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PAROXYSMAL NOCTURNAL HEMOGLOBINURIA AND Annu. Rev. Med. 1990.41:431-436. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 02/02/15. For personal use only.

DECAY-ACCELERATING FACTOR Wendell F. Rosse, M.D.

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710 KEY WORDS:

complement,

phosphotidylinositol,

genetic

diseases,

patho­

physiology. ABSTRACT

The blood cells in paroxysmal nocturnal hemoglobinuria (PNH) lack several proteins, including some that regulate the activation of complement on the cell surface. Decay-accelerating factor (DAF), the first such protein to be identified, is, like all the missing proteins, affixed to the membrane by a glycolipid anchor containing phosphotidylinositol, hexoses, and etha­ nolamine. The defect in PNH appears to be an inability to place or maintain proteins linked in this way on the cell surface. Paroxysmal nocturnal hemoglobinuria is a complex hematological dis­ order characterized to various degrees in different patients by hemolytic anemia (often with hemoglobinuria), venous thrombosis in unusual sites, and deficient hematopoiesis ( 1). The diagnosis is made by demonstrating an unusual susceptibility of the red cells to the hemolytic action of com­ plement. This is usually achieved by acidifying the serum to activate the alternative pathway of complement (2), but susceptibility may also be shown by tests in which complement is activated by antibody (3). Studies show that the red cells in PNH vary in their susceptibility to lysis by complement. The most sensitive cells, the PNH III cells, require 1/10 to 1/15 the amount of complement required by normal cells for an equal amount of lysis; other abnormal cells, the PNH II cells, require 1/4 to 1/8 the normal amount of complement for lysis (5). The proportion 431 0066-4219/90/0401--0431$02.00

Annu. Rev. Med. 1990.41:431-436. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 02/02/15. For personal use only.

432

ROSSE

of these cells varies greatly from patient to patient. The in vitro sus­ ceptibility to lysis is reflected in the in vivo survival of the cells; the PNH III cells have a mean survival in the circulation of 20 days and PNH II cells about 45 days, compared to a normal cell survival of about 90-120 days (6). The abnormalities are not confined to the red cells. Both the platelets and the granulocytes are unusually susceptible to complement lysis when complement is activated by antibody (7, 8). This suggests that PNH is a stem cell disorder since all the descendant lines are affected (9). Although it has been classified as a "myeloproliferative" disorder, it more closely resembles a "myelodysplastic" disorder because the deficient hemato­ poiesis and structurally abnormal cells are characteristic (10). Much of the work to identify the abnormality of PNH has concentrated on understanding the unusual susceptibility to complement. The efficiency of this complex system increases at two stages: (a) in the activation of C3 to C3b by the "convertase" enzyme complexes, C4b2a for the classical pathway and C3bBb for the alternative pathway (11) (this is a crucial step in amplifying the effect of activation of complement by both pathways); and (b) in the formation and function of the membrane attack complex, C5b--9. Because the convertase step is so crucial, it is carefully controlled by both cellular and humoral elements. The enzyme complexes are dissociated by at least four proteins, including decay-accelerating factor (12). All of these appear to act by binding to homologous C3b or C4b and displacing the enzymatic molecule, Bb or C2a. The decay-accelerating factor was found by Nicholson-Weller and her associates to be missing in the abnormal red cells of PNH (13). This appears to be the only complement regulatory activity missing from PNH II cells (14). When DAF is inhibited by polyclonal antibody, normal cells resemble PNH II cells; and when DAF is reinserted into PNH II cells, they become like normal cells. The complement sensitivity of PNH III cells, on the other hand, is changed relatively little by the reinsertion of DAF in equal quantities; the PNH III cells are still markedly sensitive to complement, which means that the hemolytic action of complement is still being modulated in normal, PNH I, and PNH II cells but not in PNH III cells. Decay-accelerating factor is lacking on the abnormal platelets in par­ oxysmal nocturnal hemoglobinuria (15, 16); the proportion of abnormal platelets is usually greater than the number of abnormal red cells in a given patient (16). Despite the absence of decay-accelerating factor, the platelets in PNH have a normal survival time in the circulation (16). The venous thrombosis seen in PNH is probably due to the abnormality

Annu. Rev. Med. 1990.41:431-436. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 02/02/15. For personal use only.

PNH AND DAF

433

of the platelets. It was thought at one time that the activation of comp­ lement initiated the aggregation reaction of platelets (17); however, this unusual susceptibility to aggregation appears to be due to thrombin rather than to complement (18). PNH platelets aggregate in response to as little as 1/1000th the amount of thrombin that causes normal platelets to aggregate. It is not clear that the deficiency of OAF plays a role in this susceptibility. OAF is only one of a number of membrane proteins that are missing in PNH. To date, eight other proteins have been found to be lacking on the abnormal cells (see Table I). Two of these, C8 binding protein (C8 BP) (19, 20) and membrane inhibitor of reactive lysis (MIRL, CO59) (21), modulate the formation of the membrane attack complex of complement within the membrane. Of these, MIRL, a glycoprotein of 18 kd, appears to be the more important since inhibition of this protein on normal cells by polyclonal antibody causes them to become nearly as sensitive to complement as PNH III cells, and its insertion into PNH III cells renders them nearly normal in their susceptibility to complement (1). The functional consequence of the lack of some of the other proteins is not clear. Three are membrane enzymes [acetylcholinesterase (22, 23), alkaline phosphatase (24, 25), and lymphocyte 5' -ectonucleotidase (26), and their loss does not seem to affect the function or viability of the cells. Three are immunologically functional proteins: lymphocyte function antigen-3 (LF A-3) (27), the low-affinity Fc receptor on granulocytes (28), and the COl4 molecule on monocytes (29). How their absence contributes to the deficient hematopoiesis and mildly altered immune function in PNH is being investigated. These proteins share a common characteristic: all are inserted into the Table 1

Proteins known to be lacking on the abnormal blood

cclls of patients with paroxysmal nocturnal hemoglobinuria A.

Complement regulatory proteins

I. Decay accelerating factor (DAF) 2. Membrane inhibitor of reactive lysis (MIRL)

3. C8 binding protein B.

Membrane enzymes

I. Acetylcholinesterase 2. Alkaline phosphatase 3. 5' -ectonucleotidase C.

Immune function proteins 1. Lymphocyte function antigen-3 (LFA

-

2. FC(y)III receptor of neutrophils

3. CD 14

3)

ROSSE

434

Annu. Rev. Med. 1990.41:431-436. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 02/02/15. For personal use only.

membrane by a glycolipid anchor composed of two or three acyl groups, phosphatidylinositol, three sugar moieties, and ethanolamine (see Figure 1) (30-32). This anchor is attached to the carboxyl end of the protein in the endoplasmic reticulum by an enzyme or enzymes that cleave it from its more customary membrane anchoring by hydrophobic amino acids inserted into the lipid bilayer (33, 34). Proteins anchored in this way are readily removed from the membrane by enzymes that cleave the phospha-

PROTEN

GLYCEROL

�,

.------I -

Figure

1

The general structure of the glycolipid anchor common to all proteins lacking on

the abnormal cells in PNH. Phosphatidylinositol is affixed to three acyl groups that are inserted into the lipid bilayer. It is also affixed to three hexoses, the last of which binds the carboxyl end of the protein through a molecule of ethanolamine [from Roberts et al (31)].

PNH AND DAF

435

Annu. Rev. Med. 1990.41:431-436. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 02/02/15. For personal use only.

tidylinositol moiety. The fundamental defect in PNH appears to be an inability to construct the glycolipid anchor, to attach it to the protein, or to maintain it in the face of catabolic enzymes but which of these mechanisms predominates is not yet clear. Some of the proteins may normally exist in the more usual trans­ membrane insertion as well as in the glycolipid anchor-linked form. This is certainly true for LFA-3 (35) and may be true for MIRL. Such a protein on PNH II cells and platelets would explain their relative insensitivity to complement.

Literature Cited

I. Rosse, W. F. 1989. Paroxysmal noc­ turnal hemoglobinuria. In Clinical Im­

munohematology: Basic Concepts and Clinical Applications. Boston/Oxford:

Blackwell Scientific

2. Ham,

T. H., Dingle, J.

H.

1938.

Studies

on destruction of red blood cells. II. Chronic hemolytic anemia with par­ oxysmal nocturnal hemoglobinuria: cer­ tain immunological aspects of the he­ molytic mechanism with special reference to serum complement. J. Clin. Invest. 18:

657 3. Rosse, W.

F., Dacie, J. V. 1966. Immune

lysis of normal human and paroxysmal nocturnal hemoglobinuria red blood cells. I. The sensitivity of PNH red cells to lysis by complement and specific anti­ body. J. Clin. Invest. 45: 736 4. Deleted in proof 5. Rosse, W. F., Adams, J. P., Thorpe, A. M. 1974. The population of cells in par­ oxysmal nocturnal hemoglobinuria of intermediate sensitivity to complement lysis-Significance and mechanism of increased immune lysis. Br. J. Haematol. 28: 181 6. Rosse, W.

F. 1971. The life-span of com­ plement-sensitive and -insensitive red

cells in paroxysmal nocturnal hemo­ globinuria. Blood 37: 556 7. Aster, R. H., Enright, S. E. 1969. A

platelet and granulocyte membrane de­ fect in paroxysmal nocturnal hemo­ globinuria: Usefulness for the detection of platelet antibodies. J. Clin. Invest. 48:

1199 8. Stern, M. , Rosse, W. F. 1979. Two popu­

lations of granulocytes in paroxysmal nocturnal hemoglobinuria. Blood 53:

928 9. Hartmann. R.

c., Arnold, A. B. 1977.

Paroxysmal nocturnal hemoglobinuria as a clonal disorder. Annu. Rev. Med.

28: 187

10. Rosse, W. F. 1980. Paroxysmal noc­

turnal hemoglobinuria-Present status and future prospects. West. J. Med. 132:

219 11. Parker, C. J., Baker, P. J., Rosse, W. F. 1982. Increased enzymatic activity in the alternative pathway convertase when

bound to the erythrocytes of paroxysmal nocturnal hemoglobinuria. J. Clin.

Invest. 69: 337 12. Nicholson-Weller, A., Burge, J., Fearon, E. T., Weller, P. F., Austen, K. F. 1982.

Isolation of a human erythrocyte mem­ brane glycoprotein with decay accel­ erating activity for C3 convertases of the complement system. J. Immunol. 129:

184 13. Nicholson-Weller,

A., March, 1. P., Rosenfeld, S. I., Austen, K. F. 1983. Affected erythrocytes of patients with

paroxysmal nocturnal hemoglobinuria

are deficient in the complement regu­ latory protein, decay accelerating factor.

Proc. Natl. Acad. Sci. USA 80: 5430 14. Medof, M. E., Gottlieb, A., Kinoshita, T., Hall, S., Silber, R., et al. 1987. Relationship between decay accelerat­

ing factor deficiency, diminished acetyl­ cholinesterase activity, and defective terminal complement pathway restric­ tion in paroxysmal nocturnal hemo­ globinuria erythrocytes. J. Clin. Invest. 80: 165

15. Nicholson-Weller, A., Spicer, D. B. , Austen, K. F. 1983. Deficiency of the complement regulatory protein "decay accelerating factor," on membranes of granulocytes, monocytes, and platelets in paroxysmal nocturnal hemoglobin­

uria. N. Engl. J. Med. 312: 1091 16. Devine, D. V., Siegel, R. S., Rosse, W. F. 1987. Interactions of the platelets in

paroxysmal nocturnal hemoglobinuria with complement. J. Clin. Invest. 79: 131

Annu. Rev. Med. 1990.41:431-436. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 02/02/15. For personal use only.

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ROSSE

17. Dixon, R. H., Rosse, W. F. 1977. Mech­ anism of complement activation on human blood platelets in vitro. J. Clin. Invesl. 59: 360 18. Bryant, R. M., Hall, S. E., Cole, J. S., Greenberg, C. S., Rosse, W. F. 1988. Marked sensitivity of paroxysmal noc­ turnal hemoglobinuria (PNH) platelets to thrombin: role of complement acti­ vation. Blood 72(Suppl. I): 317 (Abstr.) 19. Hansch, G. M., Hammer, C. H., Vanguri, P., Shin, M. L. 1981. Ho­ mologous species restriction in lysis of crythrocytes by terminal complement proteins. Proc. Natl. Acad. Sci. USA 78: 5118 20. Hansch, G. M., Schonermark, S., Roelcke, D. 1987. Paroxysmal nocturnal hemoglobinuria type III. Lack of an erythrocyte membrane protein restrict­ ing the lysis of C5b-9. J. Clin. Invest. 80: 7 21. Holguin, M. H., Fredrick, L. R., Bernshaw, N. J., Wilco x, L. A., Parker, C. J. 1989. Isolation and character­ ization of a membrane protein from nor­ mal human erythrocytes that inhibits reactive lysis of the erythrocytes of par­ oxysmal nocturnal hemoglobinuria J. Clin. Invest. In press

hemoglobinuria. In preparation 27. Selvaraj, P., Dustin, M. L., Silber, R., Low, M. G., Springer, T. A. 1987. Deficiency of lymphocyte function­ associated antigens 3 (LFA-3) in par­ oxysmal nocturnal hemoglobinuria. Functional correlates and evidence for a phosphatidylinositol membrane anchor. J. Exp. Med. 166: 1011 28. Selvaraj, P., Rosse, W. F., Silber, R., Springer, T. A. 1988. The major Fc receptor in blood has a phospho­ tidylinositol anchor and is deficient in paroxysmal nocturnal hemoglobinuria. Nature 33 3: 565-67 29. Simmons, D. L., Tan, S., Tenen, D. G., Nicholson-Weller, A., Seed, B. 1989. Monocyte antigen CD 14 is a phos­ pholipid anchored membrane protein. B/ood 73: 284 30. Medof, M. E., Walter, E. I., Roberts, W. L., Haas, R. , Rosenberry, T. L. 1986. Decay accelerating factor of comple­ ment is anchored to cells by a C-ter­ minal glycolipid. Biochem. J. 25: 6740 31. Roberts, W. L., Santikarn, S., Reinhold, V. N., Rosenberry, T. L. 1988. Struc­ tural characterization of the gly­ coinositol phospholipid membrane anchor of human erythrocyte acetyl­

erythrocyte acetylcholinesterase enzyme in paroxysmal nocturnal hemoglobin­ uria. Arch. Patho/. 69: 534 Chow, F.-L., Telen, M. J., Rosse, W. F. 1985. The acetylcholinesterase defect in paroxysmal nocturnal hemoglobinuria: Evidence that the enzyme is absent from the cell membrane. Blood 66: 940 Beck, W. S., Valentine, W. N. 1951. Bio­ chemical studies on leucocytes. II. Phos­ phatase activity in chronic lymphatic leukemia, acute leukemia, and mis­ cellaneous hematologic conditions. J. Lab. Clin. Med. 38: 245 Burroughs, S. F., Devine, D. V., Browne, G., Kaplan, M. E. 1988. The population of paroxysmal nocturnal hemoglobinuria neutrophils deficient in decay accelerating factor is also deficient in alkaline phosphatase. Blood 71: 1086 Devine, D. V., Rosse, W. F. 1989. Deficiency of 5'-ectonudeotidase on the

263: 18776 32. Low, M. G.,Zilversmit, D. B. 1980. Role of phosphatidylinositol in attachment of alkaline phosphatase to membranes. Biochemistry 19: 3913 33. Davitz, M. A., Low, M. G., Nussen­ zweig, V. 1986. Release of decay-ac­ celerating factor (DAF) from the cell membrane by phosphatidylinositol specific phospholipase C (pIPLC) J. Exp. Med. 163: 1150 34. Ferguson, M. A. H., Low, M. G., Cross, G. A. M. 1985. Glyco syl -sn-I ,2-di myri­ stylphosphatidylinositol is covalently linked to Trypanosoma brucei variant surface glycoprotein. J. BioI. Chem. 260: 14547 35. Springer, T. A., Dustin, M. L., Kishi­ moto, T. K., Marlin, S. D. 1987. The lymphocyte function-associated LFA-I, CD2, and LFA-3 molecules: Cell ad­ hesion n:ceptors of the immune system.

22.

23.

24.

25.

26.

Auditore, J. V., Hartmann, R. c., Fle xne r, J. M., Bal ch um , O. J. 1960. The

lymphocytes in paroxysmal nocturnal

cholinesterase by fast atom bombard­ ment mass spectrometry. J. Bioi. Chern.

Annu. Rev. Irnmunol.

5: 223

Paroxysmal nocturnal hemoglobinuria and decay-accelerating factor.

The blood cells in paroxysmal nocturnal hemoglobinuria (PNH) lack several proteins, including some that regulate the activation of complement on the c...
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