Lecture 9, Fcnal Lymphoid Anatomy

Question 1

Name 4 purposes of having lymphoid tissue.

Answer 1

• Supports lymphopoiesis
• Supports development of incredibly diverse repertoire of ag-specific lymphocytes
• Critically important for central & peripheral tolerance
• Provides sustaining signals for lymphocyte survival

Question 2

What places in the body have central lymphoid tissue?

Answer 2

Bone marrow, thymus

Question 3

What places in the body have peripheral lymphoid tissue?

Answer 3

• Lymph nodes
• Spleen
• Mucosal associated lymphoid tissue (MALT)
• Cutaneous system

Question 4

What are two main processes that the central lymphoid tissue is responsible for?

Answer 4

• Central tolerance

- Lymphopoiesis

Question 5

Where are B cells initially made?

Where are T cells initially made?

Answer 5

• Bone marrow

- Bone marrow (T cell progenitors migrate to *thymus during embryogenesis and develop there)

Question 6

Naive lymphocytes enter the LN from (blood/lymphatics)?

Answer 6

Blood

Question 7

Naive lymphocytes are activated in the (central/peripheral) lymph tissue.

Answer 7

Peripheral

Question 8

___________ tolerance occurs in central lymphoid tissue, ___________ tolerance occurs in peripheral lymphoid tissue.

Answer 8

• Central

- Peripheral

Question 9

During B cell lymphogenesis, early stem cells hang out at the ____________, just below the inner cavity of the long bones, but then move toward the _________ cells in the trabeculae.

Answer 9

• Endosteum

- Stromal

Question 10

During B cell lymphogenesis, progression of B cell development depends on _________________ provided by the stromal cells.
(general answer)

Answer 10

Maturation factors

Question 11

During B cell lymphogenesis, as B cells mature, they conveniently move from the endosteum toward the _______________ of the marrow cavity, then into circulation, bound for the _________________________.

Answer 11

• Central sinus

- Peripheral lymphoid organs

Question 12

*Are T cells continually produced throughout adult life?

Are B cells?

Answer 12

• T cells: Yes, but T-cell #s are maintained thru long-lived individual T cells together w/ the division of mature T cells outside the central lymphoid organs.
• B cells: Yes, even adults continually produce them in the marrow

Question 13

If a B cell survives central tolerance in the marrow and ends up meeting an antigenic match in a peripheral lymphoid organ, it will mature into one of these 2 types of cells:

Answer 13

• Plasma cell (secretes AB’s)

- Memory B cell

Question 14

Regarding central tolerance, what happens if an immature B cell does not react to self?

Answer 14

Migrates to periphery (probably becomes a mature B cell)

Question 15

Regarding central tolerance, what happens if an immature B cell reacts to a multivalent self molecule?

Answer 15

1. Clonal deletion -> apoptosis (in marrow)

2. Receptor editing -> if it works, migrates to periphery

Question 16

Regarding central tolerance, what happens if an immature B cell reacts to soluble self molecules?

Answer 16

Migrates to periphery and becomes anergic

Question 17

*Regarding central tolerance, what happens if an immature B cell binds w/low affinity to a non-cross-linking self molecule?

Answer 17

Migrates to periphery and becomes a clonally ignorant mature B cell (potentially leading to autoreactive plasma cells in presence of lots of large quantity of self)

Question 18

What are the 3 parts of lymphoid tissue you’d see throughout all lymphoid tissue except the MALT?

Answer 18

Capsule, subcapsular area, trabeculae

Question 19

Explain how trabecula are associated w/the capsule and what parts of the LN they separate.

Answer 19

Trabecula extended from capsule and separate cortex into superficial outer cortex with follicles and an inner paracortex or deep cortex. An inner medulla leads to a hilus where blood vessels and the efferent lymphatic is found.

Question 20

What are the 3 parts of lymphoid tissue you’d see throughout all lymphoid tissue except the spleen or MALT?

Answer 20

Cortex, corticomedullar junction, medulla

Question 21

What types of cells are stroma?

Answer 21

Non-leukocytes

Question 22

What types of cells are parenchyma?

Answer 22

Leukocytes

Question 23

What are 2 major LN regions that you’d find in the periphery but not in central lymphoid tissue?

Answer 23

• Germinal centers
• Lymphoid follicles
  (Germinal centers are w/in the follicles)

Question 24

Name the 2 major regions w/in the thymus, and what subregion divides them.

Answer 24

Cortex, corticomedullar junction, medulla (not found in spleen or MALT)

Question 25

Besides cortical epithelial cells, what 2 immunological cell types would you find in the cortex of the thymus? Which would there be more of?

Answer 25

- Immature thymocytes (mostly) | - Scattered macrophages (few)

Question 26

What 3 cell types would you find in the medulla of the thymus?

Answer 26

- Thymocytes - DCs - Macrophages

Question 27

If you had HSCs that form T cell progenitors in the marrow, but you're athymic, can T cells still develop?

Answer 27

No, need thymus

Question 28

What happens to the vast majority (98%) of thymocytes during development in the thymus?

Answer 28

They die by apoptosis and are removed by cortical macrophages

Question 29

Thymocytes depend on the thymic ______________ cells for survival.

Answer 29

Epithelial (the cytokines produced, etc.)

Question 30

When does the thymus finish development? When is rate of T cell production greatest? When does the rate of T cell production begin to decelerate? When does T cell production cease?

Answer 30

- Before birth - Before puberty - After puberty - Never (except death, dz)

Question 31

* *Explain the phases of T cell development, in terms of CD markers. (5 main phases) - Include when the 2 phases of chain rearrangement occur. - Note: progression of T cell development in the thymus is dependent on timely expression of various surface and signaling molecules.

Answer 31

1. Start as triple negative (CD3-, CD4-, CD8-) 2. Further interaction w/thymic stromal cells, now double negative (CD3+, CD4-, CD8-); mostly alpha-beta (vs. gamma-delta) - Beta-chain rearrangement occurs (while double negative) 4. Surface markers expressed, now double positive (CD3+, CD4+, CD8+) - Alpha-chain rearrangement occurs (while double positive) 5. 5% become single positive, export to periphery

Question 32

During T cell lymphopoeisis, in addition to receptor maturation, the double positive, then single positive T-cells are undergoing _________ and __________ selection.

Answer 32

Positive and negative (central tolerance)

Question 33

**Explain the pathway of T cells as they mature while in the thymus. (3 main steps)

Answer 33

1. Enter via HEV at medulla (double negative) 2. Migrate to cortex, encounter epithelial cell (become double positive) 3. Return to medulla, encounter DC or macrophages, thus becoming single positive

Question 34

During T cell central tolerance, thymic cortical epithelial cells express _________ peptide in MHC I or MHC II molecules.

Answer 34

Self

Question 35

During T cell central tolerance, does positive or negative selection come first?

Answer 35

Positive selection

Question 36

*During T cell central tolerance, what occurs during positive selection? What surface marker(s) will selected cells express? Where will the cells migrate to, if selected?

Answer 36

Double positive thymocytes with affinity for peptide:MHC complex (of the epithelial cells or medullary DCs/macrophages) will survive as either CD4+ or CD8+ single positive thymocytes and migrate to medulla.

Question 37

*During T cell central tolerance, what occurs during negative selection?

Answer 37

After positive selection, CD4+ or CD8+ T cells with too high affinity for peptide:MHC complex (of cortical thymic epithelial cells or medullary DCs/macrophages) are deleted; otherwise migrate to periphery.

Question 38

How long does it take for an adaptive immune response to an antigen that has not been encountered before does to become effective?

Answer 38

- More than 4-6 days (so about 1 week)

Question 39

When an infection occurs in a tissue such as the skin, free ag and ag-bearing DCs travel from the site of infection thru the _________________ into the draining LNs, where they activate antigen-specific lymphocytes.

Answer 39

Afferent lymphatic vessels

Question 40

The activated lymphocytes in the LN undergo a period of proliferation and differentiation, after which most leave the lymph nodes as effector cells via the ______________________.

Answer 40

Efferent lymphatic vessel

Question 41

Naive lymphocytes that do not recognize their antigen leave the LN thru the ____________________ and are returned to the blood, from which they continue to recirculate through lymphoid tissues until they recognize antigen or die.

Answer 41

Efferent lymphatic vessel

Question 42

In LNs, lymphocytes enter from ______________________, which are located within the T-cell zones.

Answer 42

High endothelial venules (HEVs)

Question 43

*Lymphocytes squeeze out of the vessels through HEVs into the __________________.

Answer 43

Paracortical areas (b/w medulla and cortex)

Question 44

Naive B cells migrate through the HEVs (to enter the LN) in the paracortical area (*mostly T cells) and come to rest in the ____________ where, unless they encounter their specific antigen and become activated, they remain for about (how long?)

Answer 44

Follicle | - a day

Question 45

The precise location of B cells, T cells, macrophages, and DCs in peripheral lymphoid tissue is controlled by______________, which are produced by both stromal cells and bone marrow derived cells.

Answer 45

Chemokines

Question 46

When a freely floating or APC-digested Ag enters the LN via the afferent lymphatics, they are brought into the ____________________.

Answer 46

Paracortical area (mostly T cells, to which the Ag is displayed)

Question 47

After the T cells in the paracortical areas interact w/free-floating or APC-digested Ag and become activated, what happens next?

Answer 47

B cells migrate to the T cells from the follicle via chemokines (they migrate towards each other, actually)

Question 48

What part of the LN contains the follicles?

Answer 48

Cortex

Question 49

Prior to interacting w/T cells, how do B cells in the follicle become exposed to Ag's? (2 ways)

Answer 49

- Free ag can travel to the follicles via conduits | - Ag can be captured by LN macrophages/resident medullary DCs

Question 50

Free ag on LN macrophages or DCs can be presented directly to follicular _____________ or passed to follicular ____________.

Answer 50

- B cells | - DCs

Question 51

Explain the general steps of lymphocyte activation towards becoming plasma cells in the LN once all cells and ag are already in the LN. What happens to extrafollicular B cells? Follicular B cells?

Answer 51

1. B cells & CD4+ T cells recognize ag 2. Activated lymphocytes migrate toward each other 3. Results in B cells proliferation/differentiation 4. Extrafollicular B cells re-stimulated by extrafollicular T cells to form short-lived plasma cells 5. Follicular B cells undergo somatic hypermutation & affinity maturation, switching & formation of long-lived plasma cells & memory B cells

Question 52

Once B cells are activated they migrate to a ________________ and start to ________________.

Answer 52

- germinal center | - proliferate

Question 53

During/after B cells proliferate in the germinal centers, what processes do they undergo?

Answer 53

Somatic mutation, affinity maturation, isotype switching. (in the follicle)

Question 54

Long-lived plasmablasts in medullary sinus go to ______________ or ______________ to become long-lived plasma cell.

Answer 54

Bone marrow or gut

Question 55

What occurs in the white pulp of the spleen?

Answer 55

Immune responses to blood-borne pathogens

Question 56

What occurs in the red pulp of the spleen?

Answer 56

RBC Disposal & Iron recycling

Question 57

Besides forming immune responses to blood-born pathogens, RBC disposal, and Fe3+ recycling, what other function can the spleen perform, if necessary?

Answer 57

(Secondary) Hematopoiesis

Question 58

*What type of organisms is the spleen especially good at clearing?

Answer 58

Encapsulated bacteria: Pneumococci, Meningococci

Question 59

Do ag enter the spleen via lymphatics or blood?

Answer 59

Blood (there are no lymphatics to spleen) | - Via splenic a.

Question 60

*After blood enters the spleen via the splenic a, some arteriolar branches end in vascular _____________ lined by ______________ which filter out RBCs & opsonized cells & microbes

Answer 60

- Sinusoids | - Macrophages

Question 61

The splenic white pulp is a collection of densely packed _____________.

Answer 61

Lymphocytes | lymphocytes surrounding the arterioles running through the spleen

Question 62

The architecture of the spleen is similar to ____________.

Answer 62

LNs

Question 63

Explain the blood drainage pattern of the spleen's white pulp.

Answer 63

Organized around central arterioles which drain into the marginal sinus

Question 64

*What types of cells are contained in the marginal zone of the spleen (to which the central arterioles drain)? What types of cells surround the central arterioles?

Answer 64

- B cells (+ macrophages) - T cells (mostly) (like in LN, ag from blood encounters T cells at HEV, then B cells)

Question 65

What are the 2 cells that can sample ag from the marginal sinus of the spleen?

Answer 65

- Circulating DCs | - Sampling by marginal zone macrophages

Question 66

In 1 general sentence, explain what is occurring w/ peripheral tolerance.

Answer 66

In the absence of an infection, mature B & T cells that encounter a strongly cross-linking antigen in the peripheral lymphoid organs will undergo clonal deletion or anergy.

Question 67

What happens to a B cell if it fails to reach a primary follicle?

Answer 67

Appears to die after several days (there is a competition amongst B cells to enter follicle)

Question 68

There is a continual positive selection of T cells in the periphery by...

Answer 68

Repeated contacts with self-peptide:self-MHC

Question 69

What is MALT? | *Where are areas where you'd find it?

Answer 69

Mucosal associated lymphoid tissue - Gastrointestinal tract, the upper and lower respiratory tract & the urogenital tract - Also includes the exocrine glands associated w/ these organs, such as the conjunctivae and lachrymal glands, salivary glands, and lactating breast

Question 70

Besides organized lymphoid tissues in MALT, there are also scattered areas of lymphoid tissue. What types of cells might you find in areas of scattered lymphoid tissues?

Answer 70

- Intraepithelial lymphocyte (tend to be toxic) - Lamina propria lymphocyte (tend to be helper) - Defensins produced in the crypts

Question 71

What's the main e.g. of organized lymphoid tissue in the gut?

Answer 71

Peyer's patches

Question 72

How are Peyer's patches different from regular LNs? Are they encapsulated? Do they have follicles/germinal centers?

Answer 72

- They are NOT encapsulated - Have lymph and blood-independent entry of antigen from the lumen (they do have follicles w/germinal centers, tho--IgA)

Question 73

What are the 2 main ways Ag enters Peyer's patches?

Answer 73

1. M cells- transcellular xport of various substances from the intestinal lumen across the epithelial barrier to underlying APCs 2. Lamina propria DCs (extend their arms paracellularly or str8 paracellular)

Question 74

*The most abundant immunoglobulin in MALT tissues is Ig__ (predominant) secreted by plasmablast which circulate back to the mucosal tissue after activation (Exception: genitourinary Ig_ )

Answer 74

IgA | IgG

Question 75

How is the spleen directly connected w/the lymphatic system?

Answer 75

It is not!

Question 76

Newly formed lymphocytes enter the spleen via the blood, exiting first in the __________________, from which they migrate to the appropriate areas of the white pulp.

Answer 76

Marginal sinus

Question 77

Lymphocytes that survive passage through the spleen probably leave via venous sinuses in the ________ pulp.

Answer 77

red

Question 78

What is a periarteriolar lymphoid sheath (PALS):

Answer 78

In the spleen, sheath of lymphocytes around a central arteriole; mainly T cells

Question 79

B cells of Peyer's patches tend to commit to producing Ig_.

Answer 79

IgA

Question 80

What types of intestinal cells produce defensins?

Answer 80

Paneth cells

Question 81

Where do long-lived plasma cells develop? What are their precursors called? Where do they then migrate to?

Answer 81

- Germinal centers - Plasmablasts - Bone marrow

Question 82

What area in the spleen forms the boundary between the red pulp and white pulp?

Answer 82

Marginal zone (outside the marginal sinus, which has the B cells and macrophages, and is drained into by the central arteries)

Question 83

*What cells do immature thymocytes encounter to become double positive? (and where?) Which do they encounter to become single positive? (and where?)

Answer 83

- TECs (cortex) | - Macrophages, DCs, or TECs (medulla)