Mutation linked to B-cell activation in lupus

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May 17, 2004

Mutation linked to B-cell activation in lupus

New York, NY - Researchers have identified a " rare, but informative "

mutation on the CD40 gene that may play a role in B-cell activation and

autoimmunity in systemic lupus erythematosus (SLE), according to new data

released here at the 7th International Congress on Systemic Lupus

Erythematosus and Related Conditions [1].

In a genetic analysis of 211 families of SLE patients, 5.2% tested positive

for the p227A mutation on the CD40 gene, reports researcher Dr Amrie C

Grammer (National Institutes of Health, Bethesda, MD). Of those who had the

gene, 77% developed SLE.

Multiple steps involved in study

Grammer and colleagues used fluorescence resonance energy transfer (FRET)

and flow cytometry to determine that the p227A mutation is associated with

TNF-receptor-associated factor 2 (TRAF2). They found a constitutive

association of p227-mutant CD40 with TRAF2, which was confirmed by confocal

FRET, she says.

Next, the team set out to determine whether TRAF2 activates certain

transcription factors involved in B-cell differentiation. They found that

TRAF2 activates the signaling molecules NFB and AP1. In a related

experiment, they examined B cells of heterozygote families exhibiting the

CD40-p227A mutation.

In sum, they report a natural mutant of CD40-p227 spontaneously associates

with TRAF2 and induces the kinase cascades leading to activation of

transcription factors NFB and AP1. Many of the CD40-related events in B-cell

differentiation involve these transcription factors.

A rare, but informative polymorphism

" The results emphasize the role of B-cell hyperactivity in the etiology of

SLE and suggest that other mutations in the CD40 signaling pathway may

contribute to the development of other kindred, " they conclude.

Calling the mutation " a rare, but informative polymorphism, " Grammer says it

" plays a role in the abnormal cellular activity underlying lupus. "

It is highly likely that in some lupus patients, this mutation contributes

to the spontaneous B-cell activation and autoimmunity that is characteristic

of this disease, they report. This group has previously studied B-cell

activation and germinal centers in lupus and conducted a preliminary trial

with the anti-CD154 antibody, as reported by rheumawire.

Mann

Source

1. Grammer AC, He L, Fischer R, et al. Presentation: A naturally occurring

mutant of CD40 (P227A) in families of patients with SLE mediates spontaneous

TRAF2 association and activation of NFkB and AP1. New York, NY: 7th

International Congress on Systemic Lupus Erythematous and Related

Conditions: Session on long-term outcome: heart and vessels; May 9-13,

2004:Abstract 6B.