2.6 about 30 minDeep Learning viewL2 p.40–46

Chronic and granulomatous inflammation

When the cause will not go away, the response changes character: macrophages and lymphocytes replace neutrophils, and injury and repair run side by side. When the cause is hard to digest, activated macrophages wall it off as a granuloma.

What makes inflammation chronic

L2 p.40–41

Chronic inflammation lasts weeks to years. It most often results from persistence of the injuring agent, though it can also begin quietly without a recognizable acute phase. Its defining feature is that three things happen at the same time: infiltration by mononuclear cells, tissue destruction by those cells and their products, and attempts at repair by angiogenesis and fibrosis.

Causes, as the lecture groups themL2 p.40

  • Persistent infection

    Why it persists
    Organisms resist killing or hide inside macrophages
    Examples
    Tuberculosis, leprosy, syphilis, some fungi and viruses

  • Autoimmune and immune-mediated disease

    Why it persists
    The antigen is self, so it can never be cleared
    Examples
    Rheumatoid arthritis, SLE, inflammatory bowel disease

  • Hard-to-clear exposures

    Why it persists
    Material cannot be digested or keeps coming back
    Examples
    Silica (silicosis), urate crystals (gout), silicone from breast implants, suture material, cholesterol in atheromas

The cells. Macrophages are the centre: blood monocytes that entered tissue. Microbial products and IFN-γ activate them classically (M1): more killing, reactive oxygen species, nitric oxide, more inflammation. IL-4 and IL-13 activate them alternatively (M2): growth factors, TGF-β and collagen deposition, repair. Lymphocytes and macrophages stimulate each other: macrophages present antigen and make IL-12; T cells answer with IFN-γ. Plasma cells (eccentric nucleus with clock-face chromatin, a pale perinuclear Golgi) make antibody, sometimes inside lymphoid follicles. Eosinophils dominate in parasitic and allergic disease (their major basic protein is toxic to helminths and to epithelium). Mast cells take part in both.

Macrophages pull both ways

Classically activated (M1)

  • Triggered by microbes, IFN-γ
  • ROS, NO, lysosomal enzymes
  • IL-1, IL-12, TNF: more inflammation
  • Kill microbes; destroy tissue

Alternatively activated (M2)

  • Triggered by IL-4, IL-13
  • TGF-β, PDGF, IL-10
  • Angiogenesis and collagen
  • Repair and fibrosis
Ref. · Robbins; Abbas

Lecture image

Fibrous stroma infiltrated by lymphocytes, plasma cells and macrophages
Chronic inflammation: lymphocytes, plasma cells and macrophages scattered through fibrous tissue, showing injury and repair together.L2 p.41

Case image

Endometrial stroma with plasma cells (arrows): eccentric nuclei with coarse chromatin
Plasma cells (arrows) in endometrial stroma: chronic endometritis in a woman using an intrauterine device (Simulation Q9).Midterm sim. p.3

Anatomy of a granuloma

L2 p.22–23, 42

A granuloma is a compact nodule of activated macrophages, formed when the body cannot destroy an agent and walls it off instead. To the eye it is a pale, white nodule; under the microscope it has three or four layers.

Teaching schematic

caseous centreLanghans giant cellepithelioid macrophageslymphocyte cuff (CD4⁺ T cells)
A caseating granuloma: necrotic centre, rim of epithelioid macrophages and Langhans giant cells, cuff of lymphocytes (mostly CD4⁺ T cells).L2 p.23, 42
  • Epithelioid cells (histiocytes): activated macrophages with abundant pale-pink, granular cytoplasm and indistinct borders, packed together like an epithelium. Their nuclei are oval and pale, often elongated like the sole of a slipper. They secrete more than they engulf.
  • Multinucleated giant cells: several macrophages fuse into one cell up to 50 µm across, with 20 or more nuclei.
  • Lymphocytes, mainly CD4⁺ Th1 cells, cuff the nodule; older granulomas gain a rim of fibroblasts and collagen.
  • ± central necrosis: caseous in tuberculosis.
L2 p.42

Lecture image

Granuloma micrograph beside a labelled drawing: lymphocytes, epithelioid histiocytes and a multinucleated giant cell
A granuloma under the microscope and the lecture's labelled drawing: lymphocytes around epithelioid histiocytes and multinucleated giant cells.L2 p.23

Teaching schematic

Langhans giant cell
Langhans: nuclei in a horseshoe at the edge. Immune granulomas (TB, sarcoidosis).
Foreign-body giant cell
Foreign-body: nuclei scattered, often around visible material (suture, talc, silica).
Two kinds of giant cell. Langhans: nuclei in a horseshoe at the periphery (immune granulomas such as TB and sarcoidosis). Foreign-body: nuclei scattered through the cytoplasm, often around visible material.L2 p.22, 42

Caseating, non-caseating and foreign-body granulomas

L2 p.44–46

Immune granulomas form around persistent antigens that drive a T-cell response. Foreign-body granulomas form around inert material too large for one macrophage to engulf (sutures, talc, silica) and need no specific immune response. The centre then tells you most about the cause.

Reading the centreL2 p.44Ch. II cases p.4, 7, 13

  • Caseating

    Centre
    Cheese-like necrosis
    Classic causes
    Tuberculosis, systemic fungi (Histoplasma, Coccidioides)
    Clues
    Acid-fast or fungal stains; upper-lobe disease, night sweats

  • Non-caseating, tight

    Centre
    No necrosis
    Classic causes
    Sarcoidosis, Crohn disease, berylliosis
    Clues
    Stains and cultures negative; hilar nodes, hypercalcemia (sarcoid)

  • Non-caseating, loose

    Centre
    No necrosis
    Classic causes
    Hypersensitivity pneumonitis (bird, farmer's, flour dust)
    Clues
    Small, poorly formed, near bronchioles; exposure history

  • Foreign-body

    Centre
    Visible material
    Classic causes
    Sutures, talc, silica, urate (gout tophus), silicone
    Clues
    Material often polarizes; foreign-body giant cells

Lecture image

Low-power granuloma with a large pink, amorphous necrotic centre surrounded by a rim of macrophages and lymphocytes
Caseating granuloma: an amorphous pink necrotic centre surrounded by epithelioid cells and lymphocytes (tuberculosis).L2 p.45

Lecture image

Tight nodule of pale epithelioid macrophages without central necrosis, ringed by lymphocytes
Non-caseating granuloma: a tight nodule of epithelioid cells with no necrosis, ringed by lymphocytes (sarcoidosis, Crohn disease).L2 p.46

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Caseating granuloma

Lecture image

Low-power granuloma with a large pink, amorphous necrotic centre surrounded by a rim of macrophages and lymphocytes
Lung in tuberculosis (lecture image).
  • Epithelioid macrophages and a lymphocyte rim
  • Central caseous necrosis: amorphous pink debris, cell outlines lost
  • Tuberculosis, systemic fungi (Histoplasma, Coccidioides)
  • Acid-fast or fungal stains often find organisms

Step 1 · What they share

What do the two granulomas share?

Select every feature that both show.

Core activity · One Fact Changes

One Fact Changes

Answer a case and name the decisive clue. Then exactly one fact changes. Decide whether the answer moves, and why.

1 · The original case

A 40-year-old woman has two months of dry cough and fatigue, and her chest radiograph shows bilateral hilar lymphadenopathy. A node biopsy shows tight granulomas with giant cells and no necrosis; acid-fast and fungal stains are negative. Her serum calcium is raised.

What is the most likely diagnosis?

Which fact decided it?

The granuloma loop: IL-12, IFN-γ and TNF

L2 p.42–43

Take Mycobacterium tuberculosis. An alveolar macrophage engulfs it, but the bacterium blocks phagolysosome maturation and keeps multiplying. The macrophage carries antigen to a lymph node and, through the steps on the lecture slide, builds the granuloma:

Teaching schematic

The granuloma loopMacrophageMHC II + antigenCD4⁺ Th1 cellIL-12 (+ antigen on MHC II)IFN-γActivated macrophages → epithelioid cells, giant cellsTNF holds the granuloma together (anti-TNF breaks it)
Each cell's product activates the other: IL-12 makes Th1 cells, IFN-γ activates macrophages, and activated macrophages make more IL-12 and TNF. TNF holds the granuloma together.L2 p.43
  1. The macrophage presents antigen on MHC class II to naive CD4⁺ T cells.
  2. It secretes IL-12, which drives the T cells to become Th1 cells.
  3. Th1 cells return to the site and secrete IFN-γ, which activates macrophages: phagolysosomes mature, nitric oxide and reactive oxygen species are made, MHC II rises. Activated macrophages become epithelioid cells and fuse into giant cells.
  4. Activated macrophages make more IL-12, so the loop sustains itself while antigen persists.
  5. TNF from macrophages and T cells recruits and organizes cells and maintains the granuloma.
L2 p.42–43

This is a type IV (delayed-type) hypersensitivity reaction. The tuberculin skin test reads the same loop in miniature: injected antigen, Th1 cells and IFN-γ produce induration 48–72 hours later. People with inherited defects in the IL-12 or IFN-γ receptors cannot complete the loop and develop disseminated mycobacterial infections.

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

Mycobacterium tuberculosis survives inside an alveolar macrophage. Complete the loop that builds a granuloma.

  1. A macrophage harbours surviving mycobacteria
  7. A stable granuloma contains the bacilli, with caseation in its centre

Cards

Tap or drag a card. Placing a used card moves it.

Anti-TNF therapy and TB reactivation

L2 p.42

In latent tuberculosis, living bacilli are contained inside granulomas for decades. TNF keeps those granulomas organized. Drugs that block TNF, the antibodies infliximab, adalimumab, golimumab and certolizumab and the receptor fusion protein etanercept, are used for rheumatoid arthritis, Crohn disease, ulcerative colitis, psoriasis and ankylosing spondylitis. Blocking TNF loosens the granulomas, and the bacilli escape: reactivation tuberculosis, often extrapulmonary or disseminated. Histoplasmosis and coccidioidomycosis can reactivate the same way.

Worked case · A Crohn patient on a new drug

A 34-year-old woman with Crohn disease starts infliximab. Her family emigrated from a country where tuberculosis is common. Five months later she has fever, night sweats and weight loss, and her chest radiograph shows innumerable tiny nodules.

What happened, and what should have been done first?

L2 p.42

Knowledge check · 2.6

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 6 correct
  1. Q1Tuberculosis: caseating granulomaL2 p.44–45Ch. II cases p.4

    A 33-year-old man has had productive cough, fever, night sweats and a 9-kg weight loss over 4 months. His chest radiograph is shown.

    Case image

    Frontal chest radiograph with patchy opacities in the upper zones

    Which best describes his most likely lung histopathology?

  2. Q2Sarcoidosis: Th1 responseL2 p.43–44, 46Ch. II cases p.7

    A 30-year-old woman has fever (38 °C) and dyspnea, erythematous patches and plaques over the front of her lower legs, increased serum calcium and prominent bilateral hilar opacities. A skin biopsy is shown.

    Case image

    Skin biopsy at low power: many round, pale nodules of epithelioid cells with little surrounding lymphocyte cuffing and no necrosis

    Which pathologic mechanism is most associated with her likely condition?

  3. Q3Granuloma cytokines: IL-12 and IFN-γL2 p.43Ch. II cases p.13

    A 38-year-old non-smoker who works at a flour mill has two months of fever, malaise, cough, dyspnea and a 4-kg weight loss. Diffuse fine crackles are heard, and the radiograph shows patchy reticulonodular infiltrates in the mid and upper zones. A lung biopsy is shown.

    Case image

    Lung biopsy with interstitial lymphocytes and a loose cluster of epithelioid cells (arrow)

    Which cytokines are most involved in forming the lesion at the arrow?

  4. Q4Giant cells: IFN-γ and IL-12L2 p.43Midterm sim. p.4–5

    A 37-year-old man with AIDS has three weeks of chest pain and dyspnea, and bilateral nodules on chest radiography. A CT-guided lung biopsy is shown.

    Case image

    Lung tissue with a multinucleated giant cell in the centre, surrounded by lymphocytes

    The multinucleated cell in the centre most likely formed through the action of which mediators?

  5. Q5Chronic inflammation: plasma cellsL2 p.40–41Midterm sim. p.3–4

    A 41-year-old woman who uses an intrauterine device has 4 months of heavy menstrual bleeding and pelvic pain. Her endometrial biopsy shows many plasma cells (arrows), macrophages and scattered lymphoid follicles in the stroma.

    Case image

    Endometrial stroma with plasma cells (arrows): eccentric nuclei with coarse chromatin

    The presence of these cells is evidence of which condition?

  6. Q6Anti-TNF and TB reactivationL2 p.42

    A 52-year-old man with rheumatoid arthritis has been well on infliximab for six months. He now has fever, weight loss and an enlarging neck lymph node; biopsy shows acid-fast bacilli in poorly formed granulomas.

    Why did this infection appear now?

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