ihs 340 exam 3 content

antigen

• substance that induces an immune response in the body

• substance specifically bound by antibodies or T lymphocyte antigen receptors

passive immunity

the short-term immunity which results from the introduction of antibodies from another person or animal.

featured cells in allergic reactions/atopy

mast cells, Th2 cells, B cells, eosinophils, basophils, dendritic cells, ILC2s

featured signals and receptors in allergic reactions/atopy

IgE, IgG1, FcR, IL-4, IL-5, IL-13, IL-9, IL-10, PGE2, PGD2, leukotrienes, alarmins (IL-33, IL-25, TSLP)

type I hypersensitivity reaction (outdated classification)

• immune reactant: IgE

• antigen: soluble antigen

• effector mechanism: mast-cell activation

• examples of reaction: allergic rhinitis, asthma, eczema, anaphylaxis, some drug allergies

• aka immediate hypersensitivity response

type IV Th2 hypersensitivity reaction (outdated classification)

• immune reactant: Th2 cells

• antigen: soluble antigen

• effector mechanism: IgE production, eosinophil activation, mastocytosis

• examples of reaction: chronic asthma, chronic allergic rhinitis

why is describing hypersensitivity reactions as different types “outdated”?

the lines between these types have been blurred as we learn more about immune and allergic responses

what is the main driver of IgE production by B cells?

IL-4

what does it mean for T cells to be polarized?

different T cell types are unique, the cytokines they release are unique to them

i.e. IL-9 only released by Th2 cells, not any other type

IgM principal effector functions

complement activation and neutralization

IgG principal effector functions

FcR-dependent phagocyte responses, complement activation, neonatal immunity

IgE and IgG4 principal effector functions

immunity against helminths, mast cell degranulation (immediate hypersensitivity response)

IgA principal effector functions

mucosal immunity, neutralization

how do mast cells and eosinophils contribute to immunity against intestinal parasites?

• a worm is marked by antibodies, so that cells know it needs to be removed

• eosinophils attach to the Fc portion of these antibodies and stuns the worm with powerful toxins

• mast cells release histamine to cause fluid movement to the vessels and activate smooth muscles to expel the worm

describe histamine effects in type I hypersensitivity reactions

they bind to H1 receptors to contract smooth muscles in bronchi, also allows BV dilation and increased permeability, resulting in edema and urticaria (hives)

how is an allergic response similar to the response in expelling a worm?

the body is using similar mechanisms like mast cell degranulation to expel the allergen

what is necessary for an effective immune response?

• need engagement of TcR with MHC class II receptors

• need engagement of costimulatory molecules between APCs and T cells

• need cytokines to allow for T cell differentiation

describe the pathway of an airborne allergen through the upper airways and its interaction with the immune system

• these allergens have protease activity, it gets through epithelial cells lining the airway lumen cleaving through epithelial cells and causing microscopic damage

• allergen uptake and processing done by dendritic cells, once they have it they migrate to the nearest lymph node

• in the lymph node, DC binds with TcR on naive T cell, which then differentiates to Th2 cell

• primed Th2 cell binds to B cell which switches isotype to make allergen-specific IgEs

• IgEs bind to mast cell, arming it and allowing it to respond to allergen in airway tissue

innate lymphoid cells (ILCs)

• an important early source of polarizing cytokines

• lack specific antigen receptors (no TcRs, no Ig) and also co-receptor complexes

• ILCs develop in bone marrow

• expression of transcription factor Id2 in lymphocyte progenitor is required for development of all ILCs, represses other lymphocyte fates

• migrate from bone marrow and populate lymphoid tissues (spleen and lymph nodes) and peripheral mucosal organs

what are three major subgroups of ILCs?

1. ILC1 and NK cells

2. ILC2

3. ILC3

how are the major subgroups of ILCs defined?

largely on the basis of the types of cytokines that each produce

group 1 ILCs

• similar to Th1 cells, but without TcRs

• release IFN gamma

group 2 ILCs

• similar to Th2 cells, but without TcRs

• secrete IL-13, IL-4, and IL-5 like Th2 cells do

group 3 ILCs

• similar to Th3 cells, but without TcRs

• release IL-17 and IL-22

what can induce distinct cytokine responses from ILCs?

• MAMPs of different microorganisms

• DAMPs from injured host cells

• cytokine signals from other cells

• other environmental signals like pollutants (ILC3 studied for most of this)

why are ILC2s an important early source of polarizing cytokines?

they can play a major role in shaping or responding to their tissue environment

what are type 2 responses characterized by?

actions of ILC2s, IgEs, and innate effector cells (eosinophils, basophils, and mast cells)

what are type 2 responses (Th2, ILC2) induced by and what are they drivers of?

they are induced by multicellular parasites like helminths and are drivers of allergic responses

alarmins

• proteins that respond to any damage to epithelium

• TSLP, IL-33, IL-25

• primarily produced by epithelial cells that sense MAMPs common to helminths or DAMPs

what do alarmins activate?

ILC2s

what do ILC2s do after activated by alarmins?

they rapidly produce IL-4, IL-5, and IL-13, it doesn’t make a lot of cytokines, just enough to get the process started

IL-13 effects

stimulates mucus production by goblet cells in the epithelium and mucosal smooth muscle contractions that facilitate worm expulsions, also activate B cells

IL-5 effects

stimulates production and activates eosinophils that can kill worms

IL-4 effects

stimulates class switching to IgE antibodies that arm mast cells and eosinophils

amphiregulin

stimulates tissue repair after a worm is cleared out

what is an example of an airborne allergen possessing enzymatic activity that damages the epithelium?

• dust mite allergen Der p1 (cysteine protease)

• it cleaves protein (occludin) that helps maintain intracellular tight junctions, damaging barrier function of epithelial cells

• the allergen and other dust mite antigens penetrate epithelial barrier and are taken up by DCs

• induces specific Th2 cells and IgEs

function of alarmin IL-33

• mediator of allergic inflammation

• localized in mucosal tissues to respond rapidly to environmental insults like allergens or epithelium damage

how does IL-33 affect dendritic cells?

• it activates them like other inflammatory signaling molecules, causing their “dendrites” to retract, and it flows with lymph towards lymph node to mature and do its job

• DCs are great at releasing costimulatory molecules and interacting with T cells after maturing in the lymph node

what antibody receptors do mast cells constitutively express?

• FcεR1, a high-affinity IgE receptor

• also constitutively expressed on basophils and inducible in eosinophils

how are mast cells activated for degranulation?

• when a multivalent allergen (multiple epitopes) binds and cross-links two or more IgEs on the surface

• this causes fast degranulation because these granules filled with proinflammatory mediators are premade

which molecules are released from mast cells rapidly?

enzymes like trypase, toxic mediators histamine and heparin

which molecules are produced and secreted by mast cells after activation?

• cytokines IL-4, IL-13, IL-33, TNF-alpha, etc.

• chemokines like CCL3

• lipid mediators like prostaglandins and leukotrienes

preformed and released molecules from eosinophils

• enzymes like eosinophil peroxidase and colleganse, MMP9

• toxic proteins like eosinophil cationic protein

molecules synthesized and released by eosinophils after activation

• cytokines IL-3, IL-5, TGF-alpha and beta

• chemokines like CXCL8 (IL-8)

• lipid mediators like leukotrienes and platelet-activating factor (also in mast cells)

describe the central effector cell in allergic responses

• mast cells, which express FcεR1 constitutively

• prominent in mucosal and epithelial tissues like in respiratory and GI tract

• also located in subuendothelial connective tissue (just on outside of blood vessels)

• can have local response (limited) or systemic response (life-threatening, shock)

how do mast cells and neurons interact?

• mast cell mediator release can affect nociceptors, increasing pain perception

• neuronal activation can release NTs which can affect mast cells

direct release of IL-4?

protease allergens can directly induce IL-4 release from mast cells and basophils, a potential mechanism for food sensitivity

IL-18-induced “innate” allergic response

• IL-18 can be produced by epithelial cells, macrophages, and other cells

• IL-18 can stimulate basophils and mast cells to produce IL-4 and IL-13, even in the absence of FcεR1 cross-linking

leukotrienes

• small molecules made of fatty acids that facilitate communication between local groups of cells

• potent activator of neutrophilic inflammation

• can also activate sensory nerves, smooth muscles

• bioactive lipids derived from enzymatic modification of arachidonic acid

• made via lipoxygenase activity

early phase of type I hypersensitivity response

• occurs within minutes

• includes histamine effects, proteases, and eosinophils

late phase of type I hypersensitivity response

• occurs after 8-12 hours

• includes Th2 cells, basophils, eosinophils, leukotrienes

mast cell-mediated immediate reaction

• vascular and smooth muscle responses predominate (occurs within minutes)

• molecules released from pre-formed granules/vesicles

mast cell-mediated late-phase reaction

• characterized by leukocyte recruitment and inflammation (takes hours to days)

  • molecules mostly synthesized and secreted after activation

early-phase allergic reaction in the skin

• wheal-and-flare response, due to release of histamine

• occurs within 5-10, welt with soft swelling with red rim around it because of BV dilation

late-phase allergic reaction in the skin

more widespread swelling response, involves leukocyte recruitment and additional released molecules from mast cell

histamine

• bioactive amine formed by decarboxylation of AA histidine via histidine decarboxylase

• found in almost all tissues of the body, high amounts along mucosa, in tissues of lungs, skin, and gastrointestinal tract (because highly concentrated in mast cells and basophils)

• important for sleep cycle, inflammation (H1 receptors), and gastric acid secretion via parietal cells (H2 receptors)

antihistamines

H1 receptor antagonists, blocking histamine binding to H1 receptor

examples of antihistamines

• benadryl (diphenhydramine) 1st gen

• zyrtec (cetirizine) 2nd gen

• allegra (fexofenadine) 2nd gen

• claritin (loratidine) 2nd gen

difference in generations of antihistamines

• 1st gen - discovered first, can cross blood-brain barrier and causes drowsiness

• 2nd gen - discovered later, don’t cross blood-brain barrier, nondrowsy (only if you take 1 every 24 hours)

specific qualities of zyrtec (cetirizine)

high doses causes it to cross the BBB and can bind to H1 receptors in the CNS with higher affinity, causing brain fog and drowsiness

specific qualities of allegra (fexofenadine)

can be prescribed at higher doses, doesn’t cross BBB even at higher doses

what stimuli can trigger histamine release from mast cells?

allergic reactions, tissue damage, drugs and foreign chemicals

prostaglandins

• bioactive lipids derived from enzymatic modifications of arachidonic acid, released from cell membranes by phospholipase A2

• made by cyclooxygenase activity (COX-1, COX-2, COX-3)

• play a role in inflammation, pain, body temp regulation, gastric acid secretion, immune response development and immune regulation, etc.

• target of NSAIDs

how are Th2 cells and prostaglandins related?

Th2 cells (allergy-driving cells) express receptor for prostaglandin D2 and express enzymes to make prostaglandins (COX-1, COX-2)

NSAIDs

• non-steroidal anti-inflammatory drugs

• provide relief from fever, pain, and inflammation through actions on COX enzymes

• ex. are aspirin, ibuprofen, naproxen, acetominophen

COX-1

• constitutively expressed in many somatic cell types

• is considered a “housekeeping” enzyme, with roles in such processes as vascular hemostasis and gastric (stomach) protection

COX-2

• expression primarily induced by factors such as endotoxins, other MAMPs, cytokines, and growth factors

• expressed at sites of inflammation and produces prostaglandins that mediate inflammatory and pain sensation responses

COX-3

• found in greatest abundance in canine and human brain

• selectively inhibited by acetoaminophen, as well as a few other analgesic and antipyretic (anti-fever) NSAIDs

why is acetaminophen more efficacious against headache and fever than other NSAIDs?

it can cross the BBB at a high enough concentration to inhibit COX-3 in the brain

warnings associated with acetaminophen

• chronic consumption causes liver damage

• consuming alcohol with acetaminophen can cause significant liver disease

why is low-dose aspirin prescribed to some patients?

• aspirin blocks formation of some prostaglandins, including thromboxane A2

• this prevents activation of platelets for clotting initiation

• clotting prevention can protect against diseases caused by clots, like heart attack and stroke

how can aspirin contribute to gastric ulcers and bleeding?

• aspirin prevents synthesis of some prostaglandins, which contribute to production of protective mucous in the stomach

• less protection and clotting leads to gastric ulcers and bleeding

corticosteroids as anti-inflammatory drugs

• bind to glucocorticoid receptor in cytosol (bcs steroid)

• principal action is to suppress multiple inflammatory genes (like cytokines), inflammatory enzymes, adhesion molecules, and inflammatory mediator receptors

• many anti-inflammatory actions of corticosteroids are accounted for by inhibiting transcription factors that regulate inflammatory gene expression

• taking a lot of steroids to reduce inflammation leads to risk of adrenal gland stopping production of endogenous corticosteroids, causes dependence and an abrupt withdrawal can cause corticosteroid insufficiency

why do allergic symptoms get worse at night?

• corticosteroids can modulate our immune system and does so in a circadian rhythm

• higher levels during day and drops off during the night

• targets include macrophages, mast cells, neutrophils

what cytokines trigger naive T cells to differentiate into Treg cells?

TGF-beta and IL-2

what cytokines do Treg cells release and what do they do?

TGF-beta and/or IL-10, they dampen the inflammatory response

counterregulation in the immune system

• Th1 cell production makes IFN-gamma, which acts on Th2 cells and inhibits their proliteration

• Treg cells suppress differentiation of Th1 and Th2 cells

• Th2 cell production makes IL-4, which acts on Th1 cells and inhibits their proliferation

• this all works in a balance, and when you have an allergic response, you lose the balance and Th2 response overwhelms

describe the neonate and infant immune system

• their initial immune response is predominantly Th2

• throughout life with microbial exposures and serial infections, you develop a Th1 response

• balanced Th1/Th2 at about 2 years of age

describe the allergic neonate and infant immune system

• delayed maturation of Th1 capacity because of reduced microbial exposures and few serial infections (hygiene, small family size, etc.)

• unbalanced Th1/Th2, with Th2 predominating

theory of allergies developing through skin

• if you develop an immune response through the skin first, subsequent oral exposure has a hard time dampening the immune response

• if the first time you see an allergen is orally, then response is much more strongly suppressive of subsequent skin exposure

• things that impact hygiene of the skin can impact development of allergic disease, like vitamin D

how does vitamin D interact with immune system?

vitamin D (spending time outside) dampens Th2 immune response (allergic response)

which transcription factor triggers induction of Treg cell development from naive T cell?

FOXP3+

how are Treg cells induced in the GI tract and the lungs?

• GI: suppressor dendritic cells along the intestinal mucosa produce TGF-beta, causing FOXP3 to induce Treg cell formation

• lungs: macrophages near the mucosa release TGF-beta, same cascade as in GI tract

major mechanisms of Treg cell-mediated suppression

• production of inhibitory cytokines (IL-10, TGF-beta)

• APC inhibition and inhibition of innate signals (ILC2, mast cells, basophils)

• promote T cell polarization away from Th2 (downregulate Th2 differentiation and proliferation)

• inhibit isotype switching to IgE or promote switching to IgA (noninflammatory antibody)

minor mechanisms of Treg cell-mediated suppression

• cytokine deprivation

• cytolysis

mechanism of preventing allergies, newer discoveries

• kill IgE-producing B cells and introduce an adjuvant that produces IgG

• form of chemotherapy

what is the signal that drives B-cells to make IgA?

TGF-beta

FcεR1

tetrameric receptor complex that binds Fc portion of epsilon heavy chain of IgE

FCɣRIIB

• a low affinity receptor fo IgG

• expressed on mast cells

• crosslinking of antigen between IgE and IgG (via FcεR1 and FCɣRIIB) has inhibitory effect on FcεR1 signaling events, mast cell activation, and product secretion

what are allergy shots?

• major form of allergy immunotherapy, aka desensitization treatment

• theorized mechanism is that it makes more IgG against allergen, promotes inhibitory crosslinking with IgE and IgG

• another mechanism is that IgG and IgAs can compete with IgE for allergen binding, inhibiting the allergic response

how do allergy shots work? describe the treatment process

• body treats shot like vaccine

• body stops producing as many allergic antibodies against allergen

• starts with small dosage and builds over time, given weekly for a couple of months and then monthly for 3-5 years

• treatment lasts for 5-10 years after allergy shots are stopped

• if you stop the shots before 3 years, allergy symptoms typically return more quickly

monoclonal antibodies

• Abs with high antigen specificity and target a specific antigen

• useful for diagnosis and treatment of diseases

monoclonal antibody and hybridoma treatment

• immunize mouse with antigen

• fuse one isotype B plasma cell (mono) to an easy-to-grow immortal tumor cell to make a hybridoma, a hyrbid immortal B cell tumor that produces a lot of identical antibodies (clonal) against antigen of interest (monoclonal antibodies)

• immortalized plasma cell!

how can you use monoclonal antibodies to treat allergic diseases?

• immunize a mouse with IL-4, and so the monoclonal antibody treatment will target and interrupt IL-4 signaling

• stopping IL-4 stops Th2 cell response, stopping allergic response

dupilumab (aka dupixent)

• FDA-approved monoclonal antibody for eczema, asthma, nasal polyps, and eosinophilic esophagitis

• targets IL-4 receptor alpha chain, blocking signaling by IL-4 and IL-13 via steric hindrance (antagonistic)

omalizumab (aka xolair)

• FDA-approved monoclonal antibody/injection for allergic response

• selectively binds to Cε3 domain of IgE molecules, blocks IgE interaction with FcεR1 on mast cells, basophils, eosinophils

• inhibits allergen-induced mast cell and basophil degranulation

“big five” for cold and flu meds

• acetopminophen - pain reliever (COX-3 inhibitor)

• dextromethorphan - antitussive, isomer of semiseynthetic morphine derivative levomethorphan (does NOT act on mu-receptor)

• guaifenesin - expectorant, it thins excess mucus in the lungs

• phenylephrine - decreases swelling in the nose and ears (alpha-1 adrenergic receptor agonist), decongestant but doesn’t really work

• triprolidine/doxylamine succinate - first gen antihistamine (not as effective antihistamine as diphenylhydramine) that makes you drowsy

issues with pseudoephedrine

• can make some people hyper

• can be used to make speed

conducting zone

areas that filter and warm/humidifies incoming air, not directly involved in gas exchange

what are conducting zones in the human upper airway?

nose/nasal cavity, pharynx, larynx, trachea