Granulomatous Inflammation Overview

Granulomatous Inflammation

• Granulomas are a focal area of chronic inflammation
• Granulomas consist of activated macrophages
• Macrophages are surrounded by lymphocytes
• Occasional plasma cells may be present
• Granulomas also include a rim of fibroblasts and granulation tissue
• Tuberculosis is a chronic infective granuloma caused by Mycobacterium Tuberculosis
• In tuberculosis, granulomas are called tubercles

Types of Granulomas

• Infective granulomas are caused by microbes that induce a cell-mediated immune response
  • Bacterial
  • Parasitic
  • Fungal
• Foreign body granulomas are caused by foreign materials
  • Silicosis
  • Sutures
  • Breast prostheses
  • Vascular grafts
• Granulomas of unknown cause, for example
  • Sarcoidosis
  • Crohn's disease

Tuberculosis (TB)

• Tuberculosis (TB) is a chronic infective granuloma
• Etiology of TB is Mycobacterium tuberculosis (human and bovine types)
• TB bacteria are non-motile, not proteolytic, and non-toxic
• TB bacteria are acid-fast and very resistant to killing
• TB bacteria are easily killed by sunlight

Route of Infection

• Inhalation is the most common method of TB transmission. Inhaled bacilli infect the tonsils or lungs
• Ingestion of raw milk contaminated with bovine (or human) bacilli can infect the tonsils or intestine
• Skin inoculation by handling infected material (like infected meat) is less common

Predisposing Factors

• Poverty
• Malnourishment
• Poor living conditions
• Lack of medical care
• Debilitating conditions
• Immunosuppressive conditions

Pathogenesis of Granulomas

• Foreign body granulomas are caused by inert foreign bodies

• Macrophages engulf the foreign material

• Macrophages present some of the foreign material to T-lymphocytes

• T-lymphocytes produce cytokines and IFN-γ

• Cytokines and IFN-γ activate macrophages and transform them into epithelioid cells and multinucleate giant cells

• Immune granulomas are caused by poorly degradable agents, triggering delayed-type hypersensitivity (DTH)

• Macrophages engulf foreign antigens, processing them into peptides

• Macrophages present peptides to naive CD4+ T cells

• IL-12 induces the differentiation of CD4+ T cells into Th1 cells

• Differentiated activated Th1 cells enter the circulation and remain in memory pools for years

Responses of Differentiated Effector T Cells

• Repeated exposure to an antigen activates Th1 cells, which secrete cytokines (lymphokines)
• The released cytokines (lymphokines) attract leucocytes to the area of inflammation
• Cytokines inhibit the migration of macrophages
• Cytokines stimulate lymphocyte proliferation
• Cytokines trigger tissue necrosis and inflammation

Pathogenesis of Tuberculosis

• TB bacteria are nonmotile; they do not produce exotoxins, endotoxins, or any lysozymes/histolytic enzymes
• They escape killing by macrophages and induce a delayed type of hypersensitivity through the reaction with their cell wall content

Tubercle Formation

• Polysaccharide fraction attracts neutrophils within a few hours
• Neutrophils phagocytose bacteria but are unable to destroy them because bacteria are protected by a lipid capsule
• Neutrophils do not contain the enzyme lipase
• Lipid fraction attracts macrophages within the first day
• Macrophages collect and phagocytose free bacilli
• Bacilli are partially digested and release tuberculoprotein
• Tuberculoprotein stimulates a cell-mediated immune response; sensitized T lymphocytes surround epithelioid cells
• Sensitized lymphocytes release various lymphokines
• Lymphokines promote macrophage activating, chemotactic, and mitogenic factors.
• More tubercles are formed in the infected area

Macroscopic Picture of Tubercle

• Tubercles fuse, forming small, rounded, grossly visible gray follicles
• Follicles are 1–2 millimeters in diameter
• When caseation occurs, lesions appear pale yellow and cheesy

Microscopic Tubercle Structure

• Tubercles consist of a collection of epithelioid cells, Langhan's giant cells, and lymphocytes

Types of Tuberculosis

• Primary Tuberculosis: the first time the lung is infected with TB bacilli
  • Frequent in children
  • Infection occurs by inhalation of human bacilli
  • The primary pulmonary complex consists of Ghon's focus, tuberculous lymphangitis, and tuberculous lymphadenitis
• Secondary Tuberculosis: occurs in individuals with pre-existing immunity when their defenses are lowered.
  • Infection is either exogenous (inhalation of human bacilli) or endogenous (reactivation of a capsulated primary focus)

Course of Tuberculosis

• Regression: occurs in cases with low numbers of bacilli and high immunity, where lesions heal by fibrosis
• Progression: occurs in individuals with moderate levels of immune response to Mycobacterium and high bacteria load. Disease can present as:
  • Chronic fibrocaseous pulmonary tuberculosis
  • Acute Caseous pneumonia
  • Bronchopneumonia
  • Typically presents with moderate or low immune response and rapid or fatal progression in the worst case scenario

Complications of Infection

• Hemoptysis: due to erosion of vessels
• Rupture of cavity: into the pleural sac resulting in pneumothorax
• Spread of infection: direct, blood (resulting in miliary tuberculosis), bronchial (leading to tuberculosis of other areas), lymphatic
• Right-sided heart failure: due to bilateral lung fibrosis
• Secondary amyloidosis due to continuous breakdown of lung tissue

Primary Intestinal Tuberculosis

• Aeitology: ingestion of infected milk (bovine bacilli)
• Pathology: A primary intestinal complex
  • Intestinal lesions: tubercles in payer's patches (terminal ileum)
  • Covering mucosa: minimal ulceration
  • Tuberculous lymphangitis
  • Tuberculous lymphadenitis (tabes mesentaris)

Secondary Intestinal Tuberculosis

• Aeitology: swallowing infected sputum in patients with chronic fibrocaseous tuberculosis
• Pathological features
  • Lesions primarily in terminal ileum and adjacent caecum
  • Bacilli reach payer's patches
  • Caseous necrosis and erosion of covering mucosa, resulting in tuberculous ulcers

Complications of Intestinal Tuberculosis

• Fibrosis leads to intestinal obstruction
• Perforation of ulcers leads to septic peritonitis, intestinal hemorrhage, or intestinal fistula
• Spread of infection
• Secondary amyloidosis

Additional Information

• Tuberculous ulcers are characterized by multiple, ragged, undermined edges; yellowish-caseous, soft floors; transversely arranged (like a girdle) ulcers
• Tubercles heal by fibrosis

Explore the characteristics and types of granulomas, focusing on the role of activated macrophages, lymphocytes, and plasma cells. This quiz covers the pathophysiology of granulomas in diseases such as tuberculosis and other causes. Understand the distinctions between infective and foreign body granulomas.