Acute Phase Proteins (APPs) - Comprehensive University Answer

Definition

The Acute Phase Response

• Liver (primary site of APP synthesis)
• Vascular system
• Bone marrow
• Central nervous system

Cytokine Regulation

Classification by Magnitude of Response

1. Major Positive APPs - Increase >1000-fold (within 2-3 days)

• C-reactive protein (CRP)
• Serum Amyloid A (SAA)

2. Moderate Positive APPs - Increase 2-4 fold (slower rise)

• Fibrinogen
• Haptoglobin
• alpha1-acid glycoprotein (orosomucoid)
• alpha1-protease inhibitor (alpha1-antitrypsin)
• alpha1-antichymotrypsin

3. Minor Positive APPs - Increase ~50-100%

• Complement C3
• Complement C9, Factor B
• Ceruloplasmin
• Ferritin
• Mannose-binding lectin (MBL)
• Fibronectin

4. Negative APPs - Decrease during inflammation

• Albumin
• Transferrin
• Pre-albumin (transthyretin)
• Apolipoprotein A-I
• Antithrombin III
• Protein S

Individual Proteins in Detail

C-Reactive Protein (CRP)

• Structure: 115 kDa pentamer of five 23 kDa subunits (non-covalently linked). Pentameric form.
• Synthesis: Liver hepatocytes. Trace baseline concentration in all humans (~0.3 mg/dL).
• Kinetics: Rises within 6-8 hours of stimulus, peaks at 2-3 days, half-life of ~19 hours. Falls rapidly once stimulus is removed.
• History: Identified in 1930 when it was found to bind the "C" polysaccharide of Streptococcus pneumoniae cell wall.
• Ligands: Binds phosphocholine, phospholipids, fibronectin, chromatin, histones (exposed on apoptotic cells and sites of tissue damage).
• Functions:
  • Opsonisation: Tags pathogens and apoptotic debris for phagocytosis
  • Complement activation: Activates the classical pathway
  • Immune bridging: Binds Fc-gamma receptors on leukocytes
  • Induction of cytokines: Promotes IL-6 receptor shedding and tissue factors
  • Anti-inflammatory role: Promotes non-inflammatory clearance of apoptotic cells; prevents neutrophil adhesion to endothelium

• Normal/minor (<1 mg/dL): vigorous exercise, common cold, pregnancy, gingivitis, depression, obesity, insulin resistance
• Moderate (1-10 mg/dL): myocardial infarction, malignancy, most autoimmune diseases
• Marked (>10 mg/dL): bacterial infections, severe RA flares, vasculitis

• Firestein & Kelley's Textbook of Rheumatology, p. 1099-1100

Serum Amyloid A (SAA)

• Type: Apolipoprotein; also classified as an acute phase protein.
• Rise: Up to 1000-fold (same order as CRP). Associates with HDL during the acute phase response.
• Clinical use: Limited by lack of standardised assays. Can be used synergistically with hsCRP.
• Significance: Chronic elevation leads to SAA deposition as AA amyloid - the mechanism underlying secondary (reactive) amyloidosis in conditions like RA, FMF, and chronic infections.

Haptoglobin

• Function: Binds free haemoglobin to prevent oxidative damage and iron loss.
• Rise: Moderate (2-4 fold).
• Note: Low haptoglobin is a marker of intravascular haemolysis (haemoglobin binds and depletes it).

Fibrinogen

• Function: Coagulation; polymerises to fibrin clot; tissue repair.
• Rise: Moderate (2-4 fold), slower peak than CRP.
• Clinical relevance: Elevated fibrinogen contributes to increased ESR (by causing RBC rouleaux formation). Also a cardiovascular risk factor.

Ceruloplasmin

• Function: Copper transport; superoxide radical scavenger (antioxidant); ferroxidase activity.
• Rise: Minor (~50%).
• Note: Plasma copper rises during acute phase response because of increased ceruloplasmin, even though zinc and iron fall.

alpha1-Antitrypsin (alpha1-Protease Inhibitor)

• Function: Antiprotease - inhibits neutrophil elastase, collagenase, and bacterial proteases, limiting tissue destruction.
• Rise: Moderate.

alpha1-Acid Glycoprotein (Orosomucoid)

• Function: Transport protein (binds basic drugs); platelet inhibitor; immunomodulatory.
• Rise: Moderate to major.

Mannose-Binding Lectin (MBL)

• Function: Pattern recognition; fixes complement via lectin pathway; opsonisation.
• Rise: Moderate. Part of the collectin family.

Ferritin

• Function: Iron storage protein; elevated ferritin sequesters iron from microbes (bacteriostatic effect).
• Regulation: Induced by IL-1, IL-6, IL-18, TNF via NF-kB pathway.
• Hyperferritinemic syndromes: Extremely high ferritin (>10,000 ng/mL) characterises a specific group: septic shock, adult-onset Still's disease, macrophage activation syndrome (MAS), catastrophic antiphospholipid syndrome, and severe COVID-19.

Negative APPs - Why They Fall

1. Increased transcapillary escape from increased microvascular permeability (albumin TER increases up to 3-fold in sepsis/major injury)
2. Redistribution of synthesis: liver redirects resources toward positive APPs
3. Transferrin specifically falls because hepcidin (itself an acute-phase peptide induced by IL-6) promotes iron sequestration, making iron transport less necessary.

• Bailey & Love's Short Practice of Surgery, 28th ed., p. 13

Functions of APPs - Summary

1. Pattern recognition and opsonisation (CRP, MBL, SAA) - bind PAMPs and DAMPs, target pathogens/debris for phagocytosis
2. Complement activation (CRP - classical; MBL - lectin pathway; C3, C9, Factor B - amplify complement)
3. Protease inhibition (alpha1-antitrypsin, alpha2-macroglobulin, alpha1-antichymotrypsin) - limit tissue destruction by neutrophil enzymes
4. Haemoglobin/haeme scavenging (haptoglobin, hemopexin) - prevent oxidative damage and iron-mediated bacterial growth
5. Iron sequestration (ferritin, hepcidin) - bacteriostatic by depriving microbes of iron
6. Coagulation and tissue repair (fibrinogen, fibronectin) - support wound healing
7. Antioxidant protection (ceruloplasmin, haptoglobin) - scavenge reactive oxygen species
8. Regulation and resolution (C1 inhibitor) - limits complement and kinin production, preventing excessive inflammation

• Roitt's Essential Immunology; Mulholland & Greenfield's Surgery, 7e

Acute Phase Response vs ESR

Clinical Applications of APPs

Key Points for University Exams

1. APPs are defined as plasma proteins changing by >25% from baseline during inflammation.
2. The liver is the primary site of synthesis, driven by IL-6 (main cytokine), with synergy from IL-1 and TNF.
3. CRP and SAA show the most dramatic rise (>1000-fold); they are the "major" APPs.
4. Albumin and transferrin fall because of increased vascular permeability, not reduced synthesis.
5. CRP acts as an opsonin and activates the classical complement pathway.
6. CRP half-life is ~19 hours - it falls rapidly once inflammation resolves; this makes it ideal for monitoring treatment response.
7. SLE is a notable exception where CRP may be paradoxically normal or only mildly elevated despite active disease.
8. Persistent SAA elevation causes secondary (AA) amyloidosis.
9. The acute phase response is a "double-edged sword" - provides defence and repair proteins but at the expense of lean tissue and energy reserves (catabolism).