Immuno Flashcards
0
Q
Where do B cells mature?
A
Fetal liver and after birth in the bone marrow.
Bursa in birds.
1
Q
What cells express CD 4?
A
T helper cells:
2
Q
What are the peripheral organs of the immune system and what are the respective functions?
A
Lymph Nodes - entrap antigen drained from tissues
Spleen - entrap antigens from blood
3
Q
What is TCR?
A
T-cell Receptor
on all T-cells. involved in initial binding event.
4
Q
What is CD2?
A
pan T-cell marker.
found on many T-cells, not all. Involved in lymphocyte adherence and signaling.
5
Q
What is CD3?
A
pan T-cell marker. found on most, but not all T-cells. Involved in signal transduction and associated with TCR
6
Q
What is CD4?
A
Marker found on T-helper cells. Stabilizes binding and has signaling function.
7
Q
What is CD8?
A
Found on cytotoxic T-cells. Accessory molecule with signaling function.
8
Q
What is MHC class II?
A
found on some activated T cells.
Antigen presentation.
9
Q
3 cell mediated (no antibodies) reactions
A
- tissue rejection
- delayed hypersensitivity
- graft vs. host reaction
10
Q
3 humoral (antibody dependent) reactions
A
- agglutination
- toxic neutralization
- immediate hypersensitivity (IgE)
11
Q
2 components of a superantigen
A
- mitogen: promotes cell division
2. antigenic component: generates immune response
12
Q
What is clonal selection?
A
B cell recognizes antigen
With help of Th: proliferation, maturation -> plasma cell: produces antibody
13
Q
What immunoglobin is synthesized in a fetus?
A
IgM
all others in fetal circulation: trans placental from mother.
14
Q
Describe active vs. passive vs. adoptive immunity
A
active: immunity carried out w/in host - long lived
passive: immune components transferred to host (Ab or cells) - transient protection (some immunizations, sIgA in breast milk)
adoptive: recreation of immune system - bone marrow transplant - histocompatibility antigen matching required.
15
Q
Antibody vs. Immunoglobin
A
Antibody: specific to antigen
Immunoglobin: generic term.
16
Q
Steps in infectious process
A
penetration of epithelium
recognition by macrophage -> activation -> release chemotactic factors (attract PMN from blood) and cytokines (inflammation)
macrophage phagocytizes pathogen, kills it
inflammation: arrival of PMN, monocyte, lymphocyte, compliment proteins, and clotting factors.
17
Q
TLR-4
A
Toll-like Receptor 4: binds bacterial lipopolysaccharides -> triggers activation of NFkB (nuclear transcription factor) -> activation of genes transcribing antibacterial proteins.
18
Q
TLR-3
A
Toll-like Receptor 3: Binds double stranded RNA -> triggers synthesis of interferons (prevent viral replication)
19
Q
What is IL1?
A
Secreted by macrophages: pro-inflammatory, activates endothelium and lymphocytes, induces fever, induces production of IL6
20
Q
What is IL6?
A
secreted by macrophages: pro-inflammatory, induces fever, activates lymphocytes, induces liver to produce acute phase proteins (CRP, mannose-binding lectin, fibrinogen)
21
Q
What is TNF-alpha?
A
Tissue Necrotic Factor alpha - secreted by macrophages. Pro-inflammatory. Activates vascular endothelium, induces permeability, induces fever and shock.
*TNF antibody - treatment for RA
22
Q
What is IL8?
A
Secreted by macrophages. Chemokine - attracts PMNs.
23
Q
What is IL12?
A
Activates NK cells, induces TH0 cells to differentiate to TH1 cells.
24
What is C-reactive protein and what does it do?
Acute phase protein produced in the liver - induced by IL-6. Clinical indicator of inflammatory response, also elevated in Cardiovascular disease. Opsonin and activates compliment.
25
How do leukocytes interact with endothelium?
Selectin on endothelium bind carbohydrates on leukocyte - weak binding - slows leukocyte.
Integrin (leukocyte) binds ICAM (endothelium and dendritic cells) - strong binding.
26
Describe the innate immune response to viral infection
Viral dsRNA binds TLR3 -> interferon a and B ->
1. inhibition of viral mRNA translation
2. activation of NK cells - kill virus infected cells w/ low MHC I
3. increase expression of MHC I - elevated expression -> killed by cytotoxic T cells.
27
NK cell origin and function
From lymphocyte precursor cell / Tcell precursor.
Involved in innate immunity: kill virus infected or tumor cells that lack MHC I. Also have receptors for antibody constant region. Binding releases lytic granules - antibody dependent cellular cytotoxicity (ADCC)
28
How does the Compliment system fight infection?
1. attraction of phagocytes (C3a, C5a)
2. opsonization (C3b)
3. direct killing of pathogens - via Membrane Attack Complex (MAC) - initiated by C5b - completed by 6-9
29
Hereditary angioneurotic edema
patients lack C1 inhibitor -> excessive C2 and C4 activation -> swelling
Also lack of bradykinin inhibition -> vasodilation, low BP, shock
30
What are 3 functions of the Fc portion of IgG?
1. compliment fixation
2. cell binding
3. trans-placental passage
31
What cell type produces the secretory chain of sIgA?
Epithelial cells of secretory gland.
32
Describe IgG structure
monomer
4 gamma subclasses
2 heavy chains (4 domains each - 3 constant, 1 variable)
Carbohydrate attachment site at Ch2 domains
2 light chains (lambda or kappa, 2 domains each - 1 constant, 1 variable)
hinge region between 2 Fab arms and 1 Fc arm - allows movement of Fab arms
33
Describe IgA structure
Monomer or polymer (10s and 11s secretory)
polymer - incorporates J chain
sIgA incorporates S chain
34
Describe IgM structure
```
pentamer
involves one J chain
Ch4 domain in H chain
1st in evolution
agglutinator, serum primary response, evidence of recent infection
```
35
Describe IgD structure
Monomer
Usually found on surface of mature B cells
H chain slightly larger than IgG
Early immune response
36
Describe IgE structure
Monomer
Free or Mast cell surface
H chain has extra domain (epsilon)
Immediate hypersensitivity, worm immunity
37
What is an Ig Isotype?
```
class vs. subclass
IgG vs IgM and IgG gamma 1-4
```
38
What is an Ig allotype?
differences between individuals of same species
| IgG vs. IgG of two people - genetic differences, usually of C region
39
What is an Ig Idiotype?
Variations associated with V regions.
Level of antibody specificity for antigen.
CDR associated and Framework associated.
40
What is the minimum recognizable molecular weight for an antigen?
1,000
41
How do immunoglobins rank in terms of half-life?
G > A > M > D > E
42
What is the most abundant Ig produced by the human body?
IgA
Extensive mucosal body surfaces.
GI produces most antibody - more than spleen, marrow, lymph nodes.
43
List 3 functions of sIGA
barrier defense
antigen transport
intracellular viral neutralization
44
What is the limiting factor in polymerization of IgM and IgA?
J chain
45
Where does the S chain of sIgA come from?
poly-immunoglobin receptor on epithelial cells.
| interacts w/ IgA dimer, brings into cell, transport to apical side, and a piece (S chain) stays w/ dimer when secreted.
46
What gene fragments compose the Variable regions of heavy and light chain Igs? Where do re-arrangements take place?
Light: V, J fragments
Heavy: V, D, J fragments
Re-arrangement: DNA re-arrangement
47
What enzymes are required for recombination of Ig variable chains?
V(DJ) recombinase (all cells), RAG1, RAG2 (all cells)
| L gene needed for production of "leader" protein that directs proteins to secretory pathway.
48
What is allelic exclusion in light chain Ig expression?
Kappa and Lambda loci are found on separate chromosomes.
Kappa re-arranges first. If successful, Lambda rearrangement is inhibited.
More Kappa than Lambda in serum. 2:1
49
What are the sequence of gene rearrangement events in Ig production?
I. Heavy Chain
1. D+J -> (DJ) DNA splicing
2. V + (DJ) -> VDJ DNA splicing
3. RNA transcription, including C region (Mu - synth of Mu silences other parental chromosome - allelic exclusion)
4. Light chain Kappa rearrangement: V+J -> VJ DNA splicing (if unsuccessful, other Kappa rearranges. If still unsuccessful, Lambda rearranges)
50
What is meant by "junctional" and "insertional" diversity?
Refers to "sloppy" links between V + J and D + J - imprecise splicing
Junctional diversity amino acid changes at junctional points that can influence Ab specificity
Insertional diversity: addition of small numbers of nucleotides at this location
51
What is somatic hypermutation?
When a mature B cell is activated by antigen and produces a clone of cells, there is a very high rate of mutation in V region genes.
Those progeny with the highest Ag affinity are selected.
52
What is receptor editing?
An immature B cell that expresses Ab to self Ag undergoes additional rearrangement of light chain gene to change specificity.
53
What immunoglobins are expressed by a mature B cell?
IgM and IgD - same specificity
54
What is class switching?
A mature B cell expressing IgM and IgD experiences a 2nd antigen exposure. Tcell cytokines induce additional heavy chain rearrangement -> IgA, G, or E
Specificity does not change
55
What is a hapten?
A small organic molecule that becomes part of an antigenic determinant when coupled with a carrier molecule
EX: DNP
56
What are the valences of Abs IgG, IgA, IgM, and IgD?
IgG: 2
IgA: 2 or 4
IgM: 10
IgD: 2
57
What is Ab avidity?
Combining power: valence + affinity
58
In a quantitative precipitation reaction, why does the precipitate weight peak after the equivalence (Ag = Ab) point?
Extensive latticing of AbAg interactions with excess antigen. As Ag excess increases, latticing decreases, so precipitate weight falls beyond peak.
59
What is a pattern of partial identity?
Precipitation in gel: two different antigens, one antibody pool
antibodies react with two determinants in one pool, only one in the other -> a 'spur' in resulting line of precipitate pointing toward the pool with a lacking determinant.
60
What is radial immunodiffusion used for?
A tool to quantitate antigens.
Agar contains IgG antibody
pools of known IgG quantity placed around agar for comparison to pool of unknown.
61
What immuno-interaction is exploited in ABO blood-typing?
Agglutination
62
What is Rhogan?
Antibody to Rh+ antigen
Given to Rh- mothers to prevent development of immunity against fetus. Could result in immune mediated destruction of future pregnancies.
63
What is erythroblastosis fetalis?
Hemolytic disease of the newborn.
Results from Rh- mother carrying Rh+ child. Mother develops antibody if blood mixes at birth -> Immune reaction w/ subsequent pregnancies - IgG crosses placenta - destruction of fetal RBCs
64
Describe the RIA process and what it is used for.
How much of X is in a sample
Radiolabeled X (constant concentration) mixed with a series of known concentrations of unbound, unlabeled X
Add known amount of AbX (in deficiency)
Separate bound from unbound and analyze with a gamma counter. Repeat with unknown and compare to control plot.
65
Describe ELISA and what it is for
Enzyme Linked Imunosorbant Assay
Used to detect antibodies and antigens
plate coated with antigen, sample containing antibody added, Fc antibody with enzyme linked added, then a reactant is added that results in a colormetric reaction catalyzed by the enzyme
66
Explain immunoflourescence and what it is used for.
Used to detect antibody or antigen expressed by a cell.
Cells/ tissue attached to glass slide. Flourescein labeled Ab is added for direct test.
For indirect test antigen specific IgG is added, then labeled anti IgG is added - stronger signal / antigen. Requires more controls.
67
Pre-B Cell receptor
Consists of Mu heavy chain and surrogate light chain. Expressed on surface of immature B Cells in close association with Ig-alpha and Ig-beta (signal transduction molecules).
On successful expression, Iga and IgB signal the B cell to begin light chain rearrangement.
68
Describe B cell negative regulation
Immature B cells react to cell bound self antigen by apoptosis
and to soluble self-antigen by anergy (inactivation) or receptor editing.
Autoreactive B cells are eliminated by this process.
69
What Ig receptors do Mature B cells express on their surfaces?
Both IgM and IgD
70
What Ig surface receptors do plasma cells express?
No Ig expressed on cell surface by plasma cells.
71
What receptors do Memory B cells express?
IgA, G or E on surface and CD44 (adhesion molecule)
72
What CD molecules are expressed during what stages of Bcell development?
CD19 ProB until Plasma cell
CD10 early: proB and preB (VDJ stage) - marker of early dev.
CD20: after CD10, until Plasma - marker of later dev.
73
What genes express pseudo or surrogate light chain?
VpreB
lambda5
surrogate light chain facilitates transfer of IgM to the cell surface.
74
Defective BTK
Bruton's Tyrosine Kinase
if defective, B cell development is arrested at PreB stage
-> X linked agammaglobulinemia
75
What help from Tcells allow B cells to activate?
Interaction between Tcell CD-40L and Bcell CD40
Tcell cytokines
augment B cell activation and Ig class switching.
Lack of CD40L -> only IgM in serum - hyper IgM syndrome
76
What is the B cell co-receptor?
Consists of CD21,19, and 81- binds compliment C3d (product of C3b breakdown)- enhances activation signals from B cell receptor 1000x
77
What receptors are involved in negative feedback on B cell surfaces?
CD 22 and 32
22: neg reg of co-receptor molecules
32: antibody feedback and B cell inactivation
78
What molecules allow B cells to act as MPCs for Tcells?
MHCII and B7
| CD40
79
What are B1 cells?
Subset of B cells found in peritoneal and pleural cavities
Have CD5 on surface
Express IgM in response to a variety of antigens. Early immune response
Little - no memory capability
80
What needs to be matched in tissue matching and what cells are primarily responsible for tissue rejection?
MHC must be matched. Highly variable between individuals.
Tcells require self-MHC for peptide binding.
In tissue rejection Tcells react with foreign MHC and are responsible for the rejection.
81
What cells express MHC II?
All APCs - dendritic, macrophages, Bcells
Thymic epithelial cells - present self to developing T cells
Can be induced in fibroblasts and endothelial cells.
82
What genes/proteins that make up MHC II?
Simultaneous expression of 3 genes: DP, DQ, DR
| Each product has alpha and Beta chains - both highly polymorphic.
83
What cells express MHC I?
All nucleated cells, including APCs
84
Explain the genetic expression of MHC I
coded by 3 loci, each expressing an alpha chain only. Each alpha chain is paired with an invariant Beta chain - Beta2 microglobulin.
Each cell coordinately expresses HLA-A, B, and C
85
What chromosome contains MHC?
Chromosome 6
86
What is MHC haplotype?
Individual genetic MHC code - the combination of MHC genes (chromosome 6) that was inherited from each parent.
Siblings have 25% chance of being same haplotype.
87
What are the domains of MHC I and what are their roles?
alpha-1 and 2 interact with 8-9 AA peptides
| alpha-3 interacts with CD8
88
What are the domains of MHC II and what are their roles?
alpha1 and Beta1interact with 12-20 AA peptides
| Beta2 interacts with CD4
89
What is the role of CD74 in MHC II assembly?
Begins as a chaperone during protein assembly in the Golgi
Cleaved to CLIP on leaving Golgi
CLIP prevents binding of endogenous proteins in vessicles
HLA-DM (other CD74 product) facilitates replacement of CLIP with high-affinity peptide for presentation.
90
Main function of MHC II
Bind foreign peptide antigen, present to T cells and generate T helper cells
91
Major fuction of MHC I
Bind foreign peptides derived from intracellular parasites (virus, some bacteria) and present to T cells to generate cytotoxic Tcells and become targets for cytotoxic Tcells.
92
What are TAP I and TAP II?
They transport protein fragments (8-15 AA) from proteosome to ER (via microsomal protein transporter) where peptides bind MHC I and are transported to cell surface.
**endogenous and foreign proteins**
93
2 reasons why self peptides do not activate Tcells
1. most self reactive Tcells are eliminated in the Thymus
| 2. self peptide in the absence of costimulatory signals do not activate Tcells
94
Describe the makeup of the TCR
2 chain molecule, alpha and Beta chains
each chain has a constant and variable domain
Variable domains interact w/ foreign antigen bound to self-MHC protein
95
What is the TCR complex?
TCR with CD3 and 2 zeta chains.
CD3 and zeta chains are the active signaling molecules
CD3 composed of gamma+epsilon and delta+epsilon subunits.
CD3 and zeta are invariant.
96
CD28
Found on the surface of Tcells
| Costimulatory - interacts with B7 on Bcells and other APCs
97
CD152
Also CTLA4
found on surface of Tcells
Negative stimulation - interacts with B7 on surface of Bcells
Higher B7 affinity than CD28
98
What are some Tcell adhesion molecules?
CD2
Integrins: LFA-1 and VLA-4
adherence to APC and endothelium
99
CD62L
(L-selectin) homing molecule found on surface of Tcell
| binds addressins on endothelium
100
What are gamma-delta Tcells?
```
express gamma-delta TCR (rather than alpha-beta) - less common cell
cytotoxic
Lack CD4. may or may not have CD8
Found in skin, lung, intestine
limited protein recognition
```
101
Explain Tcell differentiation in the thymus
Stem cell from bone marrow -> thymus
Proliferation and maturation: dendritic and epithelial cells, IL-7
Rearrangement of TCR genes beta, gamma, delta
gamma-delta leave thymus
Beta - expressed attached to pre T-alpha
pre T-alpha prevents rearrangement of B and stimulates alpha rearrangement
alpha stops rearrangement of delta (same chromosome)
CD4 and CD8 expressed on surface -> double positive cell
102
Autoimmune Regulator Gene (AIRE)
induces expression of self antigen expressed in other organs in thymic epithelial cells.
Enables negative selection.
103
What other cells develop in the thymus?
NK cells: no TCR, no CD3 - kill virus infected cells
NKT cells: TCR w/ limited variability and NK marker - regulate other Tcells
Treg cells: CD4+ cells w/ CD25 and Foxp3 - inhibit immune responses.
104
Major APC for naive T cells
Dendritic
105
How long do APC and T cells remain together?
~8 hrs
106
What are the steps in CD4+ Tcell activation?
1. TCR binds MHC II / peptide - no activation
2. MHC II binding CD4 - increase activation 100x
3. Costimulators: B7 to CD 28, CD40 to CD40L
4. Adhesion molecules: CD2 to LFA3, LFA1 to ICAM1
107
Explain the interrelation between CD 40 and B7
CD40 on APC binds CD 40 L on Tcell -> upregulation of CD 40L
| CD 40L upregulates B7
108
What molecules can B7 interract with?
B7 on APC can bind:
CD 28: Signal for Tcell proliferation / activation
CD152 (CTLA-4): negative signal - Tcell inactivation
109
What is CTLA - 4?
Binds B7 and generates negative signal - Tcell inactivation.
| Commercially available to dampen immune response, treat RA
110
Summarize the intracellular processes that take place during CD4+ Tcell activation
1. Binding of TCR to MHC/peptide activates CD3 and zeta chains
2. Fyn and Lck (tyrosine kinases) are activated - phosphorylate ITAMS on CD3 and zeta, where ZAP 70 attaches
3. ZAP70 is activated by Lck
4. ZAP70 activates adapter molecules LAT and SLP 76, which go to the membrane
5. Adapters bind PLC-gamma, which is phosphorylated by ZAP70. Also activate MAP kinases
6. PLC: PIP2 -> DAG + IP3
7. Cascades -> production of transcription factors. Especially IL-2 and IR-2R-alpha
111
Organ transplantation drugs Cyclosporin and Tacrolimus block what?
calcineurin pathway in Tcell activation.
112
How does B7 increase Tcell activation?
Binds CD28 -> increases production of IL2 100X and increases t1/2 of IL2 mRNA
113
What do TH1 cells do?
Secrete IFN-gamma: activate macrophage, NK, upregulates MHC II, induce B cells to produce IgG3
Produce IL2: growth factor for CD4 and CD8 Tcells, and NK cells
114
What to TH2 cells do?
Produce IL4 and 13: induce Bcells to produce IgE and IgG4
| IL5: growth factor for eosinophils
115
What are TH17 cells?
produce IL17 and 22 - attract PMNs
induce epithelial cells to release pro-inflammatory cytokines (IL1, 6, TNFalpha)
combat fungal pathogen Candida albicans
autoimmune diseases (RA, MS) and psoriasis
116
What do Treg cells do?
Express CD 25 (IL2R-alpha) and transcription factor FoxP3
| Suppress 3 other CD4 Tcells and B cells by direct contact and secretion of TGF-B and IL10
117
What cytokine drives development of TH2 cells?
IL-4
produced in presence of parasitic worms and allergens. Suppresses differentiation of TH1 and TH17 cells
TH2 cells produce additional IL-4.
118
What is an example of a thymic independent antigen? How do they differ from thymic dependent?
```
bacterial Pneumococcal polysaccharide
Do not induce class switching (only IgM produced), do not generate memory B cells, are weakly immunogenic in young children.
Types I (mitogen for Bcells) and II
```
119
What costimulatory factors are required for CD8+ Tcell activaton?
B7/CD28
CD40/CD40L
IL12
IL2 from CD4 cells needed for full activation / response
120
What is cross priming?
Activation of CD 8 cells in absence of CD 4 cells by dendritic cells.
Dendritic cells express MHC I as well as B7, so can activate both.
121
What are the 2 mechanisms of CD8 Tcell toxicity?
1. release of granules: perforin, granzymes, serine proteases - inserts pore in target cell membrane
2. Fas L
Both induce apoptosis -> cell death w/o release of cell contents.
122
How are Tcell responses terminated?
Fas and FasL are both expressed on activated Tcells
w/ decrease in need, more Tcell-Tcell interatcion -> apoptosis.
Memory cell induction - decreased need for B7/CD28 and altered membrane proteins.
123
Intercellular pathway for Bcell activation w/o Tcell help
crosslinking of Ig molecules by antigen
Ig-alpha and Beta activate Src kinases (fyn, lyn, blk)
ITAM phosphorylation on Ig-alpha and Beta -> Syk recruitment -> adapter protein activation -> transcription factors (NF-kB, NF-AT, AP-1)
124
What is C3d?
Degradation product of compliment protein C3b
| Binds CD21 - costimulator of Bcell activation
125
What is the function of CD32?
receptor for serum Ab on Bcell surface. Downregulates Bcell activity in presence of excess Ab.
Works via phosphatases
126
Type I hypersensitivity
IgE mediated via mast cell activation (binds Fc)
allergic response, anaphylaxis, asthma
3 phases: sensitization, activation, effector
At least bivalent antigen
127
What substances are released by mast cells that are responsible for allergic reactions?
Histamine
Chemotactic factors: IL8 (PMN) ECF (eosinophils), IL3,4,5, GM-CSF - other inflammatory cells
Newly synthesized mediators : leukotrienes, prostaglandins, thromboxanes, platelet activating factor
128
Current treatment for allergy
```
Epinepherine - relax sm. muscle, prevents bv leakage
Antihistamine, leukotriene inhibitor
Bronchodilator
Corticosteroids
Hyposensitization
```
129
Atopy
Genetic predisposition for allergy
130
IgE production is dependent on what cell group and what cytokines?
TH2 cells
| IL13, IL4
131
Histamine's role in allergic reaction
Major agent involved in symptoms
H1 receptors on smooth muscle -> bronchial constriction
H1 on vascular endothelium -> vascular permeability
H2 receptors - mucus secretion, vascular permeability, stomach acid
132
antihistamine resistant asthma
newly synthesized mediators play large role
- leukotrienes - prolonged sm. muscle contraction
- thromboxane - vasoactive, bronchial constriction, chemotactic
- platelet activating factor (PAF) - release of histamine and thromboxanes
133
What is the mechanism of specific desensitization
IgG levels elevate with repeat administration of low doses of antigen
IgG binds antigen, preventing interaction w/ IgE on mast cells.
Induces TH2 -> TH1 switch (TH1 inhibits TH2)
134
Type II hypersensitivity reactions
IgG or IgM mediated - antibody to cell bound Ag
Compliment activation or antibody dependent cellular cytotoxicity (ADCC - IgG)
phagocytosis, Ab alteration of cellular signaling
ABO incompatibility, Rh incompatibility, drugs binding platelets
135
Type III hypersensitivity reaction
Immune complexes - Ab to soluble Ag
Usually IgG - fix complement - deposit in tissues (kidney, joints)
SLE
136
Type 4 hypersensitivity
Mediated by antigen specific Tcells
Delayed type: rxn to protein (venom, mycobacteria) -> local swelling, erythema, induraton, cellular infiltrate, dermatitis.
Contact: haptens (poison ivy, DNFB) -> local epidermal rxn. erythema, cellular infiltrate, intracellular abscess, vesicles
Gluten sensitive enteropathy (Celiac): Gliadin -> villous atrophy of sm. intestine, malabsorption
137
Products of activated TH1 cells
IL2 and IL2R- autocrine driven proliferation
IFN-gamma: activate macrophages, increase B7 and MHC II
CD40L: macrophage activation
Fas Ligand: induce apoptosis
IL3 and GM-CSF: macrophage differentiation in bone marrow
TNFa and B: diapedesis of macrophages to site of infection
CXCL2: macrophage chemotactic
138
Granuloma
intracellular organism can't be totally eliminated macrophages fuse -> giant cell
walled off by Tcells - may remain dormant for years, can damage organs, infectious organism may remerge much later
Reactivation TB
139
What substances do CD8 Tcells house in their granules?
Perforin - insert channel in mem. of infected cell
Granzymes - enter via holes / pores in cell membrane to induce apoptosis
Granulysin - antimicrobial and induce apoptosis
140
What is APECED?
Defect of AIRE gene
| Decreased expression of self antigen in thymus -> defective negative selection of self-reactive Tcells
141
What diseases are CTLA-4 defects associated with?
DM type I, Grave's disease
| Failure of Tcell anergy, reduction in Tcell activation threshold.
142
What is IPEX?
defect in FoxP3 -> decreased function of Treg cells
| Immune dysregulation, polyendocrinopathy, X-linked syndrome
143
Describe molecular mimicry
Bcell specific for self antigen does not react w/o Tcell help
Tcell may recognize foreign antigen that has epitope in common w/ self -> Bcell activation and anti-self Ab production
144
What are the two main categories of autoimmune disease and how is each mediated?
Organ specific: autoreactive Tcell mediated
| Systemic: autoantibody mediated.
145
Hashimodo's Thyroiditis
Hypothyroidism (most common cause), Hypothyroid Syndrome
Most prevalent organ-specific autoimmune disease, most treatable
HLA: DR3,5
Autoimmune destruction of thyroid follicles w/ B and Tcell infiltration
Ab against thyroglobulin and thyroid peroxidase
Low thyroid hormone, High TSH and TRH
146
What are the most susceptible HLA haplotypes for IDDM?
DR3+DR4
DR3 or DR4 individually susceptible unless DR2 is present (protective)
DR/DQ linkage disequilibrium: DQ-beta AA57: aspartate switched to valine, serine, alanine -> diabetes
147
How are insulin producint Beta cells destroyed in IDDM?
cell mediated
| CD4, activated macrophages, cytotoxic Tcells
148
Multiple Sclerosis
CNS demyelination -> white matter lesions
Cell mediated: TH1 cells most strongly iplicated, but CD8 and macrophages also
May be initiated by molecular mimicry in patients w/HLA-DR2
Treat w/ IFN-Beta 30% effective but -> hepatitis and thyroid dysfunction.
149
Myasthenia Gravis
AutoAb to AChR at NMJ -> internalization, degradation
Affects 3-5/100,000 (100x < Graves)
Treat w/ AChesterase inhibitor
Thymoma found in 15% - removal may help
150
Grave's Disease
Hyperthyroidism
AutoAb against TSH receptor -> chronic activation, elevated release of thyroid hormones
Low TSH
Graves ophthalmopathy
Treat with Ag removal by radioactive iodine or thyroidectomy w/ T4 replacement for life.
151
What is Rheumatoid Factor?
IgM antibody to Fc of IgG
152
What is the major mediator of RA?
CD4 TH1 cells
| TH17 also play a role
153
Treatments for RA
anti TNF-alpha (infliximab)
| 2nd line: anti CD20
154
What is direct recognition vs. indirect recognition in graft rejection?
Direct recognition: Host Tcells recognize donor APCs presenting antigen after migration to host lymph organs
Indirect recognition: Host cells recognize host APCs presenting graft antigens
155
What is a hyperacute rejection reaction?
Occurs within minutes-hours of transplant. Mediated by preformed antibodies (previous transfusion, transplant, pregnancy)
Complement activation -> vascular occlusion
Chances of hyperacute reaction minimized by crossmatching
156
What is acute rejection?
Takes place over the course of a few days, with loss of function in 10-14 days
Intense mononuclear infiltrate.
Can usually be controlled with immunosuppressive therapy
Creatinine levels to monitor for rejection
157
Chronic rejection
Occurs months or more after graft has assumed normal function
Antibody and cell mediated
Mechanism poorly understood
Little can be done to save graft
158
What is crossmatching?
Testing recipient serum for presence of antibodies toward donor tissue. Also check major blood group antigens
159
What is the role of corticosteroids in transplant therapy?
Suppress inflamation, inhibit macrophage cytokine production
Reduce phagocytosis and killing by neutrophils. Inhibit leukocyte migration and expression of adhesion molecules- apoptosis of lymphocytes.
160
What are the roles of azathioprine, cyclophosphamide, and mycophenolate in transplant therapy?
Interferes in DNA synthesis - inhibition of lymphocyte proliferation
161
What use is cyclosporin A and tacrolimus in transplant therapy?
Inhibit Ca++ dependent calcineurin activation of NFAT (nuclear factor actiation of Tcells)
block IL-2 production and proliferation of Tcells
162
What is rampamycin
Inhibits proliferation of effector Tcells
| via Rictor dependent mTOR
163
What is fingolimod?
Interferes with sphingoline-1-phosphate receptor
| inhibits lymphocyte trafficking out of lymph tissues
164
Bcell depression - what infections likely?
high grade encapsulated organisms
| otitis media, pneumonia
165
Tcell depression - what infections?
low grade infectious agents
| fungi, viruses, pneumocystis carini (fungal pneumonia)
166
T and B cell suppression: what infections?
acute and chronic infections with
| viral, bacterial, fungal, protozoal organisms
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phagocytic cell deficiency - infections
bacteria of low virulence, superficial skin infections, infections with pyogenic organisms
168
complement component depression - infections
pyogenic microorganisms
169
What is DiGeorge syndrome?
defect in development of 3 and 4th pharyngeal pouch - failure in development of Thymus and parathyroid
deletion: 22q11
-Tcell deficiency: very susceptible to viral, fungal, protozoal infections
-absence of IgG post immunization
Poor prognosis - treat w/ fetal thyroid transplant
DO NOT GIVE LIVE VIRUS VACCINE
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Two SCID groups
T-B+: absent Tcells, normal-high Bcells
T-B-: absent T and B cells
171
Types of T-B+ immunodeficiency
SCIDs
X-linked - defect in gamma chain of IL 2,4,7,9,15 receptors
Autosomal recessive - defect in JAK3 - non-functional pathway - phenotypically identical to X-linked
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T-B- immunodeficiency examples
Adenosine deaminase deficiency -> toxic amounts of ATP in lymphocytes -> destruction
1st gene therapy: clone and insert ADA in patients
Recombinase deficiency -> RAG1 and RAG2: no rearrangement of Ig in Bcells or TCR in Tcells. Cell maturation stopped at preB and preT stages.
173
Bare lymphocyte syndrome
```
T+B+ deficiency
lack class II MHC - can't present foreign antigen
low CD4
also can be class I deficient, but usually asymptomatic. low CD8
```
174
ZAP70 deficiency
T+B+
Defective T and B cells, no CD8 cells
no signal transduction after binding of antigen
prevalent in Mennonite population (10/12 described cases)
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X-linked agammaglobulinemia
Defect in BTK -> failure in preBCR signaling -> cell dev. arrested at pre-Bcell stage.
first noticed at 5-6 mos. of age w/ loss of maternal IgG
underdeveloped tonsils
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What is the most common immunodeficiency disease?
Selective IgA deficiency
177
What is selective IgA deficiency?
unknown cause, but lack of IgA production by Bcells. Patients often healthy.
Blood transfusion w/ IgA+ blood -> immune reaction
Susceptible to certain infections: sinopulmonary viral infections, defective absorption in bowel.
Treat w/ antibiotics, not serum globulin
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What is hyper IgM syndrome?
```
XHIM
lack of CD40L in TH cells -> no signal for Bcell class switching, no germinal center formation
```
179
If missing early components of the complement system, what susceptibilities?
Encapsulated bacteria
180
What assay is used in screening for SCID?
TREC
Tcell Receptor excision circles
Fragments of DNA excised during Tcell receptor development are missing in SCID patients
181
What are the 3 phases of immunosurveillance?
Elimination: NK cells kill abnormal cells
Equilibration: Incomplete elimination, tumor variants develop
Escape: cells evade immune system - tumor - cancer develops
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3 embryonic antigens
MAGE 1 and 3: normal testicular protein. Melanoma, breast
carcinoembryonic antigen (CEA): fetal GI. liver, gall bladder, colon
alpha-fetoprotein: from fetal yolk sac - liver
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MUC-1 and cancer
mucin-1
| normal protein but under-glycosylated in some breast and pancreatic tumors
184
Role of NK cells in cancer
Produce cytokines: IL-12, IFN-gamma, TNF-alpha, has Fc receptor, CD16
Some anti-tumor ability w/o prior exposure (surveillance)
Anti-tumor activity toward cells lacking MHC1
