14_allergy_and_allergic_defense.md

Allergy and Allergic Defense

Gell + Coombs classification system:

1. IgE (+ Mast cells)
2. Complement
3. Fc effector molecules
4. Various cellular effectors (lymphocytes + myeloid)

However, becoming more clear the 1/2/3 immune module system is a better classifier of allergies.

Burden of allergy disease is actually sig. Lost time from school + work.

IgE Allergies

Immediate hypersensitivity reactions - multivalent IgE bridging on surface of mast + basophils.

Predisposition to IgE reaction is atopy

Non-IgE Allergies

First exposure called sensitization.

• nasal passages (allergic rhinitis)
• eyes (conjunctivitis, refers to the conjunctiva)
• lower lungs + airways (asthma)
• gastrointestinal tract ()

Systemic reactions can spread from initial site:

• skin
• lungs (bronchospasms)
• vascular system

atopic march is the progression of reactions as someone ages

Mechanisms of sensitization

1/ T_H2 2/ IgE class switching

1/ T_H2 differentiation

• DCs in mucosal tissue sample antigen and migrate to lymph tissue
• T_H2 cells induced by IL-4, IL-5, IL-9, IL-13
• T_H2 cells produce IL-9/IL-13, positive feedback
• Mast cells + epithelial cells produce IL-33, also helping differentiation

In healthy individuals + absence of inflammation, T_regs induced by , controlling the response.

2/ T_H2 cause class switching:

• IL-4 or IL-13 -> Jak1/Jak3 -> STAT6
• CD40L (T cell) <> CD40 (B cell)

Mast cells also present CD40L + secret IL-4.

Dendritic cells, like Langerhan cells in skin, can "trap" antigens with nets of surface IgE. eg. (Fc\epsilonR1)

Antigens that cause sensitization

Actual numbers (small amounts):

• 1 ug of ragweed pollen allergen
• 20-75 ug bee venom

It is difficult to identify common characteristics of allergens.

Some are proteases: Der p 1. Allergy in 20% of people. Cleaves occludin in epithelial junction and access to subepithelial antigen presenting cells LEKT1. (lymphoepithelial Kazal type-related inhibitor). Allergy diseases caused by mutations in protease inhibitors. SPINK5 in Netherton's syndrome

• overactive kallikrein. Shedding of keratinocytes from cleaved desmosomes.
• overexpression of TSLP, TNF, ICAM
• LEKT1 also inhibits Staph. See colonization of skin with these bacteria in Netherton's syndrome patients

Transfer of 2S albumin from brazil nut into soybean caused allergic reaction discontinuation of cell ag project

Genetic predisposition

Atopic triad:

• allergic rhinoconjuctivitis
• allergic asthma
• allergic eczema

Asthma + eczema often linked. Although each individual allergy type has own linked genes. Also ethnic differences.

Risk factors for general atopy

11q12-13

\beta subunit of Fc\epsilonRI

5q31-33

1/ IgE class switching, mast + eosinophil activation

IL-4, IL-5, IL-9, IL-13

2/ TIM family

(T-cell, Immunoglobulin domain, Mucin domain) Associated with airway hyperreacrtivity, not only to specific allergens

Expressed by T_H1 + T_H2 cells https://www.nature.com/articles/nri1111

3/ p40

Common subunit of IL-12 + IL-23

4/ \beta-andrenergic receptor

Smooth muscle contraction in airways

Risk factors for specific antigens

In contrast to above genes, which dysregulate immune response downstream of arbitrary antigen, these are MHC allele variants for specific allergens

eg. HLA-B15:02 + peptide react to carbamazepine (seizure medication) leading to rashes over the body that lead to scalding

Specific allergy disease mutations

• fillagrin (helps make "cornifying" keratinocytes tight) involved in eczema + asthma. 7-10% of Caucasians have fillagrin mutation.
• metalloproteinase ADAM33 in bronchial smooth muscle cells

Environmental risk factors

Rural Africans show less atopy than American Africans.

hygiene hypothesis - exposure to pathogens early in childhood skews immune development towards type 1 immune response from type 2.

However, negative correlation between atopy + helminth infections. Hygeine hypothesis has evolved to include all three immune response types => trigger TGF-\beta + IL-10 ->

• less differentiation of all three helper types and
• increased production T_reg

Some pathogens help and others increase risk:

• RSV skews IFN-\gamma towards IL-4 (1->2) and increase asthma development inkids

Diesel exhaust increases ROS, like ozone, increasing IgE production 20-50 fold

• dysfunction in genes that prevent oxidative stress (GSTP1, GSTM1) linked to worse asthma
• inhibitors for eg. NADPH, might help asthma

T_regs play important role

• T_regs isolated from atopic individuals when cocultured with T_H2 cells are less effective a repressing cytokines
• Mice defficient in Foxp3 have greater risk for atopy

Treatments:

• IDO
• IL-35 / Il-27 cyotkine therapy, which inhibit T_H2

Mechanisms

1/ IgE bound to surface 2/ Mast cells release factors:

• histamine (from granules)
• prostaglandin
• leukotriene
• PAF (platelet activating factor) 3/ Physiological effect of factors 4/ Recruitment of effector cells

Different IgE receptors

Immunoglobulin family Fc\epislonRI

Mast cells + basophils Activated with familiar tyrosine kinase -> ITAM -> Syk -> downstream effectors Increased IgE increases surface expression

C-type lectin family Fc\epsilonRII

Many immune + epithelial cell types, including T + B cells.

More on mast cells

Mast cells => IgE inflammatory responses (Kit knockout mice do not produce these responses)

Activated by these factors: stem-cell factor / Kit ligand IL-3 IL-4 / IL-9 (type 2)

Granule contents

Degranulation is an important component of function:

1/ histamine (short lived vasoactive amine) 2/ serine esterase (protease) -> tryptase, chymase, cathepsin G

• Histamine acts through 4 GPCRs.
• Histamine causes blood flow + vessel permeability.
• Leads to edema + local inflammation.

What do the proteases do? Activate metalloproteinase that destroy venom. Also break down tissue...

Types

Location and protease content

MC_T -> tryptase, in mucosal epithelia (lamina propria) MC_CT -> tryptase + chymase, in submucosa (deeper than the lamina propria)

Eicosanoids

Distinct from granule contents. These are lipid mediators synthesized from common pathway.

AA cleaved from membrane:

• Cyclooxygenase -> prostaglandin, thromboxane
• Lipooxygenase -> leukotriene

Prostaglandin is important in asthma C4,D4,E4 leukotrienes sustain inflammation

Cytokines

TNF-\alpha - some stored and some synthesized Recruit immune cells (and cause epithelial cells to express adhesion molecules, helping recruitment)

IL-4 -> Type II

Eosinophils

• <6% of cells in healthy people
• IgG, IgE, CR1 + CR3 receptors
• Two main effector functions:
• granule contents - proteases and ROS
• synthesize mediators (prostaglandin, leukotriene + cytokines)

How do they cause allergies?

• Kill T_H1 cells (IDO)G. T_H2 expansion might be in part explained by this.

• Located in submucosa

• Few are present without infection

Production and migration are distinct.

• GM-CSF + IL-5 cause production in bone marrow
• Migration governed by eotaxins: CCL11, CCL24, CCL26

Mice can have eosinophilia systemically with just lots of IL-5.

CCR3 (eotaxin receptor) is quite promiscuous and can bind to other chemokines

Basophils:

• similar growth factors
• reciprocal control by cytokines
• eosinophil major basic protein

Effects of IgE response

Synthetic introduction of antigen (intradermal antigen challenge) in lab leads to two distinct stages:

Immediate reaction is characterized primarily by histamin acting on different tissues:

Airway

• vascular permeability + blood flow => edema
• edema + smooth muscle contraction => airway narrowing

Vascular

• extravasation (leakage of fluid from blood vessel) -> edema
• reflex vasodilation (increase of blood vessel size from drug). Acts on nerve endings, but effect is on vessels. wheal-and-flare reaction (wheal is swollen bump)

Late-stage reaction occurs 3-9 hours. Cellular recruitment and continued synthesis of factors

(Again primarily caused by synthetic high-dose antigen and unlikely to happen naturally)

Chronic allergic inflammation is the natural long timeline allergy state

Persistent T_H2 response.

T_H2 cells release calcitonin + VEGF with effect on blood vessels.

• Can actually change size and number of cells (hypertrophy + hyperplasia of smoooth muscle cells respectively
• airway tissue remodeling

Think of allergic response as starting from the site where mast cells degranulate.

Anaphylaxis

Mast cells are often associated with blood vessels Widespread release of eg. histamine on many vessels is anaphylaxis

Can also be caused by autoantibody, to IgE or Fc\epsilon,

Symptoms:

• Utricaria - distributed version of wheal + flare
• Anaphylactic shock - lowered blood pressure + constricted airways
• Can be treated with epinephrine or \beta-adrenergic receptor modulation, relaxing blood vessels

Penicillin and structurally related drugs can cause anaphylaxis.

Hapten - \beta-lactam ring (usually essential for antimicrobial activity) binds to host proteins to form covalent conjuages

• T cell response from self-protein conjugates
• B cell response (from penicillin conjuages activating BCR)
• Can cross link IgE on Mast cells

Asthma + Rhinitis?

• allergic rhinitis
• allergic conjuctivitis
• allergic asthma

All caused by mast cell degranulation in response to allergens (within) pollen. Edema Mucus (rich in recruited lymphocytes)

Characteristiscs of chronic inflammation:

• hypertrophy
• hyperplasia
• eventually fibrosis

Why is fibrosis a bigger deal than smooth muscle cell remodeling?

• more permanent
• does not respond to asthma medication
• progressive, positive feedback

There are different asthma endotypes (different cell types + molecules):

• common allergic asthma
• exercise induced asthma
• neutrophil predominant
• eosinophil predominant
• steroid resistant sever

How do you get which type? Allergen sensitized with + genetic factors

Mechanisms of common asthma

• Familiar mast thing

Epithelial cell stimulation directly by TLRs:

• IL-25, IL-33 (This explains where some of the type 2 cytokines even come from)
• CCL5 / CCL11 <> CCR3 on T_H2, eosinophil, basophil
• ILCs activated and express the familiar array (4, 5, 9 , 13)

Important facts about this biology:

• TGF-\beta helps drive airway remodeling of epithelial cells
• IL-9/IL-13 leads to goblet cell metaplasia of epithelial cells (replacable differentiation into mature cell type)
• iNKT cells (CD1d-restricted invariant) somehow are involved

You can actually get allergic disease without allergen. Shown with mice defficient in T_H2.

Similarly chronic inflammation triggered by allergen can continue by other factors:

• smoke, sulfur dioxide
• virus, bacterial infections of respiratory tract

Rhinovirus infection is main source of asthma hospitilizations / death

Food allergies

• IgE mediated
• non-IgE mediated (celiac)
• intolerance (metabolic)
• idiosyncratic (unknown)

Peanut allergies Mast cell in gut -> fluid movement + muscle contraction Systemic effects lead to urticaria, asthma, systemic anaphylaxis

Because allergens are generally pepsin resistant, adults who suppress this with (eg. antacids) may have late onset allergies

Non IgE Mediated Allergies

Type 1 and Type 3

These aren't really allergic diseases?

Drugs covalently bind to cells

Platelets - thrombocytopenia Red blood cells - hemolytic anemia

Cleared by Fc\gamma receptors from macrophages in the spleen.

Immediate antibody mediated hypersensitivity

Conserved steps:

1/ Antibodies clump with antigen 2/ Complement (C5a + C3a) are activated 3/ Leukocytes w/ Fc\gammaRIII + CR activated; widespread tissue damage.

Soluble antigens can lead to large clumps of immune complexes:

• large clumps are cleared by monocytes (by fixing complement)
• the smaller ones get deposited on blood vessel and cause damage

Arthus reaction

Local immune response to spot in skin where antigen injected.

Serum sickness

• Originated when immunized horse serum was used to treat disease like Streptococcus pneumoniae
• 7-10 days after injection for class switched IgG reaction to occur (Normal class switching takes 3-5 days. Antigen processing + multiple discrete antigen recognition is involved in lengthening the timeline.)
• Same steps as above, leading to mast cell degranulation

Serum sickness in monoclonal tx

Can result from improperly humanized monoclonals (eg. in anti-TNF-\alpha HUMIRA for RA).

Humanization fails for patients that have strange allotypes (constant region variations). One effect is more rapid clearance of tx and reduced effect.

• Bacterial reaction persist and continue to produce antigen
• Air pathogen exposure from dust/mold -> farmer's lung

Delayed-type cell mediated hypersensitivity

T_H1 + CD8 T cells

Mantoux test - test for tuberculosis. Inject small amounts of tuberculin. Elicits local type I response.

allergic contact dermatitis

Like IgE, there are two phases: 1/ sensitization and 2/ elicitation

Langerhan cells, specialized APC / DCs, mediate sensitization in cutaneous allergies.

T_H1 response cyotkines in detail:

• IFN-\gamma: Macrophage activation + adhesion molecule expression on blood vessels
• TNF-\alpha + lymphotoxin: Local tissue destruction. Also adhesion on vessels.
• Il-3/GM-CSF: monocyte production in bone marrow

(haptens - small proteins that are immunogenic after being bound to carrier proteins. Eg. penicillin or )

Poison oak causes CD8 mediated skin dermatitis with soluble proteins that pass through membrane + present on MHCI. Comes from urushiol oil.

Insect bites can cause delayed-type hypersensitivity - itchy bump. (Also cause urticaria, swelling, anaphylactic shock from immediate hypersensitivity)

Metal ions (divalent cations)

Examples of n-valent cations

Univalent cations: Have a charge of 1, such as the Cs+ cation Divalent cations: Have a charge of 2, such as the Ca2+ cation Trivalent cations: Have a charge of 3, such as the Fe3+ cation

Celiac disease

Both allergic and autoimmune disease.

Pathology:

• Loss of finger-like villi formed by epithelial cells
• Hyperplasia of crypt cells at elbows of epithelial folds

\alpha-gliadin -> deamidation by transglutaminase (tTG) -> binds to HLA-DQ2

Autoantibodies found against tTG but don't seem to do anything.

Why don't we get oral tolerance, eg. T_regs. Not all HLA-DQ2 variant patients develop celiac disease so not that molecule alone.

• other unknown genetic factors (down syndrome 6x more likely)
• gliadin peptides might cause epithelial cells to release IL-15 + express MIC-A -> NKG2D mediated CD8 T cell -> intenstinal damage + more causal CD4 T cell activation