The reason why the body's immune cells cause so much damage and
can't regulate themselves in patients with lupus has been revealed
in a UCL study. The finding could lead to more effective ways of
treating lupus.
Using blood samples from 88 healthy people and 217 lupus
patients, the team found that immune cells, which regulate the
immune response and reduce inflammation, are instead being turned
into autoantibody-producing B cells that cause inflammation.
This miscommunication in lupus patients is caused by an
imbalance of three types of immune cells: B cells that produce
antibodies to protect the body against foreign microbes (and a main
driver of autoimmune disorders); plasmacytoid dendritic cells that
produce a molecular signal called interferon-alpha (IFNa) that
stimulates B cells; and regulatory B cells that suppress excessive
immune responses.
"Our study shows for the first time that the overproduction of
IFNa by hyperactivated plasmacytoid dendritic cells in lupus
patients is the consequence of the lack of suppressive regulatory B
cells," said senior author Professor Claudia Mauri of UCL.
"The uncontrolled production of IFNa causes an increase of
antibody-producing B cells and suppresses the division and
appearance of regulatory B cells."
The researchers also discovered a potential reason why
rituximab, a drug that has been used off-label to treat lupus by
depleting the vast majority of circulating B cells, benefits some
patients but not others. Patients for whom the drug is less
effective were found to have increased IFNa activity (measured by
IFNa-induced gene signature), which prevents the 'newly formed' B
cells from becoming suppressive regulatory B cells.
"After treatment, newly formed B cells come back into
circulation" said Dr Madhvi Menon, also of UCL. "Our study suggests
that response to rituximab is determined by the presence or absence
of an elevated IFNa-related gene activity. Thus, only in patients
that have a normal IFNa signature do the newly repopulated B cells
successfully mature into regulatory B cells."
The results suggest that a blood test could be used to
predetermine which patients could benefit most from treatment with
rituximab, providing a more effective way of treating lupus
patients."This would be an important step towards personalised
medicine for the treatment of lupus," Professor Mauri said.
The paper, A Regulatory Feedback between Plasmacytoid Dendritic Cells and
Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus,
is published in Immunity.