Delayed-Type Hypersensitivity Reactions Notes

Delayed-Type Hypersensitivity Reactions

• Not mediated by antibodies.

• Involve activation and expansion of T cells.

• Onset occurs > 12 hours up to 72 hours after antigen exposure.

• Other cells (e.g., macrophages, eosinophils, or neutrophils) may also be involved.

• Type IV reactions vary in significance from inconvenient to life-threatening.

• Subdivided into type IVa, IVb, IVc, and IVd based on the type of T cell (CD4 T-helper type 1 and type 2 cells) involved and the cytokines/chemokines produced.

T Cell Mediated Hypersensitivity Reactions (Gell and Coombs Types IVa to d)

• Type IVa

  • Cells: TH1 cells

  • Cytokines: IFNγ, TNFα

  • Antigen: Antigen presented by cells or direct T cell stimulation

  • Pathomechanism: Macrophage activation

  • Example: Tuberculin reaction, contact dermatitis (with IVC)

• Type IVb

  • Cells: TH2 cells

  • Cytokines: IL-5, IL-4/IL-13

  • Antigen: Antigen presented by cells or direct T cell stimulation

  • Pathomechanism: Cytokines, inflammatory mediators

  • Example: Chronic asthma, chronic allergic rhinitis, Maculopapular exanthema with eosinophilia

• Type IVc

  • Cells: CTL

  • Cytokines: Perforin/granzyme B

  • Antigen: Cell-associated antigen or direct T cell stimulation

  • Pathomechanism: Cytokines, inflammatory mediators

  • Example: Contact dermatitis, Maculopapular and bullous exanthema, hepatitis

• Type IVd

  • Cells: T cells

  • Cytokines: CXCLs, GM-CSF

  • Antigen: Antigen presented by cells or direct T cell stimulation

  • Pathomechanism: Cytokines, inflammatory mediators

  • Example: AGEP, Behçet disease

Delayed Hypersensitivity (DTH) Reactions

• Common reactions to endogenous or exogenous antigens.

• Normal physiological events – to fight some infections – parasites, mycobacteria and fungi.

• Dysfunction and adverse events can predispose to opportunistic infection or clinical hypersensitivity syndromes

  • Contact dermatitis (e.g., poison ivy rash)

  • Tuberculin skin test reactions

  • Granulomatous inflammation (e.g., sarcoidosis, Crohn disease)

  • Allograft rejection

  • Graft versus host disease

  • Autoimmune hypersensitivity reactions

  • Drug reactions (e.g. antibiotics and anticonvulsants)

Comparison Between Immediated (Type I) and Delayed (Type IV) Hypersensitivity Reactions

Immediate Hypersensitivity

1. Appears and recedes rapidly

2. Induced by antigen or haptens by any route

3. Circulating antibodies present and responsible for reaction; (Ab mediated reaction)

4. Passive transfer possible with serum

5. Desensitization easy but short lived

Delayed Hypersensitivity

1. Appears slowly, lasts longer

2. Antigen or hapten intradermally or with Freund's adjuvant or by skin contact

3. Circulating Abs may be absent and not responsible for reaction; cell-mediated reaction

4. Cannot be transferred with serum; but possible with T cells or transfer factor

5. Difficult but long-lasting

Delayed Hypersensitivity Pathophysiology

Nature of response depends on:

1. Underlying cause

2. Anatomic location of the response

3. Type of sensitising agent

   • TB organism → redness and induration due to influx of inflammatory cells

   • Poison ivy and low-molecular-weight chemicals → cause cell lysis and oedematous lesions

   • Chemicals such as beryllium → DTH reactions in lung

   • Immunocompetent cells try to wall off offending agent, creating granulomas and impairing lung function in the lung.

DTH - Contact Dermatitis

Dermatitis arising from direct skin exposure to a substance.

• The allergen is usually a low-molecular-weight chemical that penetrates the skin near epidermal and dermal cells.

• Dermal dendritic cells and Langerhans cells – role in antigen presentation and sensitisation to CD4 and CD8 T-cells

• Sensitised T-cells secrete cytokines and enzymes that recruit other immune cells to site of antigen exposure

• Keratinocytes also secrete cytokines such as IL-8 → Skin inflammation – swelling, itchiness and pain

• Contact dermatitis may be either allergic or irritant-induced

  • Allergic - Allergen induces a DTH immune response

  • Irritant - Trigger substance itself directly damages the skin

Allergic Contact Dermatitis - Sensitizers

Examples of sensitizers include:

• Poison ivy

• The skin of mangoes

• Nickel (jewellery)

• Rubber

• Fragrances (perfume, cosmetics)

• Preservatives (topical medications, cosmetics)

• Chemicals in shoes (both leather and synthetic)

• Medications, including topical steroids and topical antibiotics

Mechanism of Allergic Contact Dermatitis

1. Antigen is engulfed by epidermal APCs - (Langerhans cells)

2. Antigen is presented to naive T-cells in regional lymph nodes.

3. Sensitized CD4+ and CD8+ T-cells produced in the LNs and released into the circulation and arrive at sites where antigen is present as memory T-cells.

4. Released epidermal glycolipids are presented to NK-cells

5. NK-cells interact with B-cells, which produce hapten specific IgM

6. Requires approximately 10 to 14 days.

Mechanism of Allergic Contact Dermatitis - Re-exposure

1. Antigen is presented to sensitized lymphocytes

2. Sensitised lymphocytes are mobilised to the site of antigen by antigen-specific IgM

3. Antigen –specific IgM activates complement

4. CD8+ T-cells and NK-cells release cytokines which lead to the clinical picture of allergic contact dermatitis (ACD)

Dermatitis in a sensitized individual occurs within 12 to 48 hours after re-exposure to the triggering antigen.

Mechanism of Metal Allergy

Sensitization Phase:

1. Nickel penetrates skin, leads to production of pro-inflammatory cytokines (TNF-α and IL-1β), TSLP, and chemokines

2. Activation and migration of haptenated protein-loaded DCs to the draining lymph nodes (LNs).

3. Nickel directly activates the TLR4 pathway in DCs.

In the draining LNs:

1. Haptenated-peptide presentation

   • Proliferation, activation and differentiation of hapten-specific T-cells and secretion of cytokines

2. Primed specific (effector) T cells migrate out of LN to the skin.

Elicitation phase:

1. Application of the same hapten leads to uptake by cells and presentation to circulating hapten-specific T cells.

2. Activated T cells produce inflammatory cytokines and chemokines at the site of exposure causing an allergic reaction and development of characteristic skin lesions

Allergic Contact Dermatitis - Clinical Presentation

• The dermatitis may have been present for months or years, making it difficult to identify the trigger.

• May react to products they have used for months or years.

• Intensely itchy rash up to 2 weeks following exposure.

• Skin redness, sun sensitivity, dry scaly, flaky skin

• Typically a collections of fluid in the epidermis causes a papular erythematous dermatitis with indistinct margins in areas of exposure.

• The extent of the dermatitis reflects the source of exposure (e.g., cosmetics on the face, nickel where jewellery is worn).

• Remote sites may be affected by transfer of allergen by the hands

Type IV Allergy - Contact Dermatitis Diagnosis

• Suggested by physical appearance and distribution

• Confirmed by patch testing:

  • Identifies allergens in direct contact with the skin

  • Reactions read in 48 and 96 hrs for localised eczema at test site

  • Overall sensitivity - 77%

  • Specificity - 71%

Management: Multi-pronged approach:

• Identification and avoidance of the offending allergen

• Alternatives to offending products

• Avoidance of scratching

• Treatment of skin inflammation – e.g. Steroid creams

• Restoration of the skin barrier

• Skin protection

Granulomatous-Type Hypersensitivity

• Granulomatous-type hypersensitivity can occur in response to a variety of antigens.

• Macrophages unable to destroy engulfed antigens and recruit several more macrophages to the site of these antigens.

• Collection of macrophages filled with intracellular antigens → granuloma

• Granulomatous-type hypersensitivity can be seen in tuberculosis (necrotizing) and sarcoidosis (non-necrotizing).

Tuberculin-Type Hypersensitivity

• Occurs when T cells are stimulated by antigen-presenting cells that are unable to destroy engulfed antigens → Chronic process

• Eg - T-cell responses to microbes

• In TB – a T-cell mediated immune response is raised against Mycobacterium tuberculosis

• APCs become giant multinucleated cells due to the effect of cytokines such a IL-2, TNF-α and TNF-β → Granuloma

• Injury to normal tissues at the site of infection

• Tuberculin Test – Intra-dermal injection of microbial protein into skin of previously exposed or previously immunised leads to a form of DTH

Granulomatous Inflammation

Screening-Tuberculin test (Mantoux test)

• Delayed HSR against tubercular protein

• Inject intradermally 0.1 ml of 5TU PPD tuberculin

• Read reaction 48-72 hours after injection

  • Measure only induration

  • Record reaction in mm

Granulomatous-Type Hypersensitivity - Sarcoidosis

• Systemic granulomatous disease of unknown cause

• Wide variety of clinical presentations

• Most frequent organs affected – lymphatic system – especially in the mediastinum (central chest), lungs, eyes and skin

• Up to 30% - present with non-specific symptoms – weakness, weight loss, fever

• Lungs -→ shortness of breath, dry cough, chest pain

• May progress to lung fibrosis

• Progressive decline in lung function

Granulomatous-Type Hypersensitivity Management

Therapy of T-cell mediated hypersensitivity disorders – depends on the type of clinical condition

• In the case of infections – antimicrobial agents

• Sarcoidosis - designed to reduce inflammation – Corticosteroids, Methotrexate

• Cytokine antagonists – eg. TNF-inhibitors

• Other immunosuppressant drugs – eg Cyclosporine

Classification of Allergic Drug Reactions

• Immediate - (< 1 hour)

  • anaphylaxis, hypotension, laryngeal edema, urticarial/angioedema, wheezing

• Accelerated - (1- < 72 hours)

  • urticaria, angioedema, laryngeal edema, wheezing

• Late – (> 72 hours)

  • rash, serum sickness, cytopenias or haemolytic anemia, drug fever, hypersensitivity (organ involvement)

  • IgE Non-IgE

Antimicrobial Allergic Drug Reactions: Classification

Delayed Drug Hypersensitivity

• Most common: delayed non-specific skin rashes that can be drug-viral interactions - may not recur on re-exposure (e.g. CMV + antibiotics; EBV + Amoxicillin; HHV 6 + anticonvulsants)

• Drug Induced Hypersensitivity Syndrome (DHS) or DiHS/DRESS:

  • Fever, rash of varying severity and internal organ involvement

  • Particularly heart, lung, liver and kidneys

  • Involves Th2 cells and CTLs recognising drug antigens presented by HLAs and the subsequent activation of Tregs, dendritic cells, eosinophils and macrophages.

  • These activated cells release pro-inflammatory cytokines (e.g. IFNγ, TNF, IL-5, IL-4, IL-13, IL-33)

Delayed Drug Hypersensitivity - SJS/TEN

Stevens-Johnson syndrome / Toxic Epidermal Necrolysis (SJS/TEN):

• Usually drug-induced, with severe skin disease - blistering, separation and mucosal involvement. Associated fluid losses. Life-threatening – NSAIDs, anticonvulsants

• Primarily mediated by cytotoxic T lymphocytes recognising antigens presented by HLAs

• Activated CTLs, NK-cells and NK T-cells produce cytotoxic proteins (e.g. granulysin, perforin and granzyme B)

• Th1 cells and macrophages release death ligands, pro-inflammatory cytokines and alarmins

• These result in keratinocyte death, skin damage and blistering

• DHS/SJS/TEN - strong immunogenetic basis. HLA associations have been described

• Development of DHS/SJS/TEN warrants:

  • PERMANENT DRUG DISCONTINUATION

  • Avoidance of rechallenge with the drug in question

  • Potentially avoidance of other structurally related drugs

Delayed Drug Hypersensitivity - AGEP

• AGEP – Acute Generalised Exanthematous Pustulosis

  • Rare drug reaction presenting as generalized pustular rash within 24 hours after exposure to offending drug

  • Interaction of TCRs on Th17 cells with drug and HLAs. Cytokine production IL-8, GM-CSF and IL-36 attracts neutrophils to form sterile pustules

• Drug fever:

  • Drugs such as trimethoprim-sulfamethoxazole or tetracyclines can cause fever as the only manifestation. Patients with acute HIV infection are more prone to get drug fever when treated with antiretroviral therapy

Adverse Drug Reactions & Pharmacogenitics

• Routinely tested for in clinical practice prior to use of Abacavir. If present, not prescribed

• Avoid other aromatic amine anticonvulsants (oxcarbazepine, phenytoin, phenobarbital)

Extent of Epidermal Detachment in SJS/TEN

SJS:

• <10%
  OVERLAP:

• 10-30%

TEN:

• >30%

Severe Cutaneous Adverse Reactions (SCAR)

• Involvement of at least 1 mucous membrane, painful skin, fever, internal organ involvement within 8-weeks of drug initiation

• Onset much faster than DIHS or SJS/TEN (wihtin days)

Hypersensitivity Pneumonitis

• An interstitial lung disease due to immune-mediated response to a large variety of inhaled environmental antigens in susceptible and sensitised individuals

  • Organic – bacteria, fungi, animal or plant proteins, enzymes

  • Inorganic – low-molecular weight chemicals or metals

• May be referred to on the basis of provoking conditions:

  • Farmer’s lung (Mouldy hay or straw)

  • Bird-breeder’s lung (feather dust and bird droppings)

Hypersensitivity Pneumonitis

• Involves:

  • Terminal bronchioles

  • Alveoli

  • Interstitium

• Characterised by:

  • Bronchiolocentric granulomatous and cellular interstitial pneumonia

• Development, progression and clinical presentation influenced by:

  • Nature and quantity of inhaled antigen

  • Intensity and frequency of exposure

  • Environmental co-factors

  • Interaction of antigen with immune response

Pathogenesis of Hypersensitivity Pneumonitis

• Genetically susceptible individual

• Exposure to environmental factor(s)

• Innate immune response:

  1. antigen recognition

  2. phagocytosis

  3. antigen processing, MHC I and II pathways

  4. antigen expression and presentation: complex of peptide and MHC I (CD8+ cells) or MHC II (CD4+ T cells)

• Sensitization: recognition of antigen by CD8+ or CD4+ T-cells, triggering immune reaction - cellular and humoral

• Immune reaction after re-exposure to antigen:

  • Th1, Th2, and Th17 immune response leading to lymphocytic inflammation: bronchitis and bronchiolitis, alveolitis, granuloma-formation, and lymphocytic pneumonitis.

• Fibroblast accumulation and fibrosis: contribution of factors of antigen and host.

• Therapeutic targets and measures indicated by red arrows (--) and in red fonts

Hypersensitivity Pneumonitis Management

• Complete antigen avoidance – mainstay of treatment

• Identification of causative antigen(s) may be difficult

• Some have progressive diseases despite complete antigen exposure

Acute HP

• Most acute episodes are self-limited, with complete recovery after antigen removal

• Corticosteroids – often used, but scant evidence

Chronic Hypersensitivity Pneumonitis

• Optimal management – not well established

• The longer the history of antigen exposure – less likelihood of response

• Increased likelihood of response to steroids:

  • Non-fibrotic disease

  • Persistent active inflammation

  • But – treatment dose and duration of treatment have not been formally studied

• Anti-fibrotic drugs – ? May be of benefit in progressive chronic fibrotic hypersensitivity pneumonitis

• Lung Transplantation

Summary

Delayed-type hypersensitivity (DTH)

1. A unique type of cell-mediated immunity.

2. DTH includes cell-mediated reactions to bacteria or fungi infecting lungs

3. DTH includes skin responses to chemicals and plants.

4. Skin reactions to nickel and poison ivy also are DTH reactions.

5. The principal effectors of DTH reactions are CD4 Th1 lymphocytes, monocytes or macrophages, CD8 Tc1 cells, and natural killer (NK) cells.

6. The histopathology of DTH lesions varies with the nature of the antigen, the type of effector cells, and the anatomic location.

7. Cellular infiltrates cause induration and erythema at the skin test site within 24 to 72 hours.