Allergies, DTH, and AIDS

Question 1

What are the types of Allergy responses?

Answer 1

Type 1: Ag causes crosslinking of Ab bound to Fc receptors on mast cells or basophils -> release of vasoactive mediators -> anaphylaxis: fever, asthma, hives, food allergies

Type 2: Ab target cells with antigen on the surface -> destruction by ADCC or complement - IgG or IgM

Type 3: Ab-Ag complexes induce complement and recruit neutrophils - Immune complex

Type 4: sensitized T cells release cytokines -> activate macrophages or cytotoxic T cells for direct damage

Question 2

IgM/IgD class switching for which type of response?

Answer 2

IgG: TH1 intracellular
IgA: mucosal (pollen, worms) + some TH1
IgE: TH2 extracellular

Question 3

What is the immune response to pollen?

Answer 3

IgE-Ag (pollen) on granulocytes cause granule releaseTH2 response

-Histamine: muscle contracts, the opening of veins, secretion of mucus (to build a barrier), cell chemotaxis

-same for Leukotrienes and prostaglandins but stronger

-Cytokines and Chemokines: IL-4, IL-13 more IgE production, IL-5 recruits eosinophils

Question 4

What are the early and late allergic responses?

Answer 4

Early (minutes): Vasodilation, mucus, swelling bc IgE is already there, once the allergen is present it causes degranulation

Late (hours): release of Cytokines (IL-4, IL-5, IL-13) recruit neutrophils, eosinophils, and TH2 cells causing the swelling

Question 5

Types of Allergies:

Answer 5

-Localized hypersensitivity: specific tissue (pollen airways)

-Food: allergens often stable to heat, acid, proteases -> smooth muscle contraction and gut vasodilation can cause vomiting

-Systematic: caused by injected allergen (bee sting, penicillin, seafood, nuts -> cause difficulties breathing bc contraction of smooth muscles, drop in blood pressure, anaphylactic shock -> need epinephrine to reverse that

Question 6

Where do allergies come from?

Answer 6

Hypothesis: Exposure to some pathogens early in life provides better T cell balance -> if not exposed the body overreacts when a pollen comes in

For food allergies: starts in the skin, DC collects antigens and directs to Th cells -> B-cell switch to IgE -> IgE circulates in the blood -> upon second exposure IgE causes activation of ILC2, TH9, and TH2 to produce cytokines recruiting basophils and mast cells -> also gut inflammation, and symptoms

Question 7

What are treatments for Type 1 hypersensitivity?

Answer 7

Antihistamines: blocking Histamin receptors
-Leukotriene antagonists
-Inhalation corticosteroids: inhibit the innate immune response in the airways
-Anti-IgE antibodies: prevent IgE from binding to mast cells

Question 8

Desensitization immunotherapy

Answer 8

-by oral immunotherapy or allergy shots
-Repeated low-dose exposures may induce a Treg cell due to exposure in the anti-inflammatory environment (under self-background threshold)

-Treg induce a switch to TH1 response -> TH1 may also induce a switch to IgG + TH1 (IFN-gamma) inhibits TH2/IgE effects bc mast cells have Fc receptors for IgE and IgG -> IgG is useless for mast cell so they will be turned off -> less allergic reaction

Question 9

Ab-Mediated (Type II) Hypersensitivity
IgG or IgM

Answer 9

-antibodies are generated against foreign targets found on cells (surface antigen)

-Type II Ab (IgG or IgM) -> induce ADCC and complement
-Example: Transfusion reactions

Question 10

Immune Complex-Mediated (Type III)
Hypersensitivity

often IgG

Answer 10

-agglutinations of antigens, antibodies (often IgG), and complement factors C3a, C5a -> causing inflammation, no opsonization

-trigger release of inflammatory mediators and
vasoactive mediators -> neutrophils are coming from the blood vessels

*Vasculitis if in the blood vessel,
*Glomerulonephritis if in the kidney
* Arthritis if in joints (rheumatoid arthritis Ab bind Fc of Ab)

Example: Arthus reaction, immune complexes on site of entry

Question 11

What are the antibodies that act in type 1-3 hypersensitivity?

Answer 11

Type I - IgE (allergies) -TH2 (mast cells, granulocytes)
Type II - IgG/IgM (red blood cell response) - TH1
Type III - IgG (immune complexes) - TH1
Type IV - T-cells and macrophages (takes longer) - TH1

Question 12

What is an Arthus Reaction?

Answer 12

An inflammatory reaction induced by injection of an Ag, in someone with a high amount of Ab against the antigen

-Swelling and localized bleeding at the injection site (Peaks after) 4–10 hours

-Examples: insect bite (type III reactions), farmer’s lung from moldy hay

Question 13

How is Delayed-Type (Type IV) Hypersensitivity (DTH) different from Type 1-3?

Answer 13

-Purely cell-mediated (T-cells) rather than Ab mediated
-Delayed bc it takes time for the T-cells to develop?
->recruitment of macrophages at the inflammation site

-Examples: Tuberculosis and poison ivy

Question 14

How is DTH initiated?

Answer 14

-Sensitization: Initial exposure triggers the production of a T-cell response and memory cells
APC secrete IL-12 to TH1 cell -> IFN gamma (intracellular response)

-Often the CD4+ TH1 subset (M. tuberculosis -intracellular bacterial pathogen), it takes 1-2 weeks

-effector phase: Second exposure induces the production of TH1 inflammatory cytokines -> recruit macrophages -> prolonged activation of macrophages -> leads to granuloma formation

Question 15

What happens if the antigen remains?

Answer 15

-exponential inflammatory responses

• can lead to destructive multinucleate giant cells and granulomas (f.e. in TB) surrounded by T-cells and macrophages

Question 16

How can DTH be detected?

Answer 16

-by injecting a small amount of Ag under the skin

-positive when: If a red, slightly swollen, firm lesion
develops in 48–72 hours

-indicates that the person has sensitized TH1 cells against the Ag, but doesn’t tell if there is an active or the infection is overcome

Question 17

How does Sensitization occur in Contact Dermatitis?

Answer 17

-Ag binds to Urushiol-modified proteins -> taken up by DC and carried to regional lymph node, and presented on MHC class II

-TH1-formation, TH1 cells return to the skin and release cytokines that activate macrophages

-Macrophages release inflammatory cytokines, lytic enzymes, and ROS causing tissue damagae

Question 18

In class QUIZ:

Answer 18

MATCHING:
-Typ-1-D -> Cytotoxic T-cells
-Myasthenia gravis -> Neutralizing (Blocking) Ab
-Rheumatoid arthritis -> immune complex and
complement
-Systemic lupus -> Anti-DNA-Ab

Question 19

Difference between primary and secondary Immunodeficiencies:

Answer 19

-Primary immunodeficiencies are genetic mutations (vary from mild to severe)
-> Severe combined immunodeficiency
(SCID) affects lymphocyte -> no T or B-cells, no adaptive immunity

-Secondary immunodeficiencies are are
acquired: Chemotherapy, steroid treatments, stress

Question 20

What is HIV?

Answer 20

-The Retrovirus HIV-1 causes AIDS (acquired
immunodeficiency syndrome)

-Two RNA genomes and reverse transcriptase (RT) enzyme -> integrate cDNA into host cell chromosome
-spread through intimate contact with infected body fluids

Question 21

How does the infection of HIV work?

Answer 21

1. Binding on target cell CXCR4 or CCR5 + CD4
2. Release of the viral RNA genome
3. RT converts the 2 RNAs into cDNAs
4. Integrase inserts cDNA into host cells chromosome

Question 22

How does Cell tropism determine the cell target?

Answer 22

-Coreceptor expression dictates cell tropism (target cell)

-T-cell tropic strain use CXCR4 on T cells and M-cell tropics use CCR5 as co-receptor

-M-tropic variant is more predominant, as it infects DC at the site of infection -> then is passed to T-cells within secondary lymphoid organs

Question 23

How is HIV activated in infected cells?

Answer 23

1. Upon reactivation, the viral genome is converted to mRNA and exported to the cytoplasm (ssRNA transferred separately and will be packed into virion)
2. Precursor proteins are cleaved by the protease into active fragments
3. assemble with RNA genome to form new virions

Question 24

What are the phases of HIV?

Answer 24

-Acute Phase: Spike in HIV levels in the blood, CD4 T cells decrease -> eventually brought under control by the production of Ab against HIV

-Asymptomatic phase: Gradual decrease in CD4+ T cells and increase in viral load -> can last years

-AIDS: Crash in CD4+ T-cell numbers and high levels of HIV in the blood

Question 25

How is HIV treated?

Answer 25

-Antiretroviral therapy inhibits HIV replication at every step

-Chemokine receptor agonist (block CXCR4 or CC5 receptor for HIV)
-Inhibit fusion
-Inhibit reverse transcription
-Inhibit integrase
-Inhibit protease (stop the formation of viral proteins from precursor)

Question 26

What may be a way to stop the HIV epidemic?

Answer 26

-A vaccine; Combined drug therapy is very expensive and NOT a cure

-the vaccine is hard to produce, Virus mutates rapidly due to the high error rate of RT
-> Good animal models are limited and expensive
->Dangers of testing attenuated vaccines (can cause leukemia)
->

Question 27

Explain genetic resistance to HIV:

Answer 27

-M-tropic HIV uses CCR5 as a co-receptor, homozygous for CCR5Δ32 individuals are immune to HIV

-bone marrow HSC (stem cells) genetically modified -> to prevent infection

-CRISPR-Cas9 (bacterial enzyme) used to induce CCR5∆32 mutations in embryos (didn’t really work - 1 had heterozygous mutation the other had different mutations)