Chronic inflammation

• Chronic inflammation


  A response of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations
• Chronic inflammation may or may not follow acute inflammation
• Causes of chronic inflammation

  • Persistent infection and delayed-type hypersensitivity
  • Hypersensitivity diseases e.g. Autoimmune disease or unregulated immune response against microbes
  • Prolonged exposure to toxic agents; endogenous e.g. cholesterol or exogenous e.g. silica
• Morphological features of chronic inflammation

  • Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells
  • Tissue destruction, induced by the persistent offending agent or by the inflammatory cells
  • Attempts at healing by connective tissue replacement of damaged tissue, accomplished by angiogenesis and fibrosis
• Macrophages


  Dominant cells in most chronic inflammatory reactions, contribute to the reaction by secreting cytokines and growth factors, destroying foreign invaders and tissues, and activating other cells
• Two major pathways of macrophage activation

  • Classical macrophage activation induced by microbial products, bacterial endotoxin and T cell–derived signals, importantly the cytokine IFN-γ
  • Alternative macrophage activation induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells
• Classically activated (M1) macrophages

  • Produce NO and ROS, upregulate lysosomal enzymes, secrete cytokines that stimulate inflammation
• Alternatively activated (M2) macrophages

  • Secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis
• Role of lymphocytes

  Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation
• Subsets of CD4+ T lymphocytes

  • TH1 cells produce IFN-γ, which activates macrophages by the classical pathway (pro-inflammatory)
  • TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation (anti-inflammatory)
  • TH17 cells secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils [and monocytes] into the reaction
• Eosinophils


  Abundant in immune reactions mediated by IgE and in parasitic infections, have granules that contain major basic protein, which is toxic to parasites but also injures host epithelial cells
• Mast cells (and basophils)

  Express on their surface the receptor FcεRI, which binds the Fc portion of IgE antibody, and in response to antigen recognition, they degranulate and release mediators, such as histamine and prostaglandins
• Granulomatous inflammation


  Characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis
• Examples of granulomatous diseases

  • TB
  • Sarcoidosis
  • Cat-scratch disease
  • Brucellosis
  • Syphilis
  • Leprosy
• Histological features of granulomas


  • Epitheliod cells with pink, granular cytoplasm and indistinct cell boundaries
  • Aggregates of epitheliod macrophages surrounded by collar of lymphocytes
  • Older granulomas may have a rim of fibroblasts and connective tissue
  • Multinucleated giant cells called Langhans giant cells
  • Granulomas associated with certain infectious organisms often contain a central zone of necrosis (caseous necrosis)
• Granulomas in Crohn's disease, sarcoidosis, and foreign body reactions tend to not have necrotic centres and are said to be non-caseating
• Healing of granulomas is accompanied by fibrosis that may be extensive
• Histamine also stimulates the production of prostaglandins, which further increase vascular permeability.
• The release of histamine from mast cells causes vasodilation and increased vascular permeability.
• Inflammatory mediators are released by cells at the site of injury or infection, leading to vasodilation (increased blood flow) and increased permeability of capillaries.
• Prostaglandins cause vasodilation and increased blood flow to the area, leading to redness or flushing.
• Increased capillary permeability allows plasma proteins such as albumin to leak out into tissues, leading to edema formation.
• What are Paraneoplastic Syndromes?

  A group of disorders that occur in people with cancer, caused by the interaction between the cancer and the immune system.