Immune variation in infectious disease and during development early in life

The human immune system is not only a complex system but a highly dynamic and heterogenous one. It consists of many specialized cells that stimulate and inhibit each other via proteins and physical interactions. And collectively these give rise to all kinds of immune responses necessary for our survival, but also causing diseases when not regulated properly or targeting healthy tissues1. Therefore systems-level analyses that simultaneously take all cell types and many proteins into account, allows us to understand immune dysregulation at the global level. It is our goal to apply such methods to understand patients with poorly defined conditions, that likely have an inflammatory component yet are of unknown etiology and unknown pathogenesis. Integrating multiple layers of information offers a more detailed examination of cellular diversity and enhances the ability to pinpoint distinct cell types and their functions. To understand it one needs to be to be able to observe many interacting components and how they work to produce certain products. As accounting for hundreds cluster of differentiation (CD) antigens, as well as over 100 cytokines and chemokines with many cell subsets and tens of thousands of genes is daunting, it has been made more feasible by the advances in technology that have been made2.

In the first chapter, we navigate the intricate landscape of immune variation in diseases, with a specific focus on COVID-19 and post-infectious conditions such as ME/CFS and long COVID. Myalgic Encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) stands out as a complex, poorly understood multisystem ailment characterized by severe fatigue, flu-like symptoms, and an array of neurological and cognitive challenges. Recent advancements in diagnostic criteria and proposed mechanisms have uncovered possible links between energy metabolism impairment, cognitive issues, autonomic dysfunction, and immune dysfunction. ME/CFS is a heterogeneous condition affecting individuals of all ages, with a notable predilection for women. While diagnosis and treatment remain elusive, neuroimaging techniques show promise in identifying biomarkers for the disease. This section also delves into potential mechanisms underlying ME/CFS, including energy metabolism impairment, cognitive issues, autonomic dysfunction, and immune dysfunction. It explores the role of gut dysbiosis in ME/CFS, potential links between gastrointestinal issues and immune system disruptions, and how exaggeration of normal sickness behavior may contribute to symptoms. Moreover, the chapter draws parallels between ME/CFS and Nodding Syndrome in East Africa, shedding light on multifaceted disease models. Despite the lack of curative treatments, advancements in neuroimaging techniques provide hope for the identification of ME/CFS biomarkers, potentially paving the way for improved diagnostic and therapeutic strategies. The study presented delves into ME/CFS, highlighting its intricate nature, possibly stemming from immune-microbe interactions within the gut. Chronic immune activation, reflected in elevated cytokine levels and distinct cellular metabolism deficiencies, sets ME/CFS apart from other inflammatory disorders. The study underscores the condition's heterogeneity and proposes the failure to activate disease tolerance mechanisms during infections as a common denominator. These mechanisms are vital for limiting tissue damage due to infections and immune responses. Notably, the study introduces INMEST treatment, which shows promise in upregulating disease tolerance pathways and offering potential symptom relief. Variations in symptom severity may be linked to changes in the infectious disease's nature or immune activation, with some severe ME/CFS cases exhibiting mutations in the IDO2 enzyme. INMEST treatment, while promising, necessitates larger trials, and the study suggests the development of self-treatment systems for home use to alleviate the burden of clinical visits.

In the section on Acute COVID-19, we delve into the background, disease course, viral entry, immune responses, and determinants of COVID-19 severity. The COVID-19 pandemic, triggered by the novel SARS-CoV-2 virus, began in late 2019, rapidly spreading across the globe. The disease exhibits a broad spectrum of symptoms and severity, with severe cases resulting in systemic inflammation, acute respiratory distress syndrome (ARDS), and other complications. Notably, the virus can be transmitted by individuals with minimal or no symptoms, contributing to its rapid spread. The virus primarily gains entry through the angiotensin-converting enzyme 2 (ACE2) receptor, with TLR3 recognizing viral RNA and initiating innate immune responses. However, the virus has evolved mechanisms to evade host immune responses, delaying or reducing interferon production. Adaptive immune responses, including B and T cell reactions, are triggered upon infection, and pre-existing immunity to common-cold coronaviruses may play a role in disease severity. The severity of COVID-19 is influenced by various factors, including protective immunity and genetic variations. Men are generally more susceptible to severe disease. Additionally, age influences the severity of the disease, with children displaying distinct immune responses compared to adults. Older individuals are more vulnerable to autoimmune responses and the presence of autoantibodies, especially targeting type I interferons, which can significantly impact disease outcomes. These complex determinants interact to shape the course and severity of acute COVID-19.

The studies discussed in this overview provide a comprehensive perspective on the intricate immune response to COVID-19, shedding light on various aspects of the disease and potential intervention strategies to regulate this response. They emphasize the complex and variable nature of the immune response to SARS-CoV-2, which spans from mild or asymptomatic cases to severe disease. Understanding this immune landscape is vital for deciphering the determinants of COVID-19 patient outcomes, with genetics and environmental factors playing significant roles. The studies stress the value of systems-level analysis methods in comprehensively studying the multifaceted immune response. Specifically, the first study highlights the virus's ability to trigger a robust proinflammatory response, while the second study explores the potential of KAND567, a CX3CR1 antagonist, to influence the immune response. The antagonist's effects on non-classical monocytes, B cell function, and plasma protein expression are detailed, but clinical benefits were not observed, underscoring the complexities of regulating the immune landscape in COVID-19. These findings underscore the need for ongoing research to better understand and effectively modulate the immune response to COVID-19, which is crucial in the ongoing battle against this pandemic.

Furthermore, post-infectious conditions such as long COVID and ME/CFS are emerging as areas of concern. The emergence of Long COVID, also known as 'post-acute sequelae of COVID-19' (PASC), is a chronic post-infectious condition following SARS-CoV-2 infection has raised significant concerns due to its complex and severe symptoms. Long COVID is characterized by a broad range of persistent symptoms affecting multiple organ systems, and it's estimated to affect millions of individuals worldwide. The condition shares immunological, mitochondrial, and neurological dysfunctions with ME/CFS, leading to increased recognition of ME/CFS as a legitimate disease and fostering research into interventions that could benefit both conditions.

Long COVID encompasses a multitude of symptoms and potential mechanisms for its pathogenesis. These mechanisms include immune dysregulation, autoimmune responses, potential viral persistence, microbiota dysbiosis, blood clotting issues, and dysfunctional neurological signaling. Understanding the complexity and causes of Long COVID is crucial to developing effective interventions. The impact of vaccination, the presence of different SARS-CoV-2 variants, and reinfections further complicate the picture, with varying effects on the prevalence and characteristics of Long COVID. These insights are essential in addressing the long-term consequences of the COVID 19 pandemic and developing strategies for managing and mitigating Long COVID. The study presented concentrated on the most severely affected long COVID patients with objective organ damage following SARS-CoV-2 infection to explore the underlying biological disturbances, hinting at potential viral antigen persistence. Although previous research suggested the presence of viral particles and proteins in long COVID patients, our study found a shift in monocyte distribution, elevated levels of specific plasma proteins, and no significant differences in EBV-specific antibodies between long COVID and convalescent controls. The absence of well-defined diagnostic tests and standardized protocols creates research challenges, emphasizing the need for interdisciplinary research efforts to uncover the mechanisms of both ME/CFS and long COVID and explore potential overlaps between these conditions. Establishing clearer diagnostic criteria and thorough immunomonitoring is crucial for understanding these post-infectious conditions better.

The second chapter delves into the intricate realm of immune development during the early stages of life, underlining the need for a shift from traditional assumptions about neonatal immune systems being immature versions of adult ones. Recent insights reveal that neonatal immune systems are uniquely adapted to cater to the specific demands of fetuses and newborns, with feto-maternal tolerance mechanisms and regulatory T cells continuing to influence immune functions post-birth. The "window of opportunity" concept emerges as a critical period in early life, where innate and adaptive immune systems lay the foundation for immune balance, possibly relating to the hygiene hypothesis and the prevalence of atopic, autoimmune diseases, and a decline in infectious diseases. This chapter also explores the complex landscape of neonatal innate and adaptive immunity, emphasizing the role of factors like microbiome, maternal antibodies, and the nuanced responses of various immune cells during early life. It further investigates the heightened susceptibility of newborns, especially preterm infants, to infectious and inflammatory diseases, suggesting links between microbiome interactions and immune-related disorders. This chapter offers a comprehensive reevaluation of immune development in early life, challenging the conventional perception of neonatal immune systems as merely immature versions of adult counterparts. It also explores the unique adaptations of neonatal immune systems and the "window of opportunity" concept that shapes the foundation of immune balance in later life. It delves into the complexities of neonatal innate and adaptive immunity, with a focus on factors like the microbiome, maternal antibodies, and the distinct characteristics of immune cells during early life. Additionally, it discusses the increased vulnerability of newborns, especially preterm infants, to infectious and inflammatory diseases, highlighting the potential links between early-life microbiome interactions and immune-related disorders.

Research on early immune development in infants has traditionally relied on animal models or cord blood samples, but a shift towards direct immunomonitoring studies in infants is emerging. These studies aim to uncover the dynamic changes in infant immune responses influenced by environmental factors and their long-term health implications. The studies presented highlights how colonization by bifidobacteria in early life can protect infants from immune-mediated diseases and emphasizes the systemic effects of these interactions at mucosal surfaces. As well as employs cutting-edge single-cell technologies to investigate immune functionality in newborns and infants, revealing innate immune training and heightened antiviral responses in infants. Understanding these early immune mechanisms is crucial for developing efficient treatments and vaccination strategies for infants, as well as addressing the evolving disease patterns in different regions.

List of scientific papers

I. Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing disease tolerance. Rodriguez, L., Pou, C., Lakshmikanth, T., Zhang, J., Mugabo, C. H., Wang, J., Mikes, J., Olin, A., Chen, Y., Rorbach, J., Juto, J.-E., Li, T. Q., Julin, P. & Brodin, P. Oxf Open Immunol. (2023).
https://doi.org/10.1093/oxfimm/iqad003

II. Systems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19. Rodriguez, L., Pekkarinen, P. T., Lakshmikanth, T., Tan, Z., Consiglio, C. R., Pou, C., Chen, Y., Mugabo, C. H., Nguyen, N. A., Nowlan, K., Strandin, T., Levanov, L., Mikes, J., Wang, J., Kantele, A., Hepojoki, J., Vapalahti, O., Heinonen, S., Kekäläinen, E., Brodin, P. Cell Reports Medicine. 1, 100078 (2020).
https://doi.org/10.1016/j.xcrm.2020.100078

III. Fractalkine receptor blockade modulates systemic immunity in patients with severe acute COVID. Rodriguez, L., Lakshmikanth, T., Wang, J., Tan, Z., Mugabo, C., Chen, Y., Mikes, J., Schultz, J., Moshfegh, A., Mellsteldt, H., Dadfar, E., Okas, M., Wistrand, M., Brynne, N., Lundström, T., Olin, T., Brodin, P. [Manuscript]

IV. Immune system perturbations in patients with severe LongCOVID. Rodriguez, L.*, Tan, Z.*, Lakshmikanth, T., Wang, J., Barcenilla, H., Zuo, F., Abolhassani, H., Pavlovitch-Bedzyk, J., Wang, C., González, L., Mugabo, C.H., Johnsson, A., Chen, Y., Mikes, J., Sundling, C., Björnson, M., Runold, M., Meyts, I., Hammarström, Q-P., Davis, M.M., Landegren, N., the BAMSE COVID-19 study group, COVID Human Genetic Effort, Jamoulle, M., Bruchfeld, J., Brodin, P. *These authors contributed equally. [Manuscript]

V. Bifidobacteria-mediated immune system imprinting early in life. Henrick, B. M., Rodriguez, L., Lakshmikanth, T., Pou, C., Henckel, E., Arzoomand, A., Olin, A., Wang, J., Mikes, J., Tan, Z., Chen, Y., Ehrlich, A. M., Bernhardsson, A. K., Mugabo, C. H., Ambrosiani, Y., Gustafsson, A., Chew, S., Brown, H. K., Prambs, J., Bohlin, K., Mitchell, R.D., Underwood, M.A., Smilowitz, J.T., German, J.B., Frese, S.A., Brodin, P. Cell. 184, 3884-3898.e11 (2021).
https://doi.org/10.1016/j.cell.2021.05.030

VI. Functional maturation of immune cells in human newborns. Rodriguez, L., Wang, J., Johnsson, A., Mikes, J., Lakshmikanth, T., Chen, A.Y., Daniel, B., Satpathy, A.T., Bernhardsson, A.K., Brodin, P. [Manuscript]