Acute & Chronic Inflammation
Rolling to diapedesis, the LAD/CGD defects, and how granulomas form
Acute versus chronic inflammation
Two tempos. Acute inflammation is rapid (minutes to days), neutrophil-predominant and mediated by histamine, complement and prostaglandins. Chronic inflammation lasts weeks to months and is dominated by macrophages, lymphocytes and plasma cells, with angiogenesis, fibrosis and tissue destruction going on together. The cardinal signs are rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function).
| Feature | Acute | Chronic |
|---|---|---|
| Onset | Minutes to days | Weeks to months |
| Dominant cells | Neutrophils | Macrophages, lymphocytes, plasma cells |
| Main events | Vascular: exudation, edema | Tissue remodeling: angiogenesis, fibrosis |
Vascular phase and mediators
Vascular changes. A transient vasoconstriction gives way to vasodilation (histamine, NO) that increases blood flow and produces calor and rubor. Increased permeability (histamine, bradykinin) leaks protein-rich exudate, producing tumor. The resulting stasis pushes leukocytes to the vessel wall (margination).
Other mediators. Mast cells release histamine after trauma, IgE cross-linking or stimulation by the anaphylatoxins C3a and C5a. Bradykinin and PGE2 cause pain, and PGE2 also mediates fever when IL-1 and TNF act on the hypothalamus.
Leukocyte recruitment
- MarginationStasis pushes white cells to the edge
- RollingSelectins bind sialyl Lewis X
- Tight adhesionIntegrins bind ICAM-1
- DiapedesisPECAM-1 (CD31)
- ChemotaxisC5a, LTB4, IL-8, f-Met peptides
Rolling. Endothelial E-selectin (induced by TNF and IL-1) and P-selectin (stored in Weibel-Palade bodies alongside vWF and released quickly by histamine) bind sialyl Lewis X on leukocytes. L-selectin on leukocytes binds endothelial ligands. These low-affinity bonds make the cell roll rather than stop.
Firm adhesion and exit. Chemoattractants such as C5a and LTB4 activate the leukocyte integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18), which bind endothelial ICAM-1 and arrest rolling. The cell then transmigrates between endothelial cells using PECAM-1 (CD31) and follows a chemical gradient to the insult. Neutrophils arrive first, peaking at ~24 h, and macrophages follow.
Chemoattractants. The potent neutrophil chemoattractants are C5a, leukotriene B4 (LTB4), IL-8 (CXCL8) and bacterial N-formylmethionine (f-Met) peptides; kallikrein is also chemotactic.
| Step | Endothelium | Leukocyte |
|---|---|---|
| Rolling | E-selectin, P-selectin | Sialyl Lewis X |
| Rolling | Selectin ligands | L-selectin |
| Tight adhesion | ICAM-1 | LFA-1, Mac-1 (CD18 integrins) |
| Diapedesis | PECAM-1 | PECAM-1 |
Killing and phagocyte defects
Phagocytosis and the respiratory burst. The opsonins C3b and IgG coat microbes for engulfment. NADPH oxidase then converts oxygen to superoxide, which becomes H2O2, and myeloperoxidase combines H2O2 with Cl⁻ to make bleach (HOCl).
Leukocyte adhesion deficiency type 1 (LAD-1). This autosomal recessive defect in CD18, the β2 integrin, stops neutrophils from sticking and leaving vessels. They pile up in blood (marked neutrophilia) but never reach tissue, causing recurrent skin and mucosal infections WITHOUT pus, impaired wound healing and delayed umbilical cord separation (>30 days).
Chronic granulomatous disease (CGD). Defective NADPH oxidase abolishes the respiratory burst. Phagocytes can still borrow H2O2 made by catalase-negative bacteria, but catalase-positive organisms destroy it, so infections come from catalase-positive organisms: S. aureus, Serratia, Aspergillus, Nocardia, Burkholderia and E. coli. The dihydrorhodamine (DHR) flow test is abnormal, and the nitroblue tetrazolium test does not turn blue.
| Disorder | Defect | Clues |
|---|---|---|
| LAD-1 | CD18 (β2 integrin) | Delayed cord separation, no pus, neutrophilia |
| CGD | NADPH oxidase | Catalase-positive infections; abnormal DHR test |
| Myeloperoxidase deficiency | Myeloperoxidase | Often asymptomatic; Candida infections; NBT test normal |
| Chédiak-Higashi | Lysosomal trafficking (LYST) | Giant granules, partial albinism, neuropathy, pyogenic infections |
Acute-phase response
IL-6 drives the liver. Positive acute-phase reactants rise: CRP, fibrinogen, ferritin, hepcidin, serum amyloid A and C3. Negative reactants fall: albumin and transferrin. Fibrinogen promotes rouleaux and raises the ESR. Hepcidin sequesters iron, producing anemia of chronic disease with high ferritin and low transferrin. Persistently high serum amyloid A in chronic inflammation leads to AA amyloidosis.
Chronic inflammation and granulomas
Cells. Macrophages derived from blood monocytes dominate, together with T lymphocytes and plasma cells. M1 macrophages are pro-inflammatory, while M2 macrophages promote repair and fibrosis. Persistent infection, autoimmunity and foreign material drive the process.
Granuloma formation. A granuloma is a collection of activated (epithelioid) macrophages, often with giant cells and a rim of lymphocytes, built by the Th1 axis:
- Macrophage + IL-12Presents antigen
- Th1 activationCD4 T cell
- IFN-γ releaseActivates macrophages
- Epithelioid and giant cellsMultinucleated Langhans giant cells
- TNF-α maintainsBlocking it breaks granulomas down
Anti-TNF biologics such as infliximab dissolve granulomas and can reactivate latent TB, so always screen with PPD or IGRA first.
Caseating vs noncaseating. Caseating granulomas mean TB or systemic fungi. Noncaseating granulomas occur in sarcoidosis, Crohn disease, berylliosis, cat-scratch disease (stellate, Bartonella), GPA, primary biliary cholangitis and foreign-body reactions. Sarcoidosis pairs noncaseating granulomas with hypercalcemia, because granuloma macrophages make calcitriol.