IID block Flashcards
(99 cards)
1
Q
Central thymic tolerance
A
- Regular pos & neg selection - delete T cells that have receptors with high-binding affinity for intrathymic self-antigens
- Deletional tolerance
- Regulatory tolerance
- Clonal anergy: lack of costimulation –> T cells get inactivated
2
Q
What two kinds of T cells get to mature and leave the thymus to join the peripheral T cell pool?
A
- Low-affinity self-reactive T cells
- T cells with receptors specific for antigens that aren’t represented intrathymically
3
Q
Peripheral (post-thymic) tolerance
A
-
Sequestration: antigen is hidden
- self-reactive T cells in circulation ignore self-antigens that are sequestered in the tissue
-
Immunoprivileged site: Fas or cytokine (TGF-B, IL-10) blocks T cell response
- Ex) eye, brain, testes
- Deletion/anergy by CTLA4 of self-reactive T cells
- Immune regulation via Tregs secreting IL-10 –> inhibits IFN-y secretion from Th1 –> prevents inflammation
4
Q
When does B -cell deletion happen?
A
Occurs in the bone marrow after B cells with high-affinity Ig receptors react with self membrane-bound antigens
5
Q
Facotrs that influence the outcome of any immune response:
A
-
Antigen structure
- soluble antigens = good tolerangens –> no response
-
Antigen dose
- Low induces T cell tolerance
- High induces both B & T cell tolerance (clonal exhaustion)
- Intermediate is actually immunogenic –> cytokines
-
Route of administration
- Tolerogenic - oral & IV
- SC, IM, and intraderm are more immunogenic
-
Host genetics
- Women have more autoimmune disease
- More HLA class II genes –> increased risk of autommune
6
Q
Antigen-presenting cells affect immune response through
A
ability to provide or not provide costimulation to T cells
7
Q
CD4 Tregs express and require ___ in order to differentiate.
A
Foxp3 transcription factor
Foxp3 is X-linked so males are disproportionately affected
8
Q
Mutations or dysregulation in the Foxp3 gene can lead to ___.
What is treatment/presentation?
A
IPEX syndrome: Multiple organs, lethal if not treated early in childhood as several autoimmune responses will develop (RA, SLE, Diabetes)
Tx:immunosuppressive trx to combat self-specific T cell function
9
Q
What are the most suppressive cytokines?
A
IL-10
TGF-B
10
Q
While autoimmunity is common, autoimmune disease is rare.
______ persists in normal people, but autoimmune-diseased people have ____ inducing the production of autoimmune responses.
A
Autoreactive B and T cells persist in normal subjects, but in autoimmune disease, autoantigen induces the production of autoimmune responses.
11
Q
___ inhibits Th2 secretion
____ inhibits Th1 secretion
A
IFN-y inhibits Th2 secretion
IL-10 (& IL-4) inhibits Th1 secretion
12
Q
___ activates Th1 secretion
___ activates Th2 secretion
A
IFN-y & IL12 activates Th1
IL-4 activates Th2
13
Q
Th1 secretes what cytokines? What do they do?
A
IFN-y
IL-2
- Activate CD 8 cells & macrophages
- Delayed type hypersensitivity
14
Q
What cytokines does Th2 secrete? What do they do?
A
IL-4, IL-5, IL-6, IL-9, IL-10, IL-13
- Antibody response
- IL-4 & IL-5 enhances class switching
- IL-10 is anti-inflammatory
15
Q
Treg cells are CD_+ and CD_+
How does it do its job of suppressing immune response in the periphery (2 ways)?
A
- CD4+, CD25+
- Binds IL-2 receptors with its CD25+ to decrease teh IL-2 in peripheral circulation –> prevent activation of T cells
- Secretes IL-10 to suppress autoreactivity
16
Q
Positive & negative selection still applies to Treg cells. Describe it.
A
Positive selection: It needs to bind self MHC
Negative selection: It can’t be self-reactive (can’t bind MHC-peptide too tightly)
Or else - apoptosis
17
Q
Immunologic tolerance
A
immunologic unresponsiveness to a specific antigen
18
Q
3 fates of T cells in periphery
A
- No co-stimulation -> apoptosis/anergy
- B6 binds CD28 (costimulation)
- IL-2 production -> effector function
- cell proliferation & differentiation
- B7 binds CTLA4 –> cell cycle arrest
- Because CTLA4 from Tregs has a higher affinity for B7 that will outcompete CD28
- –> prevent IL2, T cell development, proliferation
- Because CTLA4 from Tregs has a higher affinity for B7 that will outcompete CD28
19
Q
Neonatal tolerance
A
Fetal becomes tolerant of mom’s antigens (toleragens)
Later in life, baby won’t react to similar antigens because of these toleragens until maturation post-partum
20
Q
B cell tolerance
A
Self-peptide but with no T cell help –> no self-antibodies
Exogenous peptide that T cell recognizes as foreign –> promote B cell isotype switching and hypermutation
21
Q
In autoimmunity, there is an increase in which Th and a decrase in which one?
A
Increased Th1 –> hyperactivation of immune response & IL-2
Decreased Th2 & Tregs
22
Q
Origins of autoimmunity
A
- Sequestered/late-developing antigens: antigens leak from immunoprivileged site to cause response
- Molecular mimicry: antigen looks like self, but immune still makes autoantibodies against it
- Neoantigens: self antigen+foreign antigen
- Anomalous antigen presentation: extremely high MHC II will overcome co-stimulation needed
- Loss of Tregs
- Lymphoproliferation
23
Q
Autoimmune pathogenesis of chronic & acute inflammation
A
• Autoreactive T cells: infiltration of CD4/8 cells ⇒ increased cytokine production ⇒ chronic inflammation
• Autoantibodies: complement-mediated lysis against own self, ADCC, immune complex deposition ⇒ acute inflammation
-
ADCC: Antibody dependent cellular cytotoxicity with NK cells
- Tolerance: NK cell + inhibitory ligand ⇒ prevention of NK activation
- Autoimmune: NK cells will kill anything with an antibody on it.
24
Q
Insulin-dependent diabetes is what type of autoimmune disease?
A
25
Rheumatoid arthritis is what type of autoimmune disease?
26
Pernicious anemia is what type of autoimmune disease
27
SLE is what type of autoimmune?
28
**Delayed Type Hypersensitivity / Type IV Hypersensitivity**
* T cell mediated
* **Direct cell cytotoxicity:** CD8+ T cells directly kill targeted cells
* **Inflammatory rxn**: CD4+ T cells recognize antigens & release inflammatory cytokines
* 4T's:
* **T** cells
* **T**ransplant rejections e.g. GVHD
* **T**B skin test
* **T**ouching - Contact dermatitis from mosquitos, bed bugs, chigger
29
Process of a mosquito bite causing delayed type hypersensitivity
1. **Dendritic cells** uptake antigens from mosquito antigens & express them on MHC II -\> go to lymph nodes to present to Th2
2. **Th2 cell** goes through blood to enter tissue at inflammation site, where it
1. Interacts with **macrophages**
2. Releases IL-5 to **recruit eosinophils via IL-5**
30
TGF-B will cause a native Th0 cell to become \_\_\_
TGF-B + IL-6 will cause a native Th0 cell to become \_\_
TGF-B alone --\> Treg
TGF-B + IL-6 --\> Th17
31
T cells survey __ cells in the \_\_\_.
B cells survey ___ cells in the \_\_.
T cells survey **dendritic cells** in the **paracortex**
B cells survey **follicular dendritic cells** in the cortex
32
If a B cell binds an antigen presented by a follicular dendritic cell, what happens next
* It will present that antigen on an MHC II
* It will produce IgM
33
B cell activation
* Helper T cells activate B cells via antigen interaction & CD40 costimulation
* Consequences of CD40 activation:
* Isotype switch from IgM to other types
* Affinity maturation: B cells with the best antigen binding sites that have the best fit will reproduce more --\> higher affinity
34
**Intermediate** Type Hypersensitivity/ Type **I** Hypersensitivity
Anaphylaxis!!
B cell activation causes it to produce a ton of IgE, whose Fc region binds mast cells.
* _Immediate:_ Antigen crosslinks pre-formed IgE on presensitized mast cells --\> degranulation --\> **histamine, tryptase, serotonin,** and **heparin** release
* _Late_: chemokines and other mediators cause inflammation & tissue damage
* Eicosanoids - **prostaglandin D2, leukotriene C4**
* Cytokines - **IL4, TNF**
35
Eicosanoids released in type I hypersensitivity recruit inflammatory cells.
How?
**Prostaglandin D2** - attract eosinophils, basophils, Th2 cells
**Leukotriene C4** - mediates vascular permeability and bronchoconstriction
36
What do IL-4 and TNF do in type i?
**Il-4**
* promotes Th2 differentiation
* promotes class switching to IgE
* upregulate MHC-II
**TNF** is a pyrogen (produce heat); makes ya feel bad
37
\_\_\_\_\_ are not present in tissue because they're very destructive, so they have to be recruited from bone in a type I hypersensitivity reaction
Eosinophil
## Footnote
Pre-formed: major basic protein, eosinophil caitonic protien, eosinophil-derived neurotoxin, eosinophil peroxidase
Newly-formed: IL-1, 2, 4, 5, 6, 8, 13, and TNF
38
Both ___ and __ have preformed granuels of histamine.
**Mast cells & basophils**
Newly formed: eicosanoids, IL-4, TNF
39
\_\_\_\_\_ has preformed elastase, cathelicidin, lactoferrin, and can phagocytose with peroxide, but no newly formed mediators.
Also makes NETs: chromatin and serine proteases
Neutrophils
40
Itch-scratch reflex
* Mast cells release histamine & other mediators; histamine causes
* **edema** at the **venules**
* **itch** at **C-fibers**
* Unmyelinated C fibers with free ends in the basal layer of skin
* Mechanosensitive: pain; Mechanoinsensitive: itch
* Spinal reflex modulated by input rom brain
* Decreases the likelihood of lyme disease bc remove tick
41
Desensitization vs Tolerance
**Desensitization**: Injection of small doses of allergen will **wash out IgE on the surfaces of mast cells**, but does not prevent plasma cels form making more IgE
**Tolerance**: high dose injections for years will induce long-term tolerance that persists even after stopping the injection; **induce IgG4 production that outcompetes IgE**
42
**Type 2** Hypersensitivity Reactions / **Cytotoxic** Reactions
Antibodies bind to cell-surface antigens to cause..
* **\*DESTRUCTION\***: opsonize the cell for death via phagocytosis, complement, or NK cells (ADCC)
* **Inflammation**: activate complement system and Fc receptor-mediated inflammation
* **Dysfunction**: blocks cell surface receptors to prevent downstream processes
43
Injecting yourself with the blood from a patient with idiopathic thrombocytopenia results in
type 2 hypersensitivity reaction:
## Footnote
IgG bind the platelet surfaces -\> complement cascade -\> DESTROY platelets or promote its phagocytosis by macrophages
44
Type 3 hypersensitivity rxns / Antigen-antibody complex disease
**Immune complex:** Antigen-antibody-complement --\> complement attracts neutrophils
* Antibody is usually IgG
* SLE, poly arteritis nodosa, PSGN
* **Serum sickness**:
45
Serum sickness
Caused by repeated administration of horse antiserum to treat Diphtheria toxin
--\> joint pain, fever, rash, lymph node enlargement, kidney damage
Type 3 HS
46
The only example of Ig**A** mediated hypersensitivity
celiac disease
**IgA** against tissue transglutaminase destroys intestinal villa
47
Early introduction of commonly allergenic foods (aka peanuts) ____ the incidence of allergies.
reduces the incidence.
feed your babies pb!!!
48
If the cell is being destroyed then it is
type 2 hypersensitivity!
49
The effectiveness of a vaccine correlates with ____ to a certain antigen
serum IgG
50
Homologous vs heterologous passive immunity
* **Homologous**: antibodies against many antigens
* Ex) Breast mlk has pooled human antibody, human hyperimmunoglobulin
* **Heterologous**: animal-derived or synthetic antibodies
* Risks serum sickness upon re-exposure
* Ex) HBAT (botulism), palimizumab (RSV)
51
The more similar a vaccine is to the pathogen, the better the immune response.
**Live attenuated** vs **Inactivated vaccines**
* **Live attenuated vaccines**: weakened form of wild-type pathogen that can replicate in you
* Ex) BCG vaccine, measles, mumps, rubella, etc
* **Inactivated vaccine**: organism can't cause disease, but still stimulates an immune response
* May be the whole thing or just a protein or polysaccharide of it
* Protein-based: **toxoid** (inactivated toxin) or a **subunit**
* Polysaccharide based: **pure** or **conjugate**
52
Inactivated \> part of an organism \> polysaccharide \> conjugated
What are conjugated vaccines?
A **polysaccharide antigen** fused to a **carrier protein**
## Footnote
Induces **T- cell _dependent_ response** & **memory cell** development
53
\_\_\_ vaccines induce a T-cell **in**dependent response, which does not work well in children \<2 years because low immunogenicity.
Pure polysaccharide vaccines
54
Name tow protein-based toxoid vaccines
Diphtheria & Tetanus
55
Difference in antibody resposne upon the first exposure vs the second exposure of the vaccine
First time: mostly IgM, low affinity
Next time: mostly Ig**G**, higher affinity
56
Adjuvants
Natural or synthetic substances that **enhance immune response to co-administered antigens**
Replaces immunological characteristic(s) lost during the conversion of the pathogen to a vaccine
57
Vaccines induce what 3 mediators?
* **Bcells** make antibodies to the pathogen/toxin
* **CD8 cells** recognize & kill infected cells via cytokines
* **CD4 cells** produce cytokines and support B and CD8 T cell response
58
Issues with vaccine development
Complex pathogens
Insufficient supply, price of production, accessibility
Refusal, lack of knowledge, misinformation
59
Vaccinating "at-risk" groups
Elderly, neonates, and immunocompromised individuals
* Increased susceptibility to disease
* Different treatment and infection control
* Different formulations are required to make an effective vaccine
60
Eradication vs Elimination
**Eradication** refers to the complete and permanent worldwide reduction to zero cases of the disease throughout deliberate efforts
**Elimination** refers to the reduction to zero of new cases in a defined geographical area
61
* Recurrent **_bacterial_ & _enteroviral_ infections in 4-6mo. _babies_**
* **No B cells**
* **No Ig's** of any class
* Absent/**scanty lymph nodes** and **tonsils**
* No primary follicles or germinal centers
* Normal WBC count & lymphocyte levels
What is the disease and its cause?
X linked Brton agammaglobulinemia
## Footnote
Defect in BTK--\> no **B cell maturation** (stuck as pre-B cells) --\> can't make antibodies
62
Treatment for X-linked Bruton agammaglobulinemia?
Pre-B cells aren't maturing due to BTK defect--\> no Igs, so tx: **gamma globulin** (IV or subcutaneously)
63
* Bacterial infections, e.g. **pneumocystitis pneumonia**
* Mouth ulcers
* Always on antibiotics
* **Decreased IgG, A, and E**
* **High IgM**
* No germinal centers
What is the disease and the cause?
* Defective CD40L on Th cells
* --\> terminal B cell can't differentiate --\> no isotype switching
* --\> Can't activate macrophages to release GM-CSF, so decreased phagocytosis & low neutrophils
64
Wha tis TX of hyper-IgM syndrome?
Defective CD40L on Th cells --\> infections due to inability to class switch & decrased phagocytosis --\> Tx: **IVIG (intravenous immunoglobulin) replacement** for infections
65
* Frequent **bacterial infections (staph, serratia, nocardia)**
* Cold **staph abscesses**
* **Pneumonia**
* **Fungal infections (**esp **aspergillus**)
* **\*Catalase positive** organisms\*
* **Males**
Disease? Cause? Test? Tx?
**Chronic granulomatomatous disease**
* Defective NADPH oxidase --\> can't perform respiratory burst in neutrophils to kill catalase + organisms
* Test:
* Nitroblue Tetrazolium (NBT) dye test _can't_ turn blue
* Abnormal flow cytometry (can't turn green)
* Tx: bone marrow transplant, bacterial & antifungal prophylaxis, IFN-gamma to upregulate neutrophils
66
* **Failure to thrive /** **Diarrhea** / **Thrush / Otitis media**
* Recurrent **infections of ALL KINDS**
* **No thymic shadow** on CXR
* **No/low TRECs**
* **No germinal centers**
* **No T cells** on flow cytometry
* **Low Ig**
Disease & cause?
**SCID**
* Cause:
* **ADA** or **PNP deficiency (aut recessive)** --\> lymphocytes can't clear purine metabolism byproducts so T & B cells don't survive
* **Gamma chain deficiency (X-linked)** --\> no receptors for T cells so they can't develop; B cells don't work
67
Best way to screen for and diagnose SCID?
Examine T cells, B cells, then NK cells
PCR to measure TRECs (DNA molecules that are byproducts of excessional rearrangements of T cell receptor genes, which in SCID, aren't working)
Tx: gene therapy, bone marrow transplant
68
What is the catch 22 of digeorge syndrome? What else presents with it?
**C**left palate
**A**bnormal facies
**T**hymic aplasia, so **absent thymic shadow!** --\> lack of T cells
**C**onotruncal abnormalities: Congenital heart disease
**H**ypocalcemia due to lack of parathyroids --\> **tetany**
Presents with: seizures, murmur
Tx: thymic transplant
69
Cause of digeorge?
22q11 deletion TBX gene due to defect in embryogenesis, 3rd and 4th pharyngeal pouches
--\> Lack of development of the thymus and parathyroid
--\> No functional T cells and depressed T cell immunity --\> thymic, parathyroid, and cardiac defects
70
* Low T cells
* Low PTH & Ca2+
* Thymic shadow absent on CXR
Digeorge syndrome - absent thymus & parathyroids
Will also see CATCH22!
71
What is the cause of autosomal scid?
RAG defects prevent VDJ recombination
--\> no T or B cell development
72
What two diseases cause problems that present at any age (including later in life)?
AIDS & CVID
73
HIV/AIDs
Cause? Presentation?
**Loss of CD4+** cells after infection with retrovirus HIV
Presentation: opportunistic infections
74
* **20 or 30 year old**
* **Sinopulmonary infections** (usu bacterial)
* **\*Bronchiectasis\***
* **Gastrointestinal, endocrine, hematological disorders**
* **Low IgG, IgA, and/or IgM**
* **Low plasma levels**
Disease? cause?
* CVID
* Defect in B cell dfiferentiation after age 2
75
**90%** is the target vaccinated/otherwise immune population for herd immunity.
**Boosters** are required for ___ of lymphocytes and ___ of antibodies.
Clonal expansion of lymphocytes
Affinity maturation of antibodies
76
**MMR**, **Varicella**, and the **Rotavirus** vaccine are ___ vaccines that stimulate what kind of response?
Live, attenuated vaccines that stimulate **cell-mediated** and **humoral responses**
77
**Killed/inactivated vaccines** (e.g. pertussis, polio) often have to use a ___ to get an adequate cell-mediated & humoral immune response.
What is the **most common** type?
**How do they do what they do**?
**Adjuvants** ; **Aluminum**
## Footnote
Delays clearance of antigen from the site of injection to increase contact with the APC
78
Subunit vaccines?
Name two toxoids
Conjugation of weak antigen + strong antigen
Two toxoids: **Diphteria** & **tetanus**
79
Immunosuppression of allergies/IgE - name the mechanisms of
* Antihistamines
* Leukotriene modifiers
* NSAIDs
**Antihistamine**: block H1 receptors to prevent histamine degranulation
**Leukotriene modifiers**: block late mediators of allergic response
**NSAIDs**: inhibit COX to block prostaglandin synthesis
80
Corticosteroids
Anti-proliferative drugs
Inhibitors of T cell activation
are all _____ drugs
globally immunosuppressive
81
The efficacy of a vaccine is dependent on the __ and \_\_\_.
Why do we have a vaccine to some microbes and not others? (low yield)
Depends on **microbe** and its **pathogenesis**.
## Footnote
Microbes that have to replicate/spread extensively to cause disease OR are only pathogenic because they secrete a **toxin are easy to make a vaccine** to because you just have to stimulate an immune response
**Microbes that are antigenic** and **ALREADY cause a potent immune response but still can't be cleared are harder**. Our vaccine can make a potent immune response, but may still not prevent disease.
82
In **targeted immunomodulation**, we want to strike a balance between anti-inflammatory and pro-inflammatory mediators. What are the two big targets
TNF-a & IL-6
83
We want **monoclonal antibodies** ("-mab") to be as close to human as possible (minimize mouse component).
## Footnote
"muro-"
"-xi-"
"-zu-" or "-iz-"
"umab"
"muro": murine
"xi": chimeric
"zu": humanized
"-umab": fully human
84
Which cytokines are targeted in asthma/allergy therapy and why?
* IgE production depends on Th2 cells producing **IL4** and **IL-13**.
* Targeted in *asthma* and *atopic dermatitis*
* Inflammation results from eosinophils' presence, mediated by **IL-5**
85
In **rheumatoid arthritis**, which cytookines are upregulated? Which Th cell is upregulated?
**IL-1, IL-6**, IL-15, IL-18, **TNF**, and chemokines.
## Footnote
**Th1** T cells are upregulated --\> increased IFN-y production,
B cells produce abnormal antibodies (ANA, RF)
86
**Steroids**, **methotrexate**, and **NSAIDs** were standard therapy for rheumatoid arthritis.
"**Salmon-colored" fleeting, migratory rash on the trunk & extremities that synchronizes with fever spikes** is associated with what arthritis?
systemic juvenile arthritis
Will see high IL-6, and in older children, high IL-1
87
Whats the big concern with **anti-TNF** therapies for rheumatoid arthritis?
**reactivating TB** & increasing lymphoma risk
88
**Probiotics** & **helminthic therapy** (triggers Th2 response to depress Th1) are therapies for what disease?
Crohn's
89
**Plasmophoresis**
**IVIG**
**Cancer treatment**: anti-HER2 & CAR & TCR
**Plasmophoresis:** filter out bad antibodies; maybe exchange for healthy Abs
**IVIG:**
low dose to replace missing IgG
high dose as immunomodulatory agent
**Cancer treatment**:
* anti-HER2 **inhibits tumor growth factors** and **tags cancerous cells** for immune respons
* CAR and TCR-modified T cells for cancer
90
# Define:
Auto-
Iso-
Allo-
Xeno-
**Autograft:** transplant from the same individual
**Isograft:** genetically identical, but different individual
**Allograft:** two different members of the same species; differ by one or more MHC alleles
**Xenograft:** totally foreign
91
Alloantigens
Antigen on the graft that isn't present in the recipient.
Ex) Blood group antigens and HLA antigens
92
Host-vs-graft reaction
vs
Graft-vs-host reaction:
**Host-versus-graft reaction:** The recipient’s immune response to the grafted organ or tissue.
**Graft-versus-host reaction:** The graft’s immune response (**donor T cells in the graft**) to the recipient following bone marrow transplantation
93
**Hyperacute rejection**
* **Preformed antibody-mediated**
* **Type II HS**
* Rapid (min-hrs)
94
Acute rejection
* **Cell-mediated:** **CD8 T cells** recognize HLA antigens on the graft --\> recognizez HLA incomptability
* **Type 4** HS
* ****Delayed: takes 10-20 days after transplant to built up significant T cell mediated response
* Likely occurs due to direct allorecognition
95
Secondary rejection reaction
Even **more rapid** rejection of a second transplant due to immunological memory
96
Chronic rejection
* Mediated by both **antibodies & T cells**
* Type **2 and 4** hypersensitivty reaction
* months-years due to lesser degree of MHC polymorphism
* **Interstitial fibrosis** (collagen)
97
Two ways T cells are activated against a donor MHC
* **Direct allorecognition:** Donor dendritic cells present w/ foreign MHC/HLA to recipient CD4 & 8 T cells --\> T cell recognizes foreign donor HLA and activates
* Exposed him damn self
* **Indirect allorecognition**: donor MHC is degraded and taken up by recipient dendritic cells and presented as a foreign antigen on a self-MHC II
* Ratted out by recipient APC
98
What happens in graft vs host disease?
**Donor T cells in the graft react with host antigens**
* 70% mortality
* Severity correlates with **MHC disparity**
* CD4/CD8-mediated, but mostly cd8
99
Antigen cross presentation
Dendritic cells can take things form the outside and present them on MHC 1 as well as MHC 2 to activate CD8 T cells
Allows **activation of both CD4 and CD8** T cells in GVHD
