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Fundamentals Prep > MIM > Flashcards

MIM Flashcards

0
Q

What is the normal number of lymphocytes in the blood?

A

1,000-4,000 no./uL or 20-40%

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1
Q

What is normal # of segmented neutrophils in the blood?

A

3,500-7,000 no./uL or 40-70%

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2
Q

How long is an epitope? How many hydrogen bonds bind an epitope to the paratope? For an MHC Class I, how long is the epitope, for MHC Class II?

A

15-22 aa
75-120 H bonds
MHC I = 9-12 aa
MHC II = 18-20 aa

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3
Q

How many AA long is each segment of the HC and LC regions of an antibody? What is the protein structure of an Ab?

A

For the variable region, the LC and HC is each 110 AA. For the constant region, HC domain and single LC segment is also 110 AA) - conserved AA
Two antiparallel beta pleated sheets held together by intra-chain S-S.

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4
Q

What cytokine promotes the switch to IgG1?

A

IFN-gamma secreted by T cells to act on B cells

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5
Q

Name the characteristics of the hinge region?

A

Located btw CH1 and CH2 domains of the heavy chain, varies in length btw different HC, contains cysteine (disulfide bonds), and prolines (flexibility)

Hinge makes monomer to proteolytic cleavage, mu and epsilon don’t have hinge region but extra domain.

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6
Q

Name the products of papain and pepsin cleavage of Ab?

A

Papain -cleavage at hinge region, produces Fab (2) binds to Ag and Fc (1) binds to Fc receptors on cell surfaces

Pepsin - cleavage below the S-S bonds of the hinge region and CH2 domain, produces F(ab’)2 (fragment is held together by disulfide bond s in the hinge region) and partial Fc fragment.

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7
Q

What additional receptors are located on the B cell surface to aid in signal transduction?

A

Ig monomer (carboxy terminal of HC) is in complex with CD79 which is made up of 2 polypeptides (Igalpha and Ig beta).

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8
Q

How many different kinds of lamba and kappa isotopes of antibodies are in humans?

A

There are 60% of Ab with kappa LC and 40% with lambda LC (has 4 subclasses)

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9
Q

How long is the length of the constant region of the HC of IgD, IgG, IgA, IgM and IgE?

A

330 AA - IgD, IgG, and IgA

440 AA - IgM and IgE

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10
Q

Name the characteristics of IgM

A
  • Monomer on B cell surface and Pentamer in solution (5 monomers linked together by interchain S-S and a polypeptide called J or joining chain)
  • Binds Ag with repeating subunits and causes agglutination
  • High Avidity
  • Binds complement the best b/c complement requires 2 adjacent constant regions
  • 1st Ab made
  • Serum level 1.5 mg/mL (5-10% of total serum)
  • t1/2 = 10 days
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11
Q

Name the characteristics of IgM

A
  • Monomer on B cell surface and Pentamer in solution (5 monomers linked together by interchain S-S and a polypeptide called J or joining chain)
  • Binds Ag with repeating subunits and causes agglutination
  • High Avidity
  • Binds complement the best b/c complement requires 2 adjacent constant regions
  • 1st Ab made
  • Serum level 1.5 mg/mL (5-10% of total serum)
  • t1/2 = 10 days
  • First antibody line of defense for rapidly controlling blood infections
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12
Q

What antibodies do the Fc receptor of natural killer cells respond to?

A

IgG1 and IgG3 - example of antibody dependent cellular cytotoxicity (ADCC)

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13
Q

Name the characteristics of IgG

A

-Not as good at activating complemented as IgM
-Antibody monomer prototype - major class of Ig in serum
-Has 4 subclasses (IgG1, 2, 3, 4), differ in hinge region by size, sequence, position and # of S-S bonds - like IgG3 has longer hinge so more likely to undergo proteolytic cleavage
IgG1 IgG2 IgG3 IgG4
Normal Serum (mg/mL) 9 3 1 0.5
Serum t1/2 21 20 7 21
Activates complement Best
Crosses Placenta Best
Binds protein antigens Best Best
Binds carb antigens Best

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14
Q

Name the characteristics of IgG

A

-Best at diffusion into extravascular sites
-Not as good at activating complemented as IgM
-Antibody monomer prototype - major class of Ig in serum
-Has 4 subclasses (IgG1, 2, 3, 4), differ in hinge region by size, sequence, position and # of S-S bonds - like IgG3 has longer hinge so more likely to undergo proteolytic cleavage
IgG1 IgG2 IgG3 IgG4
Normal Serum (mg/mL) 9 3 1 0.5
Serum t1/2 21 20 7 21
Activates complement Best
Crosses Placenta Best
Binds protein antigens Best Best
Binds carb antigens Best

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15
Q

What are the two types of responses to leprosy?

A

A Th1 response is more effective at controlling infection. It is characterized by granuloma, local inflammation, and peripheral nerve damage. There is normal Ig and T cell response. The cytokines involved are IL-2, IFN-gamma, and LT-alpha. In a Th2 response, the organism is not contained and grows within macrophages. There is hypergammaglobulinemia, and low or absent T cell response. The cytokines are IL-4, IL-5, and IL-10.

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16
Q

These cells all produce the same cytokine - transforming growth factor-beta

A

Monocytes, T cells, Chondrocytes (nonimmune cell)

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17
Q

A macrophage can secrete several cytokines which are…these cytokines are proinflammatory cytokines which can act locally or systemically

A
  • TNF: acts on vascular endothelium, increases permeability, adhesion, cells enter site, blood clotting, confines infection, stimulates dendritic cells to move to 2ndary lymphoid tissue and activate adaptive IS -CXCL8 (IL-8): chemotaxis, PMNS, basophils, T cells move out of blood to site
  • IL-1, IL-6: induce activation of lymphocytes
  • IL-12: activates NK cells induces differentiation Th1 cells
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18
Q

What is an example of an autocrine effect of cytokines?

A

Activation of T cell by antigen peptide/MHC complex leads to IL-2 production, which binds to its own receptor on that T cell –> induces proliferation and amplification

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19
Q

What is an example of a paracrine effect of cytokines?

A

Membrane Bound Cytokines: CD40 Ligand and Fas Ligand, Infected macrophage need two signals to become activated to kill intracellular pathogens: IFN-gamma and CD40 ligand (T cell)/CD40 interaction. T cells provide these signals.

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20
Q

What is X linked hyper IgM syndrome?

A

A deficiency in CD40 ligand - required to activate B cells and critical for isotype switch. Patients present with high IgM and almost no IgG, IgE or IgA. Person cannot respond to thymus dependent antigens and there are no germinal centers in secondary lymphoid tissue. Person has poor response to extracellular bacteria

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21
Q

What is Autoimmune Lymphoproliferative Syndrome (ALPS) ?

A

Defect in the Fas ligand, interaction with Fas receptor is important in removing lymphocytes after an immune response and during dvmpt (eliminate autoreactive lymphocytes). Person has extensive autoimmune response, swollen secondary lymphoid organs filled with lymphocytes that should have undergone apoptosis. Fas ligand is expressed by cytotoxic T cells and Th1 cells.

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22
Q

What is the role of IL-2

A

Pleiotropic - many effects

Indues T cell growth, augment immunoglobulin synthesis by B cells, increase killing by natural killer cells.

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23
Q

How do cytokines produce effects?

A
  • Different Cells Can Produce the Same Cytokine (monocytes, T cells and chondrocytes - TGF-beta)
  • Single Cell Can Secrete Several Cytokines (macrophage and TNF, CXCL8, IL-1, IL-6, and IL-12)
  • Pleiotropy of IL-2
  • Redundancy, different cytokines can induce similar signals (T cell growth factors: IL-2, IL-4, IL-7, and IL-15)
  • Synergistic: CD40 ligand/CD40 and IFN-gamma to activate macrophages
  • Antagonistic: IL-2 promotes T cell growth and TGF-beta inhibits T cell growth
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24
Q

What cytokines are required for B and T cell growth? What cell provides this?

A

Stromal cells (nonlymphoid cells in the bone marrow) secrete SCF, a membrane bound cytokine and IL-7

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25
Q

What cytokines are required for immune cell differentiation of monocyte and granulocytes in the bone marrow? What cell makes them?

A

Effector T cells make IL-3 and GM-CSF which act in an endocrine fashion to stimulate production of monocytes and granulocytes.

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26
Q

What is cytokine CCL21? CCL19? CXCL13?

A

CCL21: Chemokine made by vascular endothelial cells, attracts dendritic cells to 2ndary lymphoid organs. CCL21 also binds CCR7 receptors on naive T cells, activating an adhesion molecule on their surface. This stop T cells at the node so that reactive T cells can be activated.

CCL19: made by stromal and dendritic cells in the node, entice the naive T cells into the cortex of lymph node

CXCL13: made by follicular dendritic cells, bring B cells into the follicles to become plasma cells

In sum: produced by dendritic cells, stromal cells and HEV, as well as others. Functions to bring home in lymph node B, T, and dendritic cells

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27
Q

What is Cytokine CCL2?

A

Secreted at the site of infection by T cells, it recruits macrophages

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28
Q

What is cytokine CXCL8?

A

Produced by macrophages and induces chemotaxis of PMNs to site of infection

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29
Q

What cytokines produced by macrophages cause systemic endocrine effects?

A

IL-1, IL-6, and TNF-alpha

Liver - acute phase proteins to activate complement
Bone Marrow Endothelium - neutrophil mobilization
Hypothalmus - increased body temp (endogenous pyrogens)
Fat, Muscle - protein and energy metabolism to allow increased body temp.

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30
Q

What cytokine can cause septic shock?

A

Triggered by systemic infection, TNF released by macrophages in the spleen, liver and other sites can cause shock.

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31
Q

What types of procedures can result in cytokine storm?

A

Hematopoietic Stem Cell Transplantation - b/c regimen involves eliminating a patient’s malignant hsc system and making room for grafted cell. This damages tissues containing proliferative cells targeted by the therapy and can create the storm leading graft vs host disease when the adaptive immune system is activated.

Exposure to super antigens like toxic shock syndrome and staph enterotoxin can activate large #s of T lymphocytes independent of antigen presentation.

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32
Q

IL-1 is produced by what cell and has what function?

A

Macrophage

Inflammation, activate lymphocytes; fever

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33
Q

IL-2 is produced by what cell and has what function?

A

T cells

T cell proliferation, Ig synthesis by B cells, increase NK activity

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34
Q

IL-3 is produced by what cell and has what function?

A

Th1

Growth and differentiation of hematopoietic cells

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35
Q

IL-4 is produced by what cells and has what function?

A 
Th2, mast cells, basophils
Differentiation of Th2 cells; activation of B cell; influences class switch; T cell growth factor
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36
Q

IL-5 is produced by what cell and has what function?

A 
Th2
B cell differentiation, influences class switch
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37
Q

IL-6 is produced by what cells and has what function?

A

Activate T & B lymphocyte differentiation; fever; acute phase proteins from liver

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38
Q

IL-7 is produced by what cell and has what function?

A

Stromal cells

B & T cell development in marrow; T cell growth factor; survival signal for memory T

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39
Q

IL-10 is produced by what cells and has what function?

A

Regulatory T cells, Th2, macrophages

Suppression; interfere with Th1 differentiation

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40
Q

IL-12 is produced by what cells and has what function?

A

Macrophages, dendritic cells

Activate NK cells; differentiation of Th1 cells

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41
Q

IL-15 is produced by what cells and has what function?

A

Many non-T cells

T cell growth factor; survival signal for memory T cells

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42
Q

IL-17 is produced by what cell and has what function?

A

Th17

Binds to many cell types to induce inflammation

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43
Q

IL-23 is produced by what cells and has what function?

A

Innate immune cells

Differentiation of Th17 cells

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44
Q

What is type I interferon?

A

There is alpha and beta type I IFN. Synthesized by most cells infected by a virus. In the lymph node, release of these cytokines cause virally infected cells to become more susceptible to killing by NK cells and increases the resistance of unaffected cells to infection by interfering with viral replication (paracrine effect) and makes them more vulnerable to CD8 killer T cells (autocrine effect)

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45
Q

What is IFN-gamma?

A

It is made by NK, Th1, and cytotoxic T cells. Required to activate infected macrophages to kill intracellular pathogens, causes infected cells to become more vulnerable to killer cells and increases resistance to viral replication in uninfected cells.

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47
Q

What is the timeline progression of cytokines?

A

Innate: IFN alpha and beta, TNF-alpha, and IL-12
NK cell mediate killing of infected cells via IFN-gamma
Adaptive: T cell mediated killing of infected cells via IL-2

IL-12: from macrophages stimulate NK cell to produce IFN-gamma which makes NK cell to become more cytotoxic.

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47
Q

What cytokines steer T cell differentiation?

A

Th1: IFN-gamma, IL-12 made by NK, CTL, innate immune cells
Th2: IL-4, made by mast cell and basophils –> humoral (B cells make Ab)
Th17: IL-1 and IL-23 made by innate immune cells. These secrete proinflammatory cytokines

Cytokines can suppress one direction or another. For example, IL-10 inhibits antigen processing by dendritic cell and macrophages so they don’t make IL-12. NK cells are not activated and cant make IFN-gamma so Th1 is prevented.

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48
Q

What cytokines steer T cell differentiation?

A

Th1: IFN-gamma, IL-12 made by NK, CTL, innate immune cells
Th2: IL-4, made by mast cell and basophils –> humoral (B cells make Ab).
Th17: IL-1 and IL-23 made by innate immune cells. These secrete proinflammatory cytokines

Cytokines can suppress one direction or another. For example, IL-10 inhibits antigen processing by dendritic cell and macrophages so they don’t make IL-12. NK cells are not activated and cant make IFN-gamma so Th1 is prevented.

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49
Q

What mechanism is used for the development of IgD on the cell surface?

A

Alternative RNA splicing

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50
Q

Label the stages of B cell development

A
  • Multipotent progenitor cell: germline
  • Common lymphoid progenitor: germline
  • Early pro-B cell: both alleles, HC rearrangement (DJ)
  • Late pro-B cell: VDJ rearrangement HC
  • Large pre B cell: HC rearranged, invariant LC
  • Small preB cell: LC rearrangement
  • Immature B cell: IgM expression with both HC and LC arranged
  • Mature B cell: IgD and IgM expressed (occurs in bone marrow or in periphery)
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51
Q

What is the invariant LC or alpha chain?

A

A surrogate chain bound to HC or beta chain to ensure appropriate BCR and TCR respectively. Occurs during large pre-cell development or double negative development of T cell. These receptors are mainly intracellular but some are on cell surface.

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52
Q

Why are both rearrangement occur to both alleles during early pro B cell development

A

It gives the cell twice the opportunity to get a productive rearrangement of HC since so many B cells are lost in development. There are more cell lost between the pro-B to pre-B transition than the pre-B to immature B cell. The LC rearrangement has greater variability.

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53
Q

What is allelic exclusion?

A

No more rearrangement of other allele allowed to prevent variations in receptor that functions appropriately. RAG proteins are involved in gene arrangement

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54
Q

What are the four outcomes of B cells?

A

Mature B Cell
Apoptosis
Anergic B cell
Clonally Ignorant

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55
Q

What is B cell activating factor?

A

A chemical in the lymphoid tissue that positively signals B cell growth and survival in 2ndary lymphoid tissue.

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56
Q

What is central tolerance? Peripheral Tolerance

A

Negative and positive selection of T and B cells in bone marrow and thymus.

Self peptide is again tested in 2ndary lymphoid tissue - B cells

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57
Q

What are the differences btw B-1 Cells, Conventional B-2, and marginal zone B cells?

A
  • B-1 Cells: produce in fetus (mouse fetal liver) are primitive, called CD5 B cells, are good cells to react with Ag first since it has low specificity. Produces IgM, reacts with Carbs Ag, polyspecific Ab (paratope binds with many motifs) has little junctional diversity, they are the B cells that protect the pleural and peritoneal cavities, self-renewing with little or non memory dvmpt
  • Marginal Zone B Cells: found in spleen, produces IgM and mainly deals with encapsulated bacteria responding both to carb and protein antigen. No memory associated here and long lived cells
  • Conventional B Cells: produce after birth, extensive diversity, located in secondary lymphoid tissue, replaced from bone marrow, produce IgG more, respond mainly to protein Ag, has memory
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58
Q

Describe complementarity determining regions in Tcell

A

CDR1/2 - see MHC

CDR3 - sees peptide, has a lot of junctional diversity

59
Q

What is Positive Selection/Negative Selection in T Cell

A

Positive Selection is bias towards MCH

Negative Selection towards peptide

60
Q

What is NOTCH-1

A

Thymic t.f that commits incoming T cell from bone marrow to T cell lineage

61
Q

Describe T cell Stages

A

Double Negative (CD3,4,8)
DN3 Stage: gamma,delta CD3+8-9- or alpha beta CD3+4+8+ (large active double positive)
Small Resting Double Positive: alpha beta CD3+,4+, 8+
Small Resting Single Positive

20% become iNKT cell, 20% gamma delta, and 60% CD4+ or CD8+

Gamma delta cells see mucosal surface and skin

62
Q

Thymus Anatomy + Cell Types for T cell proliferation

A

Cortex: immature thymocytes, macrophages and does positive selection via cortical epithelial cells

Medulla: mature thymocytes, medullary epithelial cells, macrophages and DC cells of bone of marrow origin and does negative selection via bone marrow derived DC and macrophages

Hassall’s Corpuscles: sites of cell destruction

Cells enter at corticomedullary junctions. DN3 cells reside near subscapular region.

63
Q

What is Erk Signaling in T cell development?

A

If a complete gamma delta TCR is formed before a successful beta chain gene rearrangement, the thymocyte receives signals through gamma delta receptor shutting off rearrangement of beta gene. Signaling through this receptor induces strong activation of Erk committing cell to gamma delta lineage.

Weaker Erk activation via the pre-T cell receptor in comparison with the gamma delta receptor leads to alpha beta lineage commitment.

64
Q

What is AIRE expression

A

Autoimmune regulator - gene allows epithelial cells and macrophages to express tissue specific Ag. The thymus gets greater opportunity to purge from its repertoire self reactive T cells. Not complete though since there is a group of sequestered antigens - important for autoimmunity

65
Q

What is FOX p3 positive?

A

A transcription factor forkhead found in a population of T cells that have a strong binding at the negative selection phase to the self MHC/peptide complex. They are CD4 cells that become regulatory T cells.

66
Q

How come cells that escape positive selection do not get removed by negative selection?

A

There are differences in affinity of weak interactions that allow cells that are selected in positive selection to survive negative selection.

67
Q

How to break self tolerance?

A

A self reactive B or T cells could get activated if a raging infection is causing proinflammatory cytokines to form. These cytokines can act as signal 2 even if they are not being produced by APCs. You need 3 signals to activate T cell. But in autoimmune conditions, this can break.

69
Q

Describe structure of Class I MHC and Class II MHC

A

Both are transmembrane proteins with 2 polypeptide chains.
Class I - HLA-A, B, and C
The alpha3 domain and beta2 microglobulin pair to form platform and the two alpha (alpha1 and 2) form the antigen binding groove.

Class II - HLA-DR, DQ, and DP
The alpha2 and beta2 form the platform and alpha1 and beta1 form the Ag binding groove.

Antigenic binding site consists of a beta sheet floor walled by two alpha helices and carry 8-25 AA long peptides. Class I peptides are short 9-11 aa and class II are longer and extends out of the groove.

69
Q

What is bare lymphocyte syndrome?

A

Loss of class I or II expression due to absence of transcriptional activator CIITA. This is a severe combined immunodeficiency syndrome.

70
Q

How does Class I and II assemble?

A

Class I - via ER and Golgi

Class II - invariant chain and endocytic pathway

72
Q

What chromosome is MHC located on?

A

Chromosome 6

The beta 2 microglobulin for Class I is on chromosome 15.

73
Q

Describe the genetics of MHC Molecules?

A
  • Polygeny and Polymorphism (many alleles compared to Kappa which only has 3 alleles) - alters diversity of binding site.
  • Inherited in Mendelian fashion, no rearrangement of genes
  • Codominant expression
  • 1/4 chance that a 2nd sib will share the same alleles
  • A person can express up to 6 different class I and class II molecules because of 2 alleles at each loci of 3 different molecules.
  • Inherited as a haplotype - b/c the HLA genes are all localized (haploidentical: children that share 1 haplotype) - true unless recombination occurs.
74
Q

What is a motif?

A

Peptides that bind a specific MHC molecule share structural features called a motif (formed by specific AA). These features allow the peptide to fit into the groove of that MHC molecule.

75
Q

What is property called “recognition of missing self”

A

NK cells can detect loss of MHC class molecules when virally infected or tumor cells lose HLA expression. There is immunoselective pressure to survive. They may be invisible to T cells but not NK cells.

76
Q

What is the mechanism of action of Abacavir?

A

It is a drug that can cause hypersensitivity reaction in patients that have the specific HLA allele - B57:01. The drug binds to the antigen binding groove of this HLA molecule and when the cell introduces self peptide, it is pushed out of the groove and causes a conformation of the cell that is recognized as foreign to the T cell.

77
Q

Name some clinical diseases (autoimmune) associated with HLA alleles

A
  • Ankylosing Spondylitis
  • Multiple Sclerosis
  • Rheumatoid Artheritis
  • Celiac Disease
  • HIV/AIDS - homozygous patients since they express fewer HLA molecules
  • Transplantation Alloantigens (graft rejection & graft vs. host disease) - TCRs can recognize more than MHC-peptide complex as long as they appear physically and chemical similar called TCR cross reactivity. An antigen specific TCR from a transplant recipient can recognize a foreign MHC holding a self peptide on the transplanted tissue causing allorecognition - memory T cells do this.
78
Q

Describe the TCR for Antigen

A

T cell bound, Heterodimer associated with CD3 (signaling) contains alpha and beta polypeptide chains bound by disulfide bonds, TCR has variable (N terminal) and constant regions, TCR affinity is low, TCR cytoplasmic tails is short so not designed for signaling. Needs adhesion molecules and signaling assistance. It resembles an Ig Fab fragment recognizing MHC peptide complex.
Signaling: CD3 and CD28
Adhesion: CD4, CD8, LFA1, CD11a

79
Q

What chromosome is T cell receptor genes found on?

A

Alpha - chromosome 14

Beta - chromosome 7

80
Q

How is the variable region of the alpha and beta gene of a TCR organized? What about the constant region? What are the stages of rearrangement

A 
Alpha = 1 V + 1 J 
Beta = 1 V + 1 D + 1 J

D + J interacts w/peptide and V interacts with MHC
Constant Region does not confer any effector functions.

  • Beta locus rearranges first in thymus
  • Beta stops rearranging, cell becomes CD4+ or CD8+
  • Alpha locus rearranges
  • TCR expressed on cell surface with CD3
  • Single positive selection
81
Q

How is diversity generated in TCR?

A

Combinatorial + Junctional Diversity but no Hypersomatic Mutation

82
Q

How is TCR and Ig Gene Rearrangments used in clinical diagnosis?

A
  • Marker for T/B cell clonality - single T/B cell expansion vs polyclonal
  • Stage tumors (ex. acute leukemia = less mature cells)
  • Presence of excision circles to indicate reconstitution of IS in patient receiving hematopoietic stem cell transplant
83
Q

What is Burkitts Lymphoma and Chronic Myelogenous Leukemia?

A

Burkitts Lymphoma - oncogene MYC translocation from 8 to 14, region Ig HC locus - unregulated B cell growth

CML - translocation of BCR on 22 to ABL region of 9 leads to tyrosine kinase product that activates cell cycle - uncontrolled WBC growth (esp. granulocytes)

84
Q

What is a superantigen?

A

Bacterial toxins interacts with TCRs, crosslinks MHC and TCR stimulating T cell nonspecifically. The MHC Class II is utilized. 2-20% of T cells activates vs 1/10,000 for Ag.

85
Q

What is a framework region and complementarity determining region?

A

Within the variable region of the HC and LC, there are HVR or CDRs (loops) and framework regions (beta pleated sheets) which are conserved. The HVRs from one HC and one LC combine together to form an antigen binding site.

86
Q

What is the chromosome for B cells?

A

Kappa LC - Chromosome 2
Lambda LC - Chromosome 22 (4 subclasses) with different Constant regions coding for subclasses
HC - Chromsome 14

The size of B cell repertoire of antigen binding site is limited only by the # of B cells found in the body at any one time.

87
Q

SCID and Omenn’s Syndrome occur because of…

A

Mutations in RAG genes

88
Q

Gene rearrangement that occurs in B cell and T cell development is somatic, true or false?

A

True, somatic recombination is not passed onto offspring.

89
Q

How is the B cell LC arranged?

How is the B cell HC arranged

A

Junctional and combinatorial diversity - the differences in flanking sequences of kappa, lambda HC restrict rearrangement to within the same gene

LC (kappa): V+J segment form the HVR (CDR3) which participates in the interaction with antigen. There are 40J each is preceded by a S and is followed by 5 alternative J exons. The S segment plays a role in transporting chains to the outside of the cell. The C region is the framework region of LC.
LC (lambda): same except that there are slightly 4 different constant regions specifying the 4 subclasses. Each constant region is preceded by a J segment.
HC: includes D segment, so we have V,D and J (D&J first then V along with its S is spliced next to D&J. The constant region is divided into several exons each specifying one of the constant region domains (so 9 total) and one for the hinge region. mRNA processing controls HC carboxy terminal through choice of exons (Se for short tail in secreted form and M for cytoplasmic and transmembrane region of membrane bound)

90
Q

What Ab are generated first?

A

Mu then delta, mu is next to V/D/J exons. RNA processing results in longer transcript for delta HC.

91
Q

What is somatic hypermutation?

A

Occurs in the germinal centers of peripheral lymphoid tissue. It targets the V region of both HC and LC genes. Occurs at 1 bp/1000 base compared to 1 to every 10^10 bp in avg cells. Occurs after antigen encounter - affinity maturation.

92
Q

Describe isotype switch?

A
  • Activation of B cell w/Ag generates signals that induce the process of somatic hypermutation and isotype switch. There is a downregulation of IgD. There are switch sequences preceding the constant region encoding each class and subclass of HC except delta. Another DNA rearrangement occurs that alters the class HC constant region. The rearranged HC VDJ segment is spliced next to one of the other C regions exons downstream of delta.
  • IgM becomes IgG, E or A and is mediated by switch sequences through influence of cytokines that specify what class to use. There is no switch sequence btw mu and delta constant regions b/c the distance btw exons is too short - RNA splicing allows for expression of IgD.
  • There is no alteration of the LC
93
Q

What is hyper IgM immunodeficiency syndrome?

A

Immunodeficiency associated with failure of T help with switch. The CD40-CD40 ligand defect is occurring which is involved in help for the B cell.

94
Q

What cytokine influences isotype switch to IgG1?

A

IFN-gamma

95
Q

What is allelic exclusion?

A

Prevents a B cell from expressing a mixture of antibodies even with 2 loci expressing kappa, 2 for lambda and 2 HC loci. The rearrangement of other LC or HC loci will halt once a functional gene is generated.

96
Q

What is monoclonal Ab and their use in clinical setting?

A

Production of single B cell clone used in diagnosis, imaging, therapy, research. They are made via hybridoma technology. Ag in mice –> produces short lived Ab, fuse with immortalized mouse myeloma cells pretreated to eliminate production of own Ig. This will produce indefinite and long lived source of Abs specific to Ag used.
-Recombinant DNA tech can help make more humanized forms, this will eliminate response to foreign Ab, increase stability, increase effectiveness, and have 2 different Ag binding arms (Fv fragment - HC V region linked to a LC V region)

97
Q

What cytokine promote isotype switch to IgE, IgG2, IgG4 and IgA?

A

IL-4

98
Q

Naming MoAb

A

-Mab - monoclonal Ab
Target: tu(m) = tumor, li(m) = lymphocyte, me(l) = melanoma
Source: xi = chimeric, zu = humanized, o = mouse, a = rat
Ex. Rituximab and Basiliximab

99
Q

Compare IgG1 to IgM

A

IgG1 vs IgM

  • Mol Form: monomer vs pentamer
  • Serum level: 9 (75-85) vs 1.5 (5-10%)
  • T1/2: 21 vs 10 days
  • IgM better complement
  • Placental transfer and Fc phagocytic binding vs 1st Ab made by B cell
100
Q

Name the characteristics of IgA

A
  • Block major portal of entry for more pathogens, protects newborn
  • Found in secretions (saliva, tears, breast milk and mucus)
  • Found as monomer in serum and cell surface (nodes and spleen) but dimer in secretions (2ndary lymphoid tissues under mucosal surfaces). The dimer is held together by S-S bonds and J chain.
  • Has a high rate of synthesis
  • IgA secreted: binds to a receptor on epithelial cells called polyIg and is internalized. It is transported through epithelial cells and dumped into secretion, but portion of polyIg receptor stays attached as a secretory component.
  • IgA1 and IgA2: IgA1 hinge region is sensitive to proteases made by respiratory pathogens. IgA2 is not sensitive. A1 is prodominant in serum and A2 in mucosal secretions
  • No activation of complement - role is neutralization and not opsonization
  • Serum level: 3 (7%) (IgA1) 0.5 17% (IgA2)
  • t1/2 - 6 days
  • Fc phagocytic binding
101
Q

Name the characteristics of IgE

A
  • No hinge region with 4 constant region domains
  • Shortest serum half life
  • Low synthesis rate
  • Allergy and parasitic infections
  • Has high affinity to Fc receptors on mast cells, basophils and eosinophils
  • Monomer
  • Serum Level 5x10^-5 (0.019%)
  • t1/2 = 2 days (IgE half life on mast cell > serum)
  • Causes hypersensitivity reactions (hay fever, hives, anaphylactic shock) when IgE bound to FcR on basophils and mast cells. Killing of parasites via eosinophils
102
Q

What is isotypic determinant?
Allotypic determinant?
Idiotypic determinant?

A

Isotypic - response to species specific determinants on the constant regions of HC and LC. Ex. horse anti-snake venom antibodies to treat snake bites in humans
Allotypic - response to allelic differences of either the variable or constant regions of HC and LC within a species. Ex. transfusion and multiple pregnancies
Idiotypic - response to the variable region, specifically the antigen binding site of an Ab. It’s significance is seen in controlling the immune response by removing Ab once they are no longer required.

103
Q

What are the cytokines synthesized by Th1 activation?

A
  • IFN-gamma and CD40 ligand is the primary response to activate macrophages and kill intracellular pathogen, make cytokines that promote opsonizing Ab.
  • Fas ligand and TNF-beta
  • IL-2
  • IL-3 and GM-CSF trigger production of granulocytes and macrophages in bone marrow
  • CCL2 to recruit macrophage accumulation
  • TNF alpha and beta activates endothelium to induce macrophage binding and exit from blood vessel at site of infection
104
Q

What are the cytokines secreted by Th2 activation?

A

-IL-4 activates B cell
-IL-5 and 6 cause B cell differentiation
-CD40L/CD40 interaction is 2nd signal for B cell activation.
-IL-10, TGF-beta are suppressive for Th1 responses and control activated macrophages reducing tissue damage
Cytokines secreted by Th2 cells are anti-inflammatory cytokines

105
Q

What are the suppression and survival cytokines?

A
  • IL-10 and TGF-beta are inhibitory cytokines secreted by regulatory T cells. Limit effector T cell proliferation and play a role in tolerance. They are anti-inflammatory
  • IL-7 and Il-15 prolong survival of memory T cells and are made by many non T cells
106
Q

Features of Cytokine Receptors

A
  • Sensitivity of cell to cytokine may change over time - IL-7 receptors are expressed early in dvmp while IL-2 receptor later in dvmpt.
  • Naive T cells have a low affinity IL-2 receptor (beta and gamma chains) but activation induces high affinity receptor where alpha is incorporated. (IL-2 receptor is CD25)
  • Cytokine receptors use the JAK/STAT pathway to signal inside cell
107
Q

What is X linked SCID?

A

Mutations in the gamma chain of IL-2 receptor affect receptors for other cytokines. The common gamma chain is encoded in the X chromosome so males are mostly affected. The result is a decrease in NK, T and nonfunctional B cells (due to lack of T cell help)

108
Q

What are some drugs for immune suppression?

A

-Cyclosporine, tacromilus all inhibit calcineurin which activates transcription of IL-2. IL-2 is very important for adaptive immune response
-Monoclonal antibodies to IL-2 (Basiliximab)
-Rapamycine inhibits signaling through IL-2 receptor
-G-CSF to mobilize hematopoietic stem cells for donation by aphresis
-

109
Q

What is a basophil function?

A

Role in allergy and adaptive immunity - contribute to Th2 IgE responses via IL-4 production and antigen presentation to CD4 T cells.

110
Q

What is innate lymphoid cells?

A

Innate lymphoid cells (ILCs) differentiate from haematopoietic stem cells, via an ID2+ precursor cell, under the influence of cytokines such as interleukin-7 (IL-7), IL-15, IL-23, IL-25 and IL-33. These signals induce the expression of transcription factors that promote the differentiation of the various ILC subsets (group 1, 2 and 3 ILCs) and induce their expression of signature cytokines. The cytokines secreted by ILCs promote important physiological responses, such as wound healing, tumour surveillance and protection against infections. However, ILC-derived cytokines can also promote immunopathology in diseases such as asthma and IBD.

111
Q

What are some characteristics of NK cells?

A

Large granular lymphoid like cells, function against intracellular infections, they lack antigen specific receptors. Important for viral infections.

112
Q

What is iNKT Cells?

A

The TCRs of iNKT cells are not very diverse and recognize lipids and glycolipids presented by CD1. iNKT cells have antibody receptors and can release cytotoxic granules. They also release large quantities of cytokines.

Invariant NK cell – bridges both innate and adaptive immunity,

113
Q

Describe anatomy of a lymph node.

A

Outermost Cortex - B cell organized into lymphoid follicles or germinal centers
Paracortex (Deep) - T cell and dendritic cells
Medulla - macrophages and plasma cells (medullary cords)

Lymph comes in carrying Ag via DC cells or macrophages to the node by way of afferent lymphatic vessel and leave by efferent lymphatic vessel. Naive lymphocytes enter the node from the bloodstream through specialized post capillary venules and leave with lymph through the efferent lymphatic.

114
Q

Describe anatomy of the spleen?

A 
Red pulp (site of RBC destruction) interspersed with lymphoid white pulp surrounding a central arteriole. PALS - surround central arteriole and contains T cells
Follicular Zone - B cells, germinal center is surrounded by B cell corona --> marginal zone --> peri-follicular zone.

Blood carrying both lymphocytes and Ag flow from trabecular artery –> central arteriole –> smaller BV to white pulp.

115
Q

Describe anatomy of Peyer’s Patch

A

Contains numerous B cell follicles with germinal centers. T cells occupy the areas btw the follicles (T cell dependent areas)

Sub-epithelium Dome - layer btw surface epithelium and follicles, contains dendritic cells, T and B cells.

Have no afferent lymphatics and the antigen enters directly from the gut across a specialized epithelium called microfold (M cells) - there is efferent lymphatics though and lymph leave through here. The M cells lack microvilli and mucus and appear as sunken area on the epithelial surface.

116
Q

What 3 cells are professional APCs? What cell is the only one that can activate a naive T cell?

A

Dendritics Cells - only one to activate naive T cell (acts first as macrophage but then matures to APC which has Ag and costimulatory signals)
Macrophages
B lymphocytes

117
Q

What is the 2/3 Signal Hypothesis?

A

To activate a T cell, 3 signals are required:

  1. Ag
  2. Costimulatory signals
  3. Cytokines
118
Q

Describe distribution of lymphocytes in blood?

A

CD4+ T cells are the most numerous > CD8+ > B cells and NK cells

119
Q

What is the difference btw antigen and immunogen?

A

An antigen can react with a B cell or T cell receptor but cannot initiate an immune response de novo. This distinguishes btw immunogen and antigen. An immunogen will initiate an immune response de novo. They contains PAMPs (DAMPS) but antigen will interact with TCR and BCR. T cell see antigen held by MHC molecules. All immunogens are antigens but not all antigens are immunogens.

120
Q

Describe TCR vs BCR?

A

BCR: C terminus of molecule has no cytoplasmic tail, it cannot transduce signal into interior of the B cell, it needs accessory molecules called co receptors. It has IgB and Igalpha which have cytoplasmic tails. ITAMS motifs – these coreceptors incorporate with the BCR that transduces signal to interior of the cell. Contains 2 paratopes.
TCR: It has no cytoplasmic tail – poor transducing signal. You have heterodimers called CD3 which are coreceptors for the T cell receptor signal complex. They require crosslinking like the B Cells – have the same ITAMS. Only 1 binding site (paratope)

121
Q

What 3 properties determine immunogencity?

A

Foreigness - greater the phylogenic distance btw 2 species, the greater the antigen disparity
Molecular Size - > 100 kDa
Chemical Composition & Heterogeneity - primary, 2ndary, tertiary and quaternary org contribute to immunogenicity.

122
Q

What properties characterize whether antigen/immunogen can be processed and presented by APCs?

A
  • Ability to be degraded/metabolized. Only B cells can recognize native antigens/immunogens. T cells see it processed
  • Structural organization
  • Solubility/accessibility - an antigen must be able to form a colloidal suspensions to be accessible to APC, particulate substances are more potent as a result for phagocytic cells.
  • D- Amino Acids are poor immunogens than L AA. Human immune system can’t recognize these conformation of bacterial cell walls.
123
Q

What is high vs low zone tolerance?

A

High Zone: Lymphocytes respond to antigen on cell surfaces complexed to MHC antigens. If the antigen presenting cells are overwhelmed with excess antigen, lymphocytes bind to free antigen which prevents them from getting the second signals they need to become activated. It is overcome as the excess antigen is removed by phagocytes and serum proteases. The antigen concentration is reduced to a stimulatory level
Low Zone: Doses of antigen just below that which will induce an immune response also produce tolerance (low zone tolerance). In this case the Th cells seem to be permanently inactivated, so recovery does not occur for several months; i.e., until the Th cells have been replaced by the thymus.

124
Q

What are adjvants?

A

Substances that enhance immunogenicity. Do not form stable linkages with immunogen, convert soluble antigens into particulate, are used in vaccines, can contains PAMPs (bacterial products)
Ex. Tetanus Toxoid

Ex 1: Complete Freunds, oil in water emulsion with dead mycobacteria, activates T cell via TLR, highly toxic
Ex 2: Alum(OH), enhanced up take by APCS, but delayed release of Ag, very low toxicity
Ex 3: Immune Stimulatory Complexes (ISCOMs), matrix of Quil A(amphipathic glycoside) containing viral proteins, delivers Ags to cytosol, induce cytotoxic T cells, low toxicity

125
Q

What types of receptors are present in DC cells?

A
  • DC SIGN (binds sugars of pathogens)
  • TLR
  • ICAM-1 and LFA-1: cell adhesion molecules after DC cell is no longer phagocytic
  • MHC Class II
  • Costimulatory Signals: B7.1 and B7.2 which deliver signal 2 to naive T cell.
  • Release of cytokines = signal 3
126
Q

Name the characteristics and types of epitopes

A

An epitope is 15-22 AA. About 75-120 hydrogen bonds bind an epitope to paratope. Number of antibody molecules that can bind to a molecule of Ag at one time defines the Antigen’s valence (spatial limits)

  • The cell can display epitope in multivalent or multideterminant fashion. Multivalent: displays multiple epitopes that are identical or different. Multideterminant: displays structurally different epitopes
  • Epitopes can immunodominant (most potent epitope) , subdominant or cryptic (an epitope, i.e. neoantigenic that is exposed by conformation change of Ag like HIV-1)
127
Q

Compare antigen recognition by T and B cells

A

B cells:
-Interaction with Ag involves binary complex of membrane Ig and Ag
-It binds soluble Ag
-No need for MHC
-Ag can be protein, polysaccarhide or lipid
-Epitope is accessible, hydrophilic, mobile containing sequential or nonsequential AA
T cells
-Interaction with Ag involves ternary complex of TCR, Ag and MHC
-No binding of soluble Ag
-MHC required
-Ag is mostly protein, but some lipids and glycolipids
-Epitope is internal linear peptide, hydrophobic and bound to MHC

128
Q

What is complementarity of epitope with paratope?

A

It means that there is no absolute specificity btw them. The # of peptides generated exceeds the # of T cells. The T cell can recognize these peptides. The tighter the fit the greater the complementarity and higher the affinity for signaling. Cross reactivity can occur as a result of this concept leading to autoimmune conditions.
-Ag and Ab are held together by noncovalent forces, you can separate the two via changing pH or ionic abilities.

129
Q

What are the three terms describing the strength btw a paratope and epitope?

A

Intrinsic affinity: The goodness of fit between an epitope and paratope
Functional affinity: The increase of affinity resulting from valency, i.e., 2 or more epitope – paratope intereactions
Avidity: the average functional affinity of a population of antibody molecules recognizing the same epitope

130
Q

What is a hapten?

A
  • Small organic molecule that do not provoke Ab when injected by themselves, Ab are raised against them if they are covalently attached to a protein carrier.
  • The carrier does not need to be an immunogen but the same carrier must be used in priming and challenge
  • Anti hapten Ab formed to penicillin allergies when components attache to proteins in blood.
  • By itself, byproduct of penicillin degradation does not induce an immune response. The compound once attached to RBCs or other proteins in blood then cause IS b/c it is seen as foreign.
  • Antibodes are formed to the protein carrier+hapten but not to the hapten
131
Q

TNF (TNF-alpha) is produced by what cells and has what function?

A

Macrophage, Th1
Inflammation; increase permeability and activate vascular endothelium; dendritic cells to secondary lymphoid tissue; fever; mobilize metabolites; mobilize neutrophils

132
Q

LT-alpha (TNF-beta) is produced by what cell and has what function?

A

Th1

Activate endothelium to attract macrophages to site

133
Q

CD40 ligand (CD40L) is produced by what cell and has what function?

A

T cell

Activate B cells to make antibody; activate macrophages to kill intracellular pathogens

134
Q

Fas ligand is produced by what cell and has what function?

A

T cell

Apoptosis following immune response and during T cell development

135
Q

IFN-alpha (Type I) is produced by what cells and has what function?

A

Any cell infected by virus

Increase resistance to viral infection; increase susceptibility to killing via ag presentation; activate NK cells

136
Q

IFN-beta (Type I) is produced by what cells and has what function?

A

Any cell infected by virus

Increase resistance to viral infection; increase susceptibility to killing via ag presentation; activate NK cells

137
Q

IFN-gamma (Type II) is produced by what cells and has what function?

A 
Th1, cytotoxic T, NK
Activate macrophage to kill intracellular pathogen; increase resistance to viral infection; increase susceptibility to killing via ag presentation; differentiation of Th1 cells; interfere with Th2 differentiation; class switch specificity
138
Q

G-CSF (Colony Stimulating Factor) is produced by what cells and has what function?

A

Fibroblasts, monocytes

Neutrophil development and differentiation in marrow

139
Q

M-CSF has what function?

A

Monocyte development and differentiation in marrow

140
Q

GM-CSF is produced by what cells and has what function?

A

T cells, macrophages

Granulocyte and monocyte differentiation in marrow

141
Q

SCF (stem cell factor) is produced by what cell and has what function?

A

Stromal cells

B and T cell development in marrow

142
Q

TGF-beta is produced by what cells and has what function?

A 
Regulatory T cell, Th2, monocytes, chondrocytes
Suppression; interfere with Th1 differentiation; class switch
143
Q

CXCL8 (IL-8) is produced by what cell and has what function?

A

Macrophage

Chemotaxis of neutrophils to site of infection

144
Q

CCL2 is produced by what cell and has what function?

A

Th1

Macrophages move to site of infection

145
Q

CCL19/CCL21/CXCL13 are produced by what cells and has what function?

A

Dendritic cells, Stromal cells, HEV

Homing in lymph node of B, T, dendritic cells

Fundamentals Prep (3 decks)

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