Plasma_Proteins_modefied_Teejan.pdf

20 Abdulrahman Tarabsheh Omar Wawi Nabil Bashir 1-Antitrypsin  Synthesized by the liver and macrophages  An acute-phase protein that inhibits proteases  Proteases are produced endogenously and from leukocytes(inside body) and bacteria(outside)  Digestive enzymes (trypsin, chymotrypsin)  Oth...

20 Abdulrahman Tarabsheh Omar Wawi Nabil Bashir 1-Antitrypsin  Synthesized by the liver and macrophages  An acute-phase protein that inhibits proteases  Proteases are produced endogenously and from leukocytes(inside body) and bacteria(outside)  Digestive enzymes (trypsin, chymotrypsin)  Other proteases (elastase, thrombin)  Infection leads to protease release from bacteria and from leukocytes  A1- antitrypsin is important protease to stop the action of proteases when it is required. This is an electrophoresis pattern for plasma proteins Normal There is a depression in this peak indicating a decrease in a1antitrypsin . Abnormal Types of 1-Antitrypsin  Over 30 types are known  The most common is M type  Genetic deficiency of 1-Antitrypsin  Synthesis of the defective 1-Antitrypsin occurs in the liver but it cannot secrete the protein to the blood.  1-Antitrypsin accumulates in hepatocytes and is deficient in plasma (so the concentration of a1-antitrypsing will decrease in plasma ). This is an electrophoresis pattern for plasma proteins So if we take a blood sample of a patient who has been suspected to have deficiency in a1-antitrypsin we will see this pattern of electrophoresis (depression in a1 globulin because a1-antitrypsin is a major component of a1 globulin). Clinical Consequences of 1-Antitrypsin Deficiency  Neonatal jaundice with evidence of cholestasis ( in which the bile salts will not flow from the liver to the gallbladder)  Childhood liver cirrhosis (accumulation of a1- antitrypsin will destroy liver tissue)  Pulmonary emphysema in young adults (in adults if a1-antitrypsin is deficient it will not stop elastase protease from action on lung tissue so elastase will continue attacking the lung tissue so pulmonary emphysema will happen). We can diagnose these diseases by Laboratory Diagnosis  Lack of 1-globulin band in protein electrophoresis  Chemical method :Quantitative measurement of 1-Antitrypsin by (details are not required) :  Radial immunodiffusion  isoelectric focusing electrophoresis  nephelometry ➢ Chronic inflammation (neutrophil elastase) ➢ Oxidation of Met358 ➢ devastating in patients with PiZZ There are many types of a1- antitrypsin , the most type that is affected by smoking is protease inhibitor zz (isoform for antitrypsin) One of the amino groups in a1antitrypsin is Methionine. Due to materials that smokers have when smoking the methionine at position 358 will be oxidized and converted to Methionine-Sulfoxide Important amino acid in a1- anititrypsin in the active site It will block its activity and a1antitrypsin will not have the proper activity to attack elastase that attacks lung tissue and emphysema will happen Emphysema: gradual damage in lung tissue. -Fetoprotein (AFP)  Synthesized in the developing embryo and fetus by the parenchymal cells of the liver  AFP levels decrease gradually during intra-uterine life and reach adult levels at birth ( It has a specific physiological concentration during embryonic stage and it decreases when growing )  Function is unknown but it may protect fetus from immunologic attack by the mother HOW? It binds antibodies from mother and neutralize them. -Fetoprotein (AFP)  Elevated maternal AFP levels are associated with:  Neural tube defect in embryo due to incomplete neural tube NT closure(it must be controlled during pregnancy to make sure that NT is well developed), anencephaly ( people who are born with parts of skull and brain )  Decreased maternal AFP levels are associated with:  Increased risk of Down’s syndrome  AFP is a tumor marker for: Hepatoma (liver) and testicular cancer (AFP proteins are highly synthesized in these cancers) Ceruloplasmin  Synthesized by the liver  Contains >90% of serum copper ( stores copper)  Ceruplasmin an oxidoreductase enzyme that inactivates ROS(reactive oxygen species such as superoxide and superhydroixde )causing tissue damage in acute phase response  Important for iron absorption from the intestine( it has a ferroxidase activity so it will oxidize iron from ferrous +2 to ferric +3 which is good in absorption)  Wilson’s disease: copper metabolism defect  Due to low plasma levels of ceruloplasmin  Copper is accumulated in the liver and brain Haptoglobin  Synthesized by the liver  Binds to free hemoglobin to form complexes that are metabolized in the RES (Reticuloendothilial system)  Limits iron losses by preventing Hb loss from kidneys so the iron will be recycled and used.  Plasma level decreases during hemolysis because most of them will bind to hemoglobin after RBC are broken and the liver will not cope with more synthesis of haptoglobin . Transferrin  A major iron-transport protein in plasma  30% saturated with iron  Plasma level drops in:  Malnutrition( no enough iron which is important for their synthesis will bind to it ) , liver disease(unable to synthesize more transferrin), inflammation, malignancy  Iron deficiency results in increased hepatic synthesis because it will seek for any amount of iron to collect it and metabolize it  A negative acute phase protein(in case of inflammation, malignancy) 2–Microglobulin  A component of human leukocyte antigen (HLA)  Present on the surface of lymphocytes and most nucleated cells  Filtered by the renal glomeruli due to its small size but most (>99%) is reabsorbed  Elevated serum levels are found in  Impaired kidney function because it will not be able to reabsorb it.  Overproduction in inflammatory disease  May be a tumor marker and (prognosis/treatment ) for:  Leukemia, lymphomas, multiple myeloma  B2-micoglobulin concentration will decrease while treating these cancers in chemotherapy Fibrinogen rod like structure (like fibers) ❑Also called clotting factor1. ❑Constitutes 4-6% of total protein ❑❑Imparts maximum viscosity to blood as well as albumin. ❑Synthesized in liver ❑Made up of 6 polypeptide chains ❑Chains are linked together by S-S linkages ❑Amino terminal end is highly negative due to the presence of glutamic acid ❑Negative charge contributes to its solubility in plasma and prevents aggregation due to electrostatic repulsions between the fibrinogen molecules. C-Reactive Protein (CRP)  An acute-phase protein synthesized by the liver in response to inflammation and malignancy  Important for phagocytosis: enhancing immunsystem`s response to infection, binds the antigen`s molecule for engulfment  High plasma levels are found in many inflammatory conditions such as rheumatoid arthritis because there are many inflammatory reactions so the body will respond by synthesizing acute phase proteins such as CRP  A marker for ischemic heart disease ( due to inflammatory reactions in blood vessels making those plaques that will make atherosclerosis which will block blood vessels) Hypergammaglobulinemia High concentration of gamma globulin  May result from stimulation of  B cells (Polyclonal hypergammaglobulinemia) (because different types of B cells produce different types of gamma globulin so the total concentration of gamma globulin will increase due to different types)  Monoclonal proliferation (Paraproteinemia) (only one type of B cell will produce one specific type of gamma globulin that will be diagnostic for multiple myeloma which is a cancer) Hypergammaglobulinemia Polyclonal hypergammaglobulinemia:  Stimulation of many clones of B cells produce a wide range of antibodies  -globulin band appears large in electrophoresis  Clinical conditions: acute and chronic infections, autoimmune diseases, chronic liver diseases(impaired clearance) Normal Hypergammaglobulinemia We cannot differentiate between gamma and beta globulin because there is a bridge. Monoclonal Hypergammaglobulinemia  Proliferation of a single B-cell clone produces a single type of Ig (immunoglobulin)  Appears as a separate dense band and a sharp peak (paraprotein or M band) in electrophoresis  Paraproteins are characteristic of malignant B-cell proliferation  Clinical condition: multiple myeloma Normal Multiple myeloma Positive Acute Phase Proteins  Plasma protein levels increase in:  Infection, inflammation , malignancy, trauma, surgery  These proteins are called acute phase reactants  Synthesized due to body’s response to injury,Infection, inflammation , malignancy, trauma, surgery  Examples: 1-Antitypsin, haptoglobin, ceruloplasmin, fibrinogen, c-reactive protein Positive Acute Phase Proteins  Mediators cause these proteins to increase after injury  Mediators: Cytokines (IL-1(interleukins), IL-6), tumor necrosis factors  and  , interferons, platelet activating factor  These mediators will affect the transcription of acute phase proteins and thus increase in the rate of synthesis and translation. Functions: 1. Bind to polysaccharides in bacterial walls 2. Activate complement system 3. Stimulate phagocytosis of the foreign bodies Normal Electrophoresis under inflammatory reactions so we see increased concentration of positive acute phase proteins Negative Acute Phase Proteins  These proteins decrease in inflammation  Albumin, pre albumin, transferrin  Mediated by inflammatory response via cytokines and hormones ( will suppress transcription of these proteins so less synthesis )  Synthesis of these proteins decrease to save amino acids for positive acute phase proteins