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Comment
. 2000 Sep;106(5):637-41.
doi: 10.1172/JCI11002.

Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes "Why? Why? Why?"

N S Young  1 , J P Maciejewski
Affiliations
Comment

Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes "Why? Why? Why?"

N S Young et al. J Clin Invest. 2000 Sep.
No abstract available

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Figures

Figure 1
Figure 1
The pathophysiology of PNH. The genetic basis of the disease is diagrammed at upper left. Somatic mutations in the X-linked PIG-A gene occur in a hematopoietic stem cell. PIG-A consists of six exons with an open reading frame of 1455 bp; the putative protein product has 484 amino acids and an estimated molecular weight of 60 kDa. Small deletion and insertion mutations (dark triangles) are most common in PNH and are distributed throughout the coding sequence; missense mutations (dark circles) appear to cluster in exon 2, suggesting that this region encodes for a functionally crucial portion of the protein (see ref. for details of the GPI-anchor chemical structure). At upper right, GPI-anchored proteins and conventional transmembrane proteins are contrasted, and the structure of the GPI anchor is shown in the inset. The anchor is a glycolipid composed of the lipid phosphatidylinositol, the sugars N-glucosamine and mannose, and ethanolamine. The acyl/alkyl-glycerol of the lipid anchors the structure in the bilayer of the cell membrane; an ethanolamine links the carboxyl terminal amino acid of the protein to the oligosaccharide portion of the anchor. The PIG-A gene product contributes to the N-acetyl-glucosaminyl transferase activity that adds this sugar to inositol, an early step in construction of the anchor; the entire anchor structure is preformed and then covalently bound to the protein in a transamidation reaction in the endoplasmic reticulum (not shown). Expansion of the PIG-A– clone is required for PNH (see text and Figure 2). Absence of GPI-anchored proteins, especially CD59 (MIRL), accounts for hemolysis; the inset shows the role of MIRL in blocking the late complement attack complex, by first binding to C8 and inhibiting spontaneous binding of C9 and then preventing C9 polymerization and subsequent red cell lysis. BM, bone marrow; RBCs, red blood cells; MAC, membrane attack complex.
Figure 2
Figure 2
Models for clonal expansion in PNH. (a) In the first model, the PIG-A mutation sufficiently affects cellular function to cause an intrinsic growth advantage. (b) Extrinsic factors are invoked for other models; immune effects are illustrated, but differential responses to hematopoietic growth factors, inhibitory cytokines, or stromal cells are also possible. (c) GPI-anchor deficiency might produce a global deficit in immune recognition, as for example through absence of a costimulatory molecule on the target, providing a general selective advantage to the mutated cells. (d) Alternatively, a GPI-anchor protein might be antigenic, by resemblance to an exogenous antigen or after antigenic spread. (e) Finally, altered protein processing due to the absence of anchor structures might change the nature and quantity of peptides derived from normally GPI-anchored proteins, as well as their MHC presentation. As illustrated, cell surface proteins are normally recycled to the membrane or degraded by lysosomes for class II presentation; in PNH, anchorless proteins likely are processed by the proteasome for class I presentation. Differences in immune response to normal and PNH cells should follow.
See this image and copyright information in PMC

Comment on

References

    1. Rosse, W. 2000. A brief history of PNH. In PNH and the GPI-linked proteins. N.S. Young and J. Moss, editors. Academic Press. San Diego, California, USA. 1–20.
    1. Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997;336:1365–1372. - PubMed
    1. Frickhofen N, Rosenfeld SJ. Immunosuppressive treatment of aplastic anemia with antithymocyte globuilin and cyclosporine. Semin Hematol. 2000;37:56–68. - PubMed
    1. Luzzatto, L., and Nafa, K. 2000. Genetics of PNH. In PNH and the GPI-linked proteins. N.S.Young and J. Moss, editors. Academic Press. San Diego, California, USA. 21–48.
    1. Okazaki, I., and Moss, J. 2000. The function of GPI-anchored proteins. In PNH and the GPI-linked proteins. N.S.Young and J. Moss, editors. Academic Press. San Diego, California, USA. 159–177.

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