New Insight into Knee Osteoarthritis: Expanded Functional Scope of Immune Cells

A new publication was released by the ENDOTARGET consortium, which explores the role of immune cells in the fatty tissue behind the kneecap of people with osteoarthritis. This scientific work was published in April 2026 in the journal iScience. Authors of this study are: Kajetana Bevc, Shipin Zhang, Andres Pazos, Ivan Berest, Marina Fonti, Gian Salzmann, Valentino Bruhin, Jakob Hax, Ana Alonso Perez, Rodolfo Gomez, Florian Mair, Isabelle C. Arnold, and Marcy Zenobi Wong. The study, titled “Enrichment of HLA-DR+ neutrophils in osteoarthritic infrapatellar fat pad”, sheds new light on how inflammation develops and persists in osteoarthritis. While osteoarthritis has traditionally been viewed as a disease caused mainly by wear and tear of the joints, researchers increasingly recognise that the immune system also plays an important role in disease progression. This new research highlights a previously underappreciated area of the knee joint and identifies a unique population of immune cells that may contribute to ongoing inflammation.

Why is this research topic important?

Osteoarthritis (OA) is the most common form of arthritis worldwide and affects millions of people. It is characterised by an interplay of low-grad inflammation and mechanical damage, resulting in the progressive degeneration of joint tissues, leading to pain, stiffness, and reduced mobility. Although cartilage damage is one of the most visible features of OA, it is known that many other tissues within the joint also contribute to the disease progression. One of these tissues is the infrapatellar fat pad (IFP). Located beneath the kneecap, it acts as a shock absorber, helps lubricate the joint, and is now understood to be closely linked, both physically and functionally, to the synovial membrane. In people with OA, the IFP undergoes significant changes: its volume changes, it becomes increasingly fibrotic, and it shows signs of inflammation, including the presence of immune cells such as neutrophils.

Neutrophils are often described as the body’s “first responders” because they are among the first immune cells to arrive at sites of injury or infection. Traditionally, they have been viewed as short-lived cells whose main task is to fight invading microbes. Recent research, however, suggests that neutrophils are far more versatile than that. They can adapt to different tissues and may participate in a variety of immune functions beyond their classical role. In the synovial fluid of OA patients, their abundance has been shown to correspond to OA progression.

The aim of this study was to characterise the immune landscape of OA IFT, with particular emphasis on the under-explored role of neutrophils in this tissue

How was the study conducted?

The researchers worked with human tissue from patients undergoing knee surgery in Zurich, Switzerland. Two groups were compared throughout the study:

• OA samples: taken from patients with diagnosed knee OA who were undergoing total knee replacement surgery
• PreOA samples: taken from younger patients undergoing surgery for cartilage damage that had not yet progressed to full OA. This group acts as a useful comparison, representing an earlier or non-OA disease state.

In addition, healthy blood from a blood bank was used as control in some of the experiments.

The team used several advanced techniques to investigate both the tissue itself and the immune cells residing within it.

• Histological methods to examine the tissue for fibrosis and blood vessel formation
• Proteomics to identify and quantify proteins, providing insight into biological processes.
• Flow cytometry to identify and count different types of immune cells within a mixed cell sample, based on the specific markers (proteins) found on their surface.
• Immunofluorescence staining to locate cells and proteins within the tissue architecture.
• Cell culture experiments to examine how the identified immune cells interact with other cells of the immune system.

By combining these complementary methods, the study is able to provide a detailed picture of the immune landscape and its function within the osteoarthritic IFP.

What does the analysis show us?

The IFP changes considerably in OA

Histological analysis of OA IFP and pre-OA IFP revealed a significant alteration of the IFP in OA patients. It was significantly more fibrotic and vascularised than the preOA IFP. These findings suggest that the tissue undergoes substantial remodelling during disease progression. Further, the proteomic analysis showed that osteoarthritic IFP has a distinct molecular profile, indicating that numerous biological processes are altered within the diseased joint environment. Importantly, several pathways linked to cell survival and metabolism appeared to be more active, while pathways associated with cell death (apoptosis) were reduced. This suggests that inflammatory cells may persist for longer periods within the tissue, potentially contributing to ongoing inflammation.

Neutrophils accumulate in OA IFP

More specific cell analysis of OA IFP and pre-OA IFP revealed interesting differences. Neutrophiles were significantly enriched in OA IFP compared to pre-OA IFP. Natural killer (NK) cells were also increased, but neutrophils emerged as the most distinctive immune population associated with OA. Interestingly, the analysed neutrophil population in OA IFP exhibited higher expression of the antigen presentation protein HLA-DR than other identified cell populations. HLA-DR is a protein, that is normally found on specialist immune cells of the adaptive immune responses and is used to display antigens to T cells, which then activate the immune response. Thus, its presence on neutrophils is unusual because these cells are generally not considered as antigen-presenting cells. Neutrophils are traditionally viewed as short-lived “first responders” that rapidly attack pathogens through phagocytosis, release antimicrobial molecules, and produce inflammatory signals.

A unique population of HLA-DR+ neutrophils

More detailed analysis of the OA IFP neutrophils revealed that:

• Tissue cells co-produced neutrophil and antigen presentation proteins
• Significantly less neutrophils are present in OA IFP compared to healthy blood and matched synovial fluid, but significant more IFP neutrophiles expressed HLA-DR.
• On average, 65% of neutrophiles in OA IFP expressed the antigen presentation proteins HLA-DR and CD74.

HLA-DR+ neutrophils stimulate T cells

To investigate the function of the HLA-DR+ neutrophils, they were isolated and cultured together with T cells, both obtained from the same patients. The results showed that the neutrophils stimulated T cell proliferation, indicating that HLA-DR+ neutrophils can functionally process and present antigens to T cells.

What can we learn from the study?

This study expands our understanding of OA as a disease involving active immune processes rather than simply mechanical wear and tear. The findings indicate that the IFP is not merely a passive cushion within the knee. Instead, it appears to function as an immunologically active tissue where specialised immune cells accumulate and interact with one another.

The discovery of HLA-DR⁺ neutrophils is particularly significant because it challenges the traditional view of neutrophils as simple first responders. Instead, these cells appear capable of communicating with and influencing other immune cells, including T cells. This suggests that neutrophils may contribute to chronic inflammatory processes in ways that were previously underestimated.

While further research will be required to determine exactly how these cells influence disease progression, the study identifies a potentially important immune pathway in OA. Understanding these mechanisms could help researchers develop new strategies aimed at reducing chronic inflammation and slowing disease progression.

Read full publication here: Enrichment of HLA-DR+ neutrophils in osteoarthritic infrapatellar fat pad

 

Glossary

Antigen / antigen presentation: An antigen is any molecule, often from a bacterium, virus, or damaged tissue, that the immune system can recognise as foreign. Antigen presentation is the process by which certain immune cells display fragments of these molecules on their surface so that T cells can recognize them to activate the adaptive immune response.

Apoptosis: A controlled form of cell death that the body uses to remove unwanted or damaged cells without triggering inflammation. When apoptosis is reduced, cells can survive for longer than they normally would.

CD74: A protein found on certain immune cells that helps manage and stabilise the HLA-DR molecule, supporting its role in antigen presentation.

Fibrosis: The build-up of excess scar-like tissue, usually made of collagen, within an organ or tissue. It can make tissue stiffer and less flexible than normal.

Flow cytometry: A laboratory technique that uses lasers and fluorescently labelled antibodies to identify, count, and sort individual cells within a mixed sample, based on the specific proteins found on their surface.

HLA-DR: A protein that is normally found on specialist immune cells and used to display antigens to T cells.

(low grade) Inflammation: A mild, long-lasting activation of the immune system that can gradually damage tissues and contribute to the development and progression of chronic diseases such as osteoarthritis.

Immunefluorescence staining: A laboratory technique that uses fluorescent dyes attached to antibodies to detect and visualise specific proteins or cells within a tissue sample under a microscope.

Infrapatellar fat pad (IFP): A pad of fatty tissue located just behind and below the kneecap, which helps cushion the joint, supports lubrication, and is closely connected to the joint’s lining (synovial membrane).

Natural killer (NK) cells: A type of immune cell that can detect and destroy infected or abnormal cells without needing to recognise a specific antigen in advance.

Neutrophil: The most abundant type of white blood cell, normally known for rapidly responding to infection or injury and then dying off quickly.

Osteoarthritis (OA): A common, chronic joint condition involving the progressive breakdown of cartilage and other joint tissues, traditionally linked to mechanical wear but increasingly understood to involve immune system activity as well.

PreOA: In this study, a comparison group of patients who had cartilage damage requiring surgery but had not been diagnosed with osteoarthritis, used to represent an earlier or non-OA state.

Proliferation: The process by which cells divide and increase in number, allowing tissues to grow, repair themselves, or respond to injury

Proteomics: A scientific technique used to measure which proteins are present in a biological sample, and in what amounts, giving insight into which biological processes are active.

Synovial fluid (SF): The lubricating fluid found inside joints, which in osteoarthritis can contain elevated numbers of immune cells, including neutrophils.

Synovial membrane: A thin layer of tissue lining the inside of movable joints that produces synovial fluid to lubricate the joint and help nourish the cartilage.

T cells: A type of white blood cell central to the adaptive immune system, which can be activated by antigen-presenting cells to multiply and help coordinate an immune response.

Vascularisation: The formation or increase of blood vessels within a tissue, improving its supply of oxygen and nutrients.

 

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