John H. Stone
CLEVELAND — The IgG4 molecule has been overstated in the understanding of IgG4-related disease, and it may be more helpful to view this condition as a “symphony of inflammation,” according to John H. Stone, MD, MPH, from Massachusetts General Hospital.
“IgG4 has been overemphasized in this disease and it is a little unfortunate that we even call it IgG4-related disease,” Stone told attendees at the Biologic Therapies Summit. “It doesn’t cause the disease. It is helpful in diagnosis, and somewhat helpful in monitoring disease, but its primary role is probably counter-regulatory.”
According to Stone, IgG4 is an “unusual” antibody, relative to the other IgG4 subclasses, in that it undergoes a process called Fab-arm exchange, in which it becomes unhinged and recombines with another half-antibody in the blood.
The IgG4 molecule has been overstated in the understanding of IgG4-related disease, according to Stone.
“The upshot of that is that IgG4 doesn’t bind antibody tightly, it doesn’t activate complement and it is thought to be sort of a wimpy antibody, an anti-inflammatory antibody, for as long as we have known about it, which has been since the early 1960s,” he said. “So, it would be really surprising if this were the cause of the disease.”
Stone added that researchers believe that, in IgG4-related disease, the IgG4 molecule is “trying, and failing,” to downregulate a primary immune response.
He noted that IgG4-related disease has been shown to cause not only exocrine and endocrine pancreatic failure, but also renal failure, ureteral stents, chronic hepatobiliary failure, bone-destructive sinus lesions that can mimic granulomatosis with polyangiitis, orbital lesions and pituitary failure.
According to Stone, research published in 2018 and 2019 has been able to identify several antigens that could potentially drive the disease, including galectin-3, annexin A11 and laminin 511.
In particular, galectin-3 appears to play an important role in about 30% of patients with IgG4-realted disease, he added.
“I think it’s not a matter of only one of these groups of researchers being right, but I think it is possible that all of them are right,” Stone said. “There is probably more than one antigen driving this disease, but more is to come on this.”
“We are making some progress on this, and the lessons we learn may be extrapolated into other rheumatic diseases,” Stone added. “IgG4-related disease is a symphony of inflammation — it’s not just about one molecule in the IgG subclass, and we are beginning to identify the individual musicians in the symphony.” – by Jason Laday
Stone J. IgG4 disease — the penultimate multidisciplinary disease. Presented at: Biologic Therapies Summit VIII; May 16-17, 2019; Cleveland, Ohio.
Disclosure: Stone reports consulting fees from, and being the global principal investigator of a clinical trial for, Genentech/Roche.