Immunology insights for rheumatologists & rheumatology professionals
“A fundamental event in the pathogenesis of systemic lupus erythematosus (SLE) is the formation of immune complexes with anti-nuclear antibodies (ANAs) and nuclear antigens, producing immune complexes that have immunological activity and can mediate local and systemic inflammation,” says David Pisetsky, MD, PhD, a professor of medicine and immunology at Duke University School of Medicine and a staff rheumatologist at the Durham VA Medical Center, both in Durham, N.C. “In addition to nephritis, these immune complexes can induce more generalized immune system disturbances.”
Dr. Pisetsky, the founding editor of The Rheumatologist, is the author of a review that is part of a series on immunology for rheumatologists launched earlier this year in Arthritis & Rheumatology (A&R).1 In this new installment, Dr. Pisetsky reviews the unique interplay between ANAs—antibodies to components of the cell nucleus—and nuclear molecules in the pathogenesis of SLE. The review also advances a model that can support research and the clinical management of SLE.2
“Furthermore, the article highlights the role of genetics in influencing these pathways,” Dr. Pisetsky says. “In addition to its relevance for studies on pathogenesis, the model on the interplay of anti-nuclear antibodies and nuclear antigens provides insights into the development of new biomarkers, as well as approaches to therapy.”
Dr. Pisetsky
Case Study
Dr. Pisetsky begins the review with a hypothetical patient case.
A 29-year-old African American woman presented with fatigue, arthralgias and difficulty thinking. The patient’s family history, clinical examination and laboratory findings are discussed in the review. A rheumatologist diagnosed SLE. After a month of prednisone treatment, antibodies to DNA were no longer detectable, and the complement level moved toward normal. The patient was referred to a nephrologist for a potential renal biopsy.
Next, the review covers the current SLE model. At the end of the review, Dr. Pisetsky refers back to the hypothetical patient case, citing its relevance to the model. The review includes an informative table, detailed figures and legends, and many references.
“Rheumatologists can benefit from the article [because] it provides an overarching model to understand the pathogenesis of SLE, as well as the basis for certain clinical manifestations,” Dr. Pisetsky says. “The article also provides an approach for interpreting laboratory findings when assessing disease activity and potential effects of therapy.”
SLE Model
The current model of SLE, which originated from the study of the lupus erythematous cell, includes the roles of ANAs, immune complex formation and complement binding. ANAs can “bind to DNA, RNA and protein complexes with nucleic acids,” Dr. Pisetsky writes.
Among ANAs, anti-DNA antibodies are linked to active disease, especially lupus nephritis, and fluctuate with disease activity, suggesting they arise from newly activated B cells. Meanwhile, antibodies to RNA binding proteins (RBPs), such as Sm, RNP, Ro and La, are more stable and are produced by long-lived plasma cells.
“Despite differences in expression over time and relationship to disease activity, both anti-DNA and anti-Sm antibodies are criteria for the classification of patients with SLE. Antibodies to other RBPs (e.g., RNP, Ro and La) can be present in other diseases,” Dr. Pisetsky writes. “The lack of specificity of these antibodies for classification or diagnosis should in no way minimize their importance for pathogenesis.”
Anti-DNA antibodies can bind to DNA in the blood, forming immune complexes that lead to renal deposition, provoking nephritis and “stimulating cytokine production following uptake into innate immune cells and interaction with internal nucleic acid sensors,” Dr. Pisetsky explains. These nucleic acid sensors contribute to an internal host defense system in the cytoplasm that “can respond to DNA from infecting organisms. During cell stress, DNA from nuclear and mitochondrial sources can also trigger these sensors,” he writes.
A source of immunologically active, extracellular DNA is needed to form immune complexes. Patients with SLE have abnormal neutrophil populations predisposed to a distinct type of death, termed NETosis, which forms an extended mesh-like structure called a neutrophil extracellular trap (NET). NETs contain high molecular weight DNA. In SLE, “the combination of ANAs and immunologically active DNA can create new structures that can promote inflammation throughout the body, as well as drive organ inflammation and damage,” Dr. Pisetsky explains.
Further, SLE research has shown that type 1 interferon plays a central role in the pathogenesis. Studies show that sera of patients with SLE can induce interferon production “by immune cells in vitro, with immune complexes of ANAs and their cognate nuclear autoantigens driving these responses,” Dr. Pisetsky writes.
Genetics
Around 200 different gene loci have been associated with SLE. Genetic polymorphisms can influence the immune system by affecting B and T cell response thresholds. “Because of aberrant signaling during steps of tolerance, the B cell repertoire in patients with SLE can contain precursors for DNA and other autoantigens that, in otherwise healthy individuals, would be removed or anergized,” Dr. Pisetsky writes.
Mutations of single genes can provoke SLE, notably by involving complement and clearance systems for nucleic acids. The review provides a table of selected single-gene systems associated with SLE or related conditions.
“Sex is another major genetic influence on pathogenesis that may reflect the effects of hormones and the number of X chromosomes and the pattern of X chromosome inactivation,” Dr. Pisetsky writes.
Case Review
The hypothetical patient showed features of the SLE model.
Along with both her sex and an African ancestry placing her at high risk, the hypothetical patient had evidence of a genetic predisposition based on her family history—a sister with rheumatoid arthritis and an aunt with lupus. She also had a cluster pattern of ANA expression associated with nephritis, along with anti-DNA antibodies and anti-RBP antibodies, which contribute to heightened immune activity and nephritis. Due to proteinuria, a renal biopsy would likely show evidence of immune deposition.
If treatment with a combination of glucocorticoid steroids and mycophenolate mofetil was effective, laboratory testing would show a decrease in anti-DNA antibody levels and an increase in complement levels, Dr. Pisetsky suggests.
He explains that SLE agents can be placed at key steps in the model. Specifically, “steroids can decrease inflammation and cytokine production; hydroxychloroquine can affect endosomal function and signaling by TLR-9; hydroxychloroquine may also affect the generation of NETs; mycophenolate can affect B cell function, as can belimumab; and rituximab can eliminate CD20+ B cells without effects on plasma cells. Anifrolumab can inhibit responses to interferon by blocking the receptor.” He adds that chimeric antigen receptor T cells could be considered to eliminate B cells if the patient is unresponsive to treatment.
Katie Robinson is a medical writer based in New York.
References
- Bucala R, Solomon DH. Immunology for the rheumatologist: A&R introduces a new problem-based immunology review series with great educational potential. Arthritis Rheumatol. 2024. Jan;76(1):9–10.
- Pisetsky DS. Unique interplay between antinuclear antibodies and nuclear molecules in the pathogenesis of systemic lupus erythematosus. Arthritis Rheumatol. 2024;76(9):1334–1343.
