Introduction
Autism Spectrum Disorder (ASD) is a complex condition that affects how people communicate, interact, and behave. The causes of ASD are not fully understood, but some researchers believe that immune system dysfunction may play a role. In particular, mast cells, which are specialized immune cells that respond to various stimuli, may be involved in the development and progression of ASD.
Mast cells are found in many tissues throughout the body, especially near blood vessels, nerves, and mucous membranes. They contain granules that store different molecules, such as histamine, cytokines, and proteases. When mast cells are activated by triggers such as allergens, pathogens, or stress, they release these molecules into the surrounding environment, causing inflammation and other effects.
Some studies have shown that many children with ASD have a history of allergic symptoms, such as eczema, asthma, or food intolerance, even when they test negative for mast cell-related allergies. This suggests that mast cells may be hyperactive or hypersensitive in ASD, and that their activation may contribute to the neuroinflammation and neurotoxicity that are associated with ASD.
The aim of the paper is to review the current knowledge on the relationship between mast cells and ASD, and to discuss the key molecules and immune pathways that are involved. The paper also highlights the potential of mast cells as therapeutic targets for treating ASD.
Mast Cells and Neuroinflammation in ASD
One of the main hypotheses for the pathogenesis of ASD is that neuroinflammation, or the activation of the immune system in the brain, leads to abnormal brain development and function. Neuroinflammation can be caused by various factors, such as genetic mutations, environmental toxins, infections, or maternal immune activation during pregnancy.
Mast cells are one of the sources of neuroinflammation, as they can release pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), which can affect the development and activity of neurons and glia. Mast cells can also release neurotoxic molecules, such as histamine, glutamate, and reactive oxygen species, which can damage the brain cells and disrupt the synaptic transmission.
Several studies have reported elevated levels of mast cell-derived cytokines and histamine in the blood, cerebrospinal fluid, and brain tissue of individuals with ASD, compared to healthy controls. Moreover, some genetic variants and epigenetic changes that are linked to ASD may also affect the expression and function of mast cell-related genes and receptors.
Mast Cells and Immune Dysregulation in ASD
Another hypothesis for the pathogenesis of ASD is that immune dysregulation, or the imbalance of the immune system, leads to abnormal immune responses and autoimmunity. Immune dysregulation can be caused by various factors, such as genetic predisposition, environmental exposure, gut microbiota, or dietary factors.
Mast cells are one of the regulators of the immune system, as they can interact with other immune cells, such as T cells, B cells, dendritic cells, and macrophages, and modulate their activation and differentiation. Mast cells can also produce anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor beta (TGF-β), which can suppress the inflammatory response and promote tolerance.
Several studies have reported altered levels of mast cell-derived anti-inflammatory cytokines and immunoglobulins in the blood and brain of individuals with ASD, compared to healthy controls. Moreover, some environmental factors and dietary components that are associated with ASD may also affect the activation and function of mast cells and their receptors.
Mast Cells and Therapeutic Implications for ASD
The paper suggests that mast cells may be involved in the pathogenesis of ASD through their effects on neuroinflammation and immune dysregulation. Therefore, targeting mast cells and their mediators may offer a novel approach for treating ASD.
Some of the potential strategies for modulating mast cells in ASD include:
- Using mast cell stabilizers, such as cromolyn sodium, ketotifen, or quercetin, which can prevent the degranulation and release of mast cell mediators.
- Using mast cell inhibitors, such as disodium cromoglycate, tranilast, or luteolin, which can block the activation and function of mast cell receptors.
- Using mast cell antagonists, such as antihistamines, anti-TNF-α, or anti-IL-6, which can counteract the effects of mast cell mediators on the brain and immune system.
- Using mast cell modulators, such as probiotics, prebiotics, or omega-3 fatty acids, which can influence the maturation and function of mast cells and their interactions with the gut microbiota.
However, the paper also acknowledges that more research is needed to confirm the role of mast cells in ASD, and to evaluate the safety and efficacy of mast cell-targeted therapies in ASD. Moreover, the paper emphasizes that mast cells are not the only factor involved in ASD, and that a personalized and holistic approach is required to address the multifactorial and heterogeneous nature of ASD.
Conclusion
Mast cells are immune cells that can affect the brain and immune system through their release of various molecules. Mast cells may be implicated in the pathogenesis of ASD, as they may contribute to the neuroinflammation and immune dysregulation that are associated with ASD. Mast cells may also provide new insights and opportunities for the discovery of drug targets and biomarkers for ASD. However, more studies are needed to elucidate the relationship between mast cells and ASD, and to explore the potential of mast cell-based therapies for ASD.
Faq
What are the main types and subtypes of MCs?
MCs are classified into two main types based on their origin and location: connective tissue-type MCs (CTMCs) and mucosal-type MCs (MMCs) . CTMCs are derived from bone marrow progenitors and are found in the skin, peritoneum, and mesentery. MMCs are derived from fetal liver progenitors and are found in the respiratory, gastrointestinal, and genitourinary tracts. MCs are further classified into different subtypes based on their protease content and phenotype: MCs that contain only tryptase (MCTs), MCs that contain both tryptase and chymase (MCTCs), MCs that contain tryptase, chymase, and carboxypeptidase A (MCTCAs), and MCs that contain tryptase, chymase, carboxypeptidase A, and cathepsin G (MCTCCGs) .
What are the main roles and functions of MCs in the body?
MCs are immune cells that have various roles and functions in the body, such as:
- Defending against pathogens, such as bacteria, viruses, or parasites, by releasing antimicrobial molecules and activating other immune cells
- Mediating allergic reactions, such as anaphylaxis, asthma, or urticaria, by releasing histamine and other mediators that cause vasodilation, bronchoconstriction, and itching
- Modulating inflammation, such as in arthritis, atherosclerosis, or wound healing, by releasing cytokines and other mediators that regulate the inflammatory response and tissue repair
- Influencing neuroimmunology, such as in pain, stress, or cognition, by releasing neurotransmitters and other mediators that affect the nervous system and the brain
How are MCs distributed and differentiated in the body?
MCs are distributed and differentiated in various tissues and organs throughout the body, such as:
- The skin, where MCs are located near blood vessels, nerves, and hair follicles, and are involved in allergic and inflammatory skin diseases, such as atopic dermatitis, psoriasis, or contact dermatitis
- The respiratory tract, where MCs are located in the mucosa, submucosa, and smooth muscle, and are involved in allergic and inflammatory respiratory diseases, such as asthma, rhinitis, or sinusitis
- The gastrointestinal tract, where MCs are located in the lamina propria, submucosa, and muscularis, and are involved in allergic and inflammatory gastrointestinal diseases, such as food allergy, irritable bowel syndrome, or inflammatory bowel disease
- The brain, where MCs are located in the meninges, choroid plexus, and hypothalamus, and are involved in neuroinflammatory and neuropsychiatric diseases, such as migraine, multiple sclerosis, or depression
How are MCs activated and regulated in the body?
MCs are activated and regulated by various stimuli and signals in the body, such as:
- IgE-mediated activation, which occurs when MCs bind to IgE antibodies that are specific for certain antigens, such as allergens, and cross-link their high-affinity IgE receptors (FcεRI), leading to degranulation and release of MC mediators
- Non-IgE-mediated activation, which occurs when MCs bind to other molecules or receptors, such as complement, toll-like receptors, cytokine receptors, or neuropeptide receptors, leading to degranulation and release of MC mediators
- Autocrine and paracrine regulation, which occurs when MCs produce and respond to their own mediators, such as cytokines, chemokines, or growth factors, leading to positive or negative feedback loops that modulate MC activation and function
- Endocrine and neural regulation, which occurs when MCs interact with hormones, neurotransmitters, or neuropeptides, such as corticotropin-releasing hormone, serotonin, or substance P, leading to stimulation or inhibition of MC activation and function
How are MCs related to the gut-brain axis in ASD?
The gut-brain axis is the bidirectional communication and interaction between the gut and the brain, involving the nervous, endocrine, and immune systems. MCs are related to the gut-brain axis in ASD, as they may:
- Influence the gut microbiota, which refers to the community of microorganisms that live in the gut, and which may affect the brain and immune system by producing metabolites, such as short-chain fatty acids, or modulating cytokines, such as IL-10 and TGF-β
- Influence the intestinal permeability, which refers to the ability of the gut barrier to prevent the passage of harmful substances, such as toxins, bacteria, or antigens, and which may affect the brain and immune system by causing systemic inflammation, oxidative stress, or autoimmunity
- Influence the vagus nerve, which refers to the nerve that connects the gut and the brain, and which may affect the brain and immune system by transmitting signals, such as sensory, motor, or reflex, or modulating neurotransmitters, such as acetylcholine or norepinephrine
How are MCs related to the stress response in ASD?
The stress response is the physiological and psychological reaction to a perceived or actual threat, involving the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). MCs are related to the stress response in ASD, as they may:
- Influence the HPA axis, which refers to the cascade of hormones that regulate the stress response, such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol, and which may affect the brain and immune system by altering the mood, cognition, and inflammation
- Influence the SNS, which refers to the branch of the autonomic nervous system that prepares the body for the fight-or-flight reaction, such as by increasing the heart rate, blood pressure, and glucose levels, and which may affect the brain and immune system by altering the neurotransmission, neurogenesis, and neuroinflammation
- Influence the glucocorticoid resistance, which refers to the reduced sensitivity or responsiveness of the cells to the anti-inflammatory effects of cortisol, and which may affect the brain and immune system by causing chronic stress, depression, or anxiety
What are the symptoms of MC activation in ASD?
Many children with ASD have a history of allergic symptoms, such as eczema, asthma, or food intolerance, even when they test negative for MC-related allergies. This suggests that MCs may be hyperactive or hypersensitive in ASD, and that their activation may cause or worsen the symptoms of ASD. Some of the symptoms of MC activation in ASD may include:
- Skin rashes, itching, or flushing
- Respiratory problems, such as wheezing, coughing, or shortness of breath
- Gastrointestinal problems, such as abdominal pain, diarrhea, or constipation
- Neurological problems, such as headaches, seizures, or sleep disturbances
- Behavioral problems, such as irritability, anxiety, or aggression
What are the potential benefits of targeting MCs for treating ASD?
Targeting MCs and their mediators may offer a novel approach for treating ASD, as it may:
- Reduce the neuroinflammation and immune dysregulation that are associated with ASD
- Improve the brain development and function that are impaired by ASD
- Alleviate the symptoms and comorbidities that are caused or worsened by MC activation in ASD
- Enhance the efficacy and safety of other therapies for ASD, such as behavioral interventions, pharmacological agents, or dietary supplements
What are the challenges and limitations of targeting MCs for treating ASD?
Some of the challenges and limitations of targeting MCs for treating ASD include:
- The lack of conclusive evidence and consensus on the role of MCs in ASD, and the need for more research to confirm and clarify the relationship between MCs and ASD
- The heterogeneity and complexity of ASD, and the need for a personalized and holistic approach to address the multifactorial and individualized nature of ASD
- The diversity and variability of MCs, and the need for a specific and selective approach to target the relevant MC phenotypes, mediators, and receptors in ASD
- The potential side effects and interactions of MC-targeted therapies, and the need for a careful and cautious approach to evaluate the safety and efficacy of MC-targeted therapies in ASD
Source: