Recurrent aseptic meningitis with PIGT mutations: a novel pathogenesis of recurrent meningitis successfully treated by eculizumab

We report the case of a patient with PIGT mutations who experienced recurrent aseptic meningitis 121 times over 16 years before developing paroxysmal nocturnal haemoglobinuria (PNH). Each episode was preceded by urticaria and arthralgia. After developing PNH, haemolysis occurred prior to meningitis. Flow cytometry revealed deficiency of the glycophosphatidylinositol (GPI)-anchored complement regulatory proteins, CD59 and CD55, and he was diagnosed with PNH. All the symptoms disappeared on administering eculizumab, an anti-C5 antibody. We did not detect mutation in PIGA, which is regarded as the cause of PNH. However, we detected a germ-line mutation and a somatic microdeletion in chromosome 20q including PIGT; PIGT is essential for transferring GPI anchor to the precursors of CD59 and CD55, which play important roles in complement regulation. Loss of these proteins leads to complement overactivation, causing inflammatory symptoms, including recurrent meningitis. PIGT mutations should be considered a novel pathogenesis of recurrent meningitis of unknown aetiology.

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Mechanisms by which the surface expression of the glycosyl-phosphatidylinositol-anchored complement regulatory proteins decay-accelerating factor (CD55) and CD59 is lost in human leukaemia cell lines

Biochemical Journal ◽

10.1042/bj3140969 ◽

1996 ◽

Vol 314 (3) ◽

pp. 969-976 ◽

Cited By ~ 17

Author(s):

Michiyo HATANAKA ◽

SEYA SEYA ◽

Misako MATSUMOTO ◽

Tomoko HARA ◽

Masaru NONAKA ◽

...

Keyword(s):

Cell Lines ◽

Surface Expression ◽

Northern Blotting ◽

Regulatory Proteins ◽

Leukaemia Cell ◽

Gpi Anchor ◽

Complement Regulatory Proteins ◽

Glycosyl Phosphatidylinositol ◽

Human Leukaemia Cell ◽

Human Leukaemia

We have investigated the mechanisms of defects in the glycosyl-phosphatidylinositol (GPI)-anchored complement regulatory proteins delay-accelerating factor (DAF) and/or CD59 in a panel of human leukaemia cell lines that lack surface expression of these proteins: U937 (DAF+/CD59-), CEM (DAF-/CD59+), TALL (DAF-/CD59-) and a substrain of Ramos [Ramos(-)] (DAF-/CD59-). Northern blotting and reverse transcription-PCR revealed that the main cause of the DAF and/or CD59 deficiency is the failure of mRNA expression in most of the cell lines, except in Ramos(-) in which sufficient mRNA for DAF and CD59 was produced. U937, CEM and TALL cells were not defective in GPI anchor formation as assessed by the detection of other GPI-anchored proteins. No gene abnormality corresponding to DAF or CD59 was detected by Southern blotting. Thus the cause of the defects of DAF and/or CD59 in these leukaemia cell lines except for Ramos(-) is virtually undetectable steady-state levels of the relevant mRNA, most likely attributable to lack of transcription in these cell lines. On the other hand, Ramos(-) cells failed to generate a GPI anchor, whereas they normally expressed DAF and CD59 transcripts. The transfection of phosphatidylinositol-glycan class A (PIG-A) cDNA into Ramos(-) cells restored DAF and CD59 expression, indicating that the defective mechanism in GPI anchor formation is similar to that in paroxysmal nocturnal haemoglobinuria (PNH) cells, i.e. a deficiency of the PIG-A gene product. Thus the mechanisms of the defects of DAF and/or CD59 in human leukaemia cell lines are not uniform, and in most cases are different from that proposed to cause PNH.

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