Type IV Hypersensitivity Reaction

Type IV hypersensitivity reaction, or delayed-type hypersensitivity, is a cell-mediated response to antigen exposure. The reaction involves T cells, not antibodies, and develops over several days. Presensitized T cells initiate the immune defense, leading to tissue damage. A cytokine-mediated process is activated by T-helper cells while cytotoxic T cells directly release cytotoxins to infected or dysfunctional cells, causing cell lysis. Clinical manifestations depend on the system involved, so diagnostic tests rely on history and findings. Treatment includes controlling the effects of the immune response with glucocorticoids and immunosuppressive therapy while managing the associated disease complications.

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  • Hypersensitivity reaction
    • A “hyper” or exaggerated response to what should be considered harmless environmental antigens
    • Types I, II, and III are immediate reactions occurring within 24 hours.
    • Type IV reaction develops over several days.
  • Type IV hypersensitivity reaction
    • Cell-mediated hypersensitivity reaction
    • Unlike the other hypersensitivity reactions, which are mediated by antibodies (Abs), type IV involves antigen-specific effector T cells.
    • Does not occur until 24–72 hours after exposure of a sensitized individual (thus, delayed-type hypersensitivity)
    • The delay is due to the time required for T cell differentiation, cytokine and chemokine secretion, and accumulation of leukocytes at the site.


T cell function

  • Type IV hypersensitivity reactions do not involve antibodies.
  • Instead, T cells are involved. Major types:
    • T-helper (Th) cells
      • CD4+ T cells/Th cells
      • Regulate immune response by secreting cytokines that activate B cells, other T cells, and phagocytes
    • Cytotoxic T cells
      • CD8+ T cells/Tc (cytotoxic or killer T cells)
      • Directly kill cells or utilize cytokines in an immune response


Sensitization phase

  • Uptake, processing, and presentation of the antigen (Ag)
  • Dendritic cells/macrophages (antigen-presenting cells (APCs)) recognize Ag → presented to Th cells and T cells become primed 

Effector phase 

  • Cytokine-mediated
    • Ag (on the surface of APCs) is recognized by primed Th cells → APCs produce interleukin (IL-12), which induce differentiation to Th1 cells 
    • Th1 cells produce
      • IL-2: increases T-cell production of Th1 cells
      • Interferon-gamma (IFNγ): recruits macrophages 
      • Tumor necrosis factor (TNF): increases vascular permeability and recruits more leukocytes
    • Release of inflammatory mediators → cellular damage, then tissue injury 
    • Persistent antigen stimulation → granuloma formation
      • Ag could not be phagocytosed, so the immune system attempts to “wall off the area.”
      • Macrophages become elongated (epithelioid) and can fuse (Langhans giant cell).
      • More lymphocytes are recruited, with fibroblasts forming a “walled off-ball formation.”
  • Direct cell cytotoxicity: CD8+/cytotoxic T cells release cytotoxins → kill targeted cells → tissue injury

Clinical Presentation

Allergic contact dermatitis

  • Etiology: poison ivy (antigen: uroshiol), nickel, perfume, soap, latex
  • Pruritic rash, may be papular and/or vesicular
  • Can spread to other parts with antigen transfer by touch


  • Intradermal injection of tuberculin, a purified protein derivative (PPD) of the tubercle bacillus
  • Localized type IV reaction at site of inoculation in 24–72 hours
  • Grossly seen as a swollen firm nodule
  • Reaction is generally minimal and short-lived

 Granulomatous diseases

  • Maximal reaction time is 21–28 days
  • Examples:
    • Infections cause persistent Ag presence
      • Tuberculosis (Mycobacterium tuberculosis): pulmonary symptoms (may have extrathoracic manifestations)
      • Leprosy (M. leprae): chronic skin lesions and sensory loss 
    • Sarcoidosis 
      • Exact stimulus unclear, probable infection or environment
      • Pulmonary symptoms (also has extrathoracic manifestations)
    • Crohn’s disease (granulomatous colitis)
      • Abdominal pain, diarrhea with or without bleeding, and weight loss
      • Can lead to fistulas and intestinal abscess

Autoimmune myocarditis

  • Inflammatory disease of the heart muscle
  • Mostly arises from cardiotropic viral infection, especially with Coxsackievirus B3
  • Presentation: recent upper respiratory infection, myalgias, heart failure

Diabetes mellitus type I

  • T cells mediate destruction of beta cells in pancreatic islets
  • Presentation: weight loss, polyuria, polydipsia, polyphagia, frequent infections
  • Diabetic ketoacidosis:
    • Life-threatening complication
    • Can be the first presentation in some patients

Drug hypersensitivity

  • Delayed in onset, typically 48–72 hours following exposure to the drug
  • Most dangerous of delayed drug hypersensitivity reactions:
    • Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN):
      •  Severe blistering dermatitis, fever; Nikolsky’s sign
      •  Life-threatening
      • Common drugs: allopurinol, antiepileptics, antibacterial sulfonamides
    • Drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS):
      • Rash, fever, and multiorgan failure 
      • Liver: most common organ involved
      • Implicated in several antiepileptic drugs

Guillain-Barré syndrome

  • Post-infection (often with Campylobacter jejuni or viral illness)
  • Upper respiratory or gastrointestinal illness precedes onset by 3–4 weeks.
  • Immune reactions directed against C. jejuni capsule:
    •  Cross-react with ganglioside in myelin (molecular mimicry) → neuronal damage
  • Acute inflammatory demyelinating polyneuropathy (AIDP): 
    • Most common presentation
    • Initial symmetrical weakness of extremities developing into an ascending paralysis
  • In 25% of patients, respiratory muscle weakness → respiratory failure
Disease Target antigen Effects
Allergic contact dermatitis Environmental chemicals such as urushiol (from poison ivy and poison oak), metals (e.g., nickel), topical medication Epidermal necrosis, inflammation, skin rash, and blisters
Autoimmune myocarditis Myosin heavy chain protein Cardiomyopathy
Diabetes mellitus type I Pancreatic beta cell proteins (possibly insulin, glutamate decarboxylase) Insulitis, beta cell destruction
Granulomas Various, depending on the underlying disease Walled-off lesion containing macrophages and other cells
Some peripheral neuropathies Schwann cell antigen Neuritis, paralysis
Hashimoto’s thyroiditis Thyroglobulin antigen Hypothyroidism, hard goiter, follicular thymitis
Inflammatory bowel disease Enteric microbiota and/or self-antigens Hyperactivation of T cells, cytokine release, recruitment of macrophages and other immune cells, inflammation
Multiple sclerosis Myelin antigens (e.g., myelin basic protein) Myelin destruction, inflammation
Rheumatoid arthritis Possibly collagen and/or citrullinated self-proteins Chronic arthritis, inflammation, destruction of articular cartilage and bone
Tuberculin reaction (Mantoux test) Tuberculin Induration and erythema around injection site indicates previous exposure

Diagnosis and Management

Allergic contact dermatitis (ACD)

  • Diagnosis: Patch test
    • Allergen fixed on a patch then applied on skin (back or arm)
    • Read after 2 days and on Day 4 or 5
    • Positive result: erythema, papules, vesicles
  • Treatment:
    • Avoidance of allergen
    • Antihistamines, topical/systemic glucocorticoids depending on severity


  • Diagnosis:
    • Positive tuberculin test
    • Chest X-ray: focal infiltration in upper lobe/s
    • Sputum acid-fast bacillus (AFB) smear and mycobacterial culture
    • Molecular testing
  • Treatment: isoniazid, rifampin, ethambutol, pyrazinamide (core regimen)


  • Diagnosis:
    • Skin biopsy, skin smear (assess for AFB)
    • Polymerase chain reaction (PCR)
  • Treatment:
    • First-line: dapsone, rifampin, clofazimine


  • Diagnosis:
    • Negative tuberculin test
    • Chest X-ray: initially with bilateral hilar adenopathy, followed by reticular opacities
    • Biopsy (transbronchial or lung/lymph node): noncaseating granuloma
  • Treatment:
    • Depending on symptoms, management may be watchful waiting to steroids and immunosuppressive therapy

Crohn’s disease

  • Diagnosis: 
    • Upper gastrointestinal series with small bowel follow-through: may show “string” sign (narrow bowel lumen)
    • Ileocolonoscopy with biopsy: segments of normal-appearing bowel interrupted by large areas of disease; rectal sparing noted
    • Pathology: focal ulcerations, with granulomas noted in 30%
  • Treatment:
    • Mild disease: glucocorticoids, 5-aminosalicylates
    • Moderate to severe disease: immunomodulators, anti-tumor necrosis factor-alpha inhibitor
    • Surgery for bowel perforation, obstruction, refractory enteric fistula

Autoimmune myocarditis 

  • Diagnosis:
    • Suspect if with signs of myocardial infarction (electrocardiogram (ECG) changes, cardiac enzyme elevation) but no cardiovascular risk factors and normal coronary angiogram
    • Echocardiogram: systolic dysfunction is generally global
    • Cardiac magnetic resonance imaging (MRI): myocardial edema (high signal intensity: necrosis present)
    • Endomyocardial biopsy (EMB) only if results will change management
  • Treatment:
    • Treat sequelae (heart failure, arrhythmia)

Diabetes mellitus type I

  • Diagnosis: laboratory tests include hemoglobin A1c, metabolic panel
  • Treatment: insulin

Drug hypersensitivity

  • Diagnosis: 
    • Clinical; physical findings and history of drug exposure 
    • DRESS (drug rash with eosinophilia and systemic symptoms), typically with longer period between drug intake and symptoms
    • Skin biopsy: interface dermatitis, eczematous changes (DRESS), keratinocyte necrosis, subepidermal bullae (SJS)
  • Treatment: 
    • Remove offending drug and supportive care
    • Glucocorticoids as needed

Guillain-Barré syndrome

  • Diagnosis:
    • Lumbar puncture: elevated cerebrospinal fluid protein
    • Electromyography and nerve studies: demyelinating polyneuropathy (decreased nerve conduction velocity in motor and sensory nerves)
    • Pulmonary function test: restrictive pattern
  • Treatment:
    • Intravenous immunoglobulin (IVIG), plasmapheresis
    • Mechanical ventilation if necessary


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