Index Based on Blood Levels of Specific Antibodies and Protein Complex May Predict Lupus Risk, Study Reports

Identifying a person’s risk for lupus and possible need for early treatment might be aided by a new blood serum-based risk index created by researchers at the Feinstein Institute for Medical Research in New York.

The index assesses the levels of certain anti-DNA antibodies — IgG and IgM – and a immune system protein complex — C1q — that clears cell waste and promotes immune tolerance. All are known to respond to changes in disease activity.

Additional studies are needed to confirm its usefulness, the researchers said.

The study, “Serologic features of cohorts with variable genetic risk for systemic lupus erythematosus,” appeared in the journal Molecular Medicine.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients produce antibodies against nuclear proteins and DNA. One of the most common kind of antibodies in SLE patients are those targeting double-stranded DNA – anti-dsDNA antibodies. These are present in up to 70 percent of patients, and are often used to monitor disease activity.

But high levels of anti-dsDNA alone do not necessarily indicate disease. It depends on the kind of antibody subclass targeting the DNA.

While immunoglobulin G (IgG) anti-dsDNA antibodies are linked with lupus development and disease activity, IgM anti-dsDNA antibodies have a protective role against the disease, helping to prevent excessive immune reactivity.

It is the balance between IgM and IgG anti-dsDNA antibodies that is of particular importance for lupus.

SLE seems to be caused by a mix of genetic and environmental factors. Studies in African people, for example, show that African genes in the Caribbean population is a risk factor for the disease. But, overall, the prevalence of lupus in African countries is lower, and patients have less severe disease manifestations. Researchers attribute these discrepancies to different environments.

Another example of environmental influence is malaria — an endemic infection in sub-Saharan Africa. Patients with malaria are virtually protected from developing lupus.

While these associations are well-known, the molecular events that cause them are poorly understood.

Researchers at Feinstein Institute for Medical Research, led by professor Betty Diamond, MD, hypothesized that malaria exposure affects the levels of IgM anti-dsDNA antibodies and the C1q protein complex.

C1q is a group of proteins that work with immune cells to clear cell debris, which could otherwise be damaging and trigger unnecessary immune responses. Among individuals with deficiencies in this complex, nearly 90 percent develop SLE.

Investigators examined the levels of IgG and IgM anti-dsDNA antibodies and of C1q in women with varying risk for SLE – including women with genetic risk and malaria exposure.

The study included 51 African-American SLE patients (SLE group), 98 unaffected sisters of these patients (SIS group), 80 healthy African-American women (AAHC group), 16 healthy Caucasian women (CHC), and 40 women from Mali with a history of malaria infection (MAL).

The groups had variable levels of IgG and IgM antibodies, leading researchers to test their ratio (IgG/IgM) as a possible indicator of the progressive autoimmune response. As expected, people in the SLE group had the highest ratio of all groups, followed by those in MAL, SIS, and AAHC groups with an intermediate ratio. The CHC group had the lowest ratio.

Regarding C1q, SLE patients had the lowest levels, followed by the healthy sisters of SLE patients. The CHC and AAHC groups had intermediate C1q values, whereas individuals exposed to malaria had the highest levels of C1q.

The team then developed a SLE risk index, combining the ratio of IgG and IgM anti-dsDNA autoantibodies with the levels of C1q. The lupus risk index “was developed to measure propensity for development of SLE for each individual,” the researchers wrote.

As expected, lupus patients scored the highest in the new risk index, while healthy Caucasian women (CHC) and those from Mali infected by malaria (MAL) scored the lowest. The SIS and AAHC group had intermediate values, showing their increased likelihood of developing lupus.

“We have been curious about why individuals of West African descent have a higher prevalence of lupus,” Diamond said in a press release. “A better understanding about the risk of lupus and why it differs between populations could help us better treat or even prevent people from getting the condition.”

The study demonstrates that high levels of IgG and low levels of IgM and C1q can predispose a person to developing lupus. It also provided additional evidence that exposure to malaria both protects people against SLE and delays disease onset in genetically predisposed individuals.