Introduction

Crohn`s disease belongs to the group of chronic inflammatory bowel diseases, in which parts of the intestinal tract become inflamed.<sup>1</sup> Crohn`s disease may affect any part of the gastrointestinal tract, most commonly the end of the small intestine (terminal ileum) and colon. The inflammation can progress into deeper layers of the intestinal wall, creating ulcers beyond the surface. Crohn`s disease is a high-burden chronic condition, characterized by a relapsing-remitting course with phases of flare-ups and improvements. Patients may experience periods of active symptoms (flares) followed by periods of improvement in symptoms (remission). Fortunately, the disorder can be successfully managed with current therapeutic strategies. As a definitive cure for Crohn`s disease has not yet been found, current therapies focus on the management of symptoms. Maintaining remission is the primary goal of maintenance therapy, focusing on healing the gastrointestinal tract, relieving symptoms and inflammation, and ultimately improving the quality of life of affected individuals. Diarrhea, abdominal pain, rectal bleeding, and weight loss are the most common symptoms seen with Crohn`s disease. In addition, extraintestinal features, such as rheumatoid arthritis and idiopathic growth failure, may also be observed.²

Pediatric patients share the common characteristic symptoms of the disorder with adults, but they present important differences in clinical presentation and disease course. In 43% of pediatric Crohn's disease cases, the lesions are located in the ileocolonic and upper gastrointestinal tract, compared with only 3% of adult cases.³ The clinical impact of Crohn's disease is higher on pediatric patients, often presenting as more severe and aggressive, leading to long-term complications such as delays in growth and development, nutritional deficit, and negative impacts on the psychological well-being of affected individuals. In addition, pediatric Crohn's disease is associated with higher morbidity compared to adults. The treatment guidelines for pediatric patients follow the traditional approaches, but may require higher levels of immunosuppression therapies.^4,5,6

Research suggests that the main cause of Crohn's disease is the combination of factors such as the environment, immune response, gut microbiome, and genetic predisposition. The diagnostic characteristic of Crohn's disease is the presence of an abnormal immune response. In an individual with genetic susceptibility, environmental factors can lead to an imbalance in gut microbiota and damage the intestinal barrier, resulting in an abnormal immune response.² Abnormal immune response results in chronic intestinal inflammation and ulcers.⁷

Crohn's disease affects a significant number of individuals, primarily young adults, and since 1950, its incidence has increased up to four times across all age groups. In the past, Crohn's disease was considered rare in the pediatric population; however, it is now becoming more common. The frequency of Crohn's disease in children has increased, with a growing number of new cases diagnosed each year.⁸ This drastic increase in the number of cases has highlighted the importance of effective therapies. Currently, management strategies focus on immunosuppression as the disease is strongly associated with dysregulated immune responses. Although the exact cause remains unknown, key mediators demonstrate the central role of the immune system. Therefore, a deeper understanding of the immune system is important in the development of new therapies and the management of this lifelong condition.

Basics of the Immune System in Children

The immune system is a complex mechanism in which a collection of various cells and chemicals work together, responding to an antigen to protect humans against a wide range of infections. There are two lines of defense, including innate immunity and adaptive immunity. Innate immunity is the first line of defense, with a rapid response,  but non-specific to the infection or injury.  When a new pathogen is introduced to the body, initially, it is recognized by the innate immune system and is attacked to prevent infection. Innate immunity is composed of various components, including physical and anatomical barriers; enzymes; phagocytes (macrophages, neutrophils, and monocytes); cytokines and inflammatory mediators releasing cells (macrophages, mast cells, natural killer cells); and inflammation-related serum proteins. This mechanism is designed to prevent infection, eliminate pathogens, and stimulate the acquired immune response.⁹

On the other hand, adaptive immunity is highly specific. It is able to differentiate between different antigens and give a specialised response to the particular pathogen. The response is destructive, so it is highly important that the system is activated only in response to foreign molecules. Innate immunity response stimulates adaptive immunity, and by working together, they eliminate the pathogen. Adaptive immune response can also provide long-lasting protection by generating immunological memory after recognising that particular pathogen. Unlike the innate immune response, the adaptive immune response is slower; the recognition of the pathogen and generation of the response takes longer; however, it`s more accurate. The adaptive immune system consists of T cells, B cells, and antibodies.^10,11

Children are born with immature innate and adaptive immune systems and develop as they grow through exposure to different pathogens. During childhood, innate immunity is the predominant defense mechanism, while the adaptive immune system is still maturing. A child`s innate immune system is more active than that of adults, providing a more rapid immune response to pathogens, with interferons being expressed more strongly. As children are exposed to a wide variety of pathogens, their immune response develops immunological memory, leading to more efficient and specific responses over time. In contrast, adults rely heavily on their well-established adaptive immune system.¹²

Immune Dysregulation in Pediatric Crohn’s Disease

Dysregulation of immune cells, particularly Th1 and Th17 cells, plays a central role in the pathogenesis of pediatric Crohn`s disease.  Abnormal recognition of intestinal flora as pathogens, along with a compromised epithelial barrier function and other contributing factors, results in an overactive immune response in the gastrointestinal tract of individuals with Crohn's disease. Dysregulated T-cell responses stimulate innate immune cells to produce high levels of pro-inflammatory cytokines, IL-6, IL-12, IL-18, IL-13, IL-1β, and IL-33. These cytokines then promote pathogenic T-helper (Th) cell responses and induce intestinal inflammation. High levels of TNF-α, produced by Th1 cells, further increase the production of these cytokines. In patients with Crohn`s disease, overexpression of pro-inflammatory cytokines is a key contributing factor, resulting in persistent inflammation. IL-6, IL-1β, and IL-13 stimulate Th17 cells to produce IL-17, GM-CSF, and IFN-γ, further contributing to the intestinal inflammation. In a healthy individual, this response is controlled by regulatory T (Tr1) cells that suppress inflammation; however, in patients with Crohn's disease, these cells are downregulated. Predominance of Th1 and Th17 cells, together with reduced regulatory T cell activity, are central contributors to the pathogenesis of Crohn's disease, resulting in uncontrolled inflammation.¹³ Onset of pediatric Crohn`s disease is characterized by a Th1 response in the ileum and a Th1/Th17 response in the colon. Additionally, defects in mucosal barrier function and altered expression of SOCS1, SOCS3, which regulate the immune system by inhibiting cytokine signaling pathways, particularly the JAK-STAT pathway, exacerbate intestinal inflammation. MDR1 expression is also found to be reduced. Collectively, these abnormal immune responses attacking the gastrointestinal tract contribute to chronic, relapsing inflammation. Excessive immune cell activation and high levels of proinflammatory cytokine release result in tissue damage and persistent inflammation.¹

Genetic and Environmental Influences on Immunity

Genetic variations in NOD2, IL23R, ATG16L1, IRGM, IL10, NKX2-3, and ORMDL3 are associated with increased risks of developing Crohn's disease. Alterations in these genes result in abnormal immune response to bacteria in the digestive tract, leading to persistent bacterial infections, compromised mucosal barrier, and inflammation. The intestinal immune response fails to stay balanced and tolerant, and results in chronic inflammation against intestinal flora. According to a study, gut dysbiosis is strictly associated with the development of Crohn's disease in children.⁴ Environmental triggers, such as diet, stress, hygiene, and antibiotic use, contribute to the development of Crohn`s disease. Imbalance in the gut microbiota results in impaired T-cell response, which further triggers inflammation.¹³

Immune-Targeted Therapies in Pediatric Crohn’s Disease

The management therapies vary according to the presentation and stage of the disease. Conventional therapies such as corticosteroids (prednisolone, methylprednisolone) are prescribed as the initial therapy. The induction of remission in pediatric Crohn's disease patients is achieved either with corticosteroids or exclusive enteral nutrition. According to the guidelines, exclusive enteral nutrition is recommended as the first-line treatment to regulate the immune response and reduce inflammation. Corticosteroids are equally effective; however, their systemic side effects, such as hypertension and negative impact on bone health, and their limited effectiveness in maintaining remission, limit their use. Immunomodulators, such as methotrexate, are also widely prescribed; however, due to rare side effects associated with long-term use, they are now only considered on an individual patient basis. If clinical remission is not achieved by the conventional therapies within 12 weeks, or if the patient loses response to initial treatment, therapy can be escalated to biologic agents such as anti-TNF agents (infliximab, adalimumab) and anti-IL-12/23 agents (ustekinumab) (in anti-TNF failure). In patients presenting with severe growth delay or susceptibility to poor outcomes, biologicals can be recommended as the initial treatment. In pediatric patients, early intervention is highly important to preserve natural growth and quality of life.¹⁴

Summary

Pediatric Crohn`s disease is strongly associated with a dysregulated immune system. Both innate and adaptive immune responses are altered, with Th1 and Th17 cells dominating, leading to chronic and persistent intestinal inflammation. Genetic alterations and environmental factors contribute to the pathogenesis of Crohn's disease. Understanding the disease mechanism and immune responses has enabled the development of targeted therapies and improved the outcomes in pediatric patients.¹³ Further research and better understanding of disease mechanisms and key contributors play an important role in the development of more effective therapies.