Hypersensitivity types

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Hypersensitivity Reactions — Gell & Coombs Classification

The Gell and Coombs classification (1963) divides hypersensitivity into four types based on the immunological mechanism involved.

Type I — Immediate (IgE-Mediated)

Feature	Detail
Mediator	IgE antibodies
Cells involved	Mast cells, basophils, eosinophils
Onset	Minutes (15–30 min)
Mechanism	Antigen cross-links IgE bound to FcεRI on mast cells → degranulation → release of histamine, leukotrienes, prostaglandins
Examples	Anaphylaxis, allergic asthma, allergic rhinitis, urticaria, food allergies, bee sting allergy
Treatment	Epinephrine (anaphylaxis), antihistamines, corticosteroids, desensitization

Two phases:

Early phase (minutes): histamine-driven — itching, urticaria, bronchoconstriction
Late phase (4–12 h): leukotrienes/cytokines — sustained inflammation

Type II — Cytotoxic / Antibody-Mediated

Feature	Detail
Mediator	IgG or IgM antibodies directed against cell surface or extracellular matrix antigens
Mechanism	Antibody binding → complement activation (CDC), ADCC, or opsonization and phagocytosis
Onset	Hours
Examples	Hemolytic transfusion reactions, hemolytic disease of the newborn (Rh incompatibility), autoimmune hemolytic anemia, Goodpasture syndrome, Graves' disease, myasthenia gravis

*Graves' disease (stimulatory antibody) and myasthenia gravis (blocking antibody) are sometimes classified as Type II variants since the antibody targets a receptor rather than destroying the cell.

Type III — Immune Complex–Mediated

Feature	Detail
Mediator	IgG/IgM antigen-antibody immune complexes deposited in tissues
Mechanism	Complement activation → neutrophil recruitment → release of proteases and ROS → tissue damage
Onset	Hours to days
Examples	Serum sickness, systemic lupus erythematosus (SLE), post-streptococcal glomerulonephritis, rheumatoid arthritis, Arthus reaction (local), hypersensitivity pneumonitis, erythema nodosum leprosum (ENL)
Key test	Low complement (C3, C4), positive ANA/anti-dsDNA, granular immunofluorescence

Type IV — Delayed-Type Hypersensitivity (DTH) / Cell-Mediated

Feature	Detail
Mediator	Sensitized T lymphocytes (CD4⁺ Th1 or CD8⁺ CTL) — no antibody involved
Mechanism	Antigen-presenting cells present antigen to primed T cells → cytokine release (IFN-γ, TNF) → macrophage activation and tissue injury
Onset	48–72 hours (hence "delayed")
Examples	Contact dermatitis (poison ivy, nickel), tuberculin skin test (Mantoux), granulomatous diseases (TB, sarcoidosis, leprosy), graft rejection, type 1 diabetes mellitus
Sub-types
— Type IVa	Th1-mediated (IFN-γ → macrophage activation); TB, contact dermatitis
— Type IVb	Th2-mediated (IL-4, IL-5 → eosinophils); chronic allergic inflammation
— Type IVc	Cytotoxic T cell (CTL)-mediated; Stevens-Johnson syndrome
— Type IVd	T cell–mediated neutrophil recruitment (IL-8, GM-CSF); pustular psoriasis

Quick Comparison Table

	Type I	Type II	Type III	Type IV
Synonym	Immediate / Anaphylactic	Cytotoxic	Immune complex	Delayed / Cell-mediated
Antibody	IgE	IgG / IgM (anti-cell)	IgG / IgM (complexes)	None
Complement	No	Yes (usually)	Yes	No
Effector	Mast cells, basophils	NK cells, phagocytes	Neutrophils	T cells, macrophages
Onset	Min–hours	Hours	Hours–days	48–72 h
Prototype	Anaphylaxis	Transfusion reaction	Serum sickness	Tuberculin test

Memory Aids

Type I = Immediate, IgE
Type II = II-cell (cytotoxic, targets cell surfaces)
Type III = IIImune complexes
Type IV = IV = four letters in "cell" (T-cell mediated, delayed)

Many clinical diseases involve more than one type (e.g., SLE involves III + II; rheumatoid arthritis involves III + IV).

I am studying allergology so give me every single point about Allergens

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Here is a comprehensive, exam-level reference on allergens for allergology study.

Allergens — Complete Reference for Allergology

1. Definition

An allergen is an antigen (almost always a protein or glycoprotein) capable of inducing an IgE-mediated (Type I hypersensitivity) immune response in a genetically susceptible (atopic) individual. Most are harmless environmental proteins that the immune system misidentifies as threats.

2. Properties of an Allergen

For a substance to act as an allergen, it typically possesses:

Property	Details
Protein/glycoprotein nature	Nearly all allergens are proteins (MW 5–70 kDa); carbohydrates alone rarely sensitize
Low molecular weight	Optimally 10–70 kDa — small enough to penetrate mucosa, large enough for cross-linking IgE
Water solubility	Facilitates diffusion across mucosal surfaces
Enzymatic activity	Many allergens are proteases (e.g., Der p 1 from dust mite) that disrupt epithelial tight junctions
Low dose exposure	Sensitization occurs at trace quantities
Stability	Must survive environmental conditions to reach sensitizing surfaces
Carrier effect	Can bind to particles (pollen, dust) for airborne transport

3. Nomenclature of Allergens

The WHO/IUIS (International Union of Immunological Societies) Allergen Nomenclature uses a standardized system:

Format: First 3 letters of genus + first letter of species + Arabic number

Example	Source
Der p 1	Dermatophagoides pteronyssinus allergen 1 (house dust mite)
Fel d 1	Felis domesticus allergen 1 (cat)
Bet v 1	Betula verrucosa allergen 1 (birch pollen)
Ara h 1	Arachis hypogaea allergen 1 (peanut)
Alt a 1	Alternaria alternata allergen 1 (mold)

4. Classification of Allergens

4.1 By Route of Exposure

Route	Examples
Inhaled (aeroallergens)	Pollen, dust mite, mold spores, pet dander, cockroach
Ingested (food allergens)	Peanut, tree nuts, milk, egg, wheat, soy, fish, shellfish
Contact (cutaneous)	Nickel, latex, fragrances, cosmetics (Type IV mostly)
Injected (parenteral)	Venom (bee, wasp), drugs (penicillin), blood products
Occupational	Latex (healthcare), flour (bakers), isocyanates, animal proteins

4.2 By Source

A. Aeroallergens

1. Pollen

Major cause of allergic rhinitis and asthma
Seasonal (pollinosis/hay fever)
Categories:
- Tree pollen (spring): Birch (Betula), Oak, Olive, Plane — Bet v 1 is the most studied
- Grass pollen (late spring/summer): Timothy grass (Phleum pratense — Phl p 1, 5), Bermuda grass, Ryegrass
- Weed pollen (late summer/autumn): Ragweed (Ambrosia — Amb a 1), Mugwort (Artemisia — Art v 1), Parietaria
Characteristics: 10–100 μm in size; released in dry, windy conditions; peak morning hours
Paucimicronic particles (sub-pollen particles <5 μm) can reach the lower airway

2. House Dust Mite (HDM)

Most important perennial indoor allergen worldwide
Species: Dermatophagoides pteronyssinus (Europe), D. farinae (North America), Blomia tropicalis (tropical)
Source of allergen: fecal particles and body fragments
Key allergens:
- Der p 1 (group 1): cysteine protease — disrupts epithelial barrier, cleaves CD23 on B cells
- Der p 2 (group 2): MD-2-like protein, signals via TLR4 pathway
- Der p 23: peritrophic membrane protein, potent sensitizer
Thrives in mattresses, carpets, upholstered furniture
Optimal conditions: temperature 20–25°C, humidity >55%

3. Animal Allergens

Cat (Felis domesticus): Fel d 1 (uroglobin secretoglobin) — secreted by sebaceous and salivary glands; airborne, sticky, persists for months; 20 μg/g in settled dust
Dog (Canis familiaris): Can f 1 (lipocalin), Can f 5 (kallikrein — male-specific)
Rodents (mice, rats): Mus m 1 (urinary protein); major occupational allergen in lab workers
Cockroach: Bla g 1, Bla g 2 (aspartate protease) — major urban allergen, linked to inner-city asthma
Horse, cow, pig: Occupational importance

4. Mold (Fungal) Allergens

Outdoor: Alternaria alternata (Alt a 1), Cladosporium herbarum (Cla h 1) — peak in warm months; strongly linked to severe asthma
Indoor: Aspergillus fumigatus (Asp f allergens), Penicillium, Trichosporon
Spore sizes: 2–20 μm — reach lower airways
Allergic bronchopulmonary aspergillosis (ABPA): Th2-mediated response to Aspergillus antigens

B. Food Allergens

Big 9 (USA FDA — 2023): Milk, Egg, Peanut, Tree nuts, Fish, Shellfish, Wheat, Soy, Sesame

Allergen	Key Protein	Notes
Cow's milk	Casein, β-lactoglobulin, α-lactalbumin	Most common in infants; β-lactoglobulin absent in human milk
Egg	Ovomucoid (Gal d 1), Ovalbumin (Gal d 2)	Ovomucoid is heat-stable → no tolerance on cooking
Peanut	Ara h 1 (vicilin), Ara h 2 (2S albumin), Ara h 3 (legumin), Ara h 8 (PR-10)	Ara h 2 most predictive of severe reactions; usually lifelong
Tree nuts	Cor a (hazelnut), Jug r (walnut), Ana o (cashew)	Cross-reactive with pollen (Bet v 1 homologs)
Fish	Gad c 1 (parvalbumin) — Gadus callarias	Heat-stable; cross-reactive across species
Shellfish	Pen a 1 (tropomyosin) — shrimp	Cross-reactive with house dust mite (tropomyosin)
Wheat	Tri a 19 (ω-5 gliadin), Tri a 14 (nsLTP)	ω-5 gliadin → wheat-dependent exercise-induced anaphylaxis (WDEIA)
Soy	Gly m 4 (PR-10 — Bet v 1 homolog), Gly m 5 (β-conglycinin)	Gly m 4 → birch pollen–soy OAS
Sesame	Ses i 1 (2S albumin)	Increasing prevalence; listed as 9th major allergen

C. Venom Allergens (Hymenoptera)

Insect	Key Allergens
Honey bee (Apis mellifera)	Api m 1 (phospholipase A2), Api m 2 (hyaluronidase), Api m 10 (icarapin)
Vespid wasps (Vespula)	Ves v 1 (phospholipase A1), Ves v 5 (antigen 5)
Yellow jacket	Same as Vespula — Ves v 5 most diagnostically important
Bumblebee	Bomb p 1, Bomb p 4 — important in greenhouse workers
Fire ant	Sol i 1–4

Cross-reactive carbohydrate determinants (CCDs) cause IgE cross-reactivity between bee and wasp venoms in ~50% of cases — component-resolved diagnostics (CRD) is essential.

D. Drug Allergens

Drug	Mechanism	Key Allergen/Hapten
Penicillin	Hapten — penicilloyl group (major determinant) binds serum proteins	Pen G, Pen V; cross-reactivity with cephalosporins (~2%)
Cephalosporins	Similar β-lactam ring haptenation	R1 side chain determines cross-reactivity
NSAIDs	Pharmacological (COX-1 inhibition, not IgE) — most cases	Aspirin, ibuprofen → leukotriene overflow
Muscle relaxants	IgE-mediated; quaternary ammonium groups	Rocuronium, succinylcholine
Radiocontrast media	Non-IgE (direct mast cell activation)	Iodinated contrast
Biologics	Anti-drug antibodies (IgE or IgG4)	Cetuximab (anti-Gal-α-1,3-Gal — cross-reactive with tick bite α-gal syndrome)

E. Occupational Allergens

Occupation	Allergen
Bakers/millers	Wheat flour (Tri a 14, Tri a 19), α-amylase (Aspergillus)
Healthcare workers	Latex (Hev b 1–13), psyllium, glutaraldehyde
Lab animal workers	Mouse urinary proteins (Mus m 1), rat (Rat n 1)
Hairdressers	Persulfate compounds, PPD (para-phenylenediamine — Type IV)
Painters/spray workers	Isocyanates (MDI, TDI) — highly potent respiratory sensitizers
Farmers	Storage mites (Lepidoglyphus destructor — Lep d 1), grain dust, animal dander

5. Molecular Classification — Allergen Superfamilies/Protein Families

Protein Family	Allergen Examples	Properties
Prolamin superfamily (2S albumins, nsLTPs, prolamins)	Ara h 2, Tri a 14, Pru p 3	Heat/digestion stable → systemic reactions
Cupin superfamily (vicilins, legumins)	Ara h 1, Ara h 3	Stable storage proteins
PR-10 proteins (Bet v 1 homologs)	Bet v 1, Mal d 1, Gly m 4, Ara h 8	Heat/digestion labile → oral allergy syndrome
Profilins	Bet v 2, Phl p 12, Act d 9	Pan-allergens; cause extensive pollen-food cross-reactivity
Tropomyosins	Pen a 1 (shrimp), Der p 10 (dust mite)	Cross-reactivity shrimp↔mite
Lipocalins	Fel d 4 (cat), Can f 1/2/6 (dog), Mus m 1	Bind small hydrophobic ligands
Serum albumins	Bos d 6 (cow), Can f 3 (dog)	Cross-react across mammals (pork-cat syndrome)
Parvalbumins	Gad c 1 (fish)	Heat-stable; cause fish cross-reactivity
Tropomyosin	Pen a 1	Pan-allergen for crustaceans/insects
Defensin-like	Hev b 5 (latex)

6. Cross-Reactivity & Pollen-Food Allergy Syndrome (PFAS)

Cross-reactivity occurs when IgE antibodies raised against one allergen recognize structurally homologous proteins in another source.

Major Cross-Reactive Syndromes

Syndrome	Primary Sensitizer	Cross-Reactive Foods
Birch-fruit syndrome (PFAS)	Birch pollen (Bet v 1)	Apple (Mal d 1), pear, peach, cherry, hazelnut, carrot, celery, soy
Grass-cereal syndrome	Grass pollen	Wheat, corn
Mugwort-celery-spice	Mugwort (Art v 1, Art v 3)	Celery, carrot, fennel, coriander, mustard
Latex-fruit syndrome	Latex (Hev b 5, 6, 8)	Banana, avocado, kiwi, chestnut, papaya
Shrimp-mite syndrome	HDM tropomyosin (Der p 10)	Shrimp, crab, lobster
α-Gal syndrome	Tick bite (Amblyomma americanum) sensitization	Red meat (beef, pork, lamb) — delayed reaction 3–6 h
Pork-cat syndrome	Cat serum albumin (Fel d 2)	Pork, beef (serum albumins cross-react)
Fish-bird syndrome	Bird serum albumin	Fish (parvalbumin cross-reactivity less clear — misnomer)

7. Sensitization vs. Allergy

Term	Definition
Sensitization	Presence of specific IgE to an allergen (detected by SPT or serology) WITHOUT clinical symptoms
Allergy	Sensitization + clinical symptoms upon re-exposure
Atopy	Genetic predisposition to produce IgE against environmental allergens
Monosensitization	IgE to a single allergen source
Polysensitization	IgE to multiple unrelated allergen sources

8. Mechanism of Sensitization (Immunological Pathway)

1. Allergen exposure → penetrates epithelial barrier (aided by protease activity of some allergens)
2. Epithelium releases alarmins: TSLP, IL-25 (IL-17E), IL-33
3. Alarmins activate Group 2 Innate Lymphoid Cells (ILC2s) → IL-4, IL-5, IL-13
4. Antigen presentation by dendritic cells → naïve T cells polarize to Th2
5. Th2 cytokines:
   - IL-4 → B cell class switching to IgE
   - IL-5 → eosinophil differentiation and survival
   - IL-13 → mucus hypersecretion, smooth muscle effects
6. Plasma cells secrete allergen-specific IgE into circulation
7. IgE binds high-affinity FcεRI receptors on mast cells and basophils → SENSITIZED STATE
8. Re-exposure: Allergen cross-links IgE on mast cells → degranulation → mediator release

Mediators released on activation:

Preformed (immediate): Histamine, tryptase, heparin, chymase
Newly synthesized: Prostaglandin D2 (PGD2), leukotriene C4/D4/E4, PAF
Cytokines (late phase): TNF-α, IL-4, IL-5, IL-13

9. Component-Resolved Diagnostics (CRD)

CRD uses purified or recombinant individual allergen molecules rather than crude extracts to:

Identify genuine sensitization vs. cross-reactivity
Predict severity of reactions
Guide immunotherapy decisions

Marker	Clinical Significance
Ara h 2 (peanut 2S albumin)	Predicts severe peanut reactions
Ara h 8 (peanut PR-10)	Predicts mild OAS only (labile protein)
Bet v 1 (birch PR-10)	Primary sensitizer for PFAS — OAS only
Phl p 1 + 5 (grass)	Genuine grass sensitization → good candidate for AIT
Alt a 1 (Alternaria)	Severe asthma risk marker
Api m 1 vs. Ves v 5	Differentiates bee vs. wasp genuine sensitization
Hev b 5, 6.01 (latex)	Confirms true latex allergy
nBet v 1	PR-10 family — OAS risk

10. Factors Influencing Allergenicity

Host Factors

Genetics: HLA alleles, FcεRI polymorphisms, filaggrin (FLG) mutations (skin barrier defects → epicutaneous sensitization)
Atopic predisposition: Family history
Microbiome: Dysbiosis → reduced regulatory T cell induction
Age at exposure: Early childhood exposure (oral tolerance) vs. sensitization window
Route of exposure: Epicutaneous > airway > oral in terms of sensitization risk

Environmental Factors

Hygiene hypothesis: Reduced microbial exposure in early life → Th2 bias (less Th1/Treg counter-regulation)
Dose and duration: Both very low and very high chronic exposures may reduce sensitization; intermediate doses sensitize
Pollution: Diesel exhaust particles act as adjuvants — enhance IgE responses, increase allergen penetration
Climate change: Longer pollen seasons, higher pollen counts, altered mold distribution
Adjuvants: LPS, proteases in allergen preparations influence sensitization magnitude

11. Specific Allergen Types in Detail

Superallergens

Stimulate large fractions of T or B cells non-specifically
Staphylococcal enterotoxins (SEB, SEA) — act as superantigens on T cells; amplify atopic dermatitis; induce polyclonal IgE production
Protein A of S. aureus — cross-links IgE on mast cells via Fab variable regions

Pan-Allergens

Widely distributed proteins causing broad cross-reactivity:

Profilins (Bet v 2): plant profilins → broad pollen and food cross-reactivity
Polcalcins (Bet v 4, Phl p 7): calcium-binding proteins in pollen; cause multiple pollen sensitization
nsLTPs (Pru p 3): found across plant kingdom; heat-stable; cause systemic food reactions
Tropomyosin: invertebrate cross-reactivity (shellfish, dust mite, insects)

Recombinant vs. Natural Allergens

	Natural (n)	Recombinant (r)
Source	Purified from biological material	Produced in bacterial/yeast expression systems
Purity	Variable	High
Glycosylation	Present (CCD issues)	Often absent (unless mammalian expression)
Use	Diagnostics, some AIT	Research, CRD, next-gen AIT

12. Routes of Allergen Challenge (Clinical)

Route	Purpose	Example
Skin prick test (SPT)	Screening — detects sensitization	Standard 1st-line test
Intradermal test (IDT)	Higher sensitivity; drug/venom allergy	Second-line after negative SPT
Oral food challenge (OFC)	Gold standard for food allergy	Double-blind, placebo-controlled (DBPCFC)
Nasal provocation test	Confirm allergic rhinitis diagnosis	Rhinomanometry endpoint
Bronchial provocation test	Confirm allergen-induced asthma	FEV1 endpoint
Patch test	Type IV (contact allergy)	48–96h reading
Basophil activation test (BAT)	In vitro; CD63/CD203c upregulation	Useful when SPT/OFC contraindicated

13. Allergen Immunotherapy (AIT) — Allergen Perspective

Principle: Repeated administration of increasing doses of the causative allergen to induce immune tolerance.

Form	Route	Key Notes
SCIT (Subcutaneous)	Subcutaneous injection	Standard; updosing + maintenance phases
SLIT (Sublingual)	Sublingual drops/tablets	Safer; HDM and grass tablets FDA-approved
OIT (Oral Immunotherapy)	Ingestion	Food allergy (peanut — Palforzia FDA-approved)
EPIT (Epicutaneous)	Skin patch	Peanut (Viaskin — investigational)

Mechanisms of tolerance induction:

Increase in regulatory T cells (Tregs) → IL-10, TGF-β
Shift from IgE to IgG4 (blocking antibody)
Mast cell and basophil hyporesponsiveness
Dendritic cell tolerogenic phenotype shift

14. Measurement & Diagnosis of Allergen Sensitization

Test	Principle	Notes
Serum specific IgE (sIgE)	ELISA/fluorescent enzyme immunoassay (ImmunoCAP)	Quantitative kU/L; not always correlates with clinical severity
Total IgE	Useful if very high (parasites, ABPA); low specificity for allergy alone
Skin Prick Test	Allergen extract introduced into epidermis; wheal ≥3 mm = positive	Affected by antihistamines
Basophil Activation Test	CD63/CD203c flow cytometry	Useful for drugs, food, venom
CRD (ImmunoCAP ISAC)	Simultaneous testing of 112 allergen components on microarray	Broad sensitization profiling
Tryptase	Marker of mast cell activation; elevated in anaphylaxis	Elevated basally in mastocytosis

15. Emerging Concepts

Concept	Description
Epicutaneous sensitization	Broken skin barrier (FLG mutations in atopic dermatitis) allows allergen penetration → sensitization before oral exposure → explains sequence atopic dermatitis → food allergy ("atopic march")
Dual allergen exposure hypothesis	Early oral exposure → tolerance (LEAP trial); cutaneous exposure → sensitization
α-Gal syndrome	IgE to galactose-α-1,3-galactose (mammalian carbohydrate) induced by tick bites → delayed red meat allergy; Cetuximab reactions
MRGPRX2	Non-IgE receptor on mast cells → pseudo-allergic reactions to drugs (opioids, muscle relaxants, fluoroquinolones)
Sensitization without allergy	>50% of sensitized individuals have no clinical symptoms — highlights role of threshold and tissue context
Climate change impact	Extended pollen seasons, geographic spread of new allergen sources (e.g., ragweed northward expansion in Europe)
Adjuvant-free AIT	Hypoallergens, peptide immunotherapy, tolerogenic nanoparticles under investigation

Summary Mind Map (Key Relationships)

ALLERGEN
├── Properties: protein, 10–70 kDa, soluble, often proteolytic
├── Sources
│   ├── Aeroallergens: pollen, HDM, mold, animal dander, cockroach
│   ├── Food: Big 9, PR-10 (OAS), 2S albumins (systemic)
│   ├── Venoms: Hymenoptera
│   ├── Drugs: penicillin, NSAIDs, contrast
│   └── Occupational: latex, isocyanates, flour
├── Molecular families: prolamins, PR-10, profilins, lipocalins, tropomyosins
├── Cross-reactivity: birch-fruit, latex-fruit, shrimp-mite, α-gal
├── Sensitization pathway: alarmin → ILC2 → Th2 → IgE → mast cell priming
├── Diagnosis: SPT, sIgE, CRD, BAT, challenge tests
└── Treatment: AIT (SCIT, SLIT, OIT, EPIT) → Tregs, IgG4, tolerance

This covers the full scope of allergens as studied in allergology — from molecular biology and classification through clinical diagnostics and immunotherapy. Let me know if you want any section expanded further (e.g., specific allergen families, CRD interpretation, AIT protocols).

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