Study challenges theory of microbes as sarcoidosis cause

A study examining patients’ blood and lymph nodes at the time of sarcoidosis diagnosis and before treatment found signs of inflammation but no detectable microorganisms, challenging the long-held hypothesis that infectious microorganisms may cause sarcoidosis.

“Our findings demonstrate that the inflammatory response detected in the blood and lymph nodes of sarcoidosis patients at diagnosis can arise in the absence of active microbial presence within the affected lymph nodes,” the researchers wrote. “If an active infection is not driving the disease, it may instead result from a dysregulated host immune response.”

They described the results in the study, “Systemic and local lymph node inflammation at disease onset in sarcoidosis patients,” published in ERJ Open Research.

Sarcoidosis is an inflammatory disease characterized by granulomas — small clusters of inflammatory immune cells — that form in organs throughout the body, primarily the lungs and lymph nodes. While the exact cause of sarcoidosis remains unknown, it’s thought to begin with a triggering event, such as an allergic reaction, an infection, or exposure to certain toxins.

Whether microorganisms trigger the disease has long been debated. Previous results have been inconsistent, most likely due to differences in detection methods, tissue types, and sampling timing relative to disease onset, the researchers noted. Few studies have examined inflammation and microorganisms in the same tissue.

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Analysis looks at blood, tissue

The team of scientists in France conducted a single-center study (NCT05916638) to explore the role of microorganisms in the onset of sarcoidosis. All participating patients had tissue samples showing noncaseating granulomas, a hallmark of sarcoidosis in which there is no central area of dead tissue within the granuloma.

First, the researchers analyzed blood samples from 19 adults with sarcoidosis (47% women) prior to sarcoidosis treatment and 10 healthy individuals who served as controls.

Of the 45 proteins measured, 29 were significantly higher in sarcoidosis patients than in controls. These included the pro-inflammatory proteins CXCL-9, lymphotoxin-alpha (LTA), tumor necrosis factor (TNF), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6).

To assess whether the blood findings mirrored affected tissue, the team examined lymph node tissue from 10 additional sarcoidosis patients (50% women). All had had lymph node involvement, and eight had lung involvement. None had yet received treatment.

Because healthy lymph node samples were unavailable, the controls were individuals with metastatic adenocarcinoma, a type of cancer, who underwent collection of lymph node tissue for cancer staging. Researchers measured gene activity in these samples.

Of the 29 proteins elevated in blood samples from sarcoidosis patients, the genes encoding CXCL9, LTA, and TNF also showed significantly increased activity in sarcoidosis lymph nodes.

Further analysis identified more than 1,000 genes with significantly different activity between patients with sarcoidosis and those with cancer. Enriched pathways included three major signaling networks that control immune cell activation: IFN-gamma signaling, IL-2-STAT5, and IL-6-JAK-STAT3.

The team suggested that JAK inhibitors, a class of immunosuppressive drugs, may have therapeutic potential in sarcoidosis and should be investigated in clinical trials.

To search for microorganisms, the researchers performed comprehensive genetic analyses from preserved lymph node samples. This analysis found no evidence of bacteria, fungi, viruses, or parasites in the sarcoidosis samples taken at the time of diagnosis.

Mycobacterium tuberculosis, long suspected as an infectious trigger of sarcoidosis, was not detected. The team suggested a dysregulated host immune response may drive the disease.

“Our findings, obtained at diagnosis and restricted to lymph nodes, challenge the long-held paradigm that sarcoidosis is caused by a microorganism,” the scientists wrote. “Instead, they support the hypothesis that the disease can arise from the host’s own maladapted immune response.”