Pbl Exam 3 Case 2

Front 1

1. Where does digestion of proteins take place?

Back 1

Begins in the stomach and is completed in the intestine.

Front 2

2. Digestion of proteins is broken down by enzymes. How are these enzymes activated?

Back 2

The proteolytic enzymes, pepsin, trypsin, chymotrypsin, elastase and the carboxypetidases are produced as zymogens that are activated by cleavage after they enter the gastrointestinal lumen.

Front 3

3. Pepsinogen

Back 3

Secreted by the chief cells of the stomach. The gastric parietal cells secrete HCl. The acid in the stomach alters the conformation of pepsinogen so that is can cleave itself, producing the active protease pepsin.

Front 4

4. Pepsin

Back 4

Has a fairly broad specificity, but it tends to cleave peptide bonds in which the carboxyl group is provided by an aromatic or acidic amino acid.

Front 5

5. Trypsinogen

Back 5

Cleaved by enteropeptidase, secreted by the brush border cells of the small intestine, to form the active protease trypsin

Front 6

6. Trypsin

Back 6

Plays a key role by catalyzing the cleavage and activation of the other pancreatic zymogens.

Catalyzes the cleavages of chymotrypsinogen to chymotrypsin, proelastase to elastase, and the procarboxypeptidases to the carboxypeptidases.

Front 7

7. Which pancreatic enzymes are serine proteases that act as endopeptidases?

Back 7

1. Trypsin
2. Chymotrypsin
3. Elastase

Front 8

8. Specificity of trypsin

Back 8

Trypsin is the most specific, cleaving peptide bonds in which the carboxyl (carbonyl) group is provided by lysine or arginine.

Front 9

9. Specificity of chymotrypsin

Back 9

Chymotrypsin is less specific, but favors residues that contain hydrophobic AAs.

Front 10

10. Specificity of elastase

Back 10

Elastase cleaves not only elastin but also other proteins at bonds in which the carboxyl group is contributed by AA residues w/small side chains (alanine, glycine, and serine).

Front 11

11. Exopeptidases

Back 11

Proteases that cleave one amino acid at a time form the end of the chain.

Front 12

12. Procarboxypeptidases

Back 12

Procarboxypeptidases, zymogens produced by the pancreas, are converted by trypsin to the active carboxypeptidases.

These exopeptidases remove AAs from the carboxyl ends of peptide chains.

Carboxypeptidase A releases hydrophobic AAs, whereas carboxypeptidase B releases basic amino acids (arginine and lysine)

Front 13

13. Aminopeptidases

Back 13

Located on the brush border and cleave one AA at a time from the amino end of peptides.

Front 14

14. How are amino acids absorbed from the intestinal lumen?

Back 14

Through secondary active Na+-dependent transport systems and thru facilitated diffusion.

Front 15

15. Co-transport of Na+ and amino acids

Back 15

AA's are absorbed form the lumen of the small intestine principally by semi specific Na+-dependent transport proteins in the luminal membrane of the intestinal cell brush border.

The co-transport of Na+ and the amino acid from the outside of the apical membrane to the inside of the cell is driven by the low intracellular Na+ concentration.

Low intracellular Na+ results form the pumping of Na+ out of the cell by a Na+,K+-ATPase on the serosal membrane.

Front 16

16. What is the primary transport mechanism in this Na+ and AA co-transport?

What is the secondary mechanism?

Back 16

Primary mechanism is the creation of a sodium gradient.

The secondary mechanism is the coupling of AAs to the influx of sodium. This mechanism allows the cells to concentrate AAs from the intestinal lumen.

The AAs are then transported out of the cell into the interstitial fluid, principally by facilitated transporters in the serosal membrane.

Front 17

17. How many different Na+-dependent amino acid carriers are located in the apical brush border membrane of the epithelial cells?

Back 17

At least six.

These carriers have overlapping specificity for different amino acids. One transports neutral AAs, another transports proline and hydroxyproline, a third only acidic AAs, a fourth only basic AAs.

Most AA's are transported by more than one transport system.

Front 18

18. Amino acid transport across the serosal membrane is uni- or bi-directional?

Back 18

Bidirectional

Front 19

19. Where does Na+-dependent transport of AA's take place?

Where does facilitated transport take place?

Back 19

Na+-dependent transport takes place in the intestinal and renal epithelium but facilitated transport in other cell types.

Front 20

20. What are examples of proteins that undergo extensive synthesis and degradation?

Back 20

1. Hemoglobin
2. Muscle proteins
3. Digestive enzymes
4. Proteins of cells sloughed off from the GI tract

Front 21

21. Lysosomal protein turnover

Back 21

Lysosomes participate in the process of autophagy, in which intracellular components are surrounded by membranes that fuse w/lysosomes, and endocytosis.

Within the lysosomes, the cathepsin family of proteases degrades the ingested proteins to individual AAs. The recycles AAs can then leave the lysosome and rejoin the intracellular AA pool.

Front 22

22. How does a cell induce autophagy?

Back 22

Starvation of a cell is a trigger to induce this process.

This allows old proteins to be recycled and the newly released AAs to be used for new protein synthesis, to enable the cell to survive starvation conditions.

Front 23

23. Ubiquitin

Back 23

A small protein (76 AAs) that is highly conserved. Its AA sequence in yeast and humans differs by only three residues.

It targets intracellular proteins for degradation by covalently binding to the ε-amino group of lysine residues.

Often, the target protein is polyubiquitinylated, forming a long ubiquitin tail.

Front 24

24. Ubiquitin-proteasome pathway

Back 24

After the targeted protein is polyubiquitinylated (say that 10 times fast!) a protease complex, known as the proteasome, then degrades the targeted protein, releasing intact ubiquitin that can again mark other proteins for degradation.

Front 25

25. Proteasomes

Back 25

A cylindrical 20S protein complex w/multiple internal proteolytic sites. ATP hydrolysis is used both to unfold the tagged protein and to push the protein into the core of the cylinder.

The complex is regulated by cap protein complexes, which bind the ubiquinylated protein (a step that requires ATP) and deliver them to the complex.

Different cap complexes alter the specificity of the proteasome.

Front 26

26. Most proteins with what sequence are hydrolyzed by the ubiquitin-proteasome system?

Back 26

PEST sequence

P: Proline
E: Glutamate
S: Serine
T: Threonine

Front 27

27. Kwashiorkor

Back 27

A common problem of children in third world countries, is caused by a deficiency of protein in a diet that is adequate in calories.

These children suffer from muscle wasting and decreased concentration of plasma proteins, particularly albumin.

The result is an increase in interstitial fluid that causes edema and a distended abdomen.

Front 28

28. Where else is elastase found?

Back 28

Also found in neutrophils. Neutrophils freq act in the lung, and elastase is sometimes released into the lung as the neutrophils work.

Front 29

29. α-1-antitrypsin deficiency

Back 29

In normal individuals, the released elastase in the lungs is block from destroying lung cells by the action of circulating α-1-antitrypsin, a protease inhibitor that is synthesized and secreted by the liver.

Individuals w/this disease have a genetic mutation that leads to the production of an inactive α-1-antitrypsin protein.

The lack of enzyme activity leads to the development of emphysema caused by proteolytic destruction of lung cells.

Front 30

30. How can α-1-antitrypsin deficiency be detected?

Back 30

Rate nephelometry.

Can be measured using a dried blood spot. The blood is solublized using a buffer, and then various amts of the blood sample are incubated w/antibodies specific for α-1-antitrypsin.

The antigen-antibody complexes formed will disperse light, and the extent of light scattering is proportional to the concentration of α-1-antitrypsin in the solution.

Front 31

31. Cystic fibrosis and pancreatic exocrine secretions

Back 31

Patients w/cystic fibrosis have a genetically determined defect in the function of the chloride channels. In the pancreatic secretory ducts, which carry pancreatic enzymes into the lumen of the small intestines, this defect causes inspissation (drying and thickening) of pancreatic exocrine secretions, leading eventually to obstruction of these ducts.

One result of this problem is the inability of pancreatic enzymes to enter the intestinal lumen to digest dietary proteins.

Front 32

32. Why does the pancreas store a trypsin inhibitor?

Back 32

The need for the inhibitor is to block any trypsin activity that may occur from accidental trypsinogen activation.

If the inhibitor were not present, trypsinogen activation would lead to the activation of all of the zymogens in the pancreas, which would lead to the digestion of intracellular pancreatic proteins.

Such episodes can lead to pancreatitis.

Front 33

33. Hartnup disease

Back 33

A genetically determined and relatively rare autosomal recessive disorder. It is caused by a defect in the transport of neutral amino acids across both intestinal and renal epithelial cells.

The sign and symptoms, are caused, in part, by a deficiency of essential amino acids.

Cystinuria and Hartnup disease involve two different transport proteins. In each case, the defect is present both in intestinal cells, causing malabsorption of the AAs from the digestive products in the intestinal lumen, and in kidney tubular cells, causing a decreased resorption of these AAs from the glomerular filtrate and an increased concentration of the AAs in the urine.

Front 34

34. Why doe patients with cystinuria and Hartnup disease have hyperaminoaciduria w/o associated hyperaminoacidemia?

Back 34

Cystinuria and Hartnup disease involve two different transport proteins. In each case, the defect is present both in intestinal cells, causing malabsorption of the AAs from the digestive products in the intestinal lumen, and in kidney tubular cells, causing a decreased resorption of these AAs from the glomerular filtrate and an increased concentration of the AAs in the urine.

Therefore, they do not have hyperaminoacidemia (a high concentration in the blood).

In these diseases, much larger amts of the affected amino acids are excreted in the urine, resulting in hyperaminoaciduria.

Front 35

35. Hartnup disorder and pellagra

Back 35

Some patients with the Hartnup phenotype eventually develop pellagra-like manifestations, which usually include a photosensitivity rash ataxia, and neuropsychiatric symptoms. Pellagra results from a dietary deficiency of niacin or tryptophan.

Only rational treatment for these patients is to administer niacin, but the hyperaminoaciduria and intestinal transport defect do not respond to this therapy.

Front 36

36. γ-glutamyl cycle

Back 36

This cycle is necessary for the synthesis of glutathione.

In cells of the intestine and kidney, AAs can be transported across the cell membrane by reacting w/glutathione to form a γ-glutamyl amino acid. The AA is released into the cell, and glutathione is resynthesized.

However, the major role of this cycle is glutathione synthesis.

Front 37

37. Transaminase reactions

Back 37

Transamination is the major process for removing nitrogen from amino acids.

In most instances, the nitrogen is transferred as an amino group from the original amino acid to α-ketoglutarate, forming glutamate, whereas the original AA is converted to its corresponding α-keto acid.

Front 38

38. Example of transamination reaction

Back 38

Aspartate can be transaminated to form its corresponding α-keto acid, oxaloacetate.

In this process, the amino group is transferred to α-ketoglutarate, which is converted to its corresponding amino acid, glutamate.

Front 39

39. Which amino acids have the ability to undergo transamination reactions?

What are the most common pair involved in these reactions?

Back 39

All AAs except lysine and threonine have the ability to undergo transamination reactions.

α-ketoglutarate and glutamate → most common pair involved in these reactions

Front 40

40. Transamination reaction summary

Back 40

An amino group from one amino acid becomes the amino group of a second amino acid.

B/c these reactions are readily reversible, they can be used to remove nitrogen from AAs or to transfer nitrogen to α-keto acids to form amino acids.

Thus, they are involved both in AA degradation and in AA synthesis

Front 41

41. pKa of formation of ammonia from ammonium ion

Back 41

pKa = 9.3

Thus, at physiological pH, the equilibrium favors NH4+ by a factor of approximately 100:1.

Front 42

42. Importance of ammonia (NH3)

Back 42

This is the form that can cross cell membranes. For example, NH3 passes into the urine from kidney tubule cells and decreases the acidity of the urine by binding protons, forming NH4+.

Once the NH4+ is formed, the compound can no longer freely diffuse across membranes.

Front 43

43. Oxidative deamination of glutamate

Catalyzed by what?

Cofactors?

Back 43

Catalyzed by glutamate dehydrogenase that produces ammonium ion and α-ketoglutarate.

Either NAD+ or NADP+ can serve as the cofactor.

Glutamate can collect nitrogen from other AAs as a consequence of transamination reactions and then release ammonia thru the glutamate dehydrogenase reaction.

This process provides one source of the ammonia that enters the urea cycle.

Front 44

44. What are the three mammalian enzymes that can "fix" ammonia into organic molecules?

Back 44

1. Glutamate dehydrogenase
2. Glutamine synthetase
3. Carbamoyl phosphate

Front 45

45. What AA provides nitrogen for AA synthesis?

Back 45

Glutamate

Front 46

46. What AAs provide nitrogens for the urea cycle?

Back 46

1. Glutamate
2. Aspartate

Front 47

47. Role of alanine in transporting AA nitrogen to the liver

(AKA glucose/alanine cycle)

Back 47

Alanine is exported primarily by muscle. B/c muscle is metabolizing glucose thru glycolysis, pyruvate is available in the muscle.

The pyruvate is transaminated by glutamate to form alanine, which travels to the liver (The glutamate is formed by transamination of an AA that is being degraded)

Upon arriving in the liver, alanine is transaminated to pyruvate, and the nitrogen is used for urea synthesis.


The pyruvate formed is used for gluconeogenesis and the glucose exported to the muscle for use as energy.

Front 48

48. Role of glutamine in transporting AA nitrogen to the liver

Back 48

Glutamine is synthesized from glutamate by the fixation of ammonia, requiring ATP and the enzyme glutamine synthetase.

In the liver, glutamine synthetase is located in cell surrounding the portal vein. Its major role is to convert any ammonia that has escaped from urea production into glutamine, so that free ammonia does not leave the liver and enter the circulation.

Front 49

49. Role of PLP in transamination reactions

Where is PLP derived from?

Back 49

Pyridoxyl phosphate (PLP) → cofactor in transaminase reactions

PLP accepts an amino group from an AA and donates it to an α-keto acid.

Derived from pyridoxine (vitamin B6)

Front 50

50. Oxidative deamination

Back 50

Results in liberation of the amino group as NH4+.

Occurs primarily in the liver and kidney

Can utilize NAD+ or NADP+ as a cofactor

Front 51

51. GTP vs. ADP effects on glutamate dehydrogenase

Back 51

GTP is an allosteric inhibitor of glutamate dehydrogenase, whereas ADP is an activator

Front 52

52. Reaction scheme in the urea cycle

3 main steps...

Back 52

1. Synthesis of carbamoyl phosphate
2. Production of arginine
3. Cleavage of arginine to produce urea

Front 53

53. Overall stoichiometry of the urea cycle

Back 53

Aspartate + NH3 + CO2 + 3 ATP

↓

Urea + Fumarate + 2 ADP + AMP
+ 2 Pi + PPi + 3 H2O

Front 54

54. Step 1: Synthesis of carbamoyl phosphate

What enzyme catalyzes this step?

Back 54

NH4+, bicarbonate, and ATP react to form carbamoyl phosphate.

Carbamoyl phosphate synthetase I catalyzes this first step in the mitochondria of the liver and intestine.

Front 55

55. Step 2: Production of arginine by the urea cycle

Part I

Back 55

1. Carbamoyl phosphate reacts w/ornithine to form citrulline.

2. The product citrulline is transported across the mitochondrial membranes in exchange for cytoplasmic ornithine and enters the cytosol.

3. In the cytosol, citrulline reacts w/aspartate to produce arginosuccinate via arginosuccinate synthetase.

Front 56

56. Step 2: Production of arginine by the urea cycle

Part II

Back 56

4. Arginosuccinate is cleaved by arginosuccinate lyase to form fumarate and arginine.

5. Fumarate is converted to malate via cytoplasmic fumarase, which is used either for the synthesis of glucose by the gluconeogenic pathway or for the regeneration of oxaloacetate.

6. The oxaloacetate that is formed is transaminated to generate the aspartate that carries nitrogen into the urea cycle. Thus, the carbons of fumarate can be recycled to aspartate.

Front 57

57. Step 3: Cleavage of arginine to produce urea

Back 57

Arginine is cleaved by arginase, producing urea and regenerating ornithine.

Urea is produced from the guanidinium group on the side chain of arginine.

The portion of arginine originally derived from ornithine is reconverted to ornithine.

This ornithine can then be transported into the mitochondrion in exchange for citrulline, where it can react w/carbamoyl phosphate, initiating another round of the cycle.

Front 58

58. Origin of ornithine

Back 58

Although ornithine is normally regenerated by the urea cycle, ornithine also can be synthesized de novo if needed.

The reaction is an unusual transamination reaction catalyzed by ornithine aminotransferase under specific conditions in the intestine.

The usual direction of this rxn is the formation of glutamate semialdehyde, which is the first step of the degradation pathway for ornithine.

Front 59

59. What is the rate limiting step of the urea cycle?

Back 59

Allosteric activation of CPSI by N-acetyl-glutamate

This is the rate limiting step of the urea cycle.

Front 60

60. What three things regulate the urea cycle?

Back 60

1. Regulated by substrate availability

2. Allosteric activation of CPSI by N-acetyl-glutamate (NAG)

3. Induction/repression of the synthesis of urea cycle enzymes

Front 61

61. N-acetyl-glutamate (NAG)

How is it formed?

Back 61

Formed specifically to activate CPSI; it has no other known function.

The synthesis of NAG from acetyl CoA and glutamate is stimulated by arginine.

Front 62

62. When arginase levels increase in the liver, what two reactions does this stimulate?

Back 62

1. Synthesis of NAG, which increases the rate at which carbamoyl phosphate is produced.

2. Produces more ornithine (via the arginase reaction), so that the cycle can operate more rapidly.

Front 63

63. What conditions promote the induction of the urea-cycle enzymes?

Back 63

Occurs in response to conditions that require increased protein metabolism, such as a high-protein diet or prolonged fasting.

Front 64

64. What happens to the urea cycle during fasting?

Back 64

During fasting, the liver maintains blood glucose levels.

AAs from muscle protein are a major carbon source for the production of glucose by the pathway of gluconeogenesis.

As AA carbons are converted to glucose, the nitrogens are converted to urea.

Thus, the urinary excretion of urea is high during fasting.

Front 65

65. What is the major AA substrate for gluconeogenesis?

What does this have to do with fasting?

Back 65

Alanine, which is synthesized in peripheral tissues to act as a nitrogen carrier.

Glucagon release, which is expected during fasting, stimulates alanine transport into the liver by activating the transcription of transport systems for alanine.

Front 66

66. How many molecules of alanine are required to generate one molecule of glucose and one molecule of urea?

Back 66

Two molecules of alanine are required to generate one molecule of glucose and one molecule of urea.

Front 67

67. Ornithine transcarbamoylase (OTC) deficiency

Back 67

An X-linked disorder; occurs in 1/20,000 and 1/80,000 live births.

Predominantly affects males, although female carriers may become symptomatic; typically results in mental retardation

When OTC is deficient, the carbamoyl phosphate that normally would enter the urea cycle accumulates and floods the pathway for pyrimidine biosynthesis.

Under these conditions, excess orotic acid (orotate), an intermediate in pyrimidine biosynthesis, is excreted in the urine.

Front 68

68. Treatment of OTC deficiency

Back 68

Limiting dietary protein

and

Administration of compounds (e.g. benzoid acid and phenylacetate) that covalently bind to amino acids → nitrogen-containing molecules are then excreted in the urine

Front 69

69. Vitamin B6 Deficiency

Back 69

Symptoms include dermatitis, microcytic anemia (small, pale red blood cells), weakness, irritability and convulsions

Inability to completely metabolize amino acids → appearance of xanthurenic acid (a degradation product of tryptophan) and other compounds in the urine

Decreased ability to synthesize heme from glycine → microcytic anemia

Decreased decarboxylation of amino acids to form neurotransmitters → convulsions

Also required for the glycogen phosphorylase reaction.

Front 70

70. Diagnostic values of plasma aminotranferases in liver disease

Which is more specific - ALT or AST?

Which is more sensitive - ALT or AST?

Back 70

Plasma AST and ALT are typically elevated

Particularly high in conditions that cause extensive cell necrosis (e.g., severe viral hepatitis, toxic injury, prolonged circulatory collapse)

ALT is more specific

AST is more sensitive → liver contains larger amounts of this enzyme than ALT

Front 71

71. Diagnostic values of plasma aminotranferases in non-hepatic disease

Back 71

Aminotransferases may be elevated (e.g., myocardial infarction, muscle disorders)

Disorders can usually be distinguished clinically from liver disease

Front 72

72. Ammonia intoxication

Back 72

Capacity of hepatic urea cycle > normal rates of NH3 generation → levels of serum ammonia = 5-50 μM (normal range)

Compromised liver function → blood levels of NH3 can rise above 1,000 μM

Ammonia has a direct neurotoxic effect on the central nervous system

Ammonia intoxication → tremors, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision

High concentration of NH3 → coma and death

Front 73

73. BUN

Back 73

Blood urea nitrogen is a measurement for the urea content of the blood.

The key to measuring BUN is to split urea into CO2 and two ammonia molecules by the enzyme urease.

The ammonia levels are then determined.

Once BUN is determined, the urea concentration can be determined by multiplying the nitrogen value by 2.14

Front 74

74. γ-aminobutryic acid (GABA) and liver disease

Back 74

An important inhibitory neurotransmitter in the brain, is also shunted into the systemic circulation in increased amts in patients with hepatic failure.

Front 75

75. Acute viral hepatitis

Back 75

The serum ALT level is often elevated to a greater extend than the serum AST level.

Alkaline phosphatase is also elevated.

The rise in serum total bilirubin occurs as a result of the inability of the infected liver to conjugate bilirubin and of a partial or complete occlusion of the hepatic biliary drainage ducts caused by inflammatory swelling within the liver.

Front 76

76. Nucleotide structure

Back 76

Nitrogenous base + Pentose monosaccharide + Phosphate group(s)

Front 77

77. Four functions of nucleotides

Back 77

1. Precursor molecules to DNA, RNA

2. Involved in energy metabolism, ATP, GTP, CTP, UTP

3. Structure of many coenzymes, NAD+, FAD, CoA

4. Activated sugars in biosynthesis pathways

Front 78

78. Where does the uptake and synthesis of nucleotides takes place?

Back 78

Low dietary uptake in the intestine (about 5%) - mostly used by intestinal epithelial cells and thus de novo synthesis of purines and pyrimidines is required.

Most are made in the liver, however brain and immune cells also make their own.

Front 79

79. Purine synthesis starts with...?

Back 79

Starts with 5-phosphoribosyl-1-pyrophosphate (PRPP)

All purines are built on a ribose base and PRPP is the activated source of the ribose moiety.

The pyrophosphate will be replaced by the nucleic acid base.

Front 80

80. Production of PRPP

Back 80

It is synthesized from ATP and ribose 5'-phosphate, which is produced from glucose thru the pentose phosphate pathway which is catalyzed byt he enzyme PRPP synthetase.

Front 81

81. First committed step of the purine biosynthetic pathway

What enzyme catalyzes this step?

Back 81

1. PRPP reacts w/glutamine to form 5-phosphoribosyl 1-amine.

This reaction, which produces nitrogen 9 of the purine ring, is catalyzed by glutamine phosphoribosyl amidotranferase, a highly regulated enzyme.

Front 82

82. Second step of purine biosynthesis

What does this step require?

Back 82

An entire glycine molecule is added to the growing precursor. Glycine provides carbons 4 and 5 and nitrogen 7 of the purine ring.

This step requires energy int eh form of ATP

Front 83

83. Step three of purine biosynthesis

Back 83

Carbon 8 is provided by N^10-formyl-FH4, nitrogen 3 by glutamine, carbon 6 by CO2, nitrogen 1 by aspartate and carbon 2 by formyl FH4.

Front 84

84. How many molecules of ATP are required to synthesize the first purine nucleotide, inosine monophosphate (IMP)?

Back 84

Six molecules of ATP

Front 85

85. Importance of folate

Back 85

Folate is essential for purine synthesis

Front 86

86. Importance of IMP

Back 86

IMP serves as a branch point from which both adenine and guanine nucleotides can be produced.

Front 87

87. Formation of AMP

Back 87

Adenosine monophosphate is derived from IMP in two steps:

1. Aspartate is added to IMP to form adenylosuccinate
2. Fumarate is then released from the adenylosuccinate by the enzyme adenylosuccinase to form AMP.

In both cases, aspartate donates a nitrogen to the product, while the carbons of aspartate are released as fumarate.

Front 88

88. Formation of GMP

Back 88

Also synthesized from IMP in two steps:

1. The hypoxanthine base is oxidized by IMP dehydrogenase to produce the base xanthine and the nucleotide xanthosine monophosphate (XMP)
2. Glutamine then donates the amide nitrogen to XMP to form GMP in a reaction that is catalyzed by GMP synthetase. This reaction requires energy in the form of ATP.

Front 89

89. Phosphorylation of AMP and GMP

Back 89

AMP and GMP can be phosphorylated to the di- and triphosphate levels.

The production of nucleoside diphosphates requires specific nucleoside monophophate kinases, whereas the production of nucleoside triphosphates requires nucleoside diphosphate kinases.

Front 90

90. Regulation of purine synthesis;

What four key enzymes are regulated?

What do they regulate?

Back 90

1. PRPP synthetase
2. Amidophosphoribosyl transferase
3. Adenylosuccinate synthetase
4. IMP dehydrogenase

1 & 2 regulate IMP synthesis; 3 & 4 regulate the production of AMP and GMP, respectively.

Front 91

91. How is the first committed step of purine synthesis regulated?

Back 91

Ezyme is glutamine phosphoribosyl amidotransferase.

This enzyme is strongly inhibited by GMP and AMP.

The active enzyme is a monomer of 133,000 daltons but is converted to an inactive dimer (270,000 daltons) by binding of the end products.

*The rate of de novo purine synthesis increases as the concentration of PRPP increases because PRPP concentrations are usually below the Km

Front 92

92. What inhibits adenylsuccinate synthetase?

How about IMP dehydrogenase?

Back 92

AMP inhibits adenylosuccinate

GMP inhibits IMP dehydrogenase

Note: the synthesis of AMP is dependent on GTP, whereas the synthesis of GMP is dependent on ATP. This serves as a type of positive regulatory mechanism to balance the pools of these precursors.

Front 93

93. Salvaging of purine bases

Back 93

Salvage pathways are used to recover bases and nucleosides that are formed during degradation of RNA and DNA. This is important in some organs because some tissues cannot undergo de novo synthesis.

The salvaged bases and nucleosides can then be converted back into nucleotides.

Front 94

94. What three major enzymes are required for purine salvaging?

Back 94

1. Purine nucleoside phosphorylase
2. Phosphoribosyl tranferase
3. Deaminases

Front 95

95. Purine nucleoside phosphorylase

Back 95

This enzyme catalyzes a phosphorolysis reaction of the N-glycosidic bond that attaches the base to the sugar moiety in the nucleosides guanosine and inosine.

Thus, guanosine and inosine are converted to guanine and hypoxanthine, respectively, along with ribose 1-phosphate.

The ribose-1-phosphate can be isomerized to ribose 5-phosphate, and the free bases then salvaged or degraded, depending on cellular needs.

Front 96

96. Phosphoribosyl transferase enzymes

What are the two phosphoribosyl transferase enzymes, and what do they do?

Back 96

They catalyze the addition of a ribose 5-phosphate group from PRPP to a free base, generating a nucleotide and pyrophosphate.

Two enzymes do this: adenine phosphoribosyl transferase (ARPT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT).

The reactions they catalyze are the same, differing only in their substrate specificity.

Front 97

97. Deaminase

Back 97

Adenosine and AMP can be deaminated by adenosine deaminase and AMP deaminase, respectively, to form inosine and IMP.

Front 98

98. What is so special about adenosine?

Back 98

Adenosine is also the only nucleoside to be directly phosphorylated to a nucleotide by adenosine kinase.

Guanosine and inosine must be converted to free bases by purine nucleoside phosphorylase before they can be converted to nucleotides by HGPRT.

Front 99

99. Purine nucleotide cycle

Back 99

Important salvage pathway in muscle.

The net effect of these reactions is the deamination of aspartate to fumarate.

Under conditions in which the muscle must generate energy, the fumarate derived from the purine nucleotide cycle is used anapleurotically to replenish TCA cycle intermediates and to allow the cycle to operate at high speed.

Deficiencies in enzymes of this cycle lead to muscle fatigue during exercise.

Front 100

100. De novo synthesis of pyrimidine nucleotides

Back 100

In the synthesis of the pyrimidine nucleotides, the base is synthesized first, and then it is attached to the ribose 5'-phosphate moiety.

The origins of the atoms of the ring are from aspartate and carbamoyl-phosphate, which are derived from CO2 and glutamine.

Front 101

101. Steps of pyrimidine nucleotide synthesis (formation of UMP)

Back 101

*1. Glutamine combines with bicarbonate and ATP to form carbamoyl phosphate via CPS-II.
2. An entire aspartate molecule adds to carbamoyl phosphate via aspartate transcarbamoylase.
3. The molecule subsequently closes to produce a ring via dihydro-orotase
4. The enzyme orotate phosphoribosyl transferase catalyzes the transfer of ribose 5-phosphate from PRPP to orotate, producing orotidine 5'-phosphate, which is decarboxylated by orotidylic acid dehydrogenase to form uridine monophosphate (UMP)

*regulated step of pathway

Front 102

102. CAD enzymes

Back 102

In mammals, the first three enzymes of the pathway (CPS-II, aspartate transcarbamoylase, and dihydro-orotase) are located on the same polypeptide, designated as CAD

Front 103

103. UMP synthase

Back 103

The last two enzymes of the pathway are located on a polypeptide known as UMP synthase (the orotate phosphoribosyl transferase and orotidylic acid dehydrogenase)

Front 104

104. Formation of UTP and CTP

Why are these pyrimidines important?

Back 104

UMP is phosphorylated to UTP. An amino group, derived form the amide of glutamine, is added to carbon 4 to produce CTP via CTP synthetase.

UTP and CTP are precursors for the synthesis of RNA.

Front 105

105. Salvage of pyrimidine bases

Back 105

Salvaged by a two step route:
1. Non-specific pyrimidine nucleoside phsophorylase converts the pyrimidine bases to their respective nucleosides.
2. The more specific nucleoside kinases the react w/the nucleosides, forming nucleotides.

Front 106

106. Efficiency of pyrimidine base salvage

Back 106

The nucleoside phosphorylase-nucleoside kinase route for synthesis of pyrimidine nucleoside monophosphates is relatively inefficient for salvage of pyrimidine bases b/c of the very low concentration of bases in plasma and tissues.

Front 107

107. Preference for pyrimidine phosphorylase

Back 107

Can use all of the pyrimidines but has a preference for uracil and is sometimes called uridine phosphorylase.

The phosphorylase uses cytosine fairly well but has a very, very low affinity for thymine; therefore, a ribonucleoside containing thymine is almost never made in vivo.

Front 108

108. Thmine phosphorylase

Back 108

Has a much higher affinity for thymine and adds a deoxyribose residue.

Front 109

109. Thymidine kinase (TK)

Back 109

This enzyme is allosterically inhibited by dTTP.

Activity of thymidine kinase in a given cell is closely related to the proliferative state of that cell.

During the cell cycle the activity of TK rises dramatically as cells enter S-phase, and in general, rapidly dividing cells have high levels of this enzyme.

Front 110

110. Regulation of de novo pyrimidine synthesis

What inhibits and activates synthesis?

Back 110

The regulated step is carbamoyl phosphate synthetase II (CPS-II).

The enzyme is inhibited by UTP and activated by PRPP.

Thus, as pyrimidines decrease in concentration, CPS-II is activated and pyrimidines are synthesized.

*Also regulated by the cell cycle.

Front 111

111. How does the cell cycle regulate pyrimidine synthesis?

Back 111

As cells approach S-phase, CPS-II becomes more sensitive to PRPP activation and less sensitive to UTP inhibition.

At the end of S-phase, the inhibition by UTP is more pronounced, and the activation by PRPP is reduced.

These changes in the allosteric properties of CPS-II are related to its phosphorylation state.

Phosphorylation of the enzyme by MAP kinase leads to a more easily activated enzyme, while phosphorylation at a second site by the cAMP dependent protein kinase leads to a more easily inhibited enzyme.

Front 112

112. Production of deoxyribonucleotides

Back 112

For DNA synthesis to occur, the ribose moiety must be reduced to deoxyribose. This reduction occurs at the diphosphate level and is catalyzed by ribonucleotide reductase, which requires the protein thioredoxin.

The deoxyribonucleoside diphosphates can be phosphorylated to the triphosphate level and used as precursors for DNA synthesis.

Front 113

113. Regulation of ribonucleotide reductase

Back 113

The enzyme contains two allosteric sites, one controlling the activity of the enzyme and the other controlling the substrate specificity of the enzyme.

Front 114

114. Control of ribonucleotide reductase activity

Back 114

ATP bound to the activity site activates the enzyme; dATP bound to this site inhibits the enzyme.

Front 115

115. Control of ribonucleotide reductase substrate specificity

Back 115

ATP bound to the substrate site activates the reduction of pyrimidines (CDP and UDP), to form dCDP and dUDP. The dUDP is not used for DNA synthesis; rather, it is used to produce dTTP, which then binds to the substrate site and induces the reduction of GDP.

As dGTP accumulates, it replaces dTTP in the substrate site and allows ADP to be reduced to dADP. This leads to the accumulation of dATP, which inhibits the overall activity of the enzymes.

Front 116

116. Formation of dUMP

Back 116

dUDP can be dephosphorylated to form dUMP or dCMP can be deaminated to form dUMP.

Front 117

117. Formation of dTMP

Back 117

Methylene FH4 transfers a methyl group to dUMP to form dTMP.

Front 118

118. Formation of dTTP

Back 118

Phosphorylation reactions produce dTTP, a precursor for DNA synthesis and a regulator of ribonucleotide reductase.

Front 119

119. Degradation of purine bases

Back 119

The degradation of the purine nucleotides (AMP and GMP) occurs mainly in the liver.

Salvage enzymes are used for most of these reactions.

Front 120

120. Degradation of AMP

Back 120

AMP is first deaminated to produce IMP via AMP deaminase.

Then, IMP and GMP are dephosphorylated via 5'-nucleotidase, and the ribose is cleaved from the base by purine nucleoside phosphorylase.

Hypoxanthine, the base produced by cleavage of IMP, is converted by xanthine oxidase to xanthine, and guanine is deaminated by the enzyme guanase to produce xanthine.

The pathways for the degradation of andenine and guanine merge at this point.

Front 121

121. Degradation of xanthine to uric acid

What enzyme accomplishes this?

Back 121

Xanthine is converted by xanthine oxidase to uric acid, which is excreted in the urine.

Front 122

122. Xanthine oxidase

Back 122

This is a molybdenum-requiring enzyme that uses molecular oxygen and produces hydrogen peroxide.

Another form of xanthine oxidase uses NAD+ as the electron acceptor.

Front 123

123. Energy expenditure of purine ring degradation

Back 123

Little energy is derived from the purine ring degradation.

Thus, it is to the cell's advantage to recycle and salvage the ring, b/c it costs energy to produce and not much is obtained in return.

Front 124

124. Degradation of pyrimidine bases

Back 124

The pyrimidine nucleotides are dephosphorylated, and the nucleosides are cleaved to produce ribose 1-phosphate and the free pyrimidine bases cytosine, uracil and thymine.

These products of pyrimidine degradation are excreted in the urine or converted to CO2, H2O, and NH4+ (which forms urea).

As with the purine degradation pathway, little energy can be generated by pyrimidine degradation.

Front 125

125. Deficiency in purine nucleoside phosphorylase activity

Back 125

Leads to an immune disorder in which T-cell immunity is compromised.

B-cell immunity, conversely, may be only slightly compromised or even normal.

Children who lack this activity have recurrent infections, and more than half display neurologic complications.

Symptoms of the disorder first appear at between 6 months and 4 years of age.

Front 126

126. Lesch-Nyhan syndrome

Back 126

Caused by a defective HGPRT.

In this condition, purine bases cannot be salvaged. Instead, they are degraded, forming excessive amounts of uric acid.

Individuals with this syndrome suffer from mental retardation and are prone to self mutilation.

There is gout like damage to the brain. Treatment is allopurinol but no treatment exists for the neurological symptoms

Front 127

127. Hereditary orotic aciduria

Back 127

Orotic acid is excreted in the urine b/c the enzymes that convert it to uridine monophosphate, orotate phosphoribosyltransferase and orotidine 5'-phosphate decarboxylase, are defective.

Pyrimidines cannot be synthesized and normal growth does not occur.

Oral administration of uridine is used to treat this condition b/c it bypasses the metabolic block and provides the body w/a source of pyrimidines.

Front 128

128. Symptoms of hereditary orotic aciduria

Back 128

-Occurs in the first few months of life
-Macrocytic hypochromic megaloblastic anaemia
-Failure to thrive, developmental retardation
-Sparse hair, cardiac malformations, bilateral strabismus, inability to sit unaided, and gross crystalluria, occasionally with ureteric obstruction, have been general findings.
-Abnormalities of immune function
-Heterozygotes show mild orotic aciduria but are otherwise unaffected

Front 129

129. OTC

Back 129

Causes elevated levels of cytoplasmic carbamoyl phosphate which leads to pyrimidine production.

Thus orotic aciduria results.

Front 130

130. pK of uric acid

Back 130

pK= 5.4; It is ionized in the body to form urate.

Urate is not very soluble in an aqueous environment.

The quantity in normal human blood is very close to the solubility constant.

Front 131

121. 5-fluorouacil

Back 131

Inhibits thymidylate synthase (dUMP-to-TMP synthesis)

Used for inhibiting cell growth in cancer cells.

Front 132

122. Methotrexate

Back 132

Methotrexate inhibits dihydrofolate reductase, thereby blocking the regeneration of FH4 and de novo purine synthesis and thymidine synthesis.

Front 133

123. Hydroxyurea

Back 133

Blocks ribonucleotide reductase activity, with the goal of inhibiting DNA synthesis in leukemic cells.

Front 134

124. Adenosine deaminase deficiency

Back 134

Increases [deoxyadenosine] and this is converted back to dATP. Thus, [dATP] is 100x higher, which is toxic.

Synthesis of other 3 dNTP blocked - T and B cells are affected.

2'-deoxyadenosine also inhibits S-adenosylhomocysteine hydrolase which decreases methylation reactions vital to normal cell function.

Front 135

125. Two kinds of joints

Back 135

1. Solid (Non-synovial)
2. Cavitated (Synovial)

Front 136

126. Solid joints

Back 136

Known as synarthroses; provide structural integrity and allow for minimal movement

No joint space; grouped according to type of connective tissue by bridges at end of bones

Front 137

127. Cavitated joints

Back 137

Synovial joints

Have a joint space that allows for a wide range of motions

At the ends of bones formed by endochondral ossification; strengthened by dense fibrous capsule and reinforced by tendons and ligaments; has a synovial membrane.

Front 138

128. Synoviocytes

Back 138

Surface lining of synovial joints

Cuboidal cells; 1-4 layers deep; lacks a basement membrane and merges w/underlying loose CT

Front 139

129. Synovial fluid

Back 139

Filtrate of plasma containing hyaluronic acid

Front 140

130. Osteoarthritis

Back 140

AKA degenerative joint disease

Most common type of joint disease

Characterized by progressive erosion of articular cartilage

Not a disease of inflammation but rather a disease of articular cartilage in which biochemical metabolic processes result in the breakdown

Front 141

131. Secondary osteoarthritis

Back 141

Involves 1 or more predisposed jonts; i.e. sports injuries.

Hands are more commonly affected in women

Hips are more commonly affected in men.

Front 142

132. Normal articular cartilage

What is the function?

Back 142

Bathed in synovial fluid ensures friction free movement w/in the joint

Spreads the load across the joint surface to allow underlying bones to absorb shock and weight w/o being crushed.

Front 143

133. Aging and mechanical effects

Back 143

Mechanical stresses important role in osteoarthritis.

Increasing age = increasing freq of arthritis

Increasing occurrence in weight bearing joints

Increasing freq in conditions that predispose joints to abnormal mechanical stress

Front 144

134. Genetic factors in osteoarthritis

Back 144

Appears to play a role in susceptibility esp in hands and hips

Specific genes are not identified but linkage to chromosome 1 and 2 has been suggested.

Front 145

135. Risk of osteoarthritis

Back 145

Increased in direct proportion to bone density.

High levels of estrogens also associated w/increased risk

Front 146

136. Early characterizations of osteoarthritis

Degenerating cartilage would contain what...?

Back 146

1. Increased water content
2. Decreased concentration of proteoglycans
3. Appears to have a weakening of the collagen network; presumed decreased local synthesis of Type II collagen and increased breakdown of existing collagen
4. Increased apoptosis in chondrocytes but chondrocytes are actively proliferating

Front 147

137. Characteristics/symptoms of osteoarthritis

Back 147

Patients w/primary disease are asymptomatic until 5th decade

1. Achy pain that worsens w/use
2. Morning stiffness
3. Crepitus
4. Limited range of motion
5. Impingement on spinal foramina by osteophytes results in cervical and lumbar nerve root compression
6. Typically, only one or a few joints are involved

Front 148

138. Joints commonly involved in osteoarthritis

Back 148

1. Hips
2. Knees
3. Lower lumbar/cervical vertebrae
4. Proximal and distal IP joints of fingers
5. First carpometacarpal joints
6. First tarsometatarsal joints in feet

Front 149

139. Heberden nodes

Back 149

Characteristic in women but not in men

Prominent osteophytes at the distal IP joints of the fingers that are easily seen on xray

Front 150

140. Bone eburnation

Back 150

Exposed subchondral bone plate becomes new articular surface and friction smooths and burnishes the new bone giving it the appearance of polished ivory

Front 151

141. Joint mice

Back 151

Small fractures are common and the dislodged pieces of cartilage and subchondral bone tumble into the underlying joint

Front 152

142. Subchondral cyst

Back 152

The fractured gaps allow synovial fluid to be forced into subchondral regions in one way ball valve like mechanism

The trapped fluid collection increases in size forming a fibrous walled cyst

Front 153

143. Synovial pannus

Back 153

Fibrotic tissue that covers the diseased part of the joint

Front 154

144. Rheumatoid arthritis

Back 154

Chronic systemic inflammatory disorder that may affect tissues and organs (skin, blood vessels, heart, lungs, muscles) but principally attacks the joints producing a non-suppurative proliferative and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints

Cause is unknown but autoimmunity plays a pivotal role in its chronicity and progression

Front 155

145. Morphological alterations of RA

Back 155

Initially, synovium becomes edematous, thickened and hyperplastic; transforming its smooth contour to one covered by delicated and bulbous fronds

Front 156

146. Seven histological features of RA

Back 156

1. Infiltration of synovial stroma by dense perivascular inflammatory cells (B cells, CD4+ helper T cells, plasma cells, and macrophages)
2. Increased vascularity (caused by vasodilation and angiogenesis)
3. Aggregation of organizing fibrin covering portions of the synovium
4. Rice bodies floating in the joint space
5. Accumulation of neutrophils in the synovial fluid and synovium
6. Osteoclastic activity in the underlying bone which forms juxta-articular erosions and subchondral cysts and osteoporosis
7. Pannus formation

Front 157

147. RA nodules

Back 157

RA noduels are most common cutaneous lesions in RA.

They form in regions of skin that are subjected to pressure (i.e. elbows, occiput, and lumbosacral area)

Less commonly they form in the lungs, spleen, peri and myocardium, heart valves, aorta, and other viscera

Firm, non-tender and round to oval in shape

Front 158

148. Rheumatoid vasculitis

Back 158

Potentially dangerous complication of RA; particularly when it affects vital organs.

Freq segments of small arteries are obstructed by an obliterating endarteritis resulting in peripheral neuropathy, ulcers, and gangrene.

Leukocytoclastic venulitis produced purpura, cutaneous ulcers and nail bed infarction

Front 159

149. Pathogenesis of RA

Back 159

RA is an autoimmune disease triggered by exposure of genetically susceptible host to an unknown arthritogenic antigen.

Activation of CD4+ helper T cells and other lymphocytes, and local release of inflammatory mediators and cytokines that ultimately destroy the joint.

Front 160

150. Autoimmune reaction in RA

Back 160

Activated CD4+ helper T cells and B lymphocytes as well

The target antigen is unknown.

T cells function by stimulating other cells in the joint to produce cytokines that are essential mediators of the synovial reaction.

Evidence exists that immune complex deposition may play some role in joint destruction.

Front 161

151. Four major mediators of joint injury

Back 161

1. Cytokines
2. TNF
3. IL-1
4. TNF and IL-1 stimulate synovial cells to proliferate and produce various mediators (matrix metalloproteinases that contribute to cartilage destruction)

Front 162

152. RANKL

Back 162

Produced by activated T cell and synovial fibroblasts

Activates osteoclasts and promotes bone destruction

Front 163

153. Genetic susceptibility of RA

Back 163

Class II HLA locus (specifically a region of 4 AAs located in the antigen binding cleft)

May bind and display the arthritic antigen to T cells

The AA sequence in the cleft is inherited

Front 164

154. Five characteristics/symptoms of RA

Back 164

1. Malaise
2. Fatigue
3. Generalized musculoskeletal pain after which joints become involved
4. Small joints involved before larger ones
5. Swollen, warm, painful, and stiff joints upon arising or after painful activity

Front 165

155. Radiographic hallmarks of RA

Back 165

Juxta-articular osteopaenia and bone erosions w/narrowing of the joint space from loss of articular cartilage

Front 166

156. Lab Dx of RA

Back 166

No specific lab tests but many patients have RF factor and IgM antibody reacted w/Fc portions of the patients own IgG

May not be present, but also included in differentials of other diseases so not 100% indicative

Front 167

157. Synovial analysis of RA

Back 167

1. Nonspecific inflammatory arthritis
2. Neutrophils with high protein content and low mucin content

Front 168

158. Clinical features for a Dx of RA

Back 168

Need at least 4 of the following criteria:

1. Morning stiffness
2. Arthritis in 3 or more joints
3. Arthritis of typical hand joints
4. Symmetric arthritis
5. Rheumatoid nodules
6. RF factor
7. Typical radiographic changes

Front 169

159. Treatment of RA (Four options)

Back 169

1. Glucocorticoids
2. NSAIDS
3. Anti-rheumatic drugs (i.e. methotrexate)
4. TNF blockers

Front 170

160. Juvenile RA

Back 170

Begins before age 16 and must be present for a duration of at least 6 wks

Has a 2:1 female ratio

Front 171

161. Differences between adult and juvenile RA

Back 171

1. Oligoarthritis more common in juvenile
2. Systemic onset is more frequent in juvenile
3. Large joints are affected more in juvenile
4. Rheumatoid nodules and factor usually absent in juvenile
5. Anti-nuclear antibodies seropositivity is common in juvenile

Front 172

162. Four similarities between adult and juvenile RA

Back 172

1. Genetic association with HLA haplotypes
2. Mycobacterial or viral infection
3. Abnormal immunoregulation with CD4+ T cells within the involved joints
4. Cytokine production

Front 173

163. Systemic onset of juvenile RA

Back 173

1. High spiking fever
2. Migratory and transitory skin rash
3. Hepatosplenomegaly
4. Serositis

Front 174

164. Seronegative spondyloarthropathies

What are the three types?

Back 174

Produce inflammatory peripheral or axial arthritis and inflammation of the tendinous attachment

1. Ankylosing spondyloarthritis
2. Reactive arthritis
3. Psoriatic arthritis

Front 175

165. Ankylosing spondyloarthritis

Back 175

A chronic inflammatory joint disease of axial joints, esp the SI joints

Includes:
1. Chronic synovitis w/destruction of articular cartilage
2. Bony ankylosis in SI and apophyseal joints
3. Inflammation of tendinoligamentous insertion points leading to bony outgrowths

Become symptomatic in 2nd or 3rd decades of life

Analogous to RA

Front 176

166. Reactive arthritis

Back 176

Episode of non-infection arthritis that occurs w/in 1 month of a primary infection localized elsewhere in the body

Often associated w/genitourinary infections in the 2nd and 3rd decades of life

Waxes and wanes over a period of several weeks to 6 months

Front 177

167. Psoriatic arthritis (Five features)

Back 177

1. Distal IP joint involvement w/nail pitting
2. Asymmetrical oligoarthropathy of both large and small joints
3. Arthritis mutilans, a severe form
4. Symmetrical polyarthritis
5. Spondyloarthropathy

Front 178

168. Infectious arthritis

What are the four types?

Back 178

Caused by microorganisms lodging in joints during hematogenous dissemination

Includes:
1. Suppurative arthritis
2. Tuberculous arthritis
3. Lyme disease
4. Viral arthritis

Front 179

169. Suppurative arthritis

Back 179

Caused by bacterial infection

Individuals w/sickle cell are prone to infection

Presents w/:
1. Acutely painful hot and swollen joint w/restricted range of motion
2. Fever
3. Leukocytosis
4. Elevated sedimentation rate

Occurs in hip, shoulder, elbow, wrist, and sternoclavicular

Front 180

170. Tuberculous arthritis

What two things does it result in?

Back 180

Chronic progressive monoarticular disease, usually develops w/adjoining osteomyelitis or after dissemination of infection from lungs.

Results in:
1. Severe destruction w/fibrous ankylosis and obliteration of joint space
2. Weight bearing joints are usually affected

Front 181

171. Lyme arthritis

What are four characteristics?

Back 181

Arthritis caused by lyme disease

Infected synovium takes the form of:
1. Chronic papillary synovitis w/synoviocyte hyperplasia
2. Fibrin deposition
3. Mononuclear cell infiltrates
4. Onion-skin thickening of arterial walls

Front 182

172. Viral arthritis

Back 182

Occurs w/viral infections including parvovirus, rubella, and Hepatitis C

Symptoms: variable and range from acute to subacute

Front 183

173. Gout

Back 183

Metabolic disorder that includes acute and chronic arthritis, uric acid deposits in and around joints and skin, renal stones, and hyperuricemia

Leads to chronic gouty arthritis and tophi deposits

Front 184

174. Accumulation of uric acid results from what two conditions...?

Back 184

1. Defect in the purine uric acid metabolism leading to overproduction of uric acid
2. Primary defects in renal clearance

Front 185

175. Plasma urate levels above what value are considered clinically important?

Back 185

Above 7 mg/dL is considered elevated at normal body temp and pH

Front 186

176. Two pathways involved in purine synthesis

Back 186

1. de novo pathway in which purines are made from non-purine precursors

2. *Salvage pathway; free purine bases are derived from breakdown of AAs of endo- or exogenous origins

*uses the enzyme HGPRT

Front 187

177. Six factors that lead to gout

Back 187

1. Age
2. Genetic predisposition
3. Heavy EtOH consumption
4. Obesity
5. Certain drugs (i.e. thiazides)
6. Lead toxicity

Front 188

178. Morphology of gout (four things)

Back 188

1. Acute arthritis
2. Chronic tophaceous arthritis
3. Tophi deposits
4. Gouty nephropathy

Front 189

179. Chronic tophaceous arthritis

Back 189

Evolves from the repetitive precipitation of urate crystals which may heavily encrust the articular surfaces and form visible deposits on the synovium

Front 190

180. What is the pathognomonic hallmark of gout?

Back 190

TOPHI

Formed by large aggregates of urate crystals; surrounded by intense inflammatory reaction of macrophages, lymphocytes, and large foreign body giant cells which may have partially or completely engulfed masses of crystals.

Front 191

181. Gouty nephropathy

Back 191

Renal disorder associated w/deposition of monosodium urate crystals in the renal medullary interstitium.

Sometimes forms tophi, intratubular precipitations of free uric acid crystals (can form kidney stones)

Front 192

182. What are the four stages of gout?

How long does it take from the initial attack to reach the tophaceous stage?

Back 192

1. Asymptomatic hyperuricemia
2. Acute gouty arthritis
3. Intercritical gout
4. Chronic tophaceous gout

Takes 12 years from initial attack to reach the tophaceous stage

Front 193

183. Locations of gout

Back 193

First attacks are monoarticular and 50% occur in the first metatarsophalangeal joint

1. Insteps
2. Ankles
3. Heels
4. Knees
5. Wrists
6. Fingers
7. Elbows

Front 194

184. Dx of gout

Back 194

Acute onset of monoarthritis in joint of lower extremity.

Intracellular needle shaped, negatively birefringent crystals are essential to Dx of acute gouty arthritis

Urate crystals may also be seen in tophaceous depositis into which a joint has ruptured tophaceous deposits

Front 195

185. Treatment of gout uses what three drugs?

Back 195

1. Colchicine
2. NSAIDS
3. Glucocorticoids

Front 196

186. Treatment of intercritical gout uses what four drugs?

Back 196

1. Colchicine
2. NSAIDS
3. Probenecid
4. Allopurinol

Front 197

187. Pseudogout

Back 197

AKA calcium pyrophosphate crystal disease (CPPD)

Intra-articular crystal formation

Altered activity of the matrix enzymes that produce and degrade pyrophosphate, resulting in its accumulation and eventual recrystallization with calcium

Front 198

188. What are the three forms of pseudogout?

Back 198

1. Sporadic
2. Hereditary
3. Secondary types

Front 199

189. Hereditary form of psuedogout

Back 199

The crystals develop relatively early in life and forms severe osteoarthritis.

The autosomal dominant form of the disease has been shown to be related to a mutation in the ANKH gene, which encodes a transmembrane-inorganic pyrophospate transport channel.

Front 200

190. Secondary form of psuedogout

Back 200

Associated w/various disroders, including previous joint damage, hyperparathyroidism, hemochromatosis, hypomagnesmia, hypothroidism, ochronosis, and diabetes

Front 201

191. Morphology of pseudogout

Back 201

The crystals first develop int he articular matrix, menisci, and intervertebral discs, and may rupture and seed the joint if large enough.

Once released into the joint, they elicit the production of IL-8 which helps produce and inflammatory reaction rich in neutrophils

The neutrophils produce damage thru the release of oxygen metabolites, catabolic enzymes, and cytokines

Front 202

192. Dx of pseudogout

Back 202

May mimic other disorders such as osteoarthritis or RA.

Joint involvement may be monoarticular or polyarticular

Crystals are weakly birefringent and have geometric shapes; they are rarely deposited in masslike aggregates simulating tophi.

Front 203

193. What are the five most common joints affected in pseudogout?

Treatment?

Back 203

1. Knees
2. Wrists
3. Elbows
4. Shoulders
5. Ankles

Therapy is supportive; no known treatment prevents or retards crystal formation.

Front 204

194. Ganglion cyst

Back 204

A small 1 to 1.5 cm cyst that is almost always located near a joint capsule or tendon sheath.

It arises as a result of cystic or myxoid degeneration of connective tissue; the cyst wall makes a true cell lining.

Fluid that fills the cyst is similar to synovial fluid; however, there is no communication with the joint space.

Front 205

195. Synovial cyst

Back 205

Herniation of synovium through a joint capsule or massive enlargement of a bursa may produce a synovial cyst.

Synovial lining may be hyperplastic and contain inflammatory cells and fibrin but is otherwise unremarkable.

Front 206

196. Villonodular synovitis

What do they arise from?

Back 206

A term for several closely related benign neoplasms that develop in the synovial lining of joints, tendon sheaths, and bursae.

They arise from a clonal proliferation of cells and are neoplastic.

Front 207

197. Pigmented villonodular synovitis (PVNS)

Back 207

The normally smooth joint synovium, most often the knee, is converted into a tangled mat by red-brown folds, finger like projections, and nodules.

Aggressive tumors erode into adjacent bones and soft tissues

Usually presents as a monoarticular arthritis that affects the knee in 80% of cases.

Treatment is surgery.

Front 208

198. Giant cell tumor of tendon sheath (GCT)

Back 208

AKA localized nodular tenosynovitis

Usually occurs as a discrete nodule on a tendon sheath and may be attached to the synovium by a pedicle.

Slow growing painless mass that freq involves the tendon sheaths along wrists and fingers

Treatment is also surgery.

Front 209

199. Podagra

Back 209

The first metatarsophalangeal joint is the most commonly involved joint in acute gouty arthritis

It is termed podagra

Front 210

200. What two metabolic disorders are associated with osteoarthritis?

Back 210

1. Hemochromatosis
2. Ochronosis

Front 211

201. Primary OA

Back 211

This is the idiopathic variety, which may be localized or generalized, and its causes are multifactorial.

Front 212

202. Secondary OA

What is the most common cause?

Back 212

Occurs when a particular cause of OA overwhelms all others and serves as a sole cause of disease.

Most common cause of secondary OA is a severe joint injury, but other causes include congenital and developmental disorders (especially in the hip), inflammatory arthritis, and neurological dieases.

Front 213

203. What is the earliest finding associated with OA?

What happens next?

Back 213

Fibrillation of the most superficial layer of the articular cartilage.

With time, the disruption of the articular surface becomes deeper with extension fo the fibrillations to subchondral bone, fragmentation of cartilage with release into the joint, matrix degradation, and, eventually, complete loss of cartilage, leaving only exposed bone.

Front 214

204. Tidemark zone in OA

Back 214

The tidemark zone, separating the calcified cartilage from the radial zone, becomes invaded with capillaries.

Front 215

205. What do chondrocytes release in OA?

Back 215

Chondrocytes initially are metabolically active and release a variety of cytokines and metalloproteinases, contributing to matrix degradation, which in the later stages results in the penetration of fissures to the subchondral bone and the release of fibrillated cartilage into the joint space.

Front 216

206. What important imbalance may be "operative" in OA?

Back 216

An imbalance between tissue inhibitors of metalloproteinases and the production of metalloproteinases may b eoperative in OA.

Front 217

207. What crystals have been identified in synovial fluid and other tissues from osteoarthritic joints?

Back 217

Calcium pyrophoshate dihydrate and apatite.

Thought these crystals clearly have potent inflammatory potential, their role in the pathogenesis of OA remains uncertain.

Front 218

208. What is the characteristic clinical feature of OA?

What does it result from?

Back 218

Pain. Pain is typically deep aching discomfort, slow in onset, initially aggravated with activity, improved w/rest, and localized to the involved joint.

Occasionally, pain is referred to a distant site.

Pain may result form venous engorgement of subchondral bone, accumulation of fluid in the joint, or synovitis.

With progressive disease, pain may occur at rest. Exacerbation of symptoms with weather changes is a common feature.

Front 219

209. What does the physical exam in OA reveal?

Back 219

Reveals joint-line tenderness and bony enlargement of the joint with or without effusion. Crepitation on motion and limitation of joint motion are additional characteristic features.

Front 220

210. What are the two subtypes of OA?

Back 220

1. Nodal form of OA
2. Erosive, inflammatory form of OA

Front 221

211. Nodal form of OA

Back 221

Involves primarily the distal interphalangeal joints and is the most common in middle aged women, typically with strong family history among first-degree relatives.

Front 222

212. Erosive, inflammatory form of OA

Back 222

Associated w/prominent erosive, destructive changes, especially in the finger joints, and may suggest RA, although systemic inflammatory signs and other typical features of RA (e.g., nodules, proliferative synovitis, extra-articular features, rheumatoid factor) are absent.

Front 223

213. Joints involved in OA

Back 223

1. Distal interphalangeal joints
2. Proximal interphalangeal joints
3. First carpometacarpal joints
4. Facet joints of the cervical and lumbar spine
5. Hips
6. Knees
7. First metatarsophalangeal joint

Front 224

214. Joint deformity associated with OA is characteristic in which locations?

Back 224

Heberden's and Bouchard's nodes in the hands and, depending on the compartment of the knee, valgus or varus deformity.

Front 225

215. What are the radiographic features of OA?

Back 225

1. Subchondral sclerosis
2. Joint-space narrowing
3. Subchondral cysts
4. Osteophytes

Front 226

216. What are the available pharmacological therapies for OA?

Back 226

1. Simple analgesics
2. NSAIDs
3. COX-2 inhibitors
4. Intra-articular corticosteroids
5. Condroprotective agents
6. Anti-depressants

Front 227

217. What pharmacological therapy is most effective in OA?

Back 227

Intra-articular therapies such as corticosteroids appear to provide modest symptomatic benefit, especially in the knee.

Front 228

218. What about synthetic hyaluronate injected intra-articularly?

Ok, then... what about chondroitin sulfate and glucosamine?

Back 228

Synthetic hyaluronate injected intra-articularly appear to have little if any benefit based on current evidence.

Chondroitin and glucosamine were not significantly better than placebo in reducing knee pain.

Front 229

219. What are the four therapeutic strategies for gout?

Back 229

Most involve lowering the uric acid levels by:

1. Interfering w/uric acid synthesis with allopurinol
2. Increasing uric acid excretion with probenecid or sulfinpyrazone
3. Inhibiting leukocyte entry into the affected joint with colchicine
4. Administration of NSAIDs

Front 230

220. NSAIDS

Back 230

NSAIDs inhibit cyclooxygenase (COX) and thereby inhibit prostaglandin and thromboxane synthesis.

Front 231

221. Indomethacin

Back 231

Indomethacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2

This is one of the NSAIDs most commonly prescribed for treating acute attacks of gout.

Front 232

222. What are the adverse effects of NSAIDs?

Back 232

The serious adverse effects of NSAIDs include bleeding, salt and water retention, and renal insufficiency.

Front 233

223. COX-2 selective inhibitors and gout

Back 233

Potentially useful for the management of acute gout attacks b/c they may decrease the risk of GI bleeding, although concerns about adverse cardiovascular effects limit their long-term use.

Front 234

224. Colchicine

Back 234

A plant alkaloid, is reserved for the treatment of acute gouty attacks. It is neither a uricosuric nor an analgesic agent, although it relives pain in acute attacks of gout.

It does not prevent the progression of gout to acute gouty arthritis but it does have a suppressive, prophylactic effect that reduces the frequency of acute attacks and relieves pain.

Front 235

225. Mechanism of action of colchicine?

Back 235

Binds to tubulin, a microtubular protein, causing its depolymerization. This disrupts cellular functions, such as the mobility of granulocytes, thus decreasing their migration into the affected area.

Also, colchicine also blocks cell division by binding to mitotic spindles.

It also inhibits the synthesis and release of the leukotrienes via inhibiting neutrophil activation.

Front 236

226. How does colchicine inhibit neutrophil activation?

Four ways...

Back 236

1. Decreased trafficking of phagocytosed particles to lysosomes
2. Decreased release of chemotactic factor
3. Decreased motility and adhesion of neutrophils
4. Decreased tyrosine phosphorylation of neutrophil proteins, with a resulting decrease in leukotriene B4 synthesis

Front 237

227. Therapeutic uses of colchicine?

Back 237

1. Acute gout
2. Prevention of recurrent gout attacks

Anti-inflammatory activity is specific for gout, usually alleviating the pain of acute gout within twelve hours.

Also used for prophylaxis of recurrent attacks.

Front 238

228. Pharmacokinetics of colchicine

Back 238

Administered orally, followed by rapid absorption from the GI tract.

It is recycled in the bile and is excreted unchanged in the feces or urine.

Concomitant administration of cyclosporine, tacrolimus, or verapamil may increase plasma levels of colchine

Front 239

229. Adverse effects of colchicine

Back 239

Myelosupression, neuromyopathy

Diarrhea, abdominal pain, vomiting.

Should not be used in pregnancy and should be used w/caution in patients with hepatic, renal or cardiovascular disease.

Front 240

230. Contraindications of colchicine

Back 240

Severe cardiac, GI or renal disease

Hepatic failure

Blood dyscrasias

Front 241

231. What are the three inhibitors of uric acid synthesis?

Back 241

1. Allopurinol
2. Oxypurinol
3. Febuxostat

Front 242

232. Allopurinol

Back 242

Allopurinol is a purine analog. It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase.

When xanthine oxidase is inhibited, the circulating purine derivatives are more soluble, and therefore, are less likely to precipitate

Front 243

233. Oxypurinol

Back 243

The oxidized form of allopurinol, known as oxypurinol, inhibits xanthine oxidase by preventing molybdenum in the active site of the enzyme from interconverting between the +4 and +6 oxidation states, essentially freezing xanthine oxidase.

Xanthine oxidase is important in purine degradation, therefore, inhibint the enzyme result in increased plasma levels of hypoxanthine and xanthine, which are more soluble.

Front 244

234. Therapeutic uses of allopurinol and oxypurinol

Back 244

Used in the treatment of chronic gout, especially in cases caused by increased purine degradation.

1. Prevention of recurrent gout attacks
2. Cancer-related hyperuricemia
3. Calcium and uric acid renal calculus

Front 245

235. Pharmacokinetics of allopurinol

Back 245

Completely absorbed after oral administration.

The primary metabolite is alloxanthine (oxypurinol), which is also a xanthine oxidase inhibitor.

The half life of allopurinol is short (two hours), whereas the half life of oxypurinol is long (15 hours)

Front 246

236. Adverse effects of allopurinol

Back 246

Agranulocytosis, aplastic anemia, renal failure, hepatic necrosois, toxic epidermal necrolysis

Pruritus, rash, GI disturbance

Front 247

237. Contraindications of allopurinol

Back 247

Idiopathic hemochromatosis

Interferes with the metabolism of 6-mercaptopurine and the immunosuppressant azathioprine, requiring a reduction in dosage of these drugs

Front 248

238. Febuxostat

Back 248

A nonpurine small molecule inhibitor of xanthine oxidase also being evaluated for the treatment of chronic gout.

Unlike allopurinol, febuxostat undergoes extensive hepatic metabolism and it may not require dose adjustment in renal insufficiency.

Front 249

239. What are the four drugs that increase uric acid excretion?

Back 249

They are called uricosuric agents

1. Sulfinpyrazone
2. Probenecid
3. Losortan
4. Benzbromarone

Front 250

240. What are the therapeutic uses of agents that increase uric acid excretion?

Back 250

Prevention of recurrent gout attacks.

Front 251

241. Probenecid

Back 251

Useful for the treatment of chronic hyperuricemia.

Probenecid shifts the balance between renal excretion and endogenous formation of urate, thereby lowering plasma urate, dissolving urate crystals, and reversing the crystal deposition in synovial joints.

Front 252

242. How does probenecid work?

Back 252

Inhibitor of the basolateral anion exchanger of the proximal tubule.

This exchanger acts to enhance the secretion of many anions, including drugs.

Such inhibition decreases the plasma concentration of urate by decreasing urate reabsorption.

Front 253

243. Probenecid and urine pH

Back 253

Increasing renal urate excretion can predispose to formation of urate stones in the kidney or ureter.

This complication can be prevented by making the urine less acidic, commonly by coadministration of oral calcium citrate or sodium bicarbonate; uric acid has a pKa of 5.6 and it remains predominantly in the more soluble neutral form if the urine pH is above 6.0.

Front 254

244. Pharmacokinetics of probenecid

Back 254

Because probenecid inhibits the secretion of most anions, the dose of other drugs excreted by this pathway should be reduced when probenecid is coadministered.

Low dose aspirin may antagonize probenecid action.

It is also sometimes used to increase levels of penicllin. It can also increase the serum levels of methotrexate.

It inhibits secretion of naproxen, ketoprofen, and indomethacin.

Front 255

245. Sulfinpyrazone

Back 255

Also a uricosuric agent that acts by the same mechanism as probenecid (inhibitor of the tubular secretion of organic acids).

It is more potent than probenecid and it is effective in mild to moderate renal insufficiency.

In addition to acting as a uricosuric, it has antiplatelet effects; it should therefore be used with caution in patients taking other antiplatelet agents or anticoagulants.

Front 256

246. Drug interactions with sulfinpyrazone

Back 256

May also increase levels of penicillin and other anionic compounds; may also increase the levels of nitrofurantoin.

Front 257

247. Benzbromarone

Back 257

Also a uricosuric agent with a mechanism of action similar to that of probenecid and sulfinpyrazone.

May have greater uricosuric efficacy than probenecid and sulfinpyrazone, particularly in patients with impaired renal function. However, the frequent incidence of hepatotoxicity has limited widespread use of the drug.

It is not approved for use in the US but it is available in Europe

Front 258

248. Adverse effects of uricosuric agents

Back 258

Leukopenia, thrombocytopenia, bronchoconstriction in patients with asthma, aplastic anemia (probenecid), anaphylaxis (probenecid)

GI disturbance

Front 259

249. Contraindications of uricosuric agents (five of them)

Back 259

1. Acute gout attack
2. Blood dyscrasias (imbalance)
3. Children under 2 yrs of age
4. Coadministration of salicylates
5. Uric acid kidney stones

Front 260

250. Losartan

Back 260

An angiontensin II receptor antagonist that has modest uricosuric effect.

Losartan may be a logical therapeutic choice in patients with concomitant hypertension and gout, although no controlled studies have been performed to prove that losartan reduces the incidence of acute gouty attacks

Front 261

251. What is losartan used for?

Back 261

1. Hypertension
2. Prevention of recurrent gout attacks

Front 262

252. Adverse effects of losartan

Back 262

Angioedema, rhabdomyolysis, thrombocytopenia, anemia, fatigue, back pain, hypoglycemia

Front 263

253. Contraindications of losartan

Back 263

Pregnancy

Front 264

254. What is the name of an agent that enhances uric acid metabolism?

Back 264

Rasburicase

It is a recombinant form of Aspergillus uricase that converts sparingly soluble urate to the more soluble allantoin.

Front 265

255. What is rasburicase used for?

Back 265

Tumor lysis syndrome.

Most mammals other than humans express the enzyme uricase, which oxidizes uric acid to allantoin, a compound that is easily excreted by the kidney.

In cancer chemotherapy, the rapid lysis of tumor cells can liberate free nucleotides and greatly increase plasma urate levels, which can lead to massive renal injury.

Front 266

256. Adverse effects of rasburicase

Back 266

Hemolysis, methemoglobinemia, neutropenia, respiratory distress, sepsis, rash, GI disturbance, fever

Front 267

257. Contraindications of rasburicase

Back 267

1. G6PD deficiency
2. Known Aspergillus sensitivity

Front 268

258. What are the four classes of antigens that provoke an immune response in our bodies?

Back 268

The four classes of pathogen are: bacteria, viruses, fungi, and parasites (protozoa and worms).

Front 269

259. Identify the two major progenitor subsets of leukocytes

Back 269

The two major progenitor subsets of leukocytes are the common lymphoid progenitor and the myeloid progenitor.

Front 270

260. Name the white blood cells that differentiate from these two progenitor lineages

Back 270

The common lymphoid progenitor differentiates into three cell types: B cells, T cells, and natural killer (NK) cells.

The myeloid progenitor differentiates into six main cell types: basophils, eosinophils, neutrophils, mast cells, dendritic cells, and monocytes.

Monocytes are circulating leukocytes that enter tissues, where they then differentiate into macrophages.

Front 271

261. Name the primary lymphoid tissues in mammals and the main types of secondary lymphoid tissue

Back 271

The primary (or central) lymphoid tissues are the bone marrow (and liver in the fetus) and the thymus.

The main secondary (or peripheral) lymphoid tissues are the lymph nodes, spleen, and mucosa-associated lymphoid tissues (MALT).

The latter include gut-associated lymphoid tissue (GALT), such as the tonsils, adenoids, appendix, and Peyer's patches, and bronchial-associated lymphoid tissues (BALT).

Front 272

262. What is the primary lymphoid tissue and what are the principal events that take place in it?

Back 272

Primary (or central) lymphoid tissues are the anatomical locations where lymphocytes complete their development and reach the state of maturation required for recognition of and response to a potential pathogen. B cells mature in the bone marrow and fetal liver, and T cells mature in the thymus. Both lymphocyte lineages are derived from a common hematopoietic stem cell. Somatic recombination of antigen-receptor genes and negative selection of potentially autoreactive B and T cells (to produce self-tolerance) occurs in primary lymphoid tissues.

Front 273

263. What is the secondary lymphoid tissue and what are the principal events that take place in it?

Back 273

Secondary (or peripheral) lymphoid tissues provide the anatomical sites where lymphocytes encounter antigen and immune responses are induced. Antigen is delivered to the secondary lymphoid tissues through an afferent lymphatic vessel, where it is then filtered and retained for encounter with lymphocytes bearing antigen-specific receptors. Clonal selection and somatic hypermutation (in B cells) occur in secondary lymphoid tissues.

Front 274

264. In what way is the spleen different from the other secondary
lymphoid tissues?

Back 274

The spleen differs from the other secondary lymphoid tissues in that lymph does not filter through this organ. Instead, the spleen filters the blood and traps blood-borne pathogens.

Front 275

265. What molecules do B cells use to recognize foreign antigens?

Back 275

B cells recognize antigen through immunoglobulin on their surface.

After activation, B cells become plasma cells, which secrete a soluble form of this immunoglobulin as antigen-specific antibodies.

Front 276

266. What molecules do T cells use to recognize foreign antigens?

Back 276

T cells recognize antigen through a different, although structurally related, type of molecule called the T-cell receptor on their cell surface.

The T-cell receptor is not secreted.

Front 277

267. Explain how an antigen is prepared for T-cell recognition

Back 277

Peptides are produced and presented by mechanisms known as antigen processing and antigen presentation, respectively.

Proteins are denatured and degraded enzymatically, generating small peptide fragments that are able to bind to MHC molecules.

Proteins degraded in the cytosol bind to MHC class 1 molecules, whereas proteins degraded in endocytic vesicles bind to MHC class II molecules.

The ancillary cell that presents the MHC molecule:peptide complex to the T cell is referred to as the antigen-presenting cell.

Front 278

268. What are the three mechanisms by which antibodies eradicate infections?

Back 278

1. Neutralization
2. Opsonization
3. Complement activation

Front 279

269. Neutralization

Back 279

By binding to the surface of a pathogen antibodies interfere with the ability of the pathogen to grow and replicate.

Antibody binding to a pathogen or a bacterial toxin can also inhibit its binding to receptors on host cells and therefore prevent its entry into cells.

Front 280

270. Opsonization

Back 280

Antibody coating the surface of a pathogen or toxin can promote phagocytosis of the antibody-covered particle. Antibodies acting in this way are known as opsonins.

The antibody-bound material interacts with Fc receptors on the surface of phagocytic cells such as macrophages and neutrophils, which bind the constant region (the stem) of the antibody.

Stimulation of Fc receptors in this way stimulates engulfment and degradation of antibody-coated material by the phagocyte.

Front 281

271. Complement activation

Back 281

IgG or IgM antibody bound to a pathogen stimulates activation of the complement system, leading to the deposition of complement proteins on the surface of the pathogen.

Certain of these act as opsonins and bind to complement receptors on phagocytic cells to stimulate phagocytosis and destruction of the pathogen.

Front 282

272. What are the three types of unwanted and potentially harmful immune responses?

Back 282

1. Allergy
2. Autoimmune
3. Transplant rejection

Front 283

273. Allergies

Back 283

IgE antibodies made against normally innocuous environmental antigens trigger widespread mast-cell activation.

This can lead to allergic diseases such as asthma or to a potentially fatal anaphylactic reaction.

Front 284

274. Autoimmune reactions

Back 284

Chronic immune responses by B cells or T cells to self antigens can cause tissue damage and chronic illnesses such as diabetes, multiple sclerosis, and myasthenia gravis.

Autoimmunity is sometimes provoked as a consequence of an immune response to pathogen-derived antigen that cross-reacts on healthy host cells or tissue.

Front 285

275. Transplant rejection

Back 285

A person's immune system will make an immune response against the foreign MHC molecules on transplanted tissue that is MHC-incompatible.