Acute Phase Proteins - Acute Phase Reactants

Background

Plasma proteins termed acute phase proteins or reactants are involved in the innate system response to inflammation, tissue injury or malignancy. During inflammatory processes, the plasma concentration of these acute phase proteins increases or decreases by ≥50%.

Classification

Human plasma acute phase proteins

Human Plasma Acute Phase Proteins
Positive Acute Phase Proteins*
Complement system	C2, C3, C4, C5, C9, factor B, C1 inhibitor, C4b-BP, mannose-BP, B-2-glycoprotein-1
Coagulation system	Fibrinogen, plasminogen, urokinase, protein S, vitronectin, PAI-1, alpha-2-antiplasmin, antithrombin 3
Antiproteases	Alpha-1-antitrypsin, alpha-1-antichymotrypsin, pancreatic secretory trypsin inhibitor, inter-alpha-trypsin inhibitor, alpha-2 macroglobulin
Binding proteins	Ceruloplasmin, haptoglobin, hemopexin, LPS-BP, mannose-BP
Proteins involved in inflammatory response	Secreted phospholipase A2, IL-IRA, GM-CSF, cytokines (interleukins), tumor necrosis factor
Others	Serum amyloid A, C-reactive protein, alpha-1 acid glycoprotein, fibronectin, ferritin, angiotensinogen, hepcidin
Negative Acute Phase Proteins**
Albumin, transferrin, alpha 2-HS-glycoprotein, alpha fetoprotein, thyroxine-BP, IGF-1, factor XII, retinol binding protein, transthyretin, transcortin
* Increase in response to inflammation ** Decrease in response to inflammation

Pathophysiology

Most acute phase reactants are synthesized in the hepatocytes
- Not elevated in functional disturbances
- Usually not elevated in stable chronic diseases
- Strongly elevated in bacterial infections, juvenile arthritis, tumors, Crohn disease, surgery, polymyalgia rheumatica, systemic vasculitis, burns, fractures
- Negligible elevation in arthralgia, myalgia, back pain

Selected Acute Phase Proteins

Alpha-1 acid glycoprotein
- Function – immunomodulatory activity that may reduce collateral damage caused by inflammation
- Regulation – proinflammatory cytokines, including interleukin 1 (IL-1), interleukin 6 (IL-6), chemokines (IL-8) and glucocorticoids
Pentraxin
- C-reactive protein (CRP)
  - Functions
    - May increase a thousandfold in response to inflammation and infection
    - Acts as an opsonin for bacteria, parasites and immune complexes
      - Can act as an activator of classic complement pathway
    - Elevated in many disease states, including coronary artery disease, infections, vasculitis, acute phase of connective tissue diseases, malignancy
- Amyloid
  - Functions
    - Apolipoproteins that associate with HDL3
    - Enhances binding capacity of HDL3 to hepatocytes
    - Elevated in malignancy
- Haptoglobin
  - Functions
    - Binds free hemoglobin released from erythrocytes
    - Involved in inflammation, infections and malignancy
- Ceruloplasmin
  - Functions
    - Globulin involved in release of iron into plasma cells
    - Serum antioxidant
    - Modulates inflammatory response
    - Elevated in pregnancy, high estrogen conditions, infections, cirrhosis, malignancy, hyperthyroidism, and rheumatoid arthritis (RA)
Cytokines
- Functions
  - Major activators of acute phase proteins are IL-1 and IL-6
  - Mediators between leukocytes; 18 identified interleukins with varying effects
- Interleukin-1-beta
  - Production – activated macrophages
  - Functions – wide variety of biological actions
    - Stimulates expression of IL-2 receptors
    - Stimulates production and secretion of IL-2
  - In synergy with tumor necrosis factor alpha, elevated interleukin-1-beta is seen in the following
    - Septic shock
    - Cerebrospinal fluid
      - Meningitis
      - Multiple sclerosis
- Interleukin-6
  - Function – involved in B-cell differentiation into plasma cells
    - Usually not detected in normal serum, plasma, cerebral spinal fluid (CSF) or joint fluid
  - Elevated levels occur in the following
    - Inflammatory processes
      - Infections (endotoxemia)
      - Connective tissue disease
    - Alcoholic cirrhosis
    - Chronic renal failure
    - Central nervous system inflammation (increased CSF levels)
      - Bacterial meningitis
      - CNS involvement in systemic lupus erythematosus (SLE)
    - RA (increased synovial fluid levels)
- Interleukin-2
  - Production – activated T-cells
  - Also known as
    - T-cell growth factor
    - Thymocyte simulation factor
    - Thymocyte mitogenesis factor
    - T-cell replacing factor
    - Killer-helper factor
  - Function – most notable immunologic function is the activation, proliferation and promotion of T-cells, B-cells and NK-cells
  - Decreased IL-2 production associated with
    - SLE
    - Hodgkin lymphoma
    - Lepromatous leprosy
    - HIV/AIDS
    - Common variable immunodeficiency
    - Chronic mucocutaneous candidiasis
- Interleukin-8
  - Production – activated macrophages
  - Function – pro-inflammatory cytokine and chemoattractant for neutrophils
  - Elevated in many inflammatory processes – infections, connective tissue diseases

Tumor Necrosis Factor (TNF-α, Cachectin)

Production – mononuclear phagocytes
Functions
- Activation of T-cells
- Pyrogenicity and endotoxemia
- Mitogenic effects on fibroblasts
- Resorption of bone and cartilage
- Activation of neutrophil function
- Decreased activity of several enzymes involved in lipid metabolism
- Decreased synthesis of hepatic protein
- Cachexia
Regulation
- IL6R, IL1R and IL2RA interleukin receptors
- Granulocyte monocyte-colony stimulating factor
- MYC and FOS genes
- Epidermal growth factor

Diagnosis

Indications for Testing

Inflammation or infection not explained by other etiology
- Except for CRP, these markers are predominantly used in research settings

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: C-Reactive Protein

ARUP #: 0050180

Methodology: Quantitative Immunoturbidimetric

Use:

CRP useful in clinical scenarios associated with inflammation (cardiovascular disease, autoimmune disease, connective tissue disease, RA, or sepsis)

Test name: Alpha-1-Acid Glycoprotein, Serum

ARUP #: 0050002

Methodology: Quantitative Nephelometry

Use:

Monitor acute phase proteins associated with inflammatory conditions such as RA and malignant neoplasms

Limitations: Limited clinical use

Test name: Haptoglobin

ARUP #: 0050280

Methodology: Quantitative Immunoturbidimetric

Use:

Elevated level suggests inflammation, infection, or malignancy

Limitations:

Limited clinical use

Test name: Tumor Necrosis Factor - alpha

ARUP #: 0051539

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Elevated levels seen in septic shock, meningitis, and other central nervous system processes such as multiple sclerosis

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Test name: Cytokine Panel 12 by MAFD

ARUP #: 0051394

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Test name: Cytokine Panel, Monokines by MAFD

ARUP #: 0051524

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Test name: Interleukin 1 beta by MAFD

ARUP #: 0051536

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Test name: Interleukin 2 Receptor (Soluble) by MAFD

ARUP #: 0051529

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Test name: Interleukin 6 by MAFD

ARUP #: 0051537

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Test name: Interleukin 8 by MAFD

ARUP #: 0051538

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Test name: Interleukin 2 by MAFD

ARUP #: 0051588

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Limitations:

Limited clinical use

Additional Tests Available

Test name: Cytokine Panel, TH1 by MAFD

ARUP #: 0051408

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Comments:

Limited clinical use

Test name: Cytokine Panel, TH2 by MAFD

ARUP #: 0051518

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, 12 Cytokines

ARUP #: 0051540

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interferon gamma

ARUP #: 0051574

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 1 beta

ARUP #: 0051580

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 2

ARUP #: 0051571

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 2 Receptor (Soluble)

ARUP #: 0051572

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 4

ARUP #: 0051576

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 5

ARUP #: 0051577

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 6

ARUP #: 0051581

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Alpha-1-Antitrypsin

ARUP #: 0050001

Methodology: Quantitative Immunoturbidimetric

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, TH1 Cytokines

ARUP #: 0051558

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, TH2 Cytokines

ARUP #: 0051562

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Monokines

ARUP #: 0051566

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, Monokines

ARUP #: 0051587

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) Deficiency Screen

ARUP #: 0051393

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies

ARUP #: 0095899

Methodology: Quantitative Flow Cytometry

Comments:

Test includes percentage and absolute counts for CD2, CD3 (total T-cells), HLA-DR, CD4 (helper T-cells), CD45RA (naive helper T-cells), CD45RO (memory helper T-cells), CD8 (suppressor T-cells), CD19 (B-cells ), NK cells, and CD4:CD8 ratio

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 8

ARUP #: 0051582

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Tumor Necrosis Factor alpha

ARUP #: 0051583

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 12

ARUP #: 0051573

Methodology: Cell Culture/Quantitative Multi-Analyte Fluorescence Detection

Comments:

Limited clinical use

References

General

ARUP Institute for Clinical and Experimental Pathology®

Medical Reviewers

Delgado, Julio C., MD, MS. Medical Director, Protein Immunology at ARUP Laboratories; Associate Director, Histocompatibility and Immunogenetics Laboratory and Assistant Professor of Pathology, University of Utah

Comprehensive Review: June 2011
Last Update: June 2011