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Assessing lupus risk
MANHASSET, N.Y.—Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that results in “inflammation in connective tissues, such as cartilage and the lining of blood vessels,” according to the Genetics Home Reference website of the National Institutes of Health, and attacks a number of systems within the body, from the skin and joints to the lungs, kidneys and central nervous system. Lupus tends to affect women more than men, and is more common in African American women more than Caucasian women; Hispanic, Asian and Native American women also see higher incidence rates than Caucasian women.
At present, there is no cure for lupus, and treatment is mainly symptomatic. Similarly, the exact cause of lupus is unknown.
New information out of the Feinstein Institute for Medical Research is offering a few more answers about the autoimmune disease, however. Dr. Betty Diamond of the Feinstein Institute and colleagues have potentially found a way to determine an individual's risk for lupus via blood serum samples. The work was published in Molecular Medicine in a piece titled “Serologic features of cohorts with variable genetic risk for systemic lupus erythematosus.”
The researchers created an index to help determine a patient's risk for lupus based on a few biologic compounds in blood serum—namely the presence and amount of Immunoglobin G (IgG) and Immunoglobin M (IgM) antibodies, and the levels of C1q, a protein complex associated with protection from lupus.
The experiment focused on blood serum samples from five cohorts of women at risk for SLE: 40 Malian (West African) women with a history of malaria infection (MAL), 51 African American lupus patients (SLE), 80 healthy African American women (AAHC), 98 unaffected sisters of lupus patients (SIS) and 16 Caucasian healthy controls (CHC).
“We have been curious about why individuals of West African descent have a higher prevalence of lupus,” said Diamond, who was corresponding author of the paper. “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.”
Diamond's lab is looking at DNA-reactive B cells in SLE, as well as the role of C1q. As noted in the paper, "C1q is a complement component that is important in clearance of apoptotic debris and promotes immune tolerance through regulation of immune cell differentiation and cytokine release (Son et al. 2015). Ninety percent of individuals with severe hereditary C1q deficiency have SLE (Manderson et al. 2004)." The authors also noted that "Not only is C1q deficiency among the greatest risk factors for SLE, but C1q inversely correlates with disease activity (Horak et al. 2006). Anti-C1q antibodies have also correlated with disease activity (Bock et al. 2015)."
The team was able to confirm the hypothesis that high levels of IgG, low levels of IgM and low levels of C1q equate to a higher risk of lupus. Interestingly, being exposed to malaria was found to potentially delay the onset of lupus in those predisposed to the disease, thanks to increased levels of protective IgM antibodies and C1q. They reported that the risk index was highest in SLE patients, with risk second highest in unaffected sisters of SLE patients and third highest in healthy African American women. Healthy Caucasian women and malaria-exposed West African women presented with the lowest risk.
"The protective properties of IgM antibodies are known," the authors write. "IgM immune complexes engage C1q which will bind LAIR-1, an inhibitory surface receptor on hematopoietic cells (Son and Diamond 2015). IgM precedes IgG anti-dsDNA antibodies in mouse models of SLE and it has been shown in the NZB/W model that administration of IgM anti-DNA antibody will delay onset of disease."
Per the Diamond lab's website, previous work by the team has demonstrated “that LAIR-1 is an inhibitory receptor for C1q. Furthermore, in conjunction with HMGB1, C1q can polarize monocytes to an M2-like anti-inflammatory macrophage. The laboratory is interested in understanding how C1q interrupts pro-inflammatory pathways and in constructing a molecule with C1q-like function for therapeutic use.” LAIR1, or leukocyte-associated immunoglobulin-like receptor 1, is a protein that plays a role in immune response. As noted on the National Center for Biotechnology Information website (part of the NIH's National Library of Medicine), “The protein encoded by this gene is an inhibitory receptor found on peripheral mononuclear cells, including natural killer cells, T cells and B cells. Inhibitory receptors regulate the immune response to prevent lysis of cells recognized as self.”
"A tool such as this that can predict the risk of developing clinical SLE would be useful to assess the effectiveness of early interventions," the authors argued in the conclusion of their Molecular Medicine paper. "Therapy with hydroxychloroquine, for example, delays disease onset (Virdis et al. 2015); we would anticipate that its therapeutic effect would be reflected in the LRI. Longitudinal studies, including in our unique sisters cohort are needed to validate our findings. These observations additionally suggest new therapeutic approaches for the treatment of SLE."