JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
August 2022
I-M01 (NP)

Signalment:  Rhesus monkey (Macaca mulatta)

HISTORY:  Tissue from the eyelid 48 hours after an intradermal injection of tuberculin.

HISTOPATHOLOGIC DESCRIPTION:  Haired skin, eyelid (per contributor): The superficial and deep dermis is multifocally expanded by perivascular accumulations of many lymphocytes with fewer plasma cells and macrophages. A similar infiltrate separates and isolates collagen bundles, muscle fibers, and adnexa. The walls of associated blood vessels often contain numerous transmigrating inflammatory cells and are occasionally lined by reactive endothelial cells. Multifocally, the connective tissue is loosely arranged and expanded by hemorrhage, fibrin, and increased clear space (edema). The epidermis is mildly hyperplastic with parakeratosis and prominent intercellular bridges (spongiosis). There is a focal serocellular crust composed of eosinophilic fluid (serum), degenerate neutrophils, fibrin, and erythrocytes.

MORPHOLOGIC DIAGNOSIS:  Haired skin, eyelid (per contributor): Dermatitis, lymphohistiocytic, perivascular, multifocal, moderate, with hemorrhage and edema, rhesus monkey (Macaca mulatta), non­human primate.

CONDITION:  Positive tuberculin test (Type IV hypersensitivity / delayed type hypersensitivity)

GENERAL DISCUSSION:

• Intradermal tuberculin injection tests for previous exposure/sensitization to Mycobacterium tuberculosis (weakly gram-positive bacillus, acid-fast, non-spore forming); false positive tests have been reported
• Tuberculin is a a PPD (purified protein derivative): a protein-containing antigen of the tubercle bacillus
  • Mammalian old tuberculin (MOT) is commonly used in NHPs as an important part of preventive medicine programs
• Pathogenicity is that of a Type IV hypersensitivity/delayed type hypersensitivity (also known as cell-mediated hypersensitivity).
  • Delayed-type hypersensitivity is characterized by the accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular “cuffing”
• False negative and false positive skin test reactions
  • False negatives may occur in the setting of certain viral infections, immunosuppression, and active tuberculous disease
  • False positives may result from infection by atypical mycobacteria or vaccine adjuvant (in vaccinated animals)

PATHOGENESIS:

• Initial exposure (e.g. via natural infection) of the tubercle bacilli to macrophages induces macrophages to secrete IL-12, which causes the transformation of naïve CD4+ T cells into TH1 cells (memory cells)
• Sensitized TH1 cells enter the circulation and remain in the memory pool
• Upon re-exposure (i.e. via the tuberculin test), memory TH1 cells are activated by interactions with antigen presenting cells (e.g. processed by dendritic Langerhans cells)
• Activated TH1 cells secrete cytokines such as IFN-gamma (IFN-γ), IL-2, TNF-alpha, and lymphotoxin
  • IFN-gamma activates macrophages, improving their phagocytic ability, increasing MHC II presentation, and increasing production of IL-12, PDGF, and TGF-beta
  • IL-2 stimulates proliferation of T-cells
  • TNF-alpha and lymphotoxin stimulate endothelial cells to secrete prostacyclin which increases blood flow and vasodilation, increases expression of the adhesion molecule E-selectin, and increases expression of the chemotactic factor IL-8
• The cumulative effect is increased microvascular permeability, resulting in fluid and fibrin leakage and accumulation of monocytes and lymphocytes at the site of sensitization

TYPICAL CLINICAL FINDINGS:

• Reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, then gradually subside

TYPICAL GROSS FINDINGS:

• Thickened, firm, erythematous lesion at the site of injection (typically the eyelid)
  • The tail fold or the eye is used in cattle

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Mononuclear cell accumulations around small veins and venules (perivascular cuffing)
• Edema, hemorrhage, fibrin deposition
• Endothelial hypertrophy

OTHER DIAGNOSTIC TESTS (FOR TUBERCULOSIS):

• Acid-fast smears
• Culture (can take multiple weeks for culture results)
• PCR amplification
• IFN-γ release assays (IGRAs): In vitro tests in which lymphocytes from the patient are stimulated with protein antigens from M. tuberculosis.
  • Production of IFN-γ by the T cells is measured to assess the level of T-cell immunity to the organism
  • False-positive results are uncommon with IGRAs

COMPARATIVE PATHOLOGY:

• tuberculosis (P-B10): Responsible for the majority of human cases of tuberculosis; highly contagious fatal disease in NHPs
• Other Type IV hypersensitivities include:
  • Allergic contact dermatitis (e.g. urushiol in poison ivy)
  • Rheumatoid arthritis: Reacting to an unknown antigen in joint synovium (possibly type II collagen)
  • Johne’s disease (caused by Mycobacterium paratuberculosis ) leading to granulomatous enteritis
  • Allograft (transplant) rejection
  • Equine recurrent uveitis
  • In humans, some are rheumatoid arthritis, Multiple sclerosis, Type 1 diabetes, Inflammatory bowel disease, and psoriasis
  • Other pathogens: Bacterial (M. bovis, M. avium ssp. paratuberculosis, M. avium ssp., Listeria monocytogenes, Yersinia spp), viral (Lymphocytic choriomeningitis virus), fungal (Blastomyces dermatitidis, Histoplasma capsulatum), and protozoal (Toxoplasma gondii, Leishmania spp)
  • Contact antigens: insecticides (flea collars, sprays, and dips), chemical components of plastics, leathers, metals, and dyes and components of shampoos, topically applied drugs and pollens
• ZEW (including NHP)
  • In nondomestic ruminants, antemortem diagnosis of tuberculosis is challenging with the intradermal tuberculin skin test due to lower sensitivity and specificity
  • In NHPs, tuberculin skin tests are not always reliable due to false negatives (due to stage of disease (either early or advanced tuberculosis)) and overall immune function; false positive are more common in orangutans (generally associated with exposure to nontuberculous Mycobacterium species (e.g. fortuitum, M. terrae, M. nonchromogenicum, M. avium, and M. cheloni) without evidence of mycobacterial disease)

REFERENCES:

1. Frank KM, McAdam AJ. Infectious diseases. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier Saunders; 2021:369-71.
2. Jones MEB, Gasper DJ, Mitchell (née Lane) E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio K, McAloose, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. 1st ed. London, United Kingdom. Elsevier. 2018:131.
3. Lowenstine LJ. McManamon R. Terio KA. Apes. In: Terio K, McAloose, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. 1st ed. London, United Kingdom. Elsevier. 2018
4. Lowenstine LJ, Osborn KG. Respiratory System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T, ed. Nonhuman Primates in Biomedical Research. Volume 2: Diseases. 2nd ed. Oxford, UK: Elsevier Inc; 2012: 438.
5. Simmons J, Gibson SV. Bacterial and mycotic diseases. In: Bennett BT, Abee CR, and Henrickson R. Nonhuman Primates in Biomedical Research: Diseases. 2nd ed. London, UK: Academic Press; 2012:114-115.
6. Snyder PW. Diseases of Immunity. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier Mosby; 2022: 322-326.

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