Research Reveals How Cell Structure Deficiencies Impact Immunity

Research at the Crick Institute has uncovered critical insights into how weaknesses in cell structure can compromise the immune system and affect the relationship between the host and its microbiome. The study, led by Michael Way, focuses on the actin cytoskeleton, an essential component of cells that maintains their structure and drives movement. Mutations in the ARPC5 protein, a vital part of the Arp2/3 complex, can lead to severe health complications, including immunodeficiency and a heightened risk of fatal sepsis in early life.

Children born with mutations in ARPC5 often face devastating health challenges. As Way notes, “This is a rare and devastating condition, and until recently, it wasn’t clear how these mutations lead to such severe illness.” The only effective treatment currently recognized involves early bone marrow transplantation to replace defective immune cells with those possessing a healthy actin cytoskeleton.

Study Highlights Immune System Malfunctions

To better understand the relationship between ARPC5 mutations and immune failure, Way’s team conducted a study published in Science. Researchers Luiz Vasconcellos and Shaina Chor Mei Huang examined immune function in mice with and without ARPC5 mutations. They observed significant differences in immune responses, particularly in adult mice. Huang described the findings, stating, “The inflammation in adult mice with ARPC5 deficiency in the immune system mirrored what we see in people with the same mutation.”

At eight weeks, the affected mice exhibited underweight conditions, inflamed and damaged small intestines, and sepsis due to uncontrolled bacterial infiltration from the gut. Remarkably, the ARPC5-deficient mice were healthy at four weeks, a period coinciding with weaning when they lose maternal immune protection. Vasconcellos explained, “This also involves a big change in the bacterial composition in their gut, collectively known as the microbiome.”

The team found that this shift in the microbiome was a critical factor in triggering intestinal inflammation. By administering antibiotics to ARPC5-deficient mice at the pivotal four-week mark, researchers successfully prevented the onset of disease, highlighting the microbiome’s crucial role in immune health.

Understanding Immune Cell Dysfunction

Further investigation revealed the complexities of immune cell interactions in ARPC5-deficient mice. Vasconcellos noted a breakdown in communication between macrophages and T regulatory cells, disrupting the immune system’s balance. Huang added that macrophages had lost their typical shape, becoming elongated and less effective at consuming and eliminating bacteria.

The research indicated that replacing these dysfunctional immune cells through bone marrow transplants reversed the prevailing inflammation in the mice. This finding suggests that individuals lacking ARPC5 may benefit from similar treatment approaches.

Way emphasized the broader implications of the study, stating, “We now know that immune cells with key structural deficiencies are unable to respond in the right way to gut microbes, leading to the problems seen in patients.” He also pointed out that structurally deficient macrophages are present in various other conditions, including inflammatory bowel disease. The team is currently exploring the role of ARPC5-deficient macrophages in other body systems, such as the lungs.

Overall, this research sheds light on the critical importance of the cytoskeleton in maintaining a functional immune system and opens avenues for future therapeutic strategies.