Chronic inflammation
Chronic and granulomatous inflammation: macrophages, granulomas and their causes
Chronic inflammation, tissue macrophages, granuloma structure, IFN-gamma, granuloma causes, CGD and sarcoidosis for FCPS Part 1. Granuloma versus granulation tissue and each classic cause are explained with their clues.
What makes inflammation chronic
- Chronic inflammation lasts weeks to years, with tissue destruction and attempts at repair happening at the same time.
- Causes: persistent infection (TB, syphilis, fungi, parasites), prolonged exposure to toxic material (silica, lipids in atherosclerosis, sutures), autoimmune disease (rheumatoid arthritis, IBD, thyroiditis) and repeated acute attacks (chronic cholecystitis).
- Features: mononuclear cells (macrophages, lymphocytes, plasma cells; eosinophils with parasites), tissue destruction, and healing by angiogenesis and fibrosis.
Macrophages
- Blood monocytes from the marrow become tissue macrophages, together forming the mononuclear phagocyte (reticuloendothelial) system.
| Site | Name |
|---|---|
| Lung alveoli | Alveolar macrophages (dust cells), the first-line phagocytes of the lung |
| Liver | Kupffer cells |
| Brain | Microglia |
| Bone | Osteoclasts |
| Skin | Langerhans cells (dendritic) |
| Lymph node, spleen | Sinus histiocytes; red pulp macrophages remove old red cells |
| Placenta; kidney | Hofbauer cells; mesangial cells |
- Classical (M1) activation by IFN-gamma from Th1 cells and microbial products makes macrophages kill (nitric oxide, reactive oxygen species). Alternative (M2) activation by IL-4 and IL-13 promotes repair and fibrosis (TGF-beta, PDGF). Macrophages present antigen on MHC class II and secrete IL-12, which drives more Th1 cells: a self-sustaining loop.
Granuloma versus granulation tissue
| Feature | Granuloma | Granulation tissue |
|---|---|---|
| What it is | A pattern of chronic inflammation | The repair tissue of healing |
| Key components | Epithelioid macrophages, often giant cells, rim of lymphocytes | New capillaries (angiogenesis) and fibroblasts in oedematous matrix with scattered inflammatory cells |
| Appearance | Nodular focus, may caseate | Pink, granular, bleeds easily in a wound base |
- The two names sound alike; read the stem carefully.
How a granuloma forms
- Antigen that is hard to remove is presented to CD4 Th1 cells, which secrete IFN-gamma, the key cytokine activating macrophages and building granulomas. Activated macrophages become epithelioid cells (abundant pink cytoplasm, slipper-shaped nuclei) and fuse into multinucleated giant cells. TNF holds the granuloma together, which is why anti-TNF drugs reactivate latent TB. This is a type IV hypersensitivity reaction.
- Giant cells: Langhans (nuclei in a horseshoe at the periphery; TB), foreign-body (scattered nuclei), Touton (xanthoma, fat necrosis).
- Granuloma macrophages make 1-alpha hydroxylase, causing hypercalcaemia, and ACE (sarcoidosis).
Causes of granulomas
| Group | Causes and clues |
|---|---|
| Caseating | Tuberculosis (search for acid-fast bacilli); histoplasmosis (calcified lung granulomas) |
| Non-caseating immune | Sarcoidosis, Crohn disease (in about half), primary biliary cholangitis (granulomatous destruction of small bile ducts, antimitochondrial antibody), giant cell arteritis, de Quervain thyroiditis |
| Necrotising vasculitic | Granulomatosis with polyangiitis: epistaxis, saddle nose, haematuria, lung nodules; c-ANCA (PR3) |
| Bacterial | Leprosy (tuberculoid), syphilis (gumma), brucellosis, cat-scratch disease, lymphogranuloma venereum (stellate abscesses), actinomycosis (granuloma plus abscess) |
| Parasitic | Schistosomiasis (eggs), leishmaniasis |
| Foreign body | Sutures, talc, silica, beryllium, keratin, urate tophi |
- Cat-scratch disease: tender axillary node two weeks after a kitten scratch; stellate necrotising granulomas with central neutrophils; *Bartonella henselae*.
- Hepatosplenic schistosomiasis (*Schistosoma mansoni*): eggs lodge in portal venules and provoke granulomas, healing as "pipe-stem" periportal fibrosis. The block is presinusoidal, so a young farmer from irrigated land has varices and a big spleen with normal liver function.
- Sarcoidosis: non-caseating granulomas with asteroid and Schaumann bodies; bilateral hilar nodes, erythema nodosum, hypercalcaemia, raised ACE. Heerfordt syndrome is fever, uveitis, bilateral parotid swelling and lower motor neurone facial palsy. Sjögren syndrome swells parotids but does not cause uveitis with palsy.
- Giant cell arteritis: granulomatous arteritis of the temporal artery in someone over 50; headache, jaw claudication, scalp tenderness, visual loss, very high ESR. Give high-dose steroids immediately, then biopsy, because blindness can follow within hours and the biopsy remains positive for days to weeks.
Chronic granulomatous disease
- NADPH oxidase deficiency (mostly X-linked): phagocytes engulf but cannot make the respiratory burst. Catalase-negative bacteria supply their own hydrogen peroxide, which the cell can still use, but catalase-positive organisms destroy it: *Staphylococcus aureus*, *Aspergillus*, *Klebsiella*, *Serratia*, *Nocardia*.
- Recurrent abscesses, pneumonias and lymphadenitis with granulomas. Nitroblue tetrazolium test fails to turn blue; dihydrorhodamine flow cytometry is abnormal.
Systemic effects and special lesions
- Anaemia of chronic disease (hepcidin traps iron), raised ESR and CRP, hypergammaglobulinaemia, weight loss.
- Reactive (AA) amyloidosis: rheumatoid arthritis, bronchiectasis, TB, chronic osteomyelitis, Crohn disease, familial Mediterranean fever.
- Sinus: blind tract to a surface. Fistula: abnormal track between two epithelial surfaces.
- Pyogenic granuloma is a misnomer: a lobular capillary haemangioma (gums in pregnancy). Xanthogranulomatous inflammation: foamy lipid-laden macrophages (pyelonephritis, cholecystitis). Malakoplakia: Michaelis–Gutmann bodies in the bladder.
Remember Th1 cells make IFN-gamma, macrophages become epithelioid, TNF keeps the granuloma together.
Exam trap Granuloma (epithelioid macrophages) and granulation tissue (capillaries and fibroblasts) are different things.
Exam trap In suspected giant cell arteritis, start steroids before the biopsy.
How FCPS asks about this
- Cytokine from Th cells key to granuloma formation: interferon-gamma; the defining cell is the epithelioid macrophage.
- Recurrent S. aureus and Aspergillus infection, abnormal NBT test: chronic granulomatous disease, NADPH oxidase deficiency.
- Components of granulation tissue: new capillaries and fibroblasts.
- Kitten scratch, stellate necrotising granulomas: Bartonella henselae.
- Varices, big spleen, normal LFTs, pipe-stem fibrosis: Schistosoma mansoni.
- Uveitis, bilateral parotid swelling and facial palsy: sarcoidosis (Heerfordt syndrome).
- Temporal headache, jaw claudication, ESR 95: high-dose steroids now, then temporal artery biopsy.
Test yourself on this topic
5 of the 49 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Weeks after surgery, a firm nodule forms around a retained suture. Histology shows giant cells with nuclei scattered haphazardly through the cytoplasm. Which type of giant cell is this?
Answer: Foreign-body giant cell
Foreign-body granulomas form around inert material too large to be phagocytosed (sutures, talc, splinters, keratin, urate crystals). Macrophages fuse into foreign-body giant cells with nuclei scattered randomly, and the foreign material can often be seen (birefringent under polarised light). Langhans giant cells have nuclei arranged in a horseshoe at the periphery (TB, sarcoid). Touton cells (xanthomas, fat necrosis) have a ring of nuclei with foamy cytoplasm. Warthin-Finkeldey cells are seen in measles; Reed-Sternberg cells in Hodgkin lymphoma.
Giant cells
- Foreign-body: nuclei scattered
- Langhans: horseshoe at periphery (TB)
- Touton: ring + foamy (xanthoma)
- Warthin-Finkeldey: measles
Remember Foreign body: nuclei everywhere; Langhans: nuclei in a horseshoe.
Why the other options are wrong
- Langhans giant cell Nuclei in a peripheral horseshoe.
- Touton giant cell Ring of nuclei, foamy cytoplasm.
- Reed-Sternberg cell Owl-eye nuclei; Hodgkin lymphoma.
- Warthin-Finkeldey cell Measles lymphoid tissue.
What are the defining components of granulation tissue?
Answer: New capillaries and fibroblasts
Granulation tissue is the hallmark of repair: pink, soft, granular tissue made of new capillaries (angiogenesis driven mainly by VEGF), proliferating fibroblasts and myofibroblasts, and loose extracellular matrix with oedema and some inflammatory cells. It gradually becomes a collagen-rich scar. It must not be confused with a granuloma, which is a collection of activated epithelioid macrophages (often with giant cells) and is a pattern of chronic inflammation.
Granulation tissue
- New capillaries (VEGF)
- Fibroblasts / myofibroblasts
- Loose, oedematous matrix
- Not the same as a granuloma
Remember Granulation = vessels + fibroblasts; granuloma = macrophages.
Exam trap Granulation tissue and granuloma sound alike but are different. Read the stem carefully.
Why the other options are wrong
- Epithelioid cells, giant cells That is a granuloma.
- Dense type I collagen, few cells That is a mature scar.
- Sheets of neutrophils, pus That is an abscess.
- Caseation with lymphocytes That is a tuberculous granuloma.
A 62-year-old man has vague abdominal pain from a mass at the root of the small-bowel mesentery. Biopsy shows fat necrosis with foamy macrophages, chronic inflammation and fibrosis of the mesenteric fat, with no malignant cells. What is the diagnosis?
Answer: Sclerosing mesenteritis
Sclerosing mesenteritis is a non-specific inflammatory and fibrotic disorder of the mesenteric fat, usually at the root of the small-bowel mesentery, with stages from fat necrosis (mesenteric panniculitis) to chronic inflammation and fibrosis (retractile mesenteritis). On CT it gives a 'misty mesentery' with a halo of normal fat around the vessels (fat ring sign). It can be associated with other malignancies, so follow-up is advised.
Sclerosing mesenteritis
- Inflammation of mesenteric fat
- Fat necrosis, inflammation, fibrosis
- At the mesenteric root
- CT: misty mesentery, fat ring
Remember Inflamed, fibrosed mesenteric fat: sclerosing mesenteritis.
Exam trap Misty mesentery can accompany lymphoma or other cancers, so follow-up imaging is often advised.
Why the other options are wrong
- Mesenteric lymphoma Sheets of malignant lymphoid cells.
- Carcinoid tumour of the mesentery Nests of neuroendocrine cells with desmoplasia.
- Mesenteric venous thrombosis Thrombus in the vein with bowel wall infarction.
- Acute pancreatitis Necrosis centred on the pancreas with raised amylase.
A 32-year-old woman has a dry cough, painful ankles and tender red nodules on both shins. She has bilateral hilar lymphadenopathy. Which bronchoalveolar lavage finding best supports the likely diagnosis?
Answer: Lymphocytosis with a high CD4:CD8 ratio
Erythema nodosum, ankle arthritis and bilateral hilar lymphadenopathy form Löfgren syndrome, an acute form of sarcoidosis. The non-caseating granulomas are driven by activated CD4 Th1 cells, which gather in the alveoli, so lavage shows a lymphocytosis with a CD4:CD8 ratio above about 3.5. Hypersensitivity pneumonitis also gives a lymphocytosis but typically with a low ratio (CD8 predominant). Biopsy showing non-caseating granulomas remains the confirmation.
Sarcoidosis lavage
- Bilateral hilar nodes
- Löfgren: erythema nodosum, arthritis
- BAL: CD4:CD8 high
- Non-caseating granulomas
Remember Sarcoid is a CD4 disease: ratio high.
Exam trap Tuberculosis and lymphoma also enlarge hilar nodes, but they are usually asymmetrical.
Why the other options are wrong
- Lymphocytosis with a low CD4:CD8 ratio Typical of hypersensitivity pneumonitis.
- Many neutrophils with Gram-positive cocci Suggests bacterial pneumonia.
- Many eosinophils over 25% Suggests eosinophilic pneumonia.
- Haemosiderin-laden macrophages Suggests alveolar haemorrhage.
A 25-year-old man has fever, erythema nodosum and bilateral hilar lymphadenopathy. Biopsy of an enlarged node shows tight nodules of plump cells with pale, slipper-shaped nuclei and abundant pink cytoplasm, with occasional giant cells. What are these plump cells?
Answer: Epithelioid macrophages
A granuloma is a focal collection of activated macrophages called epithelioid cells, because their abundant cytoplasm makes them resemble epithelium. Interferon-gamma from Th1 lymphocytes transforms ordinary macrophages into these cells, which may fuse into multinucleate giant cells. A rim of lymphocytes surrounds them. Non-caseating granulomas in hilar nodes of a young adult suggest sarcoidosis; caseation points to tuberculosis.
Granuloma
- Core: epithelioid macrophages
- Fusion: giant cells
- Driver: IFN-gamma from Th1
- Rim of lymphocytes
Remember Epithelioid cells are macrophages dressed as epithelium.
Exam trap Giant cells alone do not make a granuloma; epithelioid cells are essential.
Why the other options are wrong
- Plasma cells These have eccentric clock-face nuclei and make antibody.
- Reed-Sternberg cells These are large binucleate cells of Hodgkin lymphoma.
- Activated fibroblasts Fibroblasts are spindle-shaped and lay down collagen at the edge.
- Eosinophils These have bilobed nuclei with red granules.
Where this sits in the CPSP syllabus
- Paper 1: General pathology, Chronic and granulomatous inflammation