Chronic Diseases

Question 1

Chronic Inflammation

Answer 1

• No clear dividing line between acute and chronic inflammation
• If cause of injury not eliminated, acute inflammation can lead to chronic inflammation
• Acute inflammation usually involves exudative reactions (cells and fluid leave bloodstream), chronic inflammation characterized by proliferative responses where cells are stimulated to multiply
• Most crippling disease involve CI rather than AI
• Can follow AI, or develop in absence of AI as low grade of quiet tissue damage that becomes more apparent (persistent bacterium in TB)
• CI hallmarks include infiltration by mononuclear cells (macrophages, lymphocytes, and plasma cells), proliferation of fibroblasts and vascular elements, increased scarring (fibrosis)
• Associated with irreversible destruction of cells and surrounding environment

Question 2

Chronic Inflammation and Repair

Answer 2

• Close relationship between CI and repair. Thought of as frustrated repair because of persistent irritant
• Everything required for healing and repair present in CI tissue (fibroblasts, macrophages, small vessels, etc.) and takes place concomitant but with no result

Question 3

Mycobacterium tuberculosis

Answer 3

• Tuberculosis: respiratory disease caused by mycobacterium tuberculosis
• Three types of tuberculosis:
  
  • Primary TB: results from initial infection from M. tuberculosis
  • Secondary TB: Reestablishment of active infection after period of dormancy
  • Disseminated TB: Results when infection spread throughout body

Question 4

Diagnosis, treatment, and prevention

Answer 4

• Diagnosis: tuberculin skin test (ESAT-6), chest x-rays identify individuals with active disease
• Treatment: Common antimicrobials ineffective, combination therapy used for months to treat disease
• Prevention: Immunization with BCG vaccine where TB is common

Question 5

Mycobacterium

Answer 5

• Cell wall contains a waxy lipid called mycolic acid
• Results in number of unqiue characteristics
  
  • slow growth
  • protection from lysis after phagocytosis
  • capacity for intracellular growth
  • resistance to gram staining, detergents, antimicrobial drugs and desiccation

Question 6

Cord factor

Answer 6

• Glycolipid
• Cells remain attached forming cords of daughter cells
• Inhibits migration of neutrophils and is cytotoxic
• Prevents fusion of endosomes (phagosomes) and lysosomes
• Stimulates granuloma formation via cytokine production

Question 7

Granulomatous Inflammation

Answer 7

• An agent (M. tuberculosis) that can evoke a distinctive pattern of CI is referred to as granulomatous inflammation -> characteristic feature is granuloma
• Granulomas are small (0.5mm - 2mm) collections of modified macrophages (epithlioid cells) usually surrounded by a rim of lymphocytes giving a nodular appearance. Other elements include vascular elements, fibroblasts and lots of collagen, plus PMN, and plasma cells

Question 8

TB Pathogenesis

Answer 8

• Inhalation of respiratory droplets
• Minimum infectious dose is 10 bacterium
• Adhesive pili attach to extracellular protein laminin
• Macrophages engulf bacterium eventually presenting MHC complex to helper T cell
• Helper T cell secretes factors to attract more macrophages (TNF-a, IFN-y, IL-12 -> TH1)

Question 9

Granuloma formation

Answer 9

• Phagocytosis of Mtb -> release of cytokines to recruit immune cells -> ESAT-6 induces M1 phenotype -> Efficient recruitment of innate and adaptive immune cells creating bactericidal granuloma -> ESAT 6 drives switch polarization from M1 to M2; KLF-4 and C/EBPbeta induces M2 differentiation

Question 10

M1 and M2 granuloma

Answer 10

• M1 (pro-inflammatory): early stage, support killing of bacteria
• middle phase: latency period (good health)
• M2 (anti-inflammatory): late stage, granuloma compromised, can rupture and not as good in immune -> poor health
• ESAT-6 induces both M1 and M2

Question 11

Granulomas

Answer 11

• Langhans and foreign body type giant cells are formed by the coalscence and fusion of macrophages -> 50 um diameter and may contain 50 nuclei. Usually formed in presence of large amounts of indigestible material
• Foreign body type giant cells have scattered nuclei throughout cell body
• Langhans giant cell have nuclei arranged in horseshoe formation around periphery of cell. Usually characteristic of tuberculosis