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With emerging evidence in basic and clinical scientific research, it is now understood that interactions between the central nervous system (CNS) and the immune system contribute tremendously to brain development and behaviour, precipitating the still nascent field of neuroimmunology.

Neuroimmunology posits that the relationship between the CNS and the immune system is bidirectional. Immune cells influence the cytoarchitecture of the CNS via molecular signaling pathways. In addition, immune responses help maintain the homeostatic functioning of the CNS by providing protection against foreign invaders and repair from injury. In turn, the brain regulates the immune system by mediating protein synthesis and neurotransmitter systems, thus regulating the internal environment in which immune cells perform their functions.

Whether in the context of healthy states or pathological conditions, neuroimmunology pertains to a range of cellular and subcellular processes comprising critical phenomena such as neurogenesis, neuronal cytotoxicity, immunotherapy, pain, and neural inflammation.1-2

Neural Immune Response

To better understand the pathology of certain neuroimmunological conditions,
an understanding of the appropriate neural-immune response is warranted:

Neuroimmune Pathologies

Due to the need for therapeutic interventions, most research focuses on neural-immune crosstalk in disease states. Neuroimmunopathologies can be categorized into two broad classes: neurodegenerative diseases, and neurodevelopmental diseases. In general, neurodegenerative diseases entail a progressive loss of the ability to remove toxins from CNS parenchyma. Neurodevelopmental diseases comprise impairments in CNS growth and development, with an emphasis on pre- and peri- natal trauma or infection.

Both neurodegenerative and neurodevelopmental disorders are believed to involve genetic and environmental factors and interactions:

Autism Spectrum Disorder (ASD)

1. McAllister, Patterson. Introduction to special issue on neuroimmunology in brain development and disease. Dev Neurobiol 2012; 72: 1269-127
2. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and Differentiation of microglia. Front Cell Neurosci 2013; 7: 45

Autism Spectrum Disorder

main article: Autism Spectrum Disorder
author: cdalenig

The early signs of ASD, uploaded by KennedyKrieger

Autism spectrum disorder (ASD) are a range of behavioural abnormalities comprising social interaction impairments, communication deficits, and restricted or repetitive interests.1 Diagnosistic criteria according to the current edition of the Diagnostic and Statistical Manual of Mental Disorders, DSM-V, emphasize symptoms presenting in early childhood. Prognosis is hindered by the lack of solid and complete understanding of the pathological causes or mechanisms of the disorders. Although genes are certainly involved in ASD etiology, it is becoming evident that there are also other significant contributing factors; such as epigenetic abnormalities, antibody and cytokine dysregulation, and neural or synaptic changes.

1. Rossignol, D.A., Genuis, S.J., & Frye, R.E. (2014). Environmental toxicants and autism spectrum disorders- a systematic review. Translational Psychiatry, e360. doi: 10.1038/tp.2014.4.

Fetal Alcohol Spectrum Disorder (FASD)

main article: Fetal Alcohol Spectrum Disorder (FASD)
author: VincentHr

Facial Features of Children with FASD
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Fig1. Adapted from Watterndorf et al. [2005][3]. Distinctive facial feature in children from different cultural backgrounds with FASD.

Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term which encompasses a continuum of birth defects derived from prenatal alcohol exposure caused by maternal alcohol consumption during pregnancy. The term itself is not a clinical diagnosis of a disorder, but includes the diagnostic conditions of alcohol-related neurodevelopmental disorder (ARND), fetal alcohol syndrome (FAS), partial FAS, and alcohol-related birth defects (ARBD). The diagnoses for the diagnostic conditions of FASD make use of physical and neurobehavioural examinations, and maternal alcohol consumption history. The symptoms can include, but are not limited to growth retardation, musculoskeletal disabilities, cognitive deficits in learning and memory, attention, and intellectual performance1. Additionally, individuals with FASD present a higher risk for developing behavioural issues which include psychiatric disorders, difficulty with social interactions, and substance abuse1. Although many symptoms have been identified, little is known about the underlying mechanism of the pathogenesis. However, it is understood that microglia, the resident macrophage of the central nervous system (CNS), is a target of ethanol pathogenesis and adopts lasting morphological changes resulting from CNS-wide inflammation1. Furthermore, emerging evidence suggest a Toll-like receptor 4 (TLR4) mediated inflammatory response by microglia and a reduction in histone acetylation across numerous brain regions emerging from prenatal alcohol exposure1. Despite the major advances in medical diagnosis, there is no treatment for FASD. Nevertheless, PPAR-γ agonists, a group of immunosuppressive drugs, have recently been shown to protect microglia and neurons by reducing the alcohol-induced inflammation in mouse models2. Early intervention services have also demonstrated to be effective in improving a child’s development1.

1. Kane, J.M., Phelan, K.D., Drew, P.D.. Neuroimmune mechanisms in fetal alcohol spectrum disorder. Dev Neurobiol. 72(10), 1302–1316 (2012).
2. Kane, J.M., et al. Protection of neurons and microglia against ethanol in a mouse modelof fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-y agonists. Brain Behav Immun. 25(1), 127-145 (2011).
3. Watterndorf, D.J., et al. Fetal alcohol spectrum disorders. Am Fam Physician. 15, 279-285 (2005).

Microglia in CNS Development

main article: Microglia in CNS Development
author: Aamir Subhan

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Image Source: London, Cohen, Schwartz (2013)

The development of the central nervous system (CNS) is highly influenced by neuroimmune effects. The primary cellular effectors are microglia, the resident mononuclear macrophages of the brain. Long thought to only be involved in pathogenic and damaged states, microglia are rapidly being revealed to be far more involved in all aspects of the CNS[1]. These cells have critical roles in neuronal differentiation and proliferation, synaptic networking modification/pruning, synaptogenesis, and even CNS angiogenesis[1],[2].Microglia execute their tasks by virtue of expressing a wide variety of immune molecules, including the major histocompatibility complex (MHC), toll-like receptors (TLRs), and a multitude of cytokines and receptors[Bibliography item example9 not found.]. In addition to immune response specific molecules, microglia also secrete neurotrophic factors that both support and assist in CNS development.

1. Ginhoux, F., Lim, S., Hoeffel, G., Low, D., Huber, T. Origin and differentiation of microglia. Front Cell Neurosci 7(45), 1-14 (2013).
2. T. Arnold and C. Betsholtz. The importance of microglia in the development of the vasculature in the central nervous system. Vas Cell 5(12), (2013)

Neuroimmunology of Amyotrophic Lateral Sclerosis

main article: Neuroimmunology of Amyotrophic Lateral Sclerosis
author: Adeel Danish

The Corticospinal Tract
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Figure 1: The corticospinal tract sustains damage
from upper motor neurons degeneration in ALS. These
neurons project from the cortex to the spinal cord.
Adapted form Wikimedia Commons.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative motor neuron disease that involves the deterioration and eventual death of both cortical and spinal motor neurons. Its symptoms vary from muscle weakness, fasciculation, and spasticity to severe muscle atrophy and impeded eating, moving, and breathing. After initial onset, the prognosis of ALS is usually comprised of a rapid decline of motor control, coupled with cognitive impairments, and culminates in death within three to five years[1]. Due to the aggressive nature of this disease, many studies have been conducted to further understand its etiology, although no exact mechanism for the initial cause of the disease has been delineated. Genetic analyses and transgenic model manipulations have highlighted important genes, namely SOD1, that are implicated with the disease. It is apparent that a SOD1 mutation in ALS confers gain of function that is toxic to affected motor neurons, but an exact mechanism that links the mutation to cell death is still unclear[2]. Recent, promising studies have began to investigate the immunological component of ALS: how altered microglial function and expression contributes to an inflammatory response and the degeneration of motor neurons. Evidence suggests that microglia are “activated” in individuals with the SOD1 mutation and confer toxicity to motor neurons and surrounding glial cell populations[3]. Current investigations into the immunology of this disease aim to ascertain the conditions and mechanisms that enable the conversion of microglia into their active disease state, and what consequence this transition has on the cellular and molecular functions of cells in the central nervous system.

1. Murray B, Mitsumoto H. Disorders of upper and lower motor neurons. In: Daroff RB, Fenichel GM, Jankovic J, eds. Bradley’s Neurology in Clinical Practice. 6th ed. Philadelphia, Pa:Saunders Elsevier (2012).
2. Gagliardi S, Cova E, Davin A, Guareschi S, Abel K, Alvisi E, Laforenza U, Ghidoni R,Cashman JR, Ceroni M, Cereda C. SOD1 mRNA expression in sporadic amyotrophic lateral sclerosis. Neurobiol Dis. 39(2): 198–203 (2010).
3. Parisi C, Arisi I, D'Ambrosi N, Storti AE, Brandi R, D'Onofrio M, Volonté C. Dysregulated microRNAs in amyotrophic lateral sclerosis microglia modulate genes linked to neuroinflammation. Cell Death Dis. 4:e959 (2013).

Neuroimmunopathology of Schizophrenia

main article: Neuroimmunopathology of Schizophrenia
author: Andrew Namasivayam

Neuroimmunopathology of Schizophrenia
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Image courtesy of Psychiatric News

Schizophrenia is a complex psychiatric disorder characterized by disorganized thought and behaviour, distortions of reality, and other cognitive and emotional deficits. Although symptoms of the disorder vary by patient, they typically include hallucinations, delusions, mood disturbances, and impaired motivation.[Bibliography item example1 not found.] Schizophrenia affects about 1 in 100 people and often leads to considerable social and occupational dysfunction. Treatment is most commonly in the form of drug-therapy, however a lack of understanding of the disorder has resulted in inconsistent efficacy of these drugs.[Bibliography item example1 not found.] While it is clear that schizophrenia results from interplay between genetic and environmental factors, much of the biological basis of the illness is still unknown. In recent years, however, increasing evidence has suggested a role of the immune system in the pathogenesis of the disorder. Studies have shown that maternal infections during pregnancy increase the chance of schizophrenia in the offspring in both humans and mice.[Bibliography item example2 not found.] Moreover, serum cytokine levels have been shown to be elevated in patients with schizophrenia, likely implicating inflammation as a contributing factor.[Bibliography item example2 not found.] Overall, the immunological perspective of schizophrenia provides a novel angle from which researchers can approach this mysterious disorder and develop more effective treatment options.

Kirkpatrick, B., & Miller, B. J. (2013). Inflammation and schizophrenia. Schizophrenia bulletin, 39(6), 1174–9. doi:10.1093/schbul/sbt141
Girgis, R. R., Kumar, S. S., & Brown, A. S. (2014). The cytokine model of schizophrenia: emerging therapeutic strategies. Biological psychiatry, 75(4), 292–9. doi:10.1016/j.biopsych.2013.12.002

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