SUMMARY:
UCLA researchers in the Department of Microbiology, Immunology, and Molecular Genetics have developed a strategy to quantitatively assess the functionality of macrophages, a key player of the innate immune system, using a paired experimental and computational strategy.
BACKGROUND:
The immune system is formed by two major inter-related components, namely the innate and adaptive immunity. Upon activation of immune effector cells, the resulting responses do not only neutralize the invading pathogen but can also be harmful for the host if not properly regulated. Thus, it is an imperative characteristic of the immune system to discriminate between “self” and foreign molecules. The targeted specificity against the pathogen by the adaptive arm of the immune system is exquisitely fine-tuned by specialized cells that can recognize specific antigens, promote their cell proliferation, and ultimately eliminate the pathogen by different killing mechanisms. However, in humans it takes 4-7 days for the adaptive immune system to mount a significant response, whereas the innate immune system is the first line of defense and determines whether infected person experiences symptoms or not.
Macrophages, key players of the innate immune system, act through a wide variety of receptors that can sense signals associated with the infectious agent such as genetic or protein material of the pathogen, tissue damage, and chemicals secreted by other sentinel cells. These cells, often serve as the first line of defense in mounting an immune response, making their effectiveness a key determinant in the broader response to pathogens. Once macrophages recognize a pathogen, they activate the expression of genes that 1) mount an intrinsic defense to neutralize the pathogen, 2) recruit other immune effector cells to the site of infection and 3) induce inflammation to activate the adaptive immune system. Importantly, macrophages are also responsible for decreasing immune reactions through the release of other signaling molecules to prevent the immune system from damaging the host’s tissues. While there are ways to approximate the functional state of the adaptive immunity (via lymphocyte count or antibody diversity, for instance), there are no established approaches to assess the quality of the innate immunity of a patient. Correlations with BMI, age or pre-existing conditions have been identified but do not give patient-specific information. Or account for high variability within populations. Dr. Hoffmann is a well-recognized pioneer in NFκB signaling which is a major component of the immune responsive gene expression. The Hoffmann lab was one of the first in uncover the relevance of this pathway’s temporal dynamics in regulating cell response.
INNOVATION:
UCLA researchers in the department of Microbiology, Immunology, and Molecular Genetics have developed a novel metric that enables stratification of macrophage function: a proxy for innate immune function. The importance of this technology is highlighted by the fact that while the innate immune system has crucial implications for the disease development of patients suffering from autoimmune diseases, infections, or even cancer, strategies to measure the functional state of the innate immunity remain elusive. Advances in our understanding of innate immune function on a per-patient level could inform therapies employed to treat these disorders in the clinic. The established dogma postulates that innate immune cells recognize invaders and alert and activate the adaptive immunity which in turn develops the immune system’s specificity against the targeted agent.. To quantify innate immune function, the UCLA researchers have developed an experimental workflow for single cell profiling of hundreds of immune genes responsible for the diversity of innate immune responses. They have also developed a computational workflow to quantify the Response Specificity of macrophages. They have shown this this quantity is diminished in macrophages taken from obese or aged individuals which are at elevated risk for microbial infections. These tools enable tracking of gene expression levels that are indicators of innate immune activation and response effectiveness, and can be used to stratify immune response to specific stimuli. Importantly, they have built a machine learning pipeline to model the myriad of stimulus-specific gene expression patterns of macrophages to obtain a final Innate Immune Health Score.
POTENTIAL APPLICATIONS:
• Monitoring of therapeutic effects and disease progression
• Inform the development of targeted therapies leveraging Innate Immune Health discoveries
• Risk assessment for patients diagnosed with infection
ADVANTAGES:
• Innovative novel tool is first of its kind
• Requires small amount of sample
• Metric is predictive
DEVELOPMENT-TO-DATE:
Technique has proven effective in mouse models; Currently planning clinical human studies.
Related Papers (from the inventors only):
Adelaja, A., Taylor, B., Sheu, K.M., Liu, Y., Luecke, S., Hoffmann, A. 2021 Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses. Immunity, 54, pp.916-930.e7.
Cheng Q, Ohta S, et al. 2021 NFκB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages, Science, 372, pp. 1349-1353.
Sheu K., Hoffmann, A. 2022 Functional Hallmarks of Healthy Macrophage Responses: Their Regulatory Basis and Disease Relevance. Annual Review in Immunology, in press
Luecke S, Sheu K, Hoffmann A. 2021 Stimulus-specific responses in innate immunity: Multilayered regulatory circuit, Immunity, 54, pp.1915-1932.
Sheu K, Luecke S, Hoffmann A. 2019 Stimulus-specific gene expression of immune sentinel cells, Current Opinion in Systems Biology, 18, pp.53-61.