Flashcards in Lecture 9, Fcnal Lymphoid Anatomy Deck (83):
Name 4 purposes of having lymphoid tissue.
- Supports lymphopoiesis
- Supports development of incredibly diverse repertoire of ag-specific lymphocytes
- Critically important for central & peripheral tolerance
- Provides sustaining signals for lymphocyte survival
What places in the body have central lymphoid tissue?
Bone marrow, thymus
What places in the body have peripheral lymphoid tissue?
- Lymph nodes
- Mucosal associated lymphoid tissue (MALT)
- Cutaneous system
What are two main processes that the central lymphoid tissue is responsible for?
- Central tolerance
Where are B cells initially made?
Where are T cells initially made?
- Bone marrow
- Bone marrow (T cell progenitors migrate to *thymus during embryogenesis and develop there)
Naive lymphocytes enter the LN from (blood/lymphatics)?
Naive lymphocytes are activated in the (central/peripheral) lymph tissue.
___________ tolerance occurs in central lymphoid tissue, ___________ tolerance occurs in peripheral lymphoid tissue.
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.
During B cell lymphogenesis, progression of B cell development depends on _________________ provided by the stromal cells.
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 _________________________.
- Central sinus
- Peripheral lymphoid organs
*Are T cells continually produced throughout adult life?
Are B cells?
- 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
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:
- Plasma cell (secretes AB's)
- Memory B cell
Regarding central tolerance, what happens if an immature B cell does not react to self?
Migrates to periphery (probably becomes a mature B cell)
Regarding central tolerance, what happens if an immature B cell reacts to a multivalent self molecule?
1. Clonal deletion -> apoptosis (in marrow)
2. Receptor editing -> if it works, migrates to periphery
Regarding central tolerance, what happens if an immature B cell reacts to soluble self molecules?
Migrates to periphery and becomes anergic
*Regarding central tolerance, what happens if an immature B cell binds w/low affinity to a non-cross-linking self molecule?
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)
What are the 3 parts of lymphoid tissue you'd see throughout all lymphoid tissue except the MALT?
Capsule, subcapsular area, trabeculae
Explain how trabecula are associated w/the capsule and what parts of the LN they separate.
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.
What are the 3 parts of lymphoid tissue you'd see throughout all lymphoid tissue except the spleen or MALT?
Cortex, corticomedullar junction, medulla
What types of cells are stroma?
What types of cells are parenchyma?
What are 2 major LN regions that you'd find in the periphery but not in central lymphoid tissue?
- Germinal centers
- Lymphoid follicles
(Germinal centers are w/in the follicles)
Name the 2 major regions w/in the thymus, and what subregion divides them.
Cortex, corticomedullar junction, medulla (not found in spleen or MALT)
Besides cortical epithelial cells, what 2 immunological cell types would you find in the cortex of the thymus?
Which would there be more of?
- Immature thymocytes (mostly)
- Scattered macrophages (few)
What 3 cell types would you find in the medulla of the thymus?
If you had HSCs that form T cell progenitors in the marrow, but you're athymic, can T cells still develop?
No, need thymus
What happens to the vast majority (98%) of thymocytes during development in the thymus?
They die by apoptosis and are removed by cortical macrophages
Thymocytes depend on the thymic ______________ cells for survival.
Epithelial (the cytokines produced, etc.)
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?
- Before birth
- Before puberty
- After puberty
- Never (except death, dz)
**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.
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
During T cell lymphopoeisis, in addition to receptor maturation, the double positive, then single positive T-cells are undergoing _________ and __________ selection.
Positive and negative (central tolerance)
**Explain the pathway of T cells as they mature while in the thymus. (3 main steps)
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
During T cell central tolerance, thymic cortical epithelial cells express _________ peptide in MHC I or MHC II molecules.
During T cell central tolerance, does positive or negative selection come first?
*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?
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.
*During T cell central tolerance, what occurs during negative selection?
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.
How long does it take for an adaptive immune response to an antigen that has not been encountered before does to become effective?
- More than 4-6 days (so about 1 week)
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.
Afferent lymphatic vessels
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 ______________________.
Efferent lymphatic vessel
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.
Efferent lymphatic vessel
In LNs, lymphocytes enter from ______________________, which are located within the T-cell zones.
High endothelial venules (HEVs)
*Lymphocytes squeeze out of the vessels through HEVs into the __________________.
Paracortical areas (b/w medulla and cortex)
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?)
- a day
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.
When a freely floating or APC-digested Ag enters the LN via the afferent lymphatics, they are brought into the ____________________.
Paracortical area (mostly T cells, to which the Ag is displayed)
After the T cells in the paracortical areas interact w/free-floating or APC-digested Ag and become activated, what happens next?
B cells migrate to the T cells from the follicle via chemokines (they migrate towards each other, actually)
What part of the LN contains the follicles?
Prior to interacting w/T cells, how do B cells in the follicle become exposed to Ag's? (2 ways)
- Free ag can travel to the follicles via conduits
- Ag can be captured by LN macrophages/resident medullary DCs
Free ag on LN macrophages or DCs can be presented directly to follicular _____________ or passed to follicular ____________.
- B cells
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?
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
Once B cells are activated they migrate to a ________________ and start to ________________.
- germinal center
During/after B cells proliferate in the germinal centers, what processes do they undergo?
Somatic mutation, affinity maturation, isotype switching. (in the follicle)
Long-lived plasmablasts in medullary sinus go to ______________ or ______________ to become long-lived plasma cell.
Bone marrow or gut
What occurs in the white pulp of the spleen?
Immune responses to blood-borne pathogens
What occurs in the red pulp of the spleen?
RBC Disposal & Iron recycling
Besides forming immune responses to blood-born pathogens, RBC disposal, and Fe3+ recycling, what other function can the spleen perform, if necessary?
*What type of organisms is the spleen especially good at clearing?
Encapsulated bacteria: Pneumococci, Meningococci
Do ag enter the spleen via lymphatics or blood?
Blood (there are no lymphatics to spleen)
- Via splenic a.
*After blood enters the spleen via the splenic a, some arteriolar branches end in vascular _____________ lined by ______________ which filter out RBCs & opsonized cells & microbes
The splenic white pulp is a collection of densely packed _____________.
(lymphocytes surrounding the arterioles running through the spleen)
The architecture of the spleen is similar to ____________.
Explain the blood drainage pattern of the spleen's white pulp.
Organized around central arterioles which drain into the marginal sinus
*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?
- B cells (+ macrophages)
- T cells (mostly)
(like in LN, ag from blood encounters T cells at HEV, then B cells)
What are the 2 cells that can sample ag from the marginal sinus of the spleen?
- Circulating DCs
- Sampling by marginal zone macrophages
In 1 general sentence, explain what is occurring w/ peripheral tolerance.
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.
What happens to a B cell if it fails to reach a primary follicle?
Appears to die after several days (there is a competition amongst B cells to enter follicle)
There is a continual positive selection of T cells in the periphery by...
Repeated contacts with self-peptide:self-MHC
What is MALT?
*Where are areas where you'd find it?
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
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?
- Intraepithelial lymphocyte (tend to be toxic)
- Lamina propria lymphocyte (tend to be helper)
- Defensins produced in the crypts
What's the main e.g. of organized lymphoid tissue in the gut?
How are Peyer's patches different from regular LNs?
Are they encapsulated?
Do they have follicles/germinal centers?
- They are NOT encapsulated
- Have lymph and blood-independent entry of antigen from the lumen
(they do have follicles w/germinal centers, tho--IgA)
What are the 2 main ways Ag enters Peyer's patches?
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)
*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_ )
How is the spleen directly connected w/the lymphatic system?
It is not!
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.
Lymphocytes that survive passage through the spleen probably leave via venous sinuses in the ________ pulp.
What is a periarteriolar lymphoid sheath (PALS):
In the spleen, sheath of lymphocytes around a central arteriole; mainly T cells
B cells of Peyer's patches tend to commit to producing Ig_.
What types of intestinal cells produce defensins?
Where do long-lived plasma cells develop?
What are their precursors called?
Where do they then migrate to?
- Germinal centers
- Bone marrow
What area in the spleen forms the boundary between the red pulp and white pulp?
Marginal zone (outside the marginal sinus, which has the B cells and macrophages, and is drained into by the central arteries)