Allergy

Question 1

Hypersensitivity

Answer 1

Inappropriate response to innocuous substances

Question 2

Type 1

-eg

Answer 2

Immediate hypersensitivity. IgE mediated through mast cell degranulation.
- asthma, rhinitis, systematic anaphylaxis

Question 3

Type 4

Answer 3

T cell mediated.

1) CD4 delayed hypersensitivity. Macrophage, cytokines mediated inflammation.

Question 4

IL-4

Answer 4

Induce Th2 differentiation
Proliferate B cell
Class switching to IgE

Question 5

Early Reaction

-eg

Answer 5

Rapid, acute symptoms
Mast cell mediated.
- copd (damaged alveoli)

Question 6

Late Reaction

Answer 6

6-8 hours. May resolve on its own.
Th2, eosinophils mediated.
- cat dander

Question 7

Eosinophils

1) asthma. Interaction of cytokines

Answer 7

Cytokines mediate. Il-4 Il-5 Il-13 induce eosinophilia, drive airway inflammation

Question 8

Allergic people allergen presentation

-2x

Answer 8

1) APC express more high-affinity FcERI IgE receptors

2) thus presents antigen for T cell activation more efficiently, degranulate mast cells at lower levels of antigen

Question 9

Th2 function allergy

Answer 9

Th2 protect against helminths, but create pathological response.

• intestinal mucus secretion, peristalsis(wave of contractions to move food)
• Th2 cytokines, Il-4, Il-13 involved in airway inflammation

Question 10

Il-9

- in asthma

Answer 10

Promote IgE class-switching, mast cell recruitment, mucus production

Question 11

Steroid in asthma

1) steroid sensitive/refractory.
2) Th17
3) therapy (2effects, cons)

Answer 11

1) Steroid refractory asthma patients high in Il-17.
2) Th17 induce allergic airway disease. Il-17 induce fibroblasts to produce chemokines, recruit monocytes
3) induce Il-10 anti-inflammatory synthesis. Glucocorticoid insensitive poor response to therapy. Inhibit Th2 response.
- effective but only as control not cure, hard to comply with high doses prolonged period.

Question 12

Immunodulation therapies

- eg 3x

Answer 12

Anti-histamine
Glucocorticoids
Tregs

Question 13

Therapy

- anti-Il-5

Answer 13

No significant effect on late phase response, but reduced eosinophil levels. For high eosinophilic asthma

Question 14

Immunotherapy

1) allergen immunotherapy
2) early exposure
3) natural tolerance

Answer 14

1) allergen build up and maintenance. Increased dose over time and continue for years
- effective in patients with high IgE
- reduces sensitisations to additional allergens.
- adverse risk of swelling
- improvements combine with adjuvants that enhance treg/il-10 response
2) early exposure to peanuts. Cohort study consumption group 0 prevalence of allergy
3) natural tolerance to bee stings. Increased Il-10. Decreased Th1/2 like Il-4, IFNy Il-13 days after bee stings.

Question 15

Therapy

- Lebrikizumab

Answer 15

Anti Il-13. Lowered forced expiratory volume for asthma. Used when glucocorticoids ineffective

Question 16

Therapy

- dupilumab

Answer 16

Anti Il-4 receptor antibody, blocks common Il-4 and Il-13 signalling, stops JAK/STAT pathway.
- reduces differentiation of keratinocytes so can proliferate and heal
Drug for atopic dermatitis.

Question 17

Vitamin D

Answer 17

Important in increasing sensitivity to steroids to an anti-Inflammatory

Question 18

Environment

5 eg

Answer 18

Allergic disposition

• small family size
• intestinal microflora viariable
• high antibiotic use
• low helminth burden
• good sanitation

Question 19

Omalizumab

Answer 19

Anti-IgE. Binds to IgE prevents binding to mast cells and degranulation.

Question 20

Hygiene Hypothesis

Answer 20

infection protects against atopy.

Is the failure to generate adequate regulatory pathways in early life

Question 21

Atopy

- e.g.

Answer 21

genetic tendency to develop allergic diseases. eg allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema)

Question 22

Atopic dermatitis

• symptoms
• definition
• prevalence

Answer 22

Dry, eczemous (red, itchy, flaky) skin, epidermal edema, thickening epidermis.
A Th-2 mediated disease, genetically determined skin barrier dysfunction that lends susceptibility to environmental triggers.
Worldwide 20% children, 3% adults

Question 23

Etiopathogenesis

- AD

Answer 23

Structural abnormalities in epidermis (genetically-determined).
Skin-barrier dysfunction, susceptible to environment

Question 24

Genetics

- AD

Answer 24

1) Filaggrin (FLG gene). Contribute to keratinocytes, moisture retention, skin pH and skin barrier formation.
Variants in FLG, filaggrin deficiency or loss predispose to AD.
2) Other gene loci explain 15% of risk. Innate and adaptive immunity, skin barrier formation, tissue response

Question 25

Environmental triggers - AD - 5 eg.

Answer 25

Bacteria - Staphylococcus aureus, gram+. Skin infections Airborne allergens Food allergens Water hardness Topical (applied directly to skin) products

Question 26

Immunopathogenesis - AD - 3 stages - 2 1/2 paths

Answer 26

Th2 mediated. Allergens enter barrier defect, - activate eosinophils, mast cells. Chronic stage also activate B cells, IgE. (non-Th2). - activate dendritic cells, induce Th2 to produce il-4, il-13 - also induces pro-inflammatory Th22, impacts epidermal keratinocyte differentiation Scratching and Lichenification (thick, leathery) = chronic stage.

Question 27

JAK/STAT pathway | - e.g.

Answer 27

Communicates info from outside cell to nucleus, to enable transcription and activation of genes. For cytokines, involved in immune cell division, recruitment, activation. - IL-4 induces it to stimulate STAT6 which proliferates B cells, IgE.

Question 28

Skin structure

Answer 28

Epidermis - outer layer. With keratinocytes, melanocytes and immune cells Dermis - beneath. Has hair follicles, sweat glands, nerve endings, lymphatic, blood vessels, with fibroblasts and also immune cells.

Question 29

Epidermis

Answer 29

Terminally differentiated keratinocytes are dead. Move up from bottom epidermal layers to the dead flaking surface in 28 day cycle. Slightly acidic nature (sweat, sebum, antimicrobial peptides [anti-inflam]) and KCs make up the skin barrier.

Question 30

Skin as an immune organ | - 2x

Answer 30

Immuno-protective. against trauma, UV, infections, toxins Immuno-surveillance. maintain tolerance, avoid autoimmunity and allergy food dust. - has CD8 T cells, within and other lymphocytes in dermis.

Question 31

Psoriasis - symptoms - definition - prevalence

Answer 31

1) Plaque psoriasis has red inflamed scaly plaques, excessive keratinocyte proliferation (cycle just 4-8 days, build up). Comorbidities: psoriatic arthritis, CVD, IBD. 2) Il-17 mediated disease, with pathogenic interaction between keratinocytes, DC and T cells (KC produce TNF, effect DC. DC effect T cells to produce Il-17. Il17 feedback KC TNF and IL-23) triggered by environmental factors, releasing autoantigens. 3) 2-3% of European population

Question 32

Immunopathogenesis | - Psoriasis

Answer 32

Parakeratosis - keratinocytes not terminally differentiated, still have their nucleus, so proliferate excessively, accumulate in epidermis.

Question 33

Etiopathogenesis | - Psoriasis

Answer 33

Complex, genetic predisposition, environmental factors, dysregulated immune response. - not just skin disease. immune cells present in basement membrane drive disease so if transplantation from psoriatic donor, will develop disease.

Question 34

Genetics - Psoriasis - prevalence, loci

Answer 34

Heritability 66%. High concordance in monozygotic twins. 63 loci, 28% heritability. Immune related and some skin related genes. 1) HLA-Cw0602* allele major susceptibility, OR is 4.32. 50% patients have. Interact with another gene in Ag presentation trimming that increases risk with presence.

Question 35

Genetics - Psoriasis - immune pathways

Answer 35

1) Type I IFN pathway 2) NK-kB pathway 3) Antigen presentation 4) Il-23/17 axis

Question 36

Environmental Triggers - Psoriasis - 5 e.g.

Answer 36

- Trauma - tatoos - Infections - streptococcus, HIV - Drugs - imiquimod (wart remover), - stress - smoking

Question 37

Il-17

Answer 37

pro-inflammatory. Help differentiate Th17 cells. Inflam macrophages express it. Found in autoimmune diseases, psoriasis, IBD, synovial membrane of arthritis.

Question 38

Initiation phase | - Psoriasis

Answer 38

1) LL37, IFN-a. Injured/stressed keratinocytes release inflammatory cytokines and antimicrobial peptide LL37. LL37 activates DC to produce IFN-a to promote maturation from DC to APC. 2) autoantigens LL37 however presented by APC as autoantigen by T cells in 46% psoriatic patients and activate T cells to proliferate, produce cytokines and cytotoxic molecules

Question 39

Plaque Formation | - Psoriasis

Answer 39

IL23 - Il17 axis Il23 induces differentiation of CD4+ T cell into Th17. IL17 proliferates KC. Produces chemokines CXCL8 to attract neutrophils to inflame.

Question 40

Plaque Progression | - Psoriasis

Answer 40

Il22 in epidermis promotes production of antimicrobial peptides and affects keratinocyte differentiation.

Question 41

Drugs | - Psoriasis

Answer 41

mAb targets IL23-IL17 axis, clears skin for 90%. Steroids also immunosuppressive. Anti-T cells Anti-cytokines. Ustekimumab - anti-Il-12/23 p40 subunit (inflammatory, promote th1/ctls). in mice abolished psoriatic lesions.