Chronic Inflammation Notes

Chronic Inflammation Definition

• Prolonged response involving inflammation, tissue injury, and repair attempts.
• May follow acute inflammation or begin insidiously.

Causes

• Persistent infections.
• Hypersensitivity diseases (autoimmune, allergic).
• Prolonged exposure to toxic agents (exogenous or endogenous).

Cells Involved

• Macrophages: Dominant cells that secrete cytokines and growth factors, activating other cells (T lymphocytes).
  • Functions: Phagocytosis, inflammation propagation, tissue repair, antigen presentation to T cells.
  • Activation:
    • Classical (M1): Microbicidal, inflammation (stimulated by microbial products, IFN-γ).
      • ROS, NOS, Lysosomal enzymes.
      • IL1, 12, 23.
    • Alternative (M2): Tissue repair, fibrosis (stimulated by IL 4 & IL 13).
      • Growth factors, TGF-B.
      • IL 10, TGF-B (anti-inflammatory)
• Lymphocytes:
  • T lymphocytes: Amplify and propagate chronic inflammation; activation leads to memory cells.
    • T CD4+ Lymphocytes promote inflammation.
      • Th1 cells: Secrete IFN-γ, activate macrophages (Classical Pathway).
      • Th2 cells: Secrete IL-4, IL-5, and IL-13, activate macrophages (Alternate Pathway).
      • Th17 cells: Secrete IL-17, recruit neutrophils.
  • B lymphocytes and plasma cells: Produce antibodies against persistent foreign antigens, self-antigens, or altered tissue components.
• Eosinophils: Mediate IgE reactions and parasitic infections; granules contain major basic protein.
• Mast cells: Recognize IgE antibodies, release mediators, and induce strong inflammatory responses; associated with allergic reactions.
• Neutrophils: Present in acute on chronic inflammation, induced by persistent microbes or mediators.

Morphologic Patterns

• General characteristics: Mononuclear cell infiltration (macrophages, lymphocytes, plasma cells), connective tissue replacement, angiogenesis, and fibrosis.
• Nonspecific proliferative: Infiltration of mononuclear cells, proliferation of fibroblasts, connective tissue, vessels, and epithelial cells.
• Granulomatous Inflammation: Collections of activated macrophages, often with T lymphocytes, and sometimes necrosis.

Granulomatous Inflammation

• Characterized by collections of activated macrophages, often with T lymphocytes, frequently associated with necrosis.
• Cellular attempt to contain an offending agent that is difficult to eradicate.
• Composed of aggregates of epithelioid histiocytes, with a peripheral cuff of lymphocytes and plasma cells, and occasionally a necrotic center.

Types of Granulomas

• Infectious Granulomas:
  • Caseating Granulomas (Necrotizing):
    • Cause: Mycobacterium tuberculosis (TB), histoplasmosis, coccidioidomycosis.
    • Feature: Central caseous necrosis.
    • Histology: Langhans giant cells, epithelioid macrophages, lymphocytic rim.
  • Non-Caseating Granulomas (Non-Necrotizing):
    • Cause: Sarcoidosis, Crohn’s disease, berylliosis, some fungal infections.
    • Feature: Lack of central necrosis.
    • Histology: Compact, well-formed granulomas with multinucleated giant cells.
• Foreign Body Granulomas:
  • Cause: Inert foreign material (sutures, talc, silica, beryllium, prosthetic implants).
  • Feature: Foreign material visible under polarized light.
  • Histology: Foreign body giant cells with phagocytized material.
• Immune (Hypersensitivity) Granulomas:
  • Cause: Persistent antigens that trigger T-cell mediated immune responses.
  • Example: Sarcoidosis, Crohn’s disease.
  • Histology: Epithelioid cells, multinucleated giant cells, lymphocyte infiltration.

Tuberculoid Granuloma Structure

• Epithelioid cells: Activated macrophages with pink granular cytoplasm.
• Surrounding collar of lymphocytes.
• Older granulomas may have a rim of fibroblasts and connective tissue.
• Multinucleated giant cells (Langhans giant cells): Large mass of cytoplasm with many nuclei.
• Central zone of caseous necrosis: Amorphous, structureless, eosinophilic, granular debris.

Types of Giant Cells

• Macrophage derived giant cells: *Langhan giant cells- Langhans' giant cells have horse shoe-shaped nuclei arrangement at one pole of cell. It contains more than 15 nuclei. * Seen in Tubercular granuloma, Leprosy, Syphilis, Deep fungal infection, Sarcoidosis, Leishmaniasis, Crohn's disease
  • Foreign body giant cell larger than Langhans' giant cells with nuclei randomly scattered throughout their cytoplasm
    • Seen in foreign body granuloma formed in response to various exogenous or endogenous materials.
      Touton giant cells have a central ring of nuclei while the peripheral cytoplasm is clear due to accumulated lipid
      *Seen in Fat necrosis, Xanthoma, Xanthogranulomas, Dermatofibroma
• Epidermal cell derived
  *Tzank cells are multi-nucleated giant cell with moulding of the nuclei as they are crowded together
  *Seen in Herpes simplex, Varicella and herpes zoster, Cytomegalovirus
  *Multinucleated epidermal giant cells-than three clumping nuclei has been considered an episodic and exceptional phenomenon in inflammatory skin diseases.
  *Seen in Chronic eczema or prurigo, Lichen amyloidosis, Dermatitis herpetiformis, Erythema multiforme, Pustular psoriasis, Lichen planus, Lupus erythematosus.
  *Melanocyte derived giant cells
  *Starburst giant cells are multi-nucleated melanocytes with a stellate appearance due to its prominent dendritic processes. These are useful indicator for the diagnosis of lentigo maligna
  *Balloon cells may be multi-nucleated and larger than ordinary nevus cells.Seen in baloon cell nevus and baloon cell melanoma
  *Floret like multinucleated giant cell
  *These cells have scanty cytoplasm and peripherally arranged nuclei in the intervening stroma.
  *Seen in: Gynaecomastia, Neurofibroma in NF-1, Giant cell angiofibroma, Pleomorphic lipoma
  *Tumor giant cells
  *Reed-sternberg giant cells in Hodgkins lymphoma and many other hematolymphoid neoplasms
  *Osteoclast like giant cells in giant cell tumour as well as other bone lesions
  *Giant cells in lymph node associated with anaplastic large