................ while memory cells migrate to tissues where an antigen was first encountered. Homing patterns are dictated by expression of different CAMs and chemokine receptors.

inflammation

Prior to activation, conformation does not mediate interaction with ICAM! Conformational change allows for a strong interaction between.................. and..................

integrin and ICAM.

ICAMs are all members of the Ig superfamily. ICAMs on endothelial cells mediate leukocyte attachment via .........................! ICAMs are also involved in leukocyte-leukocyte interactions, and are important to many aspects of the immune system.

integrins

What is required for attachment to occur?

interaction between surface exposed proteins called CELL ADHESION MOLECULES (CAMs).

Role of Plasmin

involved in removal of a clot. It is a protease that cleaves fibrin, and its degradation products are chemoattractants for PMNs, and also activate complement.

More than just cells are required for inflammation. Several small molecules are essential for a response. Some are involved in attracting cells to site. Others are involved in other processes essential for inflammation (vasoconstriction, vasodilation, vascular permeability, clotting). These include:

kinins, fibrin, complement components, lipids, and cytokines.

Lymphocyte Extravasation has a mechanism similar to PMN extravasation, with the same processes involved. It is...................... regulated than PMN extravasation. T- and B-cells (lymphocytes) are involved in adaptive immunity, and recirculation is important for encounter of an antigen. This requires regulation to ensure proper populations recruited to appropriate tissues. Lymphocytes exit the circulatory system at specialized epithelial cells in capillaries. These cells exhibit morphology (shape) that is substantially different from other epithelial cells associated with the capillary.

more

When it comes to PMN extravasation, the leukocyte loosely attaches to the vascular endothelium, due to interaction between.................. on leukocyte and.............. on endothelial cell. This interaction is not strong enough to allow for stable interaction, and the force of blood flow moves the leukocyte, meaning the................... interactions maintain transient contact. So, the overall effect is that the leukocyte "rolls" along the vascular endothelium.

mucin selectin mucin/selectin

Cytokines or other leukocyte activators at the site of trauma all have the same result, which is:

rearrangement of α- and β-chains of integrins.

What expresses selectins?

expressed on both vasuclar epithelial cells and leukocytes!

A local inflammatory response may cause systemic response known as an:

ACUTE PHASE RESPONSE!

COMPLEMENT COMPONENTS: several complement cleavage products are.......................... These cause degranulation of mast cells, and the contents of granules induces muscular contraction which increases vascular permeability.

ANAPHYLATOXINS

The site of trauma induces leukocyte activation. How?

Activation is induced by cytokines and other activators at the site of trauma. (Several are capable of inducing activation: IL-8, MIP-1β, PAF, C5a, C3a, C5b67, & bacterial peptides)

Attachment

Attachment is a critical step in lymphocyte migration to a site of trauma. It is when circulating lymphocytes attach to endothelial cells of blood vessels in order to gain entry to damaged tissues.

Systemic response involves elevated temperature (fever), production of hormones, and liver synthesis of ACUTE PHASE PROTEINS. An important protein in this response is what?

C REACTIVE PROTEIN

What expresses integrins?

expressed ONLY on leukocytes! * integrins have two subunits: α and β chains.

Chemokine receptor binds chemokines with a..................... affinity. Most receptors actually bind multiple chemokines! This allows multiple stimuli to activate leukocytes. Activation turns on multiple signal transduction cascades very quickly. This causes many changes (stronger adhesion, production of antimicrobial substances, size/shape, degranulation).

high