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IgG subclasses In the Pathology Lab at St. Paul’s, our breakthrough research team gathers at the new mass spectrometry machine that played such a critical role in their world first discovery. From left to right: medical biochemist Dr. Andre Mattman; Division Head of Clinical Chemistry Dr. Dan Holmes; clinical chemist Dr. Mari DeMarco; assay development scientist Grace van der Gugten; rheumatologist Dr. Mollie Carruthers; and hematologist Dr. Luke Chen.
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A relatively quiet “world first” for St. Paul’s

July 4th, 2017
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St. Paul’s medical biochemists make breakthrough advance on mysterious disease

Only in this century has the disease known as IgG4-RD begun to gain prominence. Its origins are still being defined, although research suggests it may be an autoimmune or allergic disorder. Left untreated, it can cause organ failure. It affects a minimum of one in 100,000 people, which sounds rare but this means two or three new diagnoses every month in BC alone.

Even its name, IgG4-RD, does little to promote public awareness.

Fortunately, Dr. Andre Mattman, a medical biochemist with the Department of Pathology and Laboratory Medicine at St. Paul’s, is very aware of IgG4-RD. So aware that earlier this year a breakthrough by Dr. Mattman and his colleagues changed the way this disease is diagnosed and treated.

A disease of many faces

IgG4-RD stands for Immunoglobulin G4-Related Disease. An immunoglobulin is an antibody, which is a protein used by your immune system; the “G4” refers to a subclass of antibody.

IgG4 antibodies protect you from inflammation by dampening an aggressive immune response to infection. This dampening can prevent collateral damage to healthy tissues, but it is not clear if this is their role in the case of IgG4-RD where the concentration of IgG4 is typically much higher than in other inflammatory diseases. Regardless of whether IgG4 is part of the problem—or reacting to the problem—its concentration serves as an effective biomarker, an indicator of the presence and severity of the disease.

The cause of IgG4-RD remains unknown; and a cause for concern is that it manifests in different ways.

IgG4-RD can target any organ in the body and causes inflammatory and/or fibrous growths that can appear cancer-like. IgG4-RD has been misdiagnosed as cancer of the lungs or pancreas and has been treated as such with surgical removal. However, when recognized for what it is, the disease may be treated by much less drastic measures.

The danger of misdiagnosing IgG4-RD for cancer, especially when it attacks a vital organ, makes accuracy of diagnosis critical. Unfortunately, no one in the world had yet been able to optimally measure the IgG4 biomarker, resulting in confusion in the criteria for diagnosing this mysterious disease.

Solving a conundrum

The diagnosis of IgG4-RD involves a blood test that measures each of the IgG subclasses (IgG1, IgG2, IgG3, IgG4); a large increase in IgG4 without an increase in the other IgG4 subclasses was a specific marker of disease. But according to Dr. Mattman, there had always been problems with this method, which is also used for other purposes such as the recognition of immunodeficiency.

“There were still a lot of errors in this application of the blood test when used to diagnose IgG4-RD,” says Dr. Mattman. “This made it hard to understand what was going on with a patient’s disease state.”

As a provincial referral lab, St. Paul’s is the only lab in BC that processes IgG4-RD samples, and it was in navigating such volume that Dr. Mattman kept seeing what he describes as “a conundrum of results that didn’t make sense.”

“It’s irritating to see something and not understand it,” says Dr. Mattman, “so it was the desire to understand this better that motivated us as a team.”

In the case of the IgG4-RD breakthrough, the team included rheumatologist Dr. Mollie Carruthers, a leading figure in disorders of the joints, muscles, and ligaments, and hematologist Dr. Luke Chen, an expert in the physiology of the blood. The team also included Dr. Mattman’s colleagues in the Department of Pathology and Laboratory Medicine at St. Paul’s—Dr. Dan Holmes, Division Head of Clinical Chemistry, clinical chemist Dr. Mari DeMarco and assay development scientist Grace van der Gugten.

Working as a group, and from a protocol that had originally been developed at the Mayo Clinic but never brought to clinical production, Dr. Mattman and his colleagues came to believe that the errors they were seeing could be corrected by using a form of chemical analysis called mass spectrometry.

Mass spectrometry leads to breakthrough

Mass spectrometry uses electric and magnetic fields to measure the mass of charged particles in order to quantify known materials—and identify unknown ones—within a blood sample. Thanks to support from numerous sources such an Genome Canada, Genome BC and the Hal Kettleson Foundation—as well as donors to St. Paul’s Foundation—the team’s lab was recently outfitted with a new, state-of-the-art mass spectrometry machine. The acquisition has helped keep St. Paul’s at the forefront of what is fast becoming the world’s gold standard for chemical analysis in medicine.

A first-in-world clinical assay

Dr. Mattman’s description of how his team became the first in the world to bring into clinical practice a new assay to accurately diagnose IgG4-RD sounds like a storyline from a TV procedural.

“We noticed that the more severe a person’s syndrome was, the higher the IgG4,” says Dr. Mattman. “And the higher the IgG4, the more the results did not make sense. We knew there had to be an error in one of those results and we didn’t think it was IgG4, which meant something was wrong with the method. This could mean the IgG4 was interfering with the rest of the test results. Once we identified that the IgG4 might be the problem, we felt we could test that with mass spectrometry to find out if we were right.”

To make a long (and highly complex) story short—they were right.

In February of this year, Dr. Carruthers presented the team’s findings at the 3rd International Symposium on IgG4-Related Diseases & Fibrosis, which attracts experts from around the world.

“The clinicians with expertise in this field who are treating patients are excited,” says Dr. Mattman. “It’s gratifying that we worked as a team, solved this problem and contributed these findings to global knowledge about this disease.”

St. Paul’s Foundation is a proud supporter of the Department of Pathology and Laboratory Medicine at St. Paul’s and we extend our congratulations to Dr. Mattman and his colleagues. Please continue to support life-saving research breakthroughs at St. Paul’s with your gift today.

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Want to learn more? Read an article from earlier this year on our mass spectrometer and how it brings research closer to patient care.

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