Immunology Theory - Summary (Kuby)

Front 1

How can you study the importance of the thymus in immune function?

Back 1

Using nude (athymic) mice: lack cell mediated immune responses due to absense* of T cells --> unable to produce AB. This occurs in humans as, DiGeorge's Syndrome.
* there are negligable amounts of T cells present because of "intestinal production".

Front 2

What cells provide cytokines necessary for progenitor cell development within the bone marrow?

Back 2

Stromal cells: non-hematopoetic stem cells that support the growth and differentiation of hematopoetic cells.

Front 3

How does a primary follicle become a secondary follicle?

Back 3

via AG stimulation.
primary: prior to stimulation with AG, contains network of FDCs and small resting B cells.
secondary: after stimulation with AG, concentric rings of maturing B cells surrounding a germinal center.

Front 4

Describe the functional importance of the germinal center.

Back 4

It's a focus of proliferating B cells alongside an area of non-dividing B, T helpers, macrophages, and FDCs. Few activated B reside here. The ones that do, undergo further division and AB gene mutation at an increased rate. Following this, -selec. eliminates 90% and the survivors become plasma or memory cells before leaving the center.

Front 5

When does the body make use of lymph nodes?

Back 5

During the first encounter with an AG. Langerhans cells transport AG from tissue spaces to nodes all over the body. AG are trapped within network of phagocytes, FDCs, and IDCs. They travel from the cortex to the paracortex, where IDCs present to T helpers using MHC-II. B activation also occurs here, where plasma cells then secrete IgM and IgG while forming foci with the T helpers. A few B and T helpers later migrate to primary follicles within a week. (cause of migration: unknown). The plasma cells migrate to the medulla where they continue to fight infection via secretion.

Front 6

What causes the increase in lymphocyte number within the efferent lymph?

Back 6

50Xs more lymphocytes exit.
75% were generated in the node.
25% leave post-capillary venules.
however, during AG stimulation causes the 25% to increase 10X so that this is the major source of lymphocytes.

Front 7

Which are the thymus dependent and independent areas of a lymph node?

Back 7

Paracortex = dep.
Cortex = indep.

Front 8

In what conditions does the spleen encounter AG?

Back 8

When there is a systemic infection with blood-borne AG. More recirculating lymphocytes pass through the spleen daily than all the lymph nodes combined.

Front 9

How does blood pass from the 2 pulps of the spleen?

Back 9

Blood enters the spleen via the splenic artery. This empties into the marginal zone, where AG are trapped by IDCs and carried to the PALS (white pulp). A second point of entry is through sinusoids located in the marginal zone. The PALS is T rich and contains B too. Initial activation takes place here. T are activated to T helpers which in turn activate B. Both then migrate to primary follicles in the marginal zone, which later develop into secondary follicles. The other (red pulp) is where sinusoids, macrophages, and RBCs interact to destroy old RBCs.

Front 10

What are the effects of a splenectomy?

Back 10

Depends on the age at which it is removed. In children, it causes increased incidence of bacterial sepsis. In adults, it causes increased incidence of bacteremia (less adverse).

Front 11

In which instances does MALT encounter AG?

Back 11

The mucous membrane is the major point of entry for pathogens. They include tonsils, appendix, and Peyer's patches. They house a larger population of plasma cells than the spleen, bone marrow, and lymph nodes combined. The specialized M cells transport the AG from lumen to the submucosa. At the basal surface is a cluster of B, T, and macrophages. The AG are endocytosed into vesicles and sent to the basal pocket lymphocytes.

Front 12

How does MALT initiate an immune response within the lumen?

Back 12

The activated B in the submucosa become plasma cells. Secreting IgA which travels up to the lumen in order to react with AG.

Front 13

What cells are involved in the non-specific innate immune response of the skin?

Back 13

Keratinocytes: sec. cytokines to induce = local inflammation, exp. of MHC-II on APCs
Langerhans: internalize AG then migrate to lymph node and become IDC
intraepidermal lymphocytes: γδ CD8+ T cells (same as MALT) are uniquely suited to combat epidermal AG

Front 14

How are innate and adaptive immunity related by function?

Back 14

They are cooperative and interdependent. The activation of the innate produces signals that stimulate and direct the adaptive. The adaptive then generates signal and components which increase the effectiveness of the innate.

Front 15

Describe the general features of the innate immune response.

Back 15

It includes the anatomic, physiologic, endocytic and phagocytic, and inflammatory barriers that help prevent the entrance and establishment of infectious agents.

Front 16

Describe the general features of the adaptive immune response.

Back 16

It includes: specific, diverse, memory, and self/nonself recognition features. It consists of recognition and response steps. APCs, B, and T are the main lymphocytes involved.

Front 17

What are the general differences between AG receptors on B versus T cells?

Back 17

B: =AB molecules, recognize and interact directly with the AG.
T: recognize AG while bound to MHC molecule on APC cell surface
* Both mature to recognize only ONE EPITOPE of the AG (antigenic determinant).

Front 18

What are the important differences in presenting exogenous versus endogenous AG?

Back 18

exogenous: extracellular AG are internalized and degraded before presentation on MHC-II.
endogenous: intracellular AG are degraded in cytoplasm before presentation on MHC-I.

Front 19

Describe the interaction of a mature, immunocompetent lymphocyte with its AG.

Back 19

The lymphocyte will then proliferate and differentiate into effector and memory versions of the cell. This 'initial exposure' induces a primary response which upon a later 'second exposure' permits the memory cells to induce a more rapid and intense response.

Front 20

What are the humoral and the cell-mediated responses best suited for?

Back 20

humoral: elimination of exogenous AG; effectors = plasma
cell-mediated: elimination of endogenous AG; effectors = T helpers and CTLs.
* T helpers are required for both humoral and cell-mediated.

Front 21

Explain the goal of clonal selection and how do monoclonal AB differ from polyclonal AB?

Back 21

clonal selection: AG mediated activation and proliferation of 1 BcR clone or 1 TcR/MHC clone
monoclonal AB: homogenous preparation of AB by 1 BcR (hybridoma with myloma cells) with the same AG specificity
polyclonal AB: mixed preparation of AB by many BcR (non-hybridoma) with varying AG specificity

Front 22

What does a successful immunization/vaccine result in?

Back 22

"phylaxis": protection
anaphylaxis: when subsequent exposure results in a violent, fatal reaction.
allergy is anaphylactic: IgE

Front 23

Describe how a hematopoetic stem cell becomes fully differentiated for: 0. NK cells 1. T cells 2. B cells 3. dendritic cells 4. macrophages 5. neutrophils 6. eosinophils 7. mast cells 8. basophils 9. platelets 10. RBCs

Back 23

0.IL-3-->-->
1.IL-3-->IL-3,7-->IL-2,3,5,6
2.IL-3-->IL-7-->IL-2,4,7
3.GM-CSF,IL-3-->same,IL-6-->-->
4.GM-CSF,IL-3-->same,IL-6-->GM-CSF,M-CSF-->-->
5.GM-CSF,IL-3-->same,IL-6-->GM-CSF,C-CSF-->orM-CSF-->IL-8-->
6.GM-CSF,IL-3-->same-->GM-CSF,IL-5-->
7.GM-CSF,IL-3-->same-->IL-9-->
8.GM-CSF,IL-3-->same-->GM-CSF,IL-4-->
9.GM-CSF,IL-3-->same,IL-11,EPO-->GM-CSF,IL-6,EPO-->
10.GM-CSF,IL-3-->same,EPO-->EPO-->
* activated T helpers and macrophages can stimulate myloid and lymphoid stem cells directly (bypassing the hematopoetic stem cells).
** in absense of infection, bone marrow stromal cells release stimulating cytokines for the progenitor cells.

Front 24

Describe the regulation of hematopoesis.

Back 24

To maintain 'steady state' levels of various blood cells, 3,7x10^11 WBCs must be produced everyday.
1. control levels/kinds of cytokines produced by bone marrow stromal cells
2. producing cytokines by activated T helpers and macrophages
3. regulating the expression of cytokine receptors in stem cells and progenitor cells
4. removing cells by inducing apoptosis

Front 25

What is the experimental importance of using SCID mice?

Back 25

Used to study the human pluripotent stem cell because they lack B and T and are unable to launch adaptive immune responses.
When human thymus and bone marrow, stem cells differentiate into mature hematopoetic cells. This sytem allows study of CD34+ (present on 1% of stem cells) subpopulations and the effect of various growth hormones/cytokines on lineages.

Front 26

Explain the naive B and T cells in terms of the cell cycle.

Back 26

They are found in Go = resting phase of cell cycle. They have a very short lifespan. Once they interact with AG and proper cytokines, they enter G1 and then finish the cycle as usual. The enlarge to become lymphoblasts (S phase) and divide into Go effector and memory cells.

Front 27

How do NK cells recognize their target cells and what is their role in the immune system?

Back 27

1. surface receptors find abnormalities (reduced MHC-I, unusal profile of surface AG) on tumor and virus infected cells
2. CD16 binds Fc region of anti-tumor/viral AB bound to target cell surface (ADCC)
They mediate 'cytotoxic' reactions. Especially against tumors, since loss of NK results in increased incidence of tumors.

Front 28

List the macrophage-like cells residing in various tissues.

Back 28

1. alveolar macrophages (lungs)
2. histiocytes (c.t.)
3. Kupffer cells (liver)
4. mesangial cells (kidney)
5. microglial cells (brain)
6. osteoclasts (bone)
* IFN-γ is potent activator secreted by T helpers

Front 29

What are the mediators of antimicrobial and cytotoxic activity of macrophages and neutrophils?

Back 29

1. O2 dependent:
a. reactive O2 intermediates: O2-, OH-, H2O2, ClO-
b. reactive N intermediates: NO, NO2, HNO2
c. others: NH2Cl
2. O2 independent:
a. defensins, TNF-α, lysozyme, hydrolytic enzymes
* pathogens able to proliferate within macrophages must be combated with DTH (delayed-type hypersensitivity)

Front 30

What are some factors secreted by activated macrophages?

Back 30

1. IL-1 (pro-inflammatory response)
2. IL-6, TNF-α (innate immunity and eliminate pathogens)
3. complement proteins (pro-inflammatory response and eliminate pathogens)
4. hydrolytic enzymes (pro-inflammatory response)
5. INF-α (activate cellular genes that confer an anti-viral state on the cell)
6. TNF-α (kill tumor cells)
7. GM-CSF, G-CSF, M-CSF (pro-lymphoid stem cell hematopoesis)

Front 31

Classify the various dendritic cells according to location.

Back 31

1. Langerhans (epidermis)
2. Interstitial DC (heart, lungs, liver, kidney, GI)
3. IDC (T areas of secondary lymphoid tissues and thymic medulla)
4. circulating DC (blood and lymph="veiled cells")
* FDC: are NOT a part of this family since they have a different origin and function. They do NOT express MHC-II so are not APCs. They are EXCLUSIVELY within B rich lymph node follicles where they bind AG/AB-complexes (via a high number of receptors for AB and complement). The long-term binding of complexes facilitates B activation, especially into memory B cells.

Front 32

What is the difference between immunogenicity and antigenicity?

Back 32

immuno: the ability to induce humoral and/or cell-mediated response to an AG (also called "immunogen")
anti: the ability to combine with the end products of humoral and/or cell-mediated response to an AG
*immunogens are antigens
*NOT all antigens are immunogens (Ex. haptens = alone, cannot induce a specific immune response (lack immunogenicity); they require a 'carrier protein' to be able to do so.

Front 33

Rank common immunogens according to potency. Describe cell-mediated immunogens.

Back 33

1. proteins
2. polysaccharides
3. lipids and nucleic acids are usually not immunogenic unless complexed to proteins/polysaccharides
For cell-mediated responses:
1. proteins must be processed then bound to MHC before recognized
2. lipids and glycolipids must be combined with MHC-like CR1

Front 34

What features determine the immunogenicity of an immunogen?

Back 34

1. foreignness (less conserved through evolution)
2. molecular size (worst<5-10kDa, best=100kDa)
3. chemical composition/complexity (homopolymers=bad, copolymers, aromatic a.a.=good)
4. susceptibility to processing/presentation (D-a.a., small/soluble=bad, L-a.a., large/insoluble=good)

Front 35

Explain the significance of adjuvants.

Back 35

adjuvant: immunogenic enhancing substance when mixed with AG.
1. used to boost immune system when AG fails to cause response
a. prolong AG persistence
b. enhance co-stimulatory signals
c. induce granuloma formation
d. non-specific stimulation of lymphocyte proliferation
Ex. aluminum-potassium-sulfate (alum), bacterial lipopolysaccharide (LPS), Freund's complete/incomplete adjuvants
* most of these increase the liklihood of AG-induced clonal selection.

Front 36

What are some differences between an inactive and active macrophage? What is a granuloma?

Back 36

active:
1. higher MHC-II expression
2. higher B7 expression
3. higher cytokine (IL-1) secretion
granuloma: (at the site of chronic, local inflammatory response) accumulation of phagocytes, macrophages, and lymphocytes in one mass.

Front 37

What are some features of epitope recognition by lymphocytes?

Back 37

B:epitope A, involves binary complex of Ig+AG, binds soluble AG, AG may be protein, polysaccharide, or lipid, epitope is accessible, hydrophilic, mobile peptide containing sequential/non- a.a.
T:epitope B, involves ternary complex of TcR+AG+MHC, AG may be protein or a few lipid/glycolipids+MHC-like CR1, epitops are internal, linear peptides produced by processing the AG
* They see different areas of the same AG.
** The CDR1, CDR2, CDR3: complementarity-determining regions, also called "hypervariable regions", are what make each isotype unique; these are present on both heavy and light chain parts of the variable region.

Front 38

What is an agretope? How is the MHC regulating immunodominance?

Back 38

The region of the processed AG that binds MHC.
The MHC largely determines which T epitopes in an AG will be immunodominant in each individual.

Front 39

How can haptens be used to demonstrate cross-reactivity?

Back 39

Immunizations with hapten-carrier conjugates result in: anti-hapten AB, anti-carrier AB, and anti-conjugate AB.
* When the anti-hapten AB can bind modified (slightly) hapten, it's called cross-reactivity. This illustrates which reactions can tolerate varying levels of specificity. Haptens can be drugs, peptide hormones, or steroid hormones.
** The anti-hapten AB are useful for measuring quantity in-vitro (HCG pregnancy tests).

Front 40

In which fraction can you find recirculating, polyclonal Ig in the blood?

Back 40

Early experiments determined that they are found in the γ-globulin fraction, from which the name was derived, "immunoglobulin." IgG is mostly found in this fraction, however, IgG,M,A,and E are found in all three fractions (α,β, and γ).

Front 41

Describe the common structure of all Ig-AB.

Back 41

(2) light chains: κ (60%) λ (40%); Cl, Vl
(2) heavy chains: α (IgA) γ (IgG) δ (IgD) ε (IgE) μ (IgM); Ch1, Ch2, Ch3, (Ch4: IgE,M), Vh, hinge
Fab: "arms of Y" light and heavy chains
Fc: "base of Y" heavy chain
* C-terminus inferiorly, N-terminus superiorly
* 1 disulfide bride binds light to heavy
** Ig isotypes are multiples of this formula. The interchain disulfide bridges vary, as do the number of Ig molecules.
*** Ig idiotypes are unique combinations of idiotopes (CDRx) characterizing a unique AB or TcR

Front 42

What are the general structural differences between secreted and membrane bound Ig molecules?

Back 42

The C-terminus.
secreted: hydrophilic
membrane: hydrophilic 'spacer' (variable), hydrophobic transmembrane sequence (constant), short cytoplasmic tail (variable)
* versions vary during developmet of B

Front 43

What are the major effector functions of free Ig?

Back 43

1. opsonization (IgG)
2. complement activation (IgM,G)
3. ADCC (AB-dependent cell-mediated cytotoxicity)
4. agglutination (IgM)
5. neutralization (IgG)
6. immobilizing bacteria
7. mucosal protection (IgA)
8. precipitation of soluble AG by immune complex formation
9. activation of mast, eos., and baso. (IgE)
10. conferring immunity across placenta (IgG)

Front 44

Which Ig components are allotypic?

Back 44

allotype: multiple alleles for genes encoding Ig isotypes
1. IgG1-4 (25)
2. IgA (2)
3. κ light chain (3)
* AB against each allotype produced during pregnancy and transplant.

Front 45

Describe the structure of a BcR.

Back 45

BcR: transmembrane protein complex made of mIg + (2) Ig-α/Ig-β (disulfide linked)
* Ig-α/Ig-β contain intracellular signaling domains (otherwise, the BcR is too short to conduct these)

Front 46

Name members of the immunoglobulin superfamily.

Back 46

superfamily: proteins with corresponding genes derived from common primordial gene
1. Ig-α/Ig-β (BcR)
2. Poly-Ig receptor (sIgA,sIgM)
3. TcR
4. T accessory proteins (CD2,3,4,8,28)
5. MHC-I,II
6. β2-microglobulin (MHC-I)
7. cell adhesion molecules (VCAM-1, ICAM-1,2, LFA-3)
8. PDGF (platelet-derived GF)
* 110 a.a., antiparallel β-sheets, invariant chain s-s spanning 50-70 residues
* most cannot bind AG

Front 47

What are abzymes? What's their role? Future research?

Back 47

abzyme: function as both AB and enzyme
* AB/AG interaction versus enzyme/substrate interaction?
The AB does NOT alter the AG. The enzyme catalyzes a chemical change in the substrate. However, AB CAN stabilize the transition state of an AG (reducing the Ea of modification).
** Dissolving blood clots, cleave viral glycoproteins

Front 48

Explain the organization of MHC genes.

Back 48

HLA: complex housing MHC-I,II,III genes
II:DP,DQ,DR regions
III:C4,C2,BF regions --> complement proteins, TNF-α,β
I:B,C,A regions
* non-classical I:E,F,G,H (specific cell types: cytotrophoblasts)
** higly polymorphic; each allele called a "haplotype" because they are co-dominant

Front 49

Compare the structures of MHC-I and MHC-II.

Back 49

MHC-I: α-1,2,3,β2-microglobulin
MHC-II: α-1,2,β-1,2

Front 50

Explain the variability of peptide binding in MHC molecules.

Back 50

MHC-I: 6 variations
MHC-II: 12 variations
They express little specificity in AG binding, so both self/non-self will bind. The complex is very stable.