November 10-15

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Breakthroughs point to basic mechanistic themes in SLE


3 minutes

The details of lupus pathogenesis remain murky, but it now appears that ten basic mechanistic themes interact to trigger and maintain active disease.

Chandra Mohan, MD, PhD
Chandra Mohan, MD, PhD

A genetic signature for interferon (IFN) is the first key theme in the development of lupus, said Chandra Mohan, MD, PhD, Hugh Roy and Lillie Cranz Cullen Endowed Professor of Biomedical Engineering, University of Houston. Peripheral blood samples from adult lupus patients show a strong interferon signature in B-cells, T-cells and myeloid cells.

“This interferon signature is most prominently expressed by monocytes, plasma cells, plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), CD-4 T cells, and CD-8 T cells,” Dr. Mohan said. “These signatures have predictive value in both children and adults for disease activity and treatment response.”

Dr. Mohan described the role of IFN and other themes during Immunology Update—The Decade in Review: 10 Steps to SLE. Registered attendees have on-demand access to watch a replay of the session through Wednesday, March 11.

A patient’s overall IFN score is relatively stable and does not change with disease activity, he said, but the three IFN types are associated with different disease features in SLE.

Increased IFN-λ in human lupus nephritis, for example, predicts poor treatment response. Several IFN trials have shown promising results in lupus, as do clinical and preclinical trials targeting the IFN pathway.

Increased stimulation of both endosomal and cytosolic DNA and RNA sensors help drive increased INF, Dr. Mohan added. These sensors are activated by the presence of excess immunogenic DNA and RNA in lupus, driven by the formation of neutrophil extracellular traps (NETosis), mitochondrial DNA, apoptotic microparticles, and impaired clearance of apoptotic cells.

Pathogenic T-follicular helper (TFH) cells and age-associated B cells (ABCs) also play roles. TFH cells are essential for lupus in mice. Elevated levels of circulating TFH cells in SLE patients correlate with disease activity. Multiple lupus genes affect the development of TFH cells.

ABCs are memory B cells that respond readily to IL-21 to become plasma cells that secrete multiple antibodies. ABCs are expanded in SLE, especially in African American patients, Dr. Mohan noted. And like TFH cells, ABC generation is affected by multiple SLE genes.

The next mechanistic themes focus on lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE).

Lupus nephritis kidneys have increased NET, TFH, ABC, and plasma cells, Dr. Mohan said. Urine CD163 is emerging as a potential biomarker for lupus nephritis. Single cell RNA-sequence analysis of human kidneys suggests that both tubular IFN levels and tubular fibrosis score, driven largely by ABCs and TFH cells, could be predictive of lupus nephritis.

NPSLE has similar origins in mice. TFH cells infiltrate brain tissue, increasing microglia and priming them for an inflammatory response. These reactive microglia engulf neurons and synapses to produce NPSLE symptoms.

Depleting microglia using anti CSFR1 improves NPSLE symptoms. And ACE inhibitors preserve the neuronal dendrite complexity and cognitive performance.

Three environmental factors have emerged more recently:

  • The gut microbiota is altered in both murine and human lupus, but further mechanistic studies are needed.
  • Lupus patients have a significantly higher anti-EBV seroprevalence and anti-EBV seropositivity predicts transition to SLE in individuals at risk for the disease.
  • Smoking also increases the risk of SLE. The odds ratio for current smokers is 1.56, for former smokers is 1.23.

“All of these mechanisms are under the control of genes and affected by the environment,” Dr. Mohan said. “More than 100 genes are active in lupus; some are also active in other rheumatologic diseases. Gene activity could account for the differences between our diseases.”