Newly illuminated molecular roots of lupus may lead to treatments with ‘durable benefits’
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A recent investigation into the molecular roots of systemic lupus erythematosus may point the way toward a new generation of therapeutic targets, according to the researchers.
The Nature paper, published in July by coauthors Deepak Rao, MD, PhD, a rheumatologist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, Jaehyuk Choi, MD, PhD, associate professor of dermatology, biochemistry and molecular genetics at Northwestern Medicine, in Chicago, and colleagues, noted that expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T-cell populations that provide help to B cells, feature prominently in SLE.
“We have then been searching for methods to disrupt the function of the T cells that drive B cell activation and antibody production in SLE, in particular TPH and TFH cells,” Rao told Healio. “We discovered that one specific transcription factor, the aryl hydrocarbon receptor (AHR), can strongly inhibit T-cell differentiation into TPH and TFH cells.”
The group also reported that type I interferon, a cytokine known to be produced excessively in lupus, promotes TPH and TFH cell generation, in part through suppressing the actions and downstream effects of AHR, according to Rao.
“We have known from a number of studies that type I interferon can encourage the formation of these follicular T helper cells, but we are not exactly clear on how that happens,” Timothy B. Niewold, MD, FACR, vice chair for research in the department of medicine at the Hospital for Special Surgery, told Healio. “This study does a nice job of showing some of those molecular mechanisms.”
These findings could have broad implications not only in understanding of the disease, but for the development of therapeutic targets, as well.
“When we found a molecular switch that controls the generation of disease-promoting B-helper T cells in lupus, we posited that the chemicals that control this switch must be altered in patients,” Choi said in an interview. “Indeed, patients with lupus have a deficiency in the AHR signaling pathway, which likely is sufficient to induce the cellular imbalance we see in patients.”
‘Three lines of evidence’
According to the study, the pathway controlled by the AHR receptor is implicated in lupus disease processes.
“Our initial immune profiling highlighted a consistent imbalance in T cell populations in patients with lupus, compared with controls,” Rao said. “Patients with lupus had too many B cell-helper T cells — TPH and TFH cells — and at the same time, a reduced number of IL-22+ Th22 cells.”
At this point in the study, Choi’s team executed CRISPR screens to identify critical factors that control the differentiation of these T-cell populations.
“These screens yielded the unexpected result that AHR strongly inhibits the generation of TFH and TFH cells,” Rao said.
According to Choi, this process determined “three lines of evidence.”
“One was an imbalance of the cells in patients with lupus,” he said. “The second was an imbalance of the chemicals — meaning insufficient AHR activity due to supranormal AHR antagonists — in the blood of patients with lupus. The third was the discovery that a cytokine, interferon, is an endogenous AHR antagonist.”
CRISPR screens identified AHR as a potent inhibitor of T-cell production of CXCL13, a key function of TPH and TFH cells, according to Rao.
“With this finding in hand, we tested effects of small molecule agonists and antagonists of AHR and found that activation of AHR could inhibit the ability of T cells to perform functions required for them to stimulate a B-cell response,” he said. “A very useful feature of AHR is that it is a transcription factor whose activity can be controlled by small molecule activators or inhibitors.”
AHR serves two functions, according to Choi.
“It inhibits the B-helper T-cell phenotype and also promotes a Th22 cell phenotype,” he said. “Since the seesaw exists in healthy patients and is altered in patients with lupus, we hypothesized that it could be leveraged to reprogram the cells. If patients with lupus have a deficiency in AHR signaling, why not restore AHR signaling with agonists.”
The results demonstrated the hypothesis.
“Indeed, provision of AHR agonists was sufficient to reduce B-helper T-cell function in cells isolated from patients,” Choi said.
A ‘very elegant study’
“This is an interesting study, a very elegant study that links together some of the data in the literature that fills in certain molecular gaps in our understanding of lupus,” Niewold said.
However, perhaps the most striking aspect of the study is that it has enabled deeper understanding of the role of AHR, he added.
“AHR seems to be a switch between B-cell helper cells and Th22 cells that participate in immunity across the gut and mucosal surfaces, and can be pro-inflammatory, as well,” he said.
It is thought that these T cells can be on two different poles, with AHR as a “switch” that pushes them in one direction or the other, according to Niewold.
“Murine models have shown that agonizing, or turning on, the AHR switch can lead to improvements in lupus,” he said.
The current data set, then, ties together the previous research and hypotheses.
“This study puts this AHR in the context of interferon and B-cell helpers,” Niewold said. “It shines a light on how interferons can make some of these helper cells. We have known something about many of these components for some time. This study brings together these different elements and helps us understand the relationships.”
Understanding those relationships is one step. The next will be to determine whether the findings could ultimately lead to therapeutic interventions.
‘This pathway is targetable’
According to Choi, the critical observation from the study is that a chemical imbalance may be sufficient to induce the cellular imbalance found in patients with SLE.
“Because this pathway is targetable and appears critical for pathogenesis in humans, we think restoring the chemical imbalance will be a promising therapeutic direction in the future,” he said. “In addition to targeting and deleting cell types broadly, a potential alternative is to reprogram disease promoting cells. If effective, this approach may offer durable benefits.”
As a result, the study may reveal a new potential therapeutic strategy to treat lupus, according to Rao.
“We aim to use small molecule activators of AHR, directed specifically towards T cells, as a treatment to suppress the pathologic T-cell response in lupus and reprogram those T cells towards benign or even protective functions,” he said.
In Rao added that it is also important to consider that IFN blockade with anifrolumab (Saphnelo, AstraZeneca) is increasingly used to treat lupus.
“However, the mechanisms by which IFN blockade reduces disease activity are unclear,” he said. “Our study highlights one mechanism by which anifrolumab is likely working — through reducing the generation of TPH and TFH cells and dampening the pathologic T-cell/B-cell response.”
According to Niewold, the paper additionally offers some “logical questions” about the role of AHR.
“The key question is whether stimulating AHR could be therapeutic,” he said.
The next question pertains to the type of medication that may be effective.
“There could be a small molecule that targets this process, as opposed to a biologic,” Niewold said.
However, one concern is whether shifting from B helper cells toward Th22 cells could ultimately cause more harm than good in lupus patients, according to Niewold.
“As we consider therapeutic targets, we have to think about the consequences of shifting from one T cell type to another,” he added.
Choi and Rao, meanwhile, reported that they are currently working toward this goal.
“The work so far is performed largely in vitro using T cells from patients with lupus or healthy controls,” Rao said. “We do not yet know what will happen when a strategy like this is tried in patients. We are currently working to design strategies to selectively activate AHR in T cells without broader effects on other cells or tissues. We are also evaluating to what extent this imbalance in T-cell responses is seen in other autoantibody-associated autoimmune diseases.”
References:
Law C, et al. Nature. 2024;doi:10.1038/s41586-024-07627-2.
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