2 - Cells, organs and microenvironments of the immune system

Question 1

Myeloid cells

Answer 1

basophils (and progenitor
Eosinophil (and progenitor)
Granulocyte-monocyte profenitor -> Neutrophil, monocyte ->macrophage and DC
Mast cell
Platelets (from megakaryocyte)
Erythrocyte (from erythroid progenitor)

Question 2

Lymphoid cells

Answer 2

DC
TH and TC (from T cell progenitor) [in thymus]
B cell (from B cell progenitor)
Innate lymphoid cell (ILC)

Question 3

the process by which all red and white blood cells are developed

Answer 3

hematopoesis

Question 4

HSC

Answer 4

hematopoietic stem cell

Question 5

Granulocytes

Answer 5

neutrophils, eosinophils, basophils, mast cells

Question 6

Neutrophils

Answer 6

differentiation in bone marrow, released into blood and circulate for 7-10 h, then migrate into tissues. Life span only a few days.

Developement can be incresed in response to inflammatory molecules. this is called leukocytosis (used as indication of infection)

Swarm site of infection in large numbers in response to inflammatory molecules (among the first on the scene). Defeat cells by phagocytosis, secreting antimicrobial molecules.

Question 7

Eosinophils

Answer 7

important in coordinating defence against multicellular parasitic organism, including worms. They cluster around invading worms, damage their membranes by releasing the contents of their eosinophilic granules. Motile cells, migrate from blood to tissues. most abundant in small intestine. Contributers to asthma and allergy symptoms. secrete cytokines that may regylate B and T lymphocytes

Question 8

basophils

Answer 8

nonphagocytic
relatively rare in circulation
potent responders, play a role against parasites
upon binding to circulating Ab/Ag complexes, they release the contents of their granules, including histamine (increase blood vessel permeability and smooth muscle activity). Basophils also secrete cytokines that can recruit other immune cells.

Question 9

mast cells

Answer 9

combating parasites (worms) + allergy

released from bone marrow into blood as undifferentiated cells. Mature after leaving blood into a variety of tissues; skin, connective tissues of various organs, mucosal epithelial tissue of respiratory/genitourinare/digestive tracts.

Question 10

MHC class I

Answer 10

all cells have these molecules, and can present Ag on them.

Question 11

MCH class II

Answer 11

only pAPC have them, Th cells can only rec Ag on them

Question 12

APC 3 major activities

Answer 12

1) secrete proteins that attract and activate other immune cells
2) internalize pathogens via phagocytosis, digest pathogenic proteins into peptides, and then present these peptide antigens on their membrane surfaces via MCH II
3) upregulate costimulatory molecules required for optimal activation of Th cells

Question 13

dendritic cells

Answer 13

displaying and presenting Ag to naïve T lymphocytes

can “capture” Ag in 3 ways: phagocytosis, internalize it by reveptor-mediated endocytosis, or imbibe it by pinocytosis

After Ag contact, they mature from a conformation specialized for Ag capture into one for Ag presentation. They lose phagocytosis ability and large-scale pinocytosis, and improve their ability to present Ag and ezpress costimulatory molecules essential for activation of naïve T lymphs. After maturation, they enter blood/lymphatic circulation and migrate to lymphoid organs.

NB! FDC (follicular DCs) are not APC!! they regulate the activation of B cells.

Question 14

monocytes

Answer 14

regulate inflammatory responses at sites of tissue damage and infection.inflammatory monocytes enter tissues quickly in response to infection.

Patrolling monocytes crawl slowly along blood vessels, monitoring their repair. Also provide a reservoir for tissue-resident monocytes in the absence of infection, and may quell rather than initiate immune responses

Question 15

macrophages

Answer 15

monocytes that migrate ito tissues in response to infection differentiate into macrophages. Undergo a number of key changes when stimulated by tissue damage or pathogens and have a dual role in immune response:

1) contribute directly to the clearance of pathogens from a tissue
2) act as APC for T lymphocytes

Ab/Ag complexes can bind to macrophages - this increases phagocytosis rate by 4000

Question 16

erythroids

Answer 16

red blood cells. No nucleus. high concentrations of hemoglobin. deliver oxygen. If damaged, release signals that induce innate immune activiry.

Question 17

Megakaryocytes

Answer 17

Large myeloid cells that reside in bone marrow and give rise to thousands of platelets, very small cells/-fragments that circulate in the blood and can form blood clots (prevent blood loss and provide a barrier for pathogens if they take place at epithelial barriers. No nuclei.

Question 18

CD

Answer 18

cluster differentiation (CD) nomebclature. Surface proteins expressed by cells of the IS (and other cells)

Question 19

effector cells

Answer 19

carry out specific functions to combat pathogens

Question 20

memory cells

Answer 20

persist in the host, leads to rapid and efficient response upon reencounter with same Ag

Question 21

B cells

Answer 21

maturation in bone marrow.
distinguished from other cell types bc they express B cell receptors (BCR), a membrane bound immunoglobulin (ANTIBODY) molecule that binds to antigen. Each B cell expresses a surface antibody with unique specificity, and expresses only one type of Ab.

B cells improve their ability to bind Ag through SOMATIC HYPERMUTATION and can generate Ab of several different functional classes through a process known as CLASS SWITCHING (chap 11)

Activated B cells are the only non-,myeloid cells that can act as pAPCs. They internalize Ag very efficiently, and then process and present Ag on their surface. Activated B cells also express costimulatory molecules required for activation of T cells. By presenting Ag directly to T cells, B cells also recieve T cell hepl, in the form of cytokines that induce their differentiation into Ab-producing cells (plasma cells) and memory cells.

Ultimately, activated B cells differentiate into effector cells known as plasma cells. They lose expression of surface immunoglobulin/Ab and become highly specialized for secretion of Ab. Plasma cells do not divide and can either travel to bone marrow and live for years, or sie within 1-2 weeks.

Question 22

T cells

Answer 22

mature in thymus. also have unique Ab-binding receptors calles T cell receptors (TCR). B cells can recognize soluble pathogens, TCRs cannot, they only rec processed pieces of Ag expressed via MCH complexes.

T cells divided into two major cell types; T helper cells and T cytotoxic cells, distinguished by precence of CD4 or CD8 membrane glycoproteins on their cell membranes. 
If CD4; T  helper cell, recognize MCH class II
If CD8; cytotoxic T cell, recognize MCH class I. 

Naåive CD8+ cells browse the surfaces of APC with their TCRs. if they bind to an MCH, hey become activated, proliferate and differentiate into a typoe of effector cell called cytotoxic T lymphocyte (CTL), which has vital function in monitoring cells and eliminating cels that display non-self-Ag on MHCI, such as virus-infected cells, tumor cells, and cells of a foreign tissue graft. Need help from CD4+ T clls to differentiate optimally.

Naïve CD4+ T cells also browse the surfaces of APCs with their TCRs, and become activated the same way. They proliferate and differentiate into one of a variety of effector T cell subsets. Th1 and Th17 regulate our response to intracellular pathogens, Th2 and Tfh (follicular halper) regulate our response to extracellular pathogens (bacteria or worms). Each CD4+ Th cell subtype produces a different set of cytokines that enable or help the activation of B cells, Tc cells, macrophages, and various others.

Which helper subtype dominates the response depends on the type of pathogen.

Treg (regulatory T cell) is a CD4+ T cell which can inhibit immune responses. arise during maturation in thymus from cells that bind self proteins with high affinity (autoreactive cells). They can also be induced at the site of an immune response in an antigen-dependent manner (iTreg). Treg are identified by the prescence of CD4 and CD25 on the surface, as well as by the internal transcription factor FoxP3. Treg quell autoreactive responses and play a role in limiting normal T cell responses to pathogens

Question 23

NKT cells

Answer 23

shares features with both innate and adaptive immune cells

Have T cell receptors, some express CD4, but are not diverse. recognize specific lipids and glycolipids (as opposed to protein peptides) presented by a molecule related to MCH called CD1.

Also have receptors associated with innate immune cells, such as NK cells. activated NKT cells release cytotoxic granules that kill target cells, but also large quiantities of cytokines that can either enhance or suppress the immune response.

Question 24

Innate lymphoid cells (ILCs)

Answer 24

dont express Ag-specific receptors.

three classes (IILC1, ILC2, ILC3), distinguished by which cytokines they secrete. Many provide a first line of defence against pathogens in the skin and at mucosal tissues.

NK cells (cytotoxic natural killer cells) are often classified as ILC1, and identified by expression of NK1.1 surface protein.

efficient killer cells. 2 strategies for finding abnormal cells:

1) attack cells that lack MCH class I (MCH class I can be downregulated in virus-infected cells or tumor cells). If NK meets MCH class I, they are inhibited from killing.
2) NK cells express receptors (Fc receptors, FcRs) for some Ab. By linking to Ab, NK cells can arm themselves with Ab specific for pathogenic proteins, particularly viral proteins present on the surface if infected cells. When these Ab make contact with cells, NK have contact with cells, and it releases granules and indices cell deatch (ADCC, antibody-dependent cell cytotoxicity)

Question 25

Stem cell niches

Answer 25

sequestered regions lined by supportive cells that regulate stemm cell survival, proliferation, differentiation and trafficking.

Question 26

How do feutses generate red and white blood cells?

Tviler på at vi får det

Answer 26

Hematopoiesis begins when precursor cells in the yolk sac differentiate into primitive, nucelated erythroid cells that carry pxygen the embryo needs for early development (3 weeks after fertilization in humans). Fetal HSCs capable of generating all blood cell types can be detected close to the kiney when the fetal heart starts beating. Mature HSCs capable of completely repopulating the hematopoietic system of irradiated animals can be isolated from multiple tissues. The placental HSC pool proliferates rapidly, however the number of HSCs in the placenta drops as the HSC pool in the fetal liver expands. As an embryo completes development, the fetal liver is the predominant site of HSC generation.

Question 27

The main site of hematopoiesis in adults

tror ikke det er så viktig

Answer 27

bone marrow. maintains the pool of HSCs and differentiation into all blood cell types.
bone marrow divided into two sections; endosteal niche (lining the bone) and perivascular niche (linng the blood vessels that run through the center of the bone). These niches contain stromal cells that provide structure and guidance for hematopoesis.

The stromal cells in the bone marrow that regulate HSC quiescence, proliferation, trafficking and differentiation include:
1) endothelial cells that line blood vessels

2) perivascular cells that are diverse in function and interact with endothelial cells
3) sympathetic nerves that transmit sifnals to other niche cells
4) macrophages which influence the activity of other niche cells
5) osteoblasts, which generate bone and regulate the differentiateion of lymphoid cells.

Quiescent, long lived HSCs are found in the pericascular niche, nurtured by perivascular and endothelial cells. Some remain quiescent, others divide and differentiate into progenitors that develop into myeloid or lympoid lineages. Specific nuches that support myeloid development have not yet been identified. However, the main sites of lymphocyte differentiation are well understood.

B lymphs complete most of their development in the bone marrow. progenitors of B lymphs are found in the endosteal nice in association with osteoblasts. More mature B cells are found in the central sinuses of the bone marrow and exit it to complete the final stages of their maturation in the spleen. Progenitors of T lymphs arise from bone marrow HSCs but exit at a very immature stage and complete their development in the thymus, the primary lymphoid organ for T cell maturation.

Question 28

T cell maturation (short version)

Answer 28

selection in thymus after starting in bone marrow.

mature into functional T cells by passing though well.defined developmental stages in well.defined microenvironments.

Positive and negative regulation

Unique TCRs

migrate to the thymic medulla if they pass both tests. Most die (death by neglect) bc they don’t have affinity for either

Thymocytes are distinguished by their expression of two CD Ag; CD4 and CD8. The most immature thymocytes express neither (double negative, DN).

After entering the cortex, thymocytes upregulate both CD4 and CD8 Ag (double positive, DP).

As they mature, they lose one of the CD Ag, becoming single positive (SP).

CD4+ T cells are helper cells, CD8+ T cells are cytotoxic cells. Mature SP cells exit the thymus as they eneterd, via blood vessels of the corticomedullary junction.

Maturation is finalized in the periphery, where these new T cells explore Ag presented in secondary lumphoid tissue, including the spleen and lymph nodes.

Question 29

how are the most highly secondary lymphoid organs compartmentalized from the rest of the body?

Answer 29

lymph nodes and spleen
compartmentalized by fibrous capsule

The less organized are associated with the linings of multiple organ systems, including skin + reproductive/respiratory/gastrointestinal tract (barrier tissues)

Question 30

key features of secondary lymphoid tissues

Answer 30

anatomically distinct regions of T cell and B cell activity, generate lymphoid follicles (higly organizes microencironments responsible for the debelopment and selection of B cells that produce high-affinity Ab

Question 31

Lymphatic system

Answer 31

only white blood cells have access. Vessels filled with lymph (protein-rich fluid) derived from the fluid-part of blood (plasma).

Provide a route from infected tissue to secondary lymphoid organs (immune cells can activate lymphocytes).

can also return fluid that seeps from blood back into circulatory system (interstitial fluid).

Some walls of primary lymphatic vessels are thinner than those of blood vessels and more porous. easy entry. The lymph is collected in larger vessels (lymphatic vessels).

All cells and fluids circulating the lymph system are eventually returnet to the corculatory system. Largest lymphatic vessel = thoriacic duct, empties into left subclavian vein.

Lymph system relies on a series of one-way valves.

Question 32

chemokines are secreted by

Answer 32

many cells, including epithelial, stromal, APC, lymphocytes, and granulocytes.

Question 33

Lymph nodes

Answer 33

first organized lymphoid structure to encounter Ag entering tissue spaces. It is also surrounded by stromal cells (support tissue) packed with lymphocytes, macrophages and DCs.

3 structureal regions: cortex, paracortex and medulla.

cortex has lymphocytes (mostly B), macrophages and follicular DCs arranged in follicles.

paracortex has T cells, DCs.

medulla = lymphocyte exit through lymphatics. More sparsely populated by plasma cells (B cell things) that secrete Ab

Question 34

T cells in the lymph node

Answer 34

Naïve lymphocytes enter the cortex via HIGH ENDOTHELIAL VENULES (HEVs). Once inside the paracortex, they browse APC surfaces. APCs are wrapped around FIBROBLASTIC RETICULAR CELLS (FRCs), in a FIBROBLASTIC RETICULAR CELL SONDUIT SYSTEM (FRCC). this increases the efficiency by which T cells can browse the surfaces of APCs.

T cells exit through the medulla if htey don’t find their match. T cells that bind MCH peptidestop migrating, take up residence for a few days, proliferate and differentiate into effector cells with virying funcitons. CD8+ cells (kill), CD4+ (several types of effector cells, includinf those who further activate macrophages, CD8+ and B cells).

Question 35

B cells in the lymph node

Answer 35

activated B cells differentiate into high-affinity, Ab-secreting plasma cells.
Optimal B cell activation requires both Ag engagement of the BCR and direct contact with CD4+ T cell. Both are facillitated by the lymph node anatomy.

Enter via HEVs, into lymph node follicles. May use FBCC for guidance, usually/ultimately shift to tracts generated by follicular DCs (FDCs). FDCs present particulate Ag to differentiating B cells.

B cells can rec free, unprocessed Ag. They usually meet in a lymph node follicle (B cell follicle). smaller Ag can make their way there themselves, larger need macrophages or something. If BCR binds to Ag, B cell is patially activated, engulf and process the Ag, readying it for presentation as a peptide-MCH complex to CD4+ Th cells.

partially activated B cells migrate to the paracortex, they might meet a previously activated CD4+ Th cell, and remain in contact for hours, during which the B cell recieves signals from the T cell that induce the B cell proliferation and differentiation.

Some activated B cells differentiate into plasma cells (Ab producing cells), others re-enter the follicle to establish a germinal center. SECONDARY FOLLICLE = follicle with germinal center (primary follicle = without germinal center). in germinal centers, B cells proliferate and undergo clonal selection to produce a colony of B cells with the highest affiity for a particular Ag. Some travel to medulle and release Ab into blood stream, others take up permanent residence in bone marrow, where they will continue to release Ab into circulation.

Question 36

The generation of memory T and B cells

Answer 36

in the lymph node
T cell + APC OR Th + activated B cell = memory T or B cell. take up residence in either sencondary lymph tissues or exit the lymph node and circulate to or among other tissues, including those that first encountered the pathogen.

central memory cells = memory T cells in secondary lymphoid organs.

effector memory T cells circulate among tissues. Distinct in phenotype and functional potential from central memory T cells.

tissue-resident memory T cells do what the name says, and is the first cells to respond upon reinfection.

Question 37

The spleen 3 parts

Answer 37

secondary lumphoid organ

Red pulp: red blood cells, macrophages, some lymphocytes. Old/defective red blood cells = destroyed, sometimes engulfed by macrophages.

white pulp: lymphoid rich region. B cell follicles and PALS (periateriolar lymphoid sheath) (populated by T cells). germinal centers are generated within these follicles during immune response.

Marginal zone (MZ) populated by specialized DCs, macrophages, and unique B cells, (MZ B cells). These are first line of defence against blood-borne pathogens, trapping Ag that enter. MZ B cells express both TLRs etc and unique BCRs. Once they bind Ag, MZ B cells differentiate ant secrete high levels of Ab.

Question 38

The events that initiate the adaptive immune response in spleen:

Answer 38

analogoius to thise in lymph node.

naïve B cells ancounter Ag in follicles. Circulating naïve CD8+ and CD4+ T cells meet Ag as MHC-peptide complex in T cell zone (PALS). activated Th help B cells and CD8+ T cells (also encountered Ag). Some activated B cells (along with Th cells) migrate back to follivles and generate germinal centres. Germinal center B cells can become memory cells or plasma cells.