Immuno Test 1 part 2 page 36 till end Flashcards Preview

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Flashcards in Immuno Test 1 part 2 page 36 till end Deck (337):
1

Inflamation is defined as?

the reaction of vascularized living tissues to local injury. The vascular and cellular events that highlight actue inflammation serve to deliver mediators of host defenses to sites of microbial invasion and/or tissue injury.

2

Inflammation is always an evoked response set in motion by________

It occurs only in ____.

 

 

some kind of a stimulus, eg tissue injury. It occurs only in living tissue.

 

 

 

3

Cardinal signs of Acute Inflammation?

1.) Rubor- redness (heat not fever) 2.) tumor- swelling edema 3.) Calor- heat 4.) Dolor- pain 5.) Functio laesa- loss of function

4

The local inflammatory response is always accompanied by_____________.

systemic changes collectively called the acute phase response or the systemic inflammatory response syndrome.

5

Systemic responses to infection are due to the ?

actions of proinflammatory cytokines such as tumor necrosis factor, interleukin-1 and interleukin-6 secreted by activated macrophages, mast cells, etc.

6

What are some other cytokines that also participate in the acute phase response?

colony stimulating factors that stimulate the bone marrow to produce more white blood cells.

7

What does the acute phase include?

1.) Fever- heat doesn't allow replication 2.) Leukocytosis (hematopoiesis) more WBC 3.) Increased synthesis of acute phase proteins 4.) decrease in the plasma concentration of iron. High concentration of free iron enhances bacterial replication. (battle between us and microbes takes iron away) 5.)Decrease in appetite. May deprive pathogens of nutrients, especially minerals, needed for their proliferation 6.) increased secretion of many hormones, notably ACTH and cortisol

8

What are acute phase proteins ?

plasma proteins whose concentration change by at least 25% during inflammation.

9

Some proteins decrease in plasma concentration and are called?

negative acute phase proteins Ex: albumin

10

Where are acute phase proteins synthesized? What roles do they have?

mostly by the liver. The proteins play various roles in the innate immune response to infectious agents.

11

What are some acute phase proteins?

1.) complement proteins 2.) C-reactive protein- binds to bacteria and promotes their uptake by phagocytic cells, a process referred to as opsonization. 3.) Mannose- binding protein (more opsonization, also activation of classical pathway) 4.) iron binding proteins (haptoglobin, transferrin, lactoferin) 5.) lipopolysaccharide- binding protein (increased response to G- bacteria)

12

What does the microvasculature consists of? What follows after tissue injury?

the afferent arterioles, the capillary networks and the efferent venues. initiation of inflammatory response at the capillary and post capillary venules.

13

in acute inflammation what is the initial response of arterioles? What happens within a few minutes?

transient vasoconstriction, mediated by neurogenic and chemical stimuli. Vasodilation occurs a few minutes later, increasing blood flow to inflamed area.

14

What are post capillary venules?

the venules are the primary anatomic site for inflammation-related leakage. The junctions between the endothelial cells are more permeable than those in the capillaries, additionally the endothelial cells are more sensitive to vasoactive mediators.

15

What are chemical mediators of inflammation?

they are chemical messengers that enhance blood flow, increase vascular permeability, or induce the emigration of leukocytes from the blood stream to the site of tissue injury.

16

What are examples chemotactic factors? and what do they lead to?

*C5a *Leukotriene B4 *Formylated peptides *Chemokines IL-8 CXCL8 *PAF -lead to recruitment and stimulation of inflammatory cells

17

The inflammatory response may have 3 outcomes?

1.) elimination of the causative agent 2.) walling off of the inflammation from the rest of the body with subsequent healing of the lesion 3.) persistence of the causative agent, leading to chronic inflammation or spread throughout the body.

18

Cellular sources of chemical mediators of inflammation?

Platelets, connective tissue mast cells, basophils, neutrophils, endothelial cells, fibroblasts, monocyte/tissue macrophages, injured tissue.

19

Many mediators carry out their biologic activity by?

binding to specific receptors on target cells. Most functions can be elicited by multiple mediators and most mediators serve multiple functions.

20

Many mediators exert their effects______ and do not circulate systemically in high concentration except in unusual circumstances.

locally

21

What system of checks and balances limit the extent of the inflammatory response and hence tissue injury?

Many mediators have short tissue half lives. They quickly decay or are inactivated by enzymes or inhibited.

22

LPS released from the cell wall of Gram-negative bacteria is recognized and bound by....?

lipopolysaccharide binding protein present in plasma. LBP enhances the efficiency of transfer and presentation of LPS to the CD14 receptor on macrophage cell membrane, resulting in macrophage activation.

23

The activated macrophage synthesizes and secretes vasoactive mediators of inflammation including???

IL-1 IL-6 CXCL-8 TNF alpha, PAF

24

Nitric oxide is an important mediator of inflammation. what does it cause?

it causes vasodilation by relaxing vascular smooth muscle, reduces platelet aggregation and adhesion, and is a potent microbicidal agent. It is produced by activated endothelial cells and activated macrophages.

25

What are the steps of leukocyte recruitment to the site of inflammatory response?

begins with local dilation of postcapillary venules, followed by 1.) leukocyte rolling 2.) activation 3.) margination/pavementing and 4.) transendothelial migration (chemotactic factors influence any subsequent movement through the extracellular matrix to the site of inflammation or injury)

26

What are the four major families of adhesion molecules?

1.) selectins- Lselectin P-selectin and E selectin 2.)Addressins GlyCAM1 CD34 PSGL-1 ESL-1 MAdCAM 3.)Integrins- VLA-4 CD11aCD18, CD11bCD18 etc 4.) Immunoglobulin superfamily ICAM-1 ICAM-2 ICAM-3 VCAM-1 PECAM**, CD2, CD58, etc

27

Selectins are a family of adhesion molecules expressed on?

platelets, leukocytes and endothelial cells that promote the initial localization and rolling of leukocytes along endothelium at sites of tissue injury.

28

What is P-selectin? When is it expressed on a cell?

is pre-formed and is stored within Weibel-Palade bodies of ECs and the alpha granules of platelets. When EC is activated by histamine etc., the granule fuses with the cell membrane and P-selectin is expressed on the cell surface.

29

Where do P-selectins bind?

to an addressin on neutrophil, monocyte and T- lymphocyte cell suraces called P-selectin glycoprotein Ligand-1 (PSGL-1)

30

In acute inflammation, what happens in the capillaries?

endothelial cells react to vasoactive mediators leading to EC retraction, gap formation and increased permeability

31

What are examples of vasoactive mediators? and what do they do?

histamine serotonin bradykinin nitric oxide leukotriene C4 D4 E4 Prostaglandins Platelet-Activating Factor Anaphylatoxins lipopolysaccharide cytokines -They lead to vasodilatation, increased vascular permeability and endothelial expression of adhesion molecules

32

How is selective adhesion of leukocytes to vascular endothelium achieved?

through a myriad of complementary cell adhesion molecules in endothelial cells and leukocytes. There are 4 major families of adhesion molecules.

33

What are selectin molecules composed of?

a single chain transmembrane glycoprotein with an extracellular lectin roman

34

E (endothelial)- Selectin is synthesized and expressed where and when? What are examples of E-selectin?

synthesized on and expressed by endothelial cells within 1-2 hours AFTER pro inflammatory cytokine activation (by IL-1 and TNF-alpha) ex: CD62E, ELAM-1

35

Where does E-selectin bind?

to E-selectin ligand-1 (ESL-1) on the surfaces of granulocytes, monocytes and T lymphocytes

36

L (Leukocyte)-selectin is expressed where? what is an example of L-selectin?

expressed on lymphocytes, granulocytes, monocytes and macrophages. EX: CD62L

37

Where does L-selectin bind?

binds to several receptors on ECs including CD34, glycan-bearing cell adhesion molecule-1 (GlyCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1)

38

Vascular addressins are ____-like molecules that posses carbohydrate regions that bind the ____ domain of selectins

mucin-like lectin domain

39

Where are vascular addressins expressed?

on the surfaces of leukocytes and endothelial cells

40

Is selectin-addressin binding strong? How does this affect the inflammatory response?

No, it's like a post-it note in staying power. if inflammatory stimulus is weak, and integrin-mediated attachment of the cell does not occur, the cells breaks away after a few seconds or minutes and returns to circulation

41

Integrins are transmembrane adhesive proteins expressed on___. They are composed of ___ and ___ sub units arranged as ____dimers.

leukocytes alpha beta heterodimers

42

Each of the several subfamilies of integrins expresses a ____ Beta chain that is associated with ____

conserved beta chain (e.g. Beta1/CD29, B2/CD18, B3/CD61) different alpha chains

43

What are the major functions of integrins? Some integrins also bind to proteins that participate in the ___ response?

to mediate adhesion of leukocytes to endothelial cells, extracellular matrix proteins (cell migration), and adhesion of T cells to antigen-presenting cells. inflammatory response (e.g. complement proteins)

44

True or false: integrins are always present on the surface of leukocytes?

TRUE

45

Although integrins are always present on the surface of leukocytes, how are they regulated?

quickly up-regulated in NUMBERS and ADHESIVENESS following activation of leukocytes by chemoattractants (CXCL8, etc) secreted by activated ECs and/or tissue cells [some tissue-derived mediators may diffuse from tissue into the blood vessels, bind to EC surfaces and directly contact the leukocyte]

46

How is adhesiveness of an integrin changed?

via a conformation change in the integrin; up-regulated sticky integrins on activated leukocytes bind to counterrecptors (ICAM-1 or ICAM-2) on ECs yielding STABLE ADHESION of the leukocytes to the endothelium (also called pavementing)

47

Are integrin proteins significant to leukocyte extravasation?

YES

48

What is leukocyte adhesion deficiency disease characterized by?

recurrent bacterial infections

49

For integrin VLA-4: name the subunits, give the other name, what WBCs it affects, its counter receptor and functions

CD49dCD29 Beta1, alpha4 WBCs: Lymphocytes, Monocytes/macrophages, Eosinophils counter: VCAM-1, fibronectin fcns: leukocyte-EC adhesion, leukocyte-matrix adhesion

50

For integrin CD11aCD18: name the subunits, give the other name, what WBCs it affects, its counter receptor and functions

LFA-1 Beta2, alphaL ALL WBCs ICAM-1, -2, -3 leukocyte-EC adhesion, T cell-APC adhesion

51

Members of the immunoglobulin superfamily of proteins share partial _________ that were originally identified in immunoglobulin ___ and ___ chains.

partial amino acid sequence homology and tertiary structural features (15%+) heavy light

52

Where are some immunoglobulin proteins expressed? What do they help do?

some are expressed on cell surfaces of cytokine-stimulated endothelial cells and leukocytes help localize leukocytes to areas of tissue damage

53

ICAM-1 (CD54) is an immunoglobulin protein expressed where?

by pro inflammatory cytokine activated ECs, and other cells including B lymphocytes and monocyte/macrophages

54

ICAM-2 (CD102) is an immunoglobulin protein expressed where at and what levels?

expressed at low levels on some ECs and also expressed on monocyte/macrophages and some T cells

55

VCAM-1 (CD106) is an immunoglobulin protein expressed where?

by activated ECs, macrophages and other cells

56

PECAM-1 (CD31) is short for what? Where is it present? How does it work?

platelet-endothelial cell adhesion molecule present on neutrophils, platelets, monocytes, B cells found within the junctional complex of activated ECs. It binds to the PECAM-1 molecule on another cell (i.e. it displays homotypic binding)

57

What is diapedesis?

transendothelial migration

58

After margination, how is diapedesis enhanced?

by the binding of PECAM-1 on neutrophils to PECAM-1 on ECs close to the inter-endothelial cell jcn this signals the neutrophils to exit and they squeeze through gaps and crawl into the perivascular tissue

59

During diapedesis, how do leukocytes migrate once in the tissue? is the movement random or with preference?

by interacting their integrin proteins with the proteins of the extracellular matrix (collagen, laminin, fibronectin, etc) with preference towards gradients of chemotaxins formed within the tissue

60

True or false: leukocyte aggregation at the site of inflammation follows a fairly predictable pattern?

true

61

In a bacterial infection, when do neutrophils predominate?

the first 6 to 24 hours of the inflammatory response

62

Neutrophils are the most numerous WBCs in circulation except in which two species?

pigs and cattle

63

Of the WBCs, which responds the quickest to chemotactic agents?

neutrophils. This is why the predominate during the first 6-24 hours of the inflammatory response

64

After an inflammatory reaction, when do monocytes and lymphocytes generally predominate? Is there an exception to this?

24-48 hours except in IMMEDIATE HYPERSENSITIVITY reactions and PARASITIC infections when eosinophils predominate

65

When do T cells predominate after an inflammatory response?

36-48 hours (based on the chart on page 45)

66

What is chemotaxis?

the energy dependent, unidirectional migration of cells toward increasing concentrations of a soluble chemotactic agent

67

What is a random, excited movement of cells?

chemokinesis

68

is chemotaxis a receptor mediated event?

yes

69

Chemotactic agents are ___ molecular-weight soluble compounds that are generated in ___ concentrations at sites of tissue injury with a __________.

low-molecular-weight high concentrations decreasing gradient away from the injured tissue

70

What is haptotaxis?

a fixed chemotactic gradient sometimes created by chemotactic agents that bind to the extracellular matrix protein

71

Over what distance is chemotaxis effective? What makes this so great?

up to 100 micrometers away from inflamed tissue almost no tissue is more than 50 micrometers away from a capillary, so the chemotactic signal easily brings hordes of leukocytes to the inflamed area.

72

What are the two basic types of leukocyte chemoattractants?

classical leukocyte attractants and chemokines

73

What do classical leukocyte attractants act on? what are some examples?

act broadly on several cell types including monocytes, macrophages and neutrophils *bacterial chemotaxins, N-formylated peptides *dead cells (necrotaxis), mitochondrial N-formylated peptides *plasma-derived: C5a/C3a/C5b67 and fibrinopeptides *Platelet-activating factor *leukotriene B4 (LTB4)

74

What are the most important group of chemotactic agents?

chemokines

75

What are the two types of chemokines and what do they work on?

*CXC chemokines - potent attractants and activators or neutrophils; the most significant is CXCL8 (IL-8) *CC chemokines - attract various leukocytes BUT NOT NEUTROPHILS

76

What is phagocytosis? what cells are capable of phagocytosis?

the process by which certain cells of the innate immune system, including macrophages and neutrophils (professional phagocytes) engulf large particles (>0.5 micrometers in diameter) such as bacteria, fungi, protozoa, etc

77

What did Elie Metchnikoff discover in 1882?

the russian zoologist is credited with discovering phagocytosis.

78

What type of cells was Metchnikoff studying in 1882? What happened with the thorn?

mobile cells in the transparent starfish larva when a sharp thorn was introduced into the body of the larva, mobile cells surrounded the foreign body and attacked it

79

In later experiments, what did Metchnikoff discover?

that mobile cells were able to ingest and destroy foreign matter, including bacteria

80

Name the scientist credited with seeing white blood cells migrate from tissue capillaries to form pus at sites of injuries?

Julius Cohnheim

81

Metchnikoff used Cohnheim's observations and his own to conclude what? What did he receive in 1908?

that inflammation served as an important defense reaction of the body and played a major part in recovery from bacterial infections. The nobel prize

82

What are the 7 steps of phagocytosis?

1) chemotaxis and adherence of microbe to phagocyte 2) ingestion of microbe by phagocyte 3) formation of a phagosome 4) fusion of phagosome with a lysosome to form a phagolysosome 5) digestion of ingested microbe by enzymes 6) formation of residual body containing indigestible material 7) discharge of waste materials

83

PMNs stands for what?

Polymorphonuclear neutrophils

84

What percent of total blood leukocyte population do neutrophils make up in most animal species? what are the exceptions?

40-70% swine and cattle -- lymphocytes are the predominate peripheral blood cells

85

Where are the majority of PMNs stored? When are they released?

PMNs are stored in the bone marrow and released when pro inflammatory mediators reach the bone marrow via the bloodstream, act on the marrow capillaries and on stored PMNs to mobilize them into circulating blood.

86

Once released into the blood stream, what ability to neutrophils lose?

ability to divide and give rise to new cells (terminally-differentiated cells)

87

How many neutrophils does an adult human produce in a day?

over 1 x 10^11

88

how long do neutrophils normally circulate in the blood? How long can they survive in tissues?

4-8 hours in blood before migrating to tissue may survive in tissue up to 4 or 5 days

89

True or false: a neutrophil can re-enter the bloodstream once it enters a tissue?

FALSE once it enters a tissue a neutrophil cannot return to the blood stream

90

What happens to circulating PMNs that are not recruited to inflammation sites?

undergo programmed cell death and are usually phagocytosed by resident macrophages in the LIVER or SPLEEN

91

What are the dimensions of neutrophils in circulations? during diapedesis?

spherical shaped and 10-12 micrometers in diameter can reduce width to 1 micrometer during diapedesis

92

What are heterophils? What animals are they found in?

large, reddish staining cytoplasmic granules found in neutrophils of certain animals found in chickens, rabbits and guinea pigs

93

Neutrophils carry many cell surface receptors including those that mediate attachment to ____ cells and ______.

endothelial cells opsonization

94

What does a neutrophil do when it encounters a microbe? how is this mediated?

it must BIND to it attachement is mediated by the interaction between cell surface receptors and ligands on the microbe

95

How do neutrophils and macrophages recognize microbes? What are some examples?

by their conserved microbial structures that are invariant within a pathogen class PAMPs (pathogen-associated molecular patterns): LPS, lipoteichoic acid, peptidoglycan, mannose-rich oligosaccharides, etc

96

What are the receptors on phagocytes that recognize PAMPs?

pattern recognition receptors (PRRs)

97

What is an example of PRRs binding to PAMPs?

the mannose receptor on a macrophage binds terminal mannose and fucose residues of glycoproteins and glycolipids, which are typically found on microbial cells walls

98

What are opsonins?

naturally occurring (NON-SPECIFIC) or acquired (SPECIFIC) substances that coat microbes and render them more susceptible to phagocytosis

99

Opsonins carry what kind of charge? What does this help them neutralize?

they are positively charged proteins this helps neutralize the negative charges on foreign particles by enabling them to bind to negatively charge phagocytes

100

What is an example of a specific opsonin? How does it work?

IgG Fab portions bind to epitopes on the microbe; Fc portion binds to the Fcgamma receptor on phagocyte

101

Name 6 examples of nonspecific opsonins. Are nonspecific opsonins more or less efficient than specific ones?

Complement proteins C3b, iC3b, C4b and a number of plasma reactive proteins including fibronectin, mannose-binding lectin (MBL) and C-reactive protein less efficient than IgG coating BUT it can enhance phagocytosis early in the course of infection before specific antibodies are produced.

102

Following attachment to a phagocyte, the adherent particle stimulates the formation of what on the cell membrane?

pseudopodia

103

What step of phagocytosis are pseudopodia involved in? Describe what they do

they are involved in engulfment. they meet each other on opposite sides and fuse, creating an enclose chamber surrounding the phagocytosed particle.

104

What is a phagocytic vesicle? how is it formed?

a free-floating chamber in the cytoplasm containing a phagocytosed particle. (also called a phagosome) formed when the chamber created by fused pseudopodia breaks away from the cell membrane

105

After engulfment during phagocytosis, what do lysosomal granules do?

migrate through the cytoplasm and fuse with the phagolysosome to form a phagolysosome

106

what happens inside a phagolysosome? How long does it take?

microbicidal molecules and proteolytic enzymes stored in lysosomes destroy the phagocytized microbe. It occurs within 10 to 30 minutes.

107

Give examples of primary lysosomal granules of neutrophils

defensins -- disrupt the plasma membrane myeloperoxidase - respiratory burst neutral and acid hydrolyses - degrade bacterial products lysozyme - destroys bacterial cell walls

108

Give examples of secondary granules

lysozyme (also a primary) - destroys bacterial lactoferrin - binds iron collagenase - degrades connective tissue

109

Phagocytosis stimulates a series of ____-dependent biochemical events occurring at the plasma membrane and within the phagolysosome, promoting _____ of the ingested particle. This is known as what?

O2 destruction Respiratory burst

110

What are the 3 characteristics of a respiratory burst?

1) 2-3 fold increase in O2 consumption by the cell 2) increased glucose oxidation via the hexose monophosphotase shunt 3) generation of microbicidal reactive oxygen intermediates (ROIs; also called reactive species oxygen species--ROS): superoxide anion 02-, hydrogen peroxide H2O2, hypochlorous acid HOCl, hydroxyl radical OH, and singlet oxygen O2

111

What system in the most potent microbicidal system in neutrophils?

The H202-myeloperoxidase-halide system

112

Killing of microbes can also occur by oxygen-independant mechanisms via what?

the action of chemicals in phagocyte granules

113

What kind of environment (i.e. basic or acidic) prevails in the phagolyosome? Does this affect the activity of chemicals?

acidic (pH 4-5) enhances the activities of chemicals

114

What is a lysozyme?

A mucopeptidase found in serum, sweat, tears, saliva, mucous, nasal secretions, phagocytes and tissue fluids

115

How does a lysozyme work?

Breaks down bacterial cell wall peptidoglycan by hydrolyzing the glycosidic bond between the monosaccharides of the peptidoglycan backbone. This renders the bacteria susceptible to osmotic lysis.

116

What type of bacteria are susceptible to lysozyme?

Works on Gram positive bacteria

117

What are defensins?

(cationic peptides) a group of small peptides found in phagocytes and certain intestinal cells.

118

What do defensins form?

They form ion-permeable channels in microbial cell membrane, resulting in escape of essential metabolites

119

What bacteria are susceptible to defensins?

they can kill or inactivate a wide variety of bacteria, fungi, and some enveloped viruses

120

Where do bactericidal permeability increasing proteins (BPIs) bind?

(primary granules) bind specifically to the outer membrane of gram-negative bacteria

121

What does BPI induce? Why is this important?

induces phospholipase activation, phospholipase degradation and increased permeability in the outer membrane of the bacterium. Even though the inner membrane is intact, any bacteria exposed to BPI (even for just a few seconds) lose their ability to replicate (irreversible)

122

Do lysosomal enzymes have direct bactericidal activity?

NO. Most are digestive and function after killing a microbe

123

What do neutral and acid hydolases do? what are they examples of?

degrade and digest killed bacteria within the phagolysosome. Examples of lysosomal enzymes.

124

What organelle do neutrophils lack? How does this affect them?

mitochondria they have a limited supply of energy which cannot be replenished

125

What happens to neutrophils immediately following phagocytosis?

rapid apoptotic cell death and ingestion by macrophages.

126

The Monocyte-macrophage system (MMS) consist of?

monocytes, mobile macrophages and resident or fixed tissue macrophages.

127

when monocytes are released from the bone marrow what do they do?

they circulate in the blood for 10-20 hours before migrating into tissues, where they undergo maturation to become tissue macrophages.

128

A large portion of monocytes, after becoming macrophages, what happens to them?

they become attached to the tissues and remain attached for months to years; they form the basis of the tissue macrophage sytem.

129

Where are resident macrophages and macrophage-like cells located?

they are strategically placed at all the sites where microorganisms may gain entry into the host, thereby providing a continuing defense in the tissues against infection ( they serve as the first line of defense when microorganisms breach the physical barriers).

130

Where are histocytes?

Connective tissue

131

Where are mesangial cells?

The kidneys

132

Where are microglial cells?

Central nervous system

133

All species have alveolar macrophages but ruminants, cats, and pigs In addition to alveolar macrophages also have_____?

PIMs- pulmonary intravascular macrophages

134

Where are Free macrophages derived from?

blood monocytes

135

What makes up the majority of macrophages at inflammatory sites?

free macrophages derived from blood monocytes.

136

________ have been referred to as the most dynamic and gifted of the leukocytes.

Macrophages

137

Macrophages play a central role in _____________________?

In innate and adaptive immunity and are important effector cells for the elimination of microorganisms.

138

How long can macrophages live?

They can live for months to years unless they are destroyed by performing phagocytic functions.

139

Macrophages do not possess _____ and ____ granules, however the lysosomal contents of macrophages are similar in many ways to those of neutrophils.

1* and 2* granules

140

Unlike neutrophils, macrophage lysosomes also contain large amounts of_________, which digest the thick lipid membranes possessed by some bacteria.

lipases

141

Similar to neutrophils macrophages possess several cell membrane receptors, including____________?

Cytokine receptors, complement receptors, antibody receptors, and integrins.

142

Mannose-binding receptors on cell membrane bind to _______ or _______ in the capsule or LPS of invading bacteria, allowing macrophages to bind directly to nonopsonized bacteria.

mannose or flucose residues.

143

Macrophages respond to the same chemoattractants as________.

neutrophils, but in addition, they respond to CC chemokines, cationic peptides released by dead and dying neutrophils, and lymphokines released by activated T cells, eg. migration inhibition factor and macrophage chemotactic factor

144

Unlike ________, macrophages are sluggishly motile.

neutrophils

145

Macrophages are more powerful phagocytes than _________, capable of sustained, repeated phagocytic activity.

Neutrophils

146

Macrophages have the ability to engulf much larger particles, such as _____,______,.

Red blood cells, neutrophils, necrotic debris, etc.

147

Compared to neutrophils, a macrophage is capable of phagocytizing as many as _________ bacteria.

100

148

Activated macrophages can synthesize ____ ____, a very powerful microbicidal agent.

nitric oxide

149

How do macrophages eventually disappear?

either by dying or making their way into the circulatory system via the lymphatic system

150

In chronic inflammation, macrophage accumulation will persist, this is mediated by multiple mechanisms such as:

1.) recruitment of monocytes from the circulation

2.) Macrophage proliferation. Unlike neutrophils, macrophages are not terminally differentiated cells and can proliferate in situ at sites of chronic inflammation and form still more macrophages.

3.) immobilization of macrophages. Some cytokines, eg, migration inhibition factor, complement fragment Bb, etc. can immobilize macrophages at the site of inflammation.

 

151

When stimulated, macrophages may increase in size and form clusters of ______________.

Epithelloid cells ( resemble epithelial cells) or several may fuse to form multinucleated giant cells.

152

Multinucleated giant cells and epitheliod cells are found only in ___________ conditions, such as chronic inflammatory reactions.

pathological

 

153

Activated macrophages are major secretory cells, able to synthesize over 100 products including:

Several immunoinflammatory mediators, such as complement proteins, cytokines, proteinases, etc and lipid mediators of inflammation ( leukotrienes, prostaglandins, PAF, etc)

154

Macrophages playt a crucial role in_____________ and ___________

tissue reorganization and wound healing.

155

What do macrophage proteinases ( elastases, collagenases) do?

they degrade connective tissue, the cellular debris is then phagocytized.

156

Macrophage proteinases also synthesize and secrete many growth factors that promote the proliferation of _______ and the growth of new blood vessels ( angiogenesis factor)

fibroblasts

157

Name the functions of Macrophages:

1.

2.

3.

4.

5.

 

1.) antigen presentation

2) tissue reorganization and wound healing

3.) secretion of cytokines, enzymes and other factors

4.) tumor cell destruction

5.) phagocytosis and destruction of bacteria.

158

When neutrophils and macrophages engage in phagocytosis, they can injure normal host tissues by release of ______ and ________

 

ROI and lysosomal enzymes

159

What are antiproteinases?

synthesized by the liver, leukocytes, and connective tissue cells, present in plasma and tissue eg alpha 2 macroglobulin and alpha 1 antitrypsin, inhibit leukocyte proteinases, thereby preventing and/ or minimizing tissue damage.

160

Name the parts of this diagram:

Q image thumb

A: NADPH Oxidase

B: Superoxide dismutase

C: myeloperoxidase

161

What do Cytosolic and plasma moleculare "scavengers" of oxyradicals do?

Q image thumb

Limit damage to cells and tissues.

162

What "scavengers" of oxyradicals limit damage to cells and tissues?

Cytosolic and plasma molecular scavengers

163

What enzymes convert escaped H202 to H20 and O2?

Are these enzymes present in cells?

catalase and glutathione peroxidase

yes, both are present in cells

A image thumb
164

What type of substances can damage the membrane of a phagolysosome?

Give examples.

membranolytic substances

ex: bacterial leukocidin, urate crystals

165

What happens when a membranolytic substance damages the membrane of a phaygolysosome?

the potent hydrolytic enzymes spill out, killing the leukocyte and releasing these enzmes into tissues

166

When large numbers of bacteria are present, enhanced feeding may result in what?

What does this give lytic enzymes access to?

The fusion of the lysosome with the developing phagosome prior to the complete closure of the phagosome

 

This causes lytic enzymes in the lysosome to have direct access to the extracellular environment

167

What happens when a phagocyte encounters a phaygocytic stimuli that is too large to be internalized?

What are examples of these stimuli?

the pahgocyte releases lysosomal enzymes into the surrounding environment, leading to tissue injury (vasculitis)

Examples: helminth larvae, bacteria immobilized against a fibrin meshwork, antigen-antibody immune complexes fixed against a basement membrane or endothelium or joint surface, etc

168

Where are the cells of the adaptive immune response located? Name the cells

localized and concentrated in organs and tissues of the lymphoid system

(lymphocytes, accessory cells, antigen-presenting cells)

169

Where are foreign antigens transported and concentrated?

in the organs and tissues of the lymphoid system

170

Where are lymphoid stem cells produced in the young fetus?

In the older fetus and neonates?

By the yolk sac mesoderm and fetal liver in the very young fetus, in the bone marrow of the older fetuses and neonates

171

How are lymphoid tissues and organs classified?

based on the 1) level to which they participate in the maturation of lymphocytes and 2) provision of a suitable environment for the interaction between foreign antigen and antigen-sensitive T and B lymphocytes.

A image thumb
172

Where are central lymphoid organs and tissues located?

What do they regulate?

located in the thymus, bone marrow, peyer's patches, and bursa of fabricius

regulate production and maturation of lymphocytes--generate lymphocytes that are individually different to meet the threat posed to an animal or individual by the large number of microbial pathogens, the concept being "ONE CELL, ONE SPECIFICITY"

173

Central lymphoid organs develop early in embryonic life and involute after puberty, except for which organ?

bone marrow

174

What do mature lymphocytes acquire?

What do they learn to discriminate between?

acquire specific antigen receptors and other phenotypic characteristics

learn to discriminate between self-peptides (which are tolerated) and foreign antigens (which are not) [self vs nonself]

175

True or false: maturation and differentiation of lymphocytes depends upon antigenic stimulation?

FALSE; maturation and differentiation are INDEPENDENT of foreign antigenic stimulation

176

If central/primary organs are removed early in life, what happens to lymphocytes?

(this is on page 57, make sure I understood this correctly)

There is a loss of lymphocytes, resulting in loss of immune responsiveness

177

What is the thymus the site of?

T cell development and maturation

178

Where is the thymus located? Are there any exceptions?

located in the anterior mediastenal space

yes; in horses, pigs, sheep, cattle and chickens the thymus can extend up the neck as far as the thyroid gland

179

What is the thymus organized into? What are these separated by?

organized into lobules, separated by connective tissue septae

180

The thymus has a ____ _____ supply and _____ ______ vessels that drain into ______ lymph nodes

rich blood supply

efferent lymphatic vessels

mediastinal lymph node

181

How was the role of the thymus in a host immune response determined? 

What was the result?

following a neonatal thymectomy of day-old mice

there was a dramatic decrease in circulating T lymphocytes [lymphopenia] and total loss of the cell-mediated immune response

182

What are the two compartments of the thymus?

Cortex (outer compartment) and medulla (inner compartment)

183

The cortex of the thymus contains what percentage of total thymocytes?

85%

184

What is a thymocyte?

An immature lymphocyte in the thymus

185

What do thymocytes acquire as they mature in the cortex?

Where do they migrate as they mature?

antigent receptors (TCRs) and other functional and phenotypic characteristics of mature T cells.

migrate to the medulla

186

The medulla of the thymus is sparsely populated with what?

Mostly mature lymphocytes

187

A network of what three cells are found throughout the thymus, especially at the corticomedullary junction?

1) epithelial cells

2) macrophages

3) dendritic cells

188

What do the epithelial cells, macrophages and dendritic cells provide to assist the proliferation and maturation of thymocytes?

the stimuli, including cytokines (especially IL-7) thymic hormones (thymosin, thymic hormon factor, thymopoietin, thymulin, etc) and major histocompatibility comples (MHC) molecules that are REQUIRED for proliferation and maturation of thymocytes

189

Developing thymocytes, also called pre ___, acquire TCRs via what?

pre-T cells

gene arrangement

190

True or false: TCRs are selected for either self-MHC restriction or self-tolerance

False: TCRs are selected for BOTH self-MHC restriction AND self-tolerance

191

What is self-tolerance?

the ability to distinguish between self and nonself by MHC self peptide complexes expressed on THYMIC STROMAL CELLS

192

What does the thymus do to thymocytes whose TCRs cannot recognize antigen-MHC complexes or whose TCRs react strongly with self antigen-MHC complexes?

induces death by apoptosis

193

What percent of developing thymocytes die by apoptosis?

95%

194

In humans, thymic involution begins when and ends when?

begins at puberty and continues throughout adulthood (doesn't end)

195

Where does thymic involution begin? what happens to cells stored there?

begins within the cortex, which may disappear completely while the medullary remnants persist

immature cortical thymocytes from the cortex are lysed--cortical atrophy is related to corticosteroid sensitivity (lysis) of these cells

196

When was the bursa of fabricius first described? by whom?

first described in the 16th century by Hieronymus Fabricius

197

What is the bursa of fabricius? What does it look like?

It is a lymphoepithelial organ found in birds BUT NOT IN MAMMALS; it is a sac-like structure dorsal to the cloaca 

198

Describe the development of the bursa of fabricius

reaches maximum size 1-2 weeks after hatchin, followed by gradual involution; by the time the bird reaches sexual maturity (6 months) only atrophied vestiges remain of the BF and the thymus

199

How was the function of the bursa of fabricius determined? What happened?

following a bursectomy of day-old chicks

there was only a slight drop in the numbers of circulation lymphocytes, but there was a dramatic decline in antibody immune response

200

Describe B cell differentiation and maturation

Similar to the T cells, the majority of B cells (90-95%) die through apoptosis because of negative selection of self-reactive B cells.

Mature B cells begin to migrate from the bursa to the peripheral lymphoid organs a few days prior to hatching

201

Bone marrow is a site for what? What type of lymphoid organ is it considered in mammals?

the site of generation of all circulating blood cells (hematopoeisis) and a fat depot (as the animal ages more than 50% of the marrow will become filled with fat)

in mammals it is a primary and secondary lymphoid organ

202

What are the two compartments of bone marrow? 

1) hematopoietic

2) vascular

203

What does the hematopoietic compartment of bone marrow contain?

what does it do?

the hematopoietic compartment contains precurses of all the blood cells (self-renewing stem cells) as well as stromal cells, macrophages and lymphocytes

hematopoietic cytokines produced by these cells stimulate proliferation and maturation of precursor cells

204

In most mammals the bone marrow is a site of early events of what?

B cell development

205

What do the stromal cells of bone marrow do?

1) secrete various cytokines required for B cells development

2) selection of  immature B cells (B cells that acquire self-reactive antigen receptors are allowed to die)

206

How long do the numerous plasma cells in bone marrow product antibodies for?

Where are these plasma cells produced?

for many months or years

Plasma cells are also produced in peripheral lymphoid organs as a result of antigenic stimulation of B Cells and then migrate into the bone marrow

207

What are Peyer's Patches aggregations of? Where are they located?

aggregations of lymphatic nodules 

found in the walls of all three segments of the small intestine

208

There are two types of Peyer's patches. Describe the first. 

What do they contain?

How long do they last?

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Numerous discrete lymphatic follicles that function as peripheral lymphatic organs. 

They contain B cells, T Cells, APC's, etc

they persist throughout the life of the individual or animal

209

Describe the second type of Peyer's Patches.

What specific animals are these type located in?

What is it the site of?

When does it undergo involution?

In ADDITION to the discrete lymphatic follicles in te jejunum, there is a single large ileal Peyer's Patch that functions as a primary lymphatic organ

Exists in ruminants, pigs and dogs

it si the site of early B cell development (populated by IgM+ immature B cells)

undergoes involution by 1.5 years of age

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210

When do peripheral lymphoid organs arise? how long do they persist for?

 

arise late in fetal life

persist through adulthood

211

What happens when peripheral (secondary) lymphoid organs are removed?

there is not any significant reduction to an individual's immune capacity

212

What is the role of peripheral (secondary) lymphoid organs (i.e. what develops there)

sites where mature lymphocyte responses to foreign antigens are initiated and develop

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213

Lymph nodes are the only lymphatic organ with what type of lymph vessels?

only organ with BOTH afferent and efferent lymph vessels

214

What are lymph nodes the site of?

How are antigens carried to the nodes?

Sites where immune responses to antigens entering the body via the skin and mucos, or from parenchymal organs and connective tissues are initiated

carried by lymphatic fluid

215

All lymph nodes eventually drain into ________ and back to the ______

thoracic duct system

back to the peripheral blood

216

What are the main parts of lymph nodes?

cortex

paracortex

medulla

efferent lymphatic vessels

217

what happens in the cortex of lymph nodes?

B cells are organized into primary and secondary follicles

 

218

What is a primary follicle?

what does it contain?

where is it located?

follicles without germinal centers

contain mostly resting mature B cells, follicular dendritic cells (FDCs) and macrophages

located in the cortex of lymph nodes

219

What is a secondary follicle?

How do they develop?

What happens to B cells here?

Where are secondary follicles located?

primary follicles WITH germinal centers (GCs)

GCs develop in response to antigenic stimulation of B cells

B cell proliferation, selection of B cells producing high affinity antibodies, and generation of memory B Cells occurs in GCs

located in cortex of lymph nodes

220

What does the paracortex of lymph nodes contain?

How does the paracortex affect lymphocytes?

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mostly T cells, some macrophages and dendritic cells. 

lymphocytes enter the node from the circulation through the high endothelial venules (HEVs) in the paracortex

221

What does the medulla of the lymph node contain?

Contains mostly macrophages, antibody-secreting plasma cells and some lymphocytes

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222

What does lymph leaving via an efferent lymphatic vessel contain?

contains newly secreted antibodies, effector lymphocytes (due to clonal expansion of T cells) and mostly naive lymphocytes that migrated from the blood into the lymph node through the paracortical HEVs

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223

What type of lymphoid organ is the spleen?

What is so important about the spleen?

It's the largest secondary lymphoid organ

because it is the largest, it is the major organ in the body in which antibodies are produced

224

The spleen is the major site of immune response to what specific type of antigen?

what does a splenectomy lead to?

blood-born antigens

increase in blood-borne microbial infections

225

What are the major sections of the Spleen?

White pulp

red pulp

marginal zone

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226

Describe the White Pulp of the spleen.

Where are T cells found?

Where are B cells organized and what do these areas contain?

The lymphoid tissue of the white pulp is organized around the central arteriole to form the periarteriolar lymphoid sheath (PALS)

T cells are mostly around the central arteriole

B cells are organized into primary and secondary follicles. The follicles also contain macrophages and follicular dendritic cells (FDCs). The follicles are anatomically and functionally the same as in lymph nodes

227

What cells does the red pulp of the spleen contain?

What happens in the red pulp (and spleen) as a result of these cells?

contains macrophages, some activated B cells and plasma cells. It is a storage site for erythrocytes, platelets and granulocytes

macrophages in the red pulp phagocytose old platelets and RBCs and also clear the blood of microorganisms and other particles--thus the spleen is the major site for phagocytosis of antibody-coated (opsonized) microbes

228

What is the marginal zone of the spleen? what does it contain?

separates the white pulp from the red pulp

contains macrophages and some lymphocytes

229

What is MALT?

What are the cells of MALT?

Mucosal-Associated Lymphoid Tissue

comprises all lymphoid cells present as either solitary or aggregated nodules in epithelia, lamina propria and submucosa of the gastrointestinal tract

230

What are the main sites of MALT?

Gut-associated lymphoid tissues (GALT)

Bronchial-associated lymphoid tissues (BALT) and genitourinary tract

Cutaneous immune system

231

Where is GALT located?

Lymphoid tissues in the lamina propria of the intestines, Peyer's pathces, appendix and tonsils

232

What does the cutaneous immune system contain?

lymphocytes and accessory cells in the epidermis and dermis that respond to environmental antigens

233

What is lymphocyte recirculation?

the continuous movement of lymphocytes from one lymphatic organ or tissue to another via the blood and lymph, and, if activated, to peripheral inflammatory sites

234

True or false: naive lymphocytes specific for any given antigen account for a high percentage of lymphocytes?

FALSE; account for about 1 in every 10^5 lymphocytes

235

What two things does lymphocyte recirculation ensure?

1) ensures that an antigen-specific lymphocyte will come in contact with that antigen no mater where in the body the antigen is located.

2) ensures that activated (effector) lymphocytes are delivered to the particular tissue where they are required for elimination of the antigen

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236

How often does a lymphocyte recirculate from blood to the tissues and lymph and back again?

as often as 1-2 times per day

237

What are the predominant lymphocytes in blood?

T lymphocytes

238

What are HEVs?

What happens at HEVs?

Where are they located?

modified postcapillary venules within the paracortex of lymph nodes - High endothelial Venules

extravasation of native lymphocytes from blood into a peripheral lymph node

HEVs are present in each secondary lymphoid organ (peyer's patches, tonsils, etc) BUT NOT IN THE SPLEEN

239

What type of endothelial cells are in HEVs?

What do they contain that other cells in ordinary venules do not have?

cuboidal (plump) endothelial cells

cytokine-activated--allows them to express a variety of adhesion molecules no found on flat resting endothelial cells of ordinary venules

240

What do the adhesion molecules on HEV endothelial cells have to do with the recirculation of T lymphocytes?

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recirculation patterns of native T lymphocytes is government by the combination of adhesion molecules (eg, L-selectin) and chemokine receptors (eg CCR7) that they express

241

What happens to the normal, continuous lymphocyte movement through nodes when an antigen enters the nodes?

What does this allow to happen?

temporary shut down in lymphocyte traffic

allows antigen-specific lymphocyte to be activated and change into effector cells or memory cells

242

What happens to naive T cells that do no encounter antigen?

They exit through an efferent lymphatic vessel, re-enter the circulation and home in on another lymph node

243

Where do mature B lymphocytes reside?

do they recirculate?

why would it not matter much if they do or do not recirculate?

Do other types of B cells recirculate?

reside mainly in follicles of peripheral lymphoid organs

recirculate, migrate from one peripheral lymphoid organ to the next

because only a small fraction of blood lymphocytes are B cells

yes; memory B cells, some activated B cells, and some plasma cells also recirculate

244

What is MHC?

What functions does it perform in the immune response?

Major Histocompatability Complex; a cluster of genes located in close proximity that encode the MHC proteins (molecules)

Functions: 1) positive selection of T cells in the thymus, 2) presentation of antigenic peptides to T cells, 3) encodes some complement proteins, some cytokines, and proteins invloved in antigen processing 4) class I and class II MHC proteins are the most important antigens recognized in the graft rejection process

245

True or false: all mammals and birds have an MHC complex?

TRUE; the structure and function are basically the same

246

How does naming work for MHC complexes?

initial of the species, followed by LA for leukocyte antigen (because proteins are readily detected by blood leukocytes)

247

What is HLA?

Human MHC complex

248

What is DLA?

Dog MHC complex; chromosome 12

249

What is ELA?

Equine MHC complex; chromosome 20

250

What is OLA?

Ovine MHC complex; chromosome 20

251

What is BoLA?

Bovine MHC complex; choromsome 23

252

What is CLA?

Caprine MHC complex, chromosome 23

253

What is SLA?

Swine MHC complex, chromosome 7

254

What is B locus?

Chicken MHC complex, chromosome 16

255

Where are human MHC genes located?

Does the MHC always look the same in the human genome?

on a segment of the short arm of chromosome 6.

It is the most polymorphic gene cluster in the human genome, with large numbers of alleles (variants of polymorphic genes) at several different loci

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256

How is MHC polymorphism usually detected?

What are MHC proteins often referred to as?

Using antibody

major histocompatability complex proteins

257

What is an MHC haplotype?

How many are within a family?

the set of MHC alleels present on each chromosome

there are only 4HLA haplotypes within a family

 

258

How are haplotypes from both parents inherited and expressed?

codominantly; each individual expresses the MHC alleles on both chromosomes that are inherited from both parents

259

True or false: because MHC proteins are so polymorphic, they are not specific for any species?

FALSE; MHC proteins are HIGHLY SPECIFIC for each individual species, hence MHC proteins are considered as species or strain markers

260

What do Class I MHC molecules consist of?

Where are these expressed?

Are there any exceptions?

two noncovalently linked polypeptide chains that are constituitively expressed on the cell membranes of most nucleated cells except primitive cells in early embryonic life, sperms, neurons and erythrocytes of most mammals

261

How is MHC class I expression enhanced?

by exposure to cytokines such as interferons alpha, beta and gamma

262

Each individual expresses how many different class I molecules on EVERY cell?

What do they contain?

6 different class I molecules

contain alpha chains derived from the two alleles of HLA-A, HLA-B and HLA-C genes that are inherited from both parents

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263

What does the alpha chain of class I MHC molecules contain?

three external domains (alpha1, alpha2, alpha3 domains), a transmembrane segment and a cytoplasmic tail

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264

What is located on the MHC class I molecules between domains alpha1 and alpha2? What does it bind? When/how many can it bind?

the peptide-binding cleft or groove

binds peptides containing 8-11 amino acids

a single class I molecule can bind several different antigenic peptides BUT IT CAN ONLY BIND ONE AT A TIME

265

What does the alpha3 segment of MHC Class I molecules contain? what does it serve for?

contains a loop

serves as the binding site for the T cell coreceptor, CD8

266

Where are the polymorphic amino acid residues confined to in Class I MHC molecules?

confined to alpha1 and alpha2 domains

267

What is Beta2M?

Where is it encoded?

Is it invariant or variant?

B2M is a non-MHC-encoded protein that associates noncovalently with the alpha3 domain of the alpha chain. It is 

encoded by a gene on chromosome 15

it is invarient (nonpolymorphic)--i.e. all B2M chains of Class I molecules are the same

268

How does the assemblying of class I MHC molecules begin?

What does it form and how is it stabilized?

What is the name of the completed complex?

Where is it transported?

begins with the folding heavy chain first interacting with Beta2M

the 'empty' dimeric molecular complex is then stabilized by the binding of a peptide (self peptide or foreign peptide)

 trimolecular complex (alpha chain, Beta2M

transported to the cell membrane

269

What happens to Class I MHC cells in the absence of Beta2m?

The class I heavy chain is NOT EXPRESSED on the cell surface

270

What is the function of MHC Class I proteins?

the presentation of peptides derived from proteins in the cytosol, eg, viral proteins, to CD8+ T cells.

271

What do Class II MHC molecules consist of?

How and where are they expressed?

How is expression enhanced?

two nonidentical protein chains (alpha and beta chains) 

constituitively expressed on the cell membranes of dendritic cells and B lymphocytes and on activated macrophages

enhanced by interferon-gamma

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272

What three regions are Class II molecules encoded by?

How many Class II molecules does each individual possess?

HLA-DP, HLA-DQ, HLA-DR

6-12 class II molecules

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273

Each chain of MHC Class II molecules has how many domains?

what are they?

Where are the polymorphic amino acid residues located?

 

two domains

transmembrane segment and a cytoplasmic tail

in alpha1 and beta1 domains

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274

What is the peptide binding groove on Class II molecules formed by?

What does it bind and how many?

formed by interaction of the alpha1 and beta1 domans,

binds peptides containing 10 to 30 amino acids. 

a single class II molecule can bind several different peptides (but only ONE peptide at a time)

275

On the Class II MHC molecules, what is the binding site for the T cell coreceptor, CD4?

a loop in the Beta2 domain

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276

What is the invariant chain (Ii) of Class II molecules? 

What is it associated with?

a nonpolymorphic protein

associated with newly synthesized class II molecules (plays a role in antigen presentation)

277

What is the function of MHC Class II proteins?

present peptides derived from protein antigens degraded in cellular vesicles (phagosome or endosome) to CD4+ T cells

278

What does the stable expression of Class II molecules depend on?

just like class I molecules a fully assembled class II molecule consists of an alpha chain, beta chain and a bound peptide

stable expression on cell surfaces requires the presence of all 3 components

279

What is located within the locus of Class II molecules?

Name the three.

genes that encode several proteins important in antigen processing

HLA DM

Proteasome

TAP

280

HLA DM is one of the genes found in the Class II locus.

What does HLA DM do?

facilitates removal of invariant chain-derived CLIP protein and the binding of endosomal peptide to class II MHC molecules

281

Proteasome is one of the genes found in the Class II locus. What does it do?

a cytoslic protease complex that cleaves proteins into small peptide fragments that are subsequently presented by class I MHC molecules

282

 TAP is one of the genes found in the Class II locus. What does it stand for? and what does it do?

transporter associated with antigen processing

transports peptides from the cytosol into the endoplasmic reticulul where the peptides associate with newly synthesized Class I molecules

283

Describe the structural differences between Class I MHC and Class II MHC

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Class I: alpha chain and Beta2m

Class II: alpha and beta chains

284

Describe the distribution differences between Class I MHC and Class II MHC

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Class I: most nucleated cells

Class II: Professional APCs (B cells, dendritic cells, macrophages)

285

Describe the sites of polymorphic resides for Class I and Class II MHC

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Class I: alpha1 and alpha2 domains

Class II: alpha1 and Beta1 domains

286

Describe the peptide binding cleft of Class I and Class II MHC

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Class I: closed; binds peptides of 8-11 amino acids

Class 2: open; binds peptides of 10-30 amino acids

287

Describe the sources of peptides for Class I and Class II MHC

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Class I: cytosol

Class II: endosome

288

Describe the peptide presented to for Class I and Class II MHC?

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Class I: CD8+

Class II: CD4T Cells

289

Describe the outcome for Class I and Class II MHC

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Class I: T cell-mediated cytotoxicity

Class II: T cell-mediated help

290

What does the Class III MHC region contain?

genes that code for several complement proteins, cytokines such as tumor necrosis factor, etc

291

What is MHC restriction?

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The concept that a given T cell will recognize antigen ONLY after it is processed and the ensuing antigenic peptide is bound to a particular class I or II MHC molecule.

292

During T cell development in the thymus, a pre-T cell acquires TCR that is specific for what?

both an antigenic peptide and a self-MHC molecule

293

What do CD8T Cells recognize?

what are these cells also called?

recognize peptide antigen ONLY in association with PARTICULAR SELF-MHC class I molecules

294

What do CD4+ T Cells recognize?

what are these cells also called?

recognize peptide antigen associated with particular Self-MHC CLASS II MOLECULES

helper T cells

295

What is associated with possesion of  certain MHC haplotypes?

certain diseases, such as various allergies, some viral infections and certain auto immune diseases

296

What are the four hypotheses that attempt to explain the relationship with MHC and disease susceptibility?

1) the absence of an MHC molecule that can bind and present an antigenic peptide

2) the absence of TCRs that can recognize the complex of antigenic peptide MHC molecule

3) the MHC allelic gene may encode molecules that are recognized as RECEPTORS by bacterial toxins or viruses

4) within a species, a reduction in MHC polymorphism may predispose that species to infectious diseases, eg cheetahs and the Florida panther

297

What is antigen processing and presentation defined as?

the series of events that result in the conversion of protein antigens to self-MHC-associated peptide fragments that are then presented to antigen-sensitive T lymphoctes.

298

T lymphocytes respond only to what?

processed protein antigens

299

What does the high degree of polymorphism of MHC class I and II molecules concentrated at the peptide-binding region ensure?

What is the limiting factor?

that a particular species has the potential to effectively respond to and eliminate any antigen it encounters

no single individual expresses as finite number of MHC molecules; no single individual is capable of responding vigorously to each and every pathogen requiring a T cell response for elimination

300

When a peptide binds to an MHC molecule, how long may it stay bound for?

What does this allow?

hours to several days

peptide-MHC complexes persist long enough on the cell membranes of antigen-presenting cells and target cells to ensure productive interaction with antigen-specific T cells

301

MHC molecules bind to and present what kinds of peptides to T cells?

both self-peptides and foreign peptides

302

In a normal, healthy cell, why do Class I molecules display self peptides?

a result of normal turnover of self proteins

if the cell is infected by a virus or viral particles self peptides will be displayed by class I MHC molecules, but the T cells usually respond ONLY to FOREIGN PEPTIDES

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303

What are the phases of Naive T cell responses?

antigen recognition, lymphocyte activation, clonal expansion, differentiation and effector functions

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304

Fill in the chart:

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305

A cell is divided into what two compartments?

In which can microorganisms replicate?

1) cytosol

2) vesicular system, including the endosome, ER, lyososomes, etc

microorgs can replicate in either compartment

306

What happens to cytosolic antigens?

antigenic peptides are presented in association with class I MHC molecules to CD8T cells

307

What happens to endosomal antigens?

antigenic peptides are presented in association with Class II MHC molecules to CD4+ T cells

308

The MHC Class II processing pathway occurs for what type of antigen?

Endosomal antigens

309

What are the cells called that present peptides assoicated with Class II MHC molecues to helper T cells 

professional antigen-presenting cells (APCs)

310

What do APCs express on their cell membranes?

What are the best defined APCs?

express both class I and class II MHC molecules on cell membranes

macrophages, B cells, and dendritic cells

311

Where do dendritic cells arise from?

where are they found?

What do they possess that gives them their name?

arise from hematopoeitic stem cells in the bone marrow

found in the t cell areas of lymphatic tissues

possess long thin cytoplasmic processes called dendrites

312

What do dendritic cells express?

How do they express them?

How important are dendritic cells regarding stimulation?

express many monlecules associated with naive T cell activation, eg class I and II MHC molecules, the costimulatory B7 molecules, and the cell adhesion molecules ICAM-1, ICAM-2, LFA-1, and LFA-3 (CD58).

CONSTITUITIVELY

dendritic cells are the most potent stimulators of native T cell responses

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313

Besides their main expressors, what else do dendritic cells express at a high level?

What do dendritic cells secrete and what does it do?

dendritic cell-specific adhesion molecule DC-SGN

chemokine called CD-CK (CCL 18) that specifically attracts naive T cells

314

What are immature dendritic cells called?

where are they found?

What do they do?

Do they express co-stimulatory molecules?

Langerhans cells (LCs)

found in nonlymphoid tissues such as the skin and mucous membranes

they are actively phagocytic

they do no express co-stimulatory molecules

315

Describe what LCs do when a protein antigen invades skin or mucosa?

LCs bind the antigen to their surfaces,

endocytose it into vesicles and process it,

migrate as "veiled cells" via the afferent lymphatics into the paracortex of the draining lymph nodes where they mature and become interdigitating dendritic cells (IDCs; mature nonphagocytic cells)

316

What does the migration of LCs provide a mechanism for?

for transporting antigens from the skin and mucosa to the T cells located in the lymph nodes

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317

What happens to most of the antigen ingested by macrophages? 

What happens to some of the antigens?

Most are degraded and eliminated by exocytosis

some peptide products form complexes with MHC class II molecules and are displayed on the cell surface and presented to TH cells 

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318

Macrophages do not express MHC class II proteins unless what?

unless they are activated by phaocytosing microorganisms

319

What are macrophages beneficiaries of?

TH cell effector functions, i.e. cytokines secreted by activated TH cells activate macrophages to kill phagocytosed microbes

320

B cells bind to antigens using what?

What do B cells do to the bound antigens?

What do cytokines do to B cells?

B cell receptors (BCRs)

endocytose them and present processed peptides from the antigens to TH cells.

cytokines produced by effector TH cells stimulate B cells to produce antibodies against protein antigens

321

What happens to extracellular protein antigens?

They are phagocytosed or endocytosed into vesicles

the vesicles fuse with lysosomes containing acidic proteases

partial degradation of the antigen occurs int he acidic endosomes, leading to the generation of short peptide fragments of 10-20 amino acid residues

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322

Describe the 5 stages of uptake of extracellular proteins through expression of MHC

1) uptake of extracellular proteins into vesicular compartments of APC

2) processing of internalized proteins in endosomal/lysosomal vesicles

3) biosynthesis and transport of class II MHC molecules to endosomes

4) association of processed peptides with class II MHC molecules in vesicles

5) expression of peptide-MHC complexes on cell surface

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323

What do newly synthesized class II MHC molecules in the ER associate with?

a MHC class II-assocation trimeric invariant chain (Ii, CD74)

324

What happens when Ii chaiin bind to the class II molecule?

What does this promote?

What happens to Class II molecules witout Ii?

Where does Ii direct newly formed class II molecules?

part of the Ii polypeptide chain lies within the peptide-binding cleft, ensuring that class II molecules cannot bind and present peptides they encounter in the ER

promotes the folding and assembly of Class II MHC molecules. 

in its absence, many class II molecules remain in the eER as complexes and misfolded proteins

directs newly formed class II molecules to the specialized endosomal compartment called MIIC (MHC class II Compartment) where peptide loading takes place.

325

Name the specialized MHC class II-like molecule that is found in the MIIC and facilitates the loading of class II molecules with peptides?

HLA-DM

326

What is the main function of the HLA-DM in the MIIC?

in the MIIC the Ii chain is cleaved by proteases to leave a fragment bound to the peptide groove called CLIP (CLass II-associated Invariant chain Peptide). HLA-DM catalyzes the release of CLIP

327

What are two secondary functions of HLA-DM in the MIIC

1) stabilizes the empty class II molecules so they do not aggregate; catalyzes the binding of peptides to the empty peptide groove

2) facilitates the release of weakly bound peptides from the peptide grooves and allows other peptides to replace them. This ensures that the peptide-MHC II complexes on the cell surface of teh APC will survive long enough to enounter the antigen-specific TH cell

328

What happens to individuals with mutations in the HLA-DM genes?

demonstrate defective antigen presentation. The class II molecules assemble correctly with the Ii chain howver the MHC molecules fail to bind endosome-derived peptides and are displayed at the cell surface still bound to the CLIP peptide

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329

What happens to Class II molecules with bound peptides?

If an APC is not processing a foreign antigen, what will happen to MHC class II molecules?

transported to the surface of an APC where they are displayed for recognistion by CD4+ helper T cells.

they are displayed at the cell surface with bound self peptides

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True or false: the presentation of antigen (signal 1) to a naive helper T cell by an MHC class II molecule on an APC is, BY ITESELF, enough to trigger an immune response

FALSE; it is insufficicent to trigger an immune response

the T cell must also be exposed to co-stimulating molecules (signal 2) such as cytokines and cell membrane proteins, produced by the APC

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What are examples of co-stimulatory molecules for helper T cells?

cytokine interleukin 1 (IL-1) and the cell membrane proteins B7-1 (CD80) and B7-2 (CD86)

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Describe the events of costimulation of T cells related to signal 1

Signal 1 leads to the induction of various transcription factors, some of which bind to the promoter regions of the IL-2 and IL2R genes, enhancing their transcription in the T cell

Delivery of the co-stimulatory signal increases the half-life of IL-2 mRNA, resulting in IL-2 production (T cell autocrine growth factor)

This leads to the proliferation and differentation of naive T helper cell into effector T cells and memory T cells

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What does signal 2 induce during co-stimulation of T cells?

induces the synthesis of anti-apoptotic proteins

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What happens in the absence of the co-stimulatory signal?

IL-2 mRNA is rapidly degraded, preventing the synthesis of IL-2. 

as a result the activation process is terminated and the naive T cell either fails to respond and dies by apoptosis or enters a state of unresponsiveness called anergy

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The inflammatory response may have three outcomes. Name them.

1) elimination of the causative agent,

2) "walling off" of the inflammation from the rest of the body (delays the spread of bacteria or toxic products) with subsequent healing of the lesion, and

3) persistence of the causative agent, leading to chronic inflammation or spread throughout the body

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Inflammation is an overlapping series of events that form a continuum.

Name the progression of events.

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What are the two main categories of sources of chemical mediators of inflammation?

exogneous - bacterial lipopolysaccharide (LPS), etc

endogenous - from plasma and host cells