Biochem

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Rate of migration depends on:

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•Charge of the molecule

•Size and shape of the molecule

•pH of the medium

•Voltage

•Properties of the supporting medium •Temperature

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SDS (sodium dodecyl sulfate, a detergent)

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–SDS gives all proteins an uniformly negative charge

–The native shape of proteins does not matter

–Rate of movement will only depend on size: small proteins will move faster

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acute phase proteins

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The level of certain proteins in blood may increase or decrease 50 to 1000 folds in various inflammatory and neoplastic conditions

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Nonspecifics (APP

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serve as a core of immune response, serve to prevent infection, clear potential pathogens, initiate inflammatory processes, the healing process, etc.  Exp: CRP, α1-antitrypsin, haptoglobin, α1-acid glycoprotein, and fibrinogen.

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Positive Acute Phase Proteins

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 Plasma protein levels increase in infection, inflammation, malignancy, trauma, surgery  Synthesized due to body’s response to injury  Examples: a1-Antitypsin, α1-acid glycoprotein (orosomucoid), haptoglobin, ceruloplasmin, fibrinogen, CRP

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Negative Acute Phase Protein

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 These proteins decrease in inflammation: Albumin, prealbumin, transferrin  Mediated by inflammatory response via cytokines and hormones  Synthesis of these proteins decrease to save amino acids for positive acute phase proteins

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1) Prealbumin [Transthyretin, Thyroxine-binding prealbumin (TBPA)]

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A transport protein for thyroid hormones [T3 (triiodothyronine) & T4 (thyroxine); More affinity to T3] and retinol (vitamin

A)Negative acute phase protein (reactant)/ (These proteins decrease in inflammation

Lower levels found in liver disease, nephrotic syndrome, acute phase inflammatory response, malnutrition.

 Nephrotic syndrome is a kidney disorder that causes your body to excrete too much protein in your urine which leads to edema

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Hypoalbuminemia

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Causes  Decreased albumin synthesis (liver cirrhosis, malnutrition)  Increased losses of albumin  Excessive excretion by the kidneys (nephrotic syndrome)  Excessive loss in bowel  Increased catabolism in infections  Thermal injury to the skin or severe eczema

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Effects

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 Edema due to low oncotic pressure –Albumin level drops in liver disease causing low oncotic pressure –Fluid moves into the interstitial spaces causing edema  Reduced transport of drugs and other substances in plasma  Reduced protein-bound calcium –Total plasma calcium level drops

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Liver damage – Cirrhosis

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 Cirrhosis can be caused by chronic alcohol abuse or viral hepatitis.

 ↓ albumin

 ↓ α1, α2 and β globulins 

↑ Ig A in γ-fraction

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Nephrotic syndrome

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 The kidney damage illustrates the long term loss of lower molecular weight proteins (↓ albumin and IgG – they are filtered in kidney)

 Retention of higher molecular weight proteins (↑↑ α2-macroglobulin and ↑β-globulins)

 A2 proteins take the function of albumin in case of nephrotic syndrome.

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Monoclonal Hypergammaglobulinemia

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 Caused by monoclonal proliferation of β-lymphocytal clones. These altered β-cells produce an abnormal immunoglobulin, paraprotein.

 Production of paraprotein is associated with benign monoclonal gammopathy (leucemia) and multiple myeloma

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Acute inflammatory response

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 Immediate response occurs with stress or inflammation caused by infection, injury or surgical trauma.

 Normal or ↓ albumin

 ↑ α1 and α2 globulins

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Chronic inflammatory response

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 Late response is correlated with chronic infection (autoimmune diseases, chronic liver disease, chronic infection, cancer)  Normal or ↓ albumin  ↑α1 or α2 globulins  ↑↑ γ globulins

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A1-GLOBULINS

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A1-ANTITRYPSIN (ATT

A1-ANTICHYMOTRYPSIN

Α1-ACID GLYCOPROTEIN (Orosomucoid

A-FETOPROTEIN (AFP)

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Α2-GLOBULINS

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A2 MACROGLOBULIN (AMG)

HAPTOGLOBIN

CERULOPLASMIN (Cu oxidase, ferroxidase)

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Β-GLOBULINS

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TRANSFERRIN

C-REACTIVE PROTEIN (CRP)

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A1-ANTITRYPSIN (ATT

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protease inhibitor

An acute-phase protein that inhibits proteases

inhibits elastese so no elastic tissue damage

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Increased a1-Antitrypsin

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A1-Antitrypsin is increased as part of the acute phase response, in patients with hyperestrogenemia caused by pregnancy, oral contraceptives, tamoxifen, tumors or with liver disease.

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a1-Antitrypsin Deficiency

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•Pulmonary emphysema (a chronic, irreversible disease of the lungs characterized by abnormal enlargement of air spaces in the lungs accompanied by destruction of the tissue lining the walls of the air spaces) in young adults 6 • Some affected individuals develop neonatal hepatitis (those who do are highly likely to develop serious liver disease

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A1-ANTICHYMOTRYPSIN

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A serine protease inhibitor

 Acute-phase reactant (increases in acute phase response)

.  Mostly functions if ATT is not abundant

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Α1-ACID GLYCOPROTEIN (Orosomucoid)

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Orosomucoid is considered to be a reliable indicator of acute inflammation.

 Orosomucoid binds the hormone progesterone and functions as a transport protein for this hormone.

 Probably serves to carry needed carbohydrate constituents to the sites of tissue repair following injury, since it has a high carbohydrate content (41%).

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A-FETOPROTEIN (AFP)

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Synthesized in the developing embryo and fetus by the parenchymal cells of the liver.

Elevated maternal AFP levels are associated with neural tube defect, anencephaly.  Decreased maternal AFP levels are associated with increased risk of Down’s syndrome.  AFP is a tumor marker for: Hepatoma and testicular cancer

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A2 MACROGLOBULIN (AMG)

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Increases in nephrotic syndrome

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HAPTOGLOBIN

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Binds to free hemoglobin to form complexes (Hp-Hb complex)  Limits iron losses by preventing Hb loss from kidneys: preserve body iron and protein stores.  Increases in acute inflammatory conditions (acute phase reactant).

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CERULOPLASMIN (Cu oxidase, ferroxidase)

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90% of Cu is carried by ceruloplasmin.

It mainly functions as a ferroxidase and helps in oxidation of Fe++ to Fe+++ which can be incorporated into transferrin

Wilson’s disease: In hepatocytes Cu transport to ER-Golgi network is absent due to ATP7B deficiency. Cu is accumulated in the liver and brain • Menkes disease: Cu does not cross the intestinal barrier due to ATP7A deficiency ATP7A protein that secrets Cu to the bile

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TRANSFERRIN

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A negative acute phase protein Increase: Transferrin is increased in patients with iron deficiency anemia Decrease: Malnutrition, liver disease, inflammation, malignancy Iron deficiency results in increased hepatic synthesis.

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C-REACTIVE PROTEIN (CRP)  An acute-phase protein synthesized by the liver.

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Marker of inflammation