Neuroimmune Disorders Research Articles

Therapeutic plasma exchange in neuroimmune diseases. Rehabilitation in myasthenia gravis patients treated with apheresis procedures

Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique which removes large molecular weight particles, like autoantibodies, from plasma. Double filtration plasmapheresis (DFPP) is a newer technique in which plasma is not entirely removed, only the antibodies, using special filters. Myasthenia gravis (MG) is a well-known autoimmune disease characterized by antibodies against postsynaptic nicotinic acetylcholine receptors and fluctuating weakness, sometimes life-threatening. TPE is a therapeutic modality well established in MG with a positive recommendation based on strong consensus of class III evidence and in the category I of American society for apheresis. There are no adequate randomized control trial, but many cases report short-term benefit from plasma exchange in MG especially MGC. We analyzed the cases of neuroimmune disorders that were presented to our Emergency Care Unit between 2012-2020 and we concluded that good acceptance of procedure (TPE/DFPP) was observed in 72% of patients. TPE is cost-effective rapid therapy for myasthenic crisis and progressive myasthenia gravis. It reduces ICU stays and improves outcome.All in all recent studies show that the combination of rehabilitation and other forms of treatment, appropriately selected activities contribute to alleviating the symptoms of the disease, improving physical fitness, increasing muscle strength, and thus improving the quality of life. Keywords: therapeutic plasma exchange, plasmapheresis, neuroimmune disorders,rehabilitation,

Rehabilitation challenges in COVID-19 induced acute polyradiculoneuropathies

Introduction. SARS-COV 2 infection causes damage of the peripheral nervous system: loss of smell loss of taste and demyelination or axonal injury in the spinal roots and motor and sensory nerves with acute polyradiculoneuritis. As many people are affected by COVID-19, the number of patients with secondary peripheral nervous system damage is increasing. Material and method. There are a significant number of Guillain Barre syndrome (GBS) cases reported in COVID-19 positive patients, leading to the recognition of GBS as one of the peripheral nervous system complications of SARS-COV 2 infection. We are trying to summarise the particularities of specific rehabilitation in post-COVID patients. Results and discussions. The rehabilitation of a COVID patients has particularities, first – because of infectious risk carried by the patient during the procedures, second by the patient’s pulmonary and physical impairments induced by the Coronavirus. Conclusions. There is scarce evidence for rehabilitation interventions, and many recommendations are based on methods developed in other viral infections or chronic pulmonary and neurologic conditions. There is a urgent need for studies regarding the efficacy of interventions in COVID rehabilitation, as the number of patients is constantly increasing. Keywords: therapeutic plasma exchange, plasmapheresis, neuroimmune disorders,rehabilitation,

Consensus Curriculum for Fellowship Training in Multiple Sclerosis and Neuroimmunology.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

The effects of frankincense extract on depression and anxiety-like behaviors induced by lipopolysaccharide in rats

The neuroimmune system has been suggested to play a role in the ethiology of depression and anxiety. Frankincense extract is an herb that has been considered to be an anti-inflammatory agent potentially useful in the treatment of specific neuroimmune system disorders. The present study examined the effects of frankincense ethyl acetate extract on lipopolysaccharide (LPS) - induced depression and anxiety-like behavior in rats.Fifty male Wistar rats received vehicle, 1 mg/kg LPS or 50, 100 or 200 mg/ kg of extract with LPS for 6 days. Forced swim test (FST), elevated plus-maze (EPM) and open field (OF) tests were done in order to assess depression and anxiety-like behaviors. Serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) levels were evaluated to measure the anti-inflammatory properties of the extract.LPS resulted in depression and anxiety-like behaviors (increased immobility in the FST, decreased time in the central area in the OF, and reduced time in the open arms in the EPM, as well as increased markers of inflammation (IL-6 and TNF-α). Behaviors consistent with anxiety and depression, as well as increased markers of inflammation were reduced by frankincense extract treatment, especially at the highest, 200 mg/kg dose. We conclude that the ethyl acetate extract of frankincense extract can mitigate the LPS-induced depression and anxiety-like behaviors in behavioral testing through reduction of inflammatory cytokines.

Jacqueline Palace: a force for good in neuroimmune disorders

Personified as a whirlwind, by a colleague who had a talent for cartooning her co-workers, is a good way to introduce neurologist Jacqueline Palace. “This was when I was in my early thirties”, she adds, but I think people would still describe me like that, even though I don't feel I have much energy these days”. Palace is a full-time clinical consultant at Oxford University (Oxford, UK), she is internationally recognised for her expertise in multiple sclerosis, neuromyelitis optica, and the myasthenias, and she manages specialist national services for patients with neuromyelitis optica and congenital myasthenic syndromes. New therapies for neuromyelitis optica spectrum disorderNeuromyelitis optica spectrum disorder is an autoimmune disease of the CNS that primarily affects the optic nerves and spinal cord. Most patients have serum antibodies targeting the aquaporin-4 water channel expressed on the end-feet of astrocytes. Although the prevalence of neuromyelitis optica spectrum disorder is limited to around 1–2 people per 100 000, severe immune-mediated attacks can quickly lead to blindness and paralysis if undiagnosed and untreated. However, diagnosis is straightforward when the highly specific serum aquaporin-4 antibodies are detected with cell-based assays. Full-Text PDF

Acute Disseminated Encephalomyelitis: Current Perspectives.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated central nervous system (CNS) disorder, characterized by polyfocal symptoms, encephalopathy and typical magnetic resonance imaging (MRI) findings, that especially affects young children. Advances in understanding CNS neuroimmune disorders as well as the association of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) with both monophasic and recurrent forms of ADEM have led to new insights into its definition, management and outcome. In this review, we aim to provide an update based on current epidemiologic, clinical, radiological and immunopathological aspects and clinical outcome of ADEM.

Сахарный диабет как следствие нейроиммуноэндокринных нарушений

The review article presents an analysis of domestic and foreign scientific literature devoted to the study of neuroimmune disorders leading to the development of diabetes mellitus. It has been established that the nervous, immune and endocrine systems act as a regulatory triad that maintains the constancy of the organism and dysfunctional changes in one of the systems, lead to changes in others, which is accompanied by the launch of various pathological processes. The unity of the regulatory triad is explained by the structural and functional features of the hypothalamic-pituitary system, the dysregulation of which can act as a triggering mechanism for the development of both nervous and endocrine and immune pathologies, while the initial link in the pathology of each system can be dysregulation disorders in other integrative systems. Thus, disturbances in the melanocortin and dopamine signaling systems, as well as immune-mediated destruction of insulin-producing cells in the pancreas, can lead to diabetes. The cause of the development of diabetes mellitus is also considered an immune pathology, accompanied by a violation of cytokine regulation, namely the predominance of pro-inflammatory cytokines, such as IL-1β, IL-2, TNF-α, etc. In turn, diabetes mellitus can cause disorders from the nervous (neuropathy), immune (decreased body resistance), blood circulation (angiopathy), as well as other body systems. Based on the data of the World Health Organization about an excessively high increase in the incidence of diabetes mellitus, the aggravating development of comorbid pathologies, as a result of leading to disability of the population, a detailed study of the mechanisms of the development of this disease is necessary in order to further search for new means of correcting pathological conditions.

Experimental Models of Neuroimmunological Disorders: A Review.

Immune-mediated inflammatory diseases of the central nervous system (CNS) are a group of neurological disorders in which inflammation and/or demyelination are induced by cellular and humoral immune responses specific to CNS antigens. They include diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), acute disseminated encephalomyelitis (ADEM) and anti-NMDA receptor encephalitis (NMDAR encephalitis). Over the years, many in vivo and in vitro models were used to study clinical, pathological, physiological and immunological features of these neuroimmunological disorders. Nevertheless, there are important aspects of human diseases that are not fully reproduced in the experimental models due to their technical limitations. In this review, we describe the preclinical models of neuroimmune disorders, and how they contributed to the understanding of these disorders and explore potential treatments. We also describe the purpose and limitation of each one, as well as the recent advances in this field.

Neuropeptide system parameters in acute herpes zoster

The neuropeptides comprise an important part in the nervous system interacting with endocrine and immune systems. Peptide regulators are responsible for the continuity of communicating elements, which support homeostasis, however, despite abundant research examining neuropeptides, not all specific mechanisms and features of interacting proteins with cells and immune components have been uncovered. Objective: to perform a comprehensive assessment of neuropeptide system in patients with herpes zoster. Materials and methods: 106 in-hospital patients were examined diagnosed with herpes zoster within 2016–2019 period. Control group consisted of 30 healthy age- and sex-matched volunteers. Blood serum was collected after verifying diagnosis on day 1. After discharge, patients were monitored for signs of pain syndrome and overall state within 3 months. It allowed to divide patients into 3 groups retrospectively. Group 1 — patients with herpes zoster, accompanied by mild or moderate pain syndrome; group 2 — patients with herpes zoster, accompanied by severe pain; group 3 — patients with herpes zoster, complicated by postherpetic neuralgia. Level of serum protein s100B, myelin basic protein, nerve growth factor, brain-derived neurotrophic factor, neuron specific enolase was measured by using specific reagents purchased from “RD Diagnostics Inc.” (США). Results. it was found that level of serum protein S100B in all groups was significantly increased compared to control group, showing no inter-group differences. Amount of myelin basic protein in all study groups vs. control was significantly higher. Moreover, level of these parameters in group 2 vs. group 1 and 3 was significantly elevated. In addition, level of nerve growth factor was significantly increased in group 1 vs. groups 2 and 3, whereas in group 3 it was significantly lower than in control and group 2. Brain-derived neurotrophic factor was significantly decreased in all the study groups compared to control, showing no significant intergroup differences. Level of neuron-specific enolase was significantly increased in group 3 vs. control as well as group 1 and 2. The data obtained allowed to identify two parameters for assessing a risk of postherpetic neuralgia in acute herpes zoster, as well as provided deeper insights into the pathogenesis of neuroimmune disorders accompanying herpes zoster.

Brain changes in depression.

The present review addresses major depressive disorder (MDD) and the implications of antidepressant treatment in the field of brain neuroplasticity, an effect initially considered adjacent but currently passed as central in the process of remission of MDD. Both in experimental animal studies and in human studies in subjects with mood disorders, neuroplasticity is considered the fundamental mechanism of neural defense against stress. Stress is the mediator between neurofunctional, neuroendocrine, neurobiological and neuroimmune disorders and depressive pathology of various intensities. Neurons have a high potential to adapt to the influences of internal and external factors. We are talking about neuroplasticity at different levels: structural neuroplasticity involving adult neurogenesis (such as plastic changes, dendritic reconstruction, when the morphology of the spine is affected); synaptic functional neuroplasticity and molecular and cellular mechanisms involved. These two major dimensions explain the pathophysiology of depression, as well as the convergence of the mechanisms involved in stress, major depressive decompensations, and the concept of neuroplasticity as the present target for new effective and potent antidepressant treatments.

Understanding Childhood Neuroimmune Diseases of the Central Nervous System.

Immune-mediated diseases of the central nervous system (CNS) in childhood are a heterogeneous group of rare conditions sharing the inflammatory involvement of the CNS. This review highlights the growing knowledge of childhood neuroimmune diseases that primarily affect the CNS, outlining the clinical and diagnostic features, the pathobiological mechanisms and genetics, current treatment options, and emerging challenges. The clinical spectrum of these conditions is increasingly expanded, and the underlying mechanisms of dysregulation of the immune system could vary widely. Cell-mediated and antibody-mediated disorders, infection-triggered and paraneoplastic conditions, and genetically defined mechanisms can occur in previously healthy children and can contribute to different stages of the disease. The careful evaluation of the clinical presentation and temporal course of symptoms, the specific neuroimaging and immunological findings, and the exclusion of alternative causes are mandatory in clinical practice for the syndromic diagnosis. A common feature of these conditions is that immunotherapeutic agents could modulate the clinical course and outcomes of the disease. Furthermore, specific symptomatic treatments and comprehensive multidisciplinary care are needed in the overall management. We focus on recent advances on immune-mediated demyelinating CNS disorders, autoimmune encephalitis, interferonopathies, and possible neuroimmune disorders as Rasmussen encephalitis. Better knowledge of these conditions could allow prompt diagnosis and targeted immunotherapy, to decrease morbidity and mortality as well as to improve clinical outcomes, reducing the burden of the disease due to possible long-term neuropsychiatric sequelae. Persisting controversies remain in the rigorous characterization of each specific clinical entity because of the relative rarity in children; moreover, in a large proportion of suspected neuroimmune diseases, the immune “signature” remains unidentified; treatment guidelines are mostly based on retrospective cohort studies and expert opinions; then advances in specific molecular therapies are required. In the future, a better characterization of specific immunological biomarkers may provide a useful understanding of the underlying pathobiological mechanisms of these conditions in order to individualize more tailored therapeutic options and paradigms. Multicenter collaborative research on homogeneous groups of patients who may undergo immunological studies and therapeutic trials could improve the characterization of the underlying mechanisms, the specific phenotypes, and tailored management.

Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25− and CD8 + Foxp3+ CD25− splenocyte T-cell populations compared to controls. Further evaluation of SBI-425’s effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis.

2.2 DEMYSTIFYING THE DEMYELINATING DISORDERS

Demyelinating neuroimmune disorders are a heterogeneous group of severe neurologic conditions characterized by inflammatory responses in the white matter of the central nervous system (CNS). Demyelinating disorders typically manifest in previously healthy, developmentally normal, and neurologically normal children and adolescents. Patients develop acute monophasic or relapsing neurologic and neuropsychiatric impairment, sometimes controlled with immune therapy. Research shows that this pediatric population has higher rates of anxiety, stress-related, and somatoform disorders, ADHD, and intellectual disability; in addition, they demonstrate a lower health-related quality of life than peers. Furthermore, the impact of neuroimmune disorders on maturing neural networks may become more apparent as the child ages and fails to normally develop pathways injured during the acute phase of illness.

The effects of IVIg therapy on serum levels of neuropeptide Y and cytokines in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a common acute immune-mediated inflammatory disorder affecting the peripheral nervous system (PNS) of humans. Studies in humans and in animal models revealed that neuropeptide Y (NPY) levels are altered in some neurodegenerative and neuroimmune disorders. Herein, we investigated the levels of NPY and cytokines in the serum of GBS patients and explored the roles of NPY in the disease severity and its short-term prognosis. Twenty patients with GBS (case group) and twenty healthy individuals (control group) were enrolled in this study. NPY levels were analyzed by enzyme-linked immunosorbent assay (ELISA). The levels of pro- and anti-inflammatory cytokines (including interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, IL-12p70, IL-17A, and tumor necrosis factor-α (TNF-α)) were analyzed using cytometric beads array (CBA). The clinical characteristics, disease severity, and short-term prognosis were compared between the two groups. Compared with the control group, the levels of NPY and cytokines were significantly increased in the serum of patients with GBS. NPY levels in the serum of GBS patients were correlated with the disease severity. Our results suggest that NPY and cytokines are involved in the pathogenesis of GBS. The levels of NPY can help to predict the severity of the disease.

Roles of Neuropeptide Y in Neurodegenerative and Neuroimmune Diseases.

Neuropeptide Y (NPY) is a neurotransmitter or neuromodulator that mainly exists in the nervous system. It plays a neuroprotective role in organisms and widely participates in the regulation of various physiological processes in vivo. Studies in both humans and animal models have been revealed that NPY levels are altered in some neurodegenerative and neuroimmune disorders. NPY plays various roles in these diseases, such as exerting a neuroprotective effect, increasing trophic support, decreasing excitotoxicity, regulating calcium homeostasis, and attenuating neuroinflammation. In this review, we will focus on the roles of NPY in the pathological mechanisms of neurodegenerative and neuroimmune diseases, highlighting NPY as a potential therapeutic target in these diseases.

Utility and safety of plasma exchange in paediatric neuroimmune disorders

Our aim was to ascertain the indications, side effects, and outcomes in children receiving therapeutic plasma exchange (TPE) for neurological disorders. Medical records were retrospectively reviewed for 58 consecutive children (age ≤16y) undergoing 67 courses of TPE across four tertiary centres. Patient characteristics, treatment schedules, complications, and outcomes were analysed. Median age at initiation of TPE was 9years (range 1-15y). Indications included peripheral nervous system (PNS; n=18) and central nervous system (CNS; n=40) disorders. Courses comprised a median six exchanges (range 2-179) over 8days (range 3-466). Forty-two out of 58 (73%) children were severely disabled (bedridden) at initiation and 24 out of 58 (41%) were admitted to intensive care units. Treating clinicians' impression of response was positive in 16 out of 18 of those with PNS disorders versus 22 out of 40 with CNS disorders (p=0.016). Improvements in disability (modified Rankin Scale) occurred in 13 out of 58 (22%) children by completion of TPE (p=0.003). Complications occurred in 40 out of 67 (60%) courses, of which 16 out of 67 (24%) were line related. Potentially life-threatening complications occurred in 2 out of 67 (3%) courses. This cohort study provides safety and efficacy information for clinicians and families and a basis for future prospective studies. Disability scores for severe neuroimmune disorders remained stable or improved during therapeutic plasma exchange treatment. Complications occurred frequently but were typically mild and correctable.

THERAPEUTIC PLASMA EXCHANGE AND DOUBLE FILTRATION PLASMAPHERESIS IN SEVERE NEUROIMMUNE DISORDERS.

SUMMARYTherapeutic plasma exchange (TPE) is an extracorporeal blood purification technique, which removes large molecular weight particles such as autoantibodies from plasma. TPE is accepted by the American Society for Apheresis as first line treatment for some severe neuroimmune disorders. Double filtration plasmapheresis (DFPP) is a newer technique in which plasma is not entirely removed, only the antibodies, using special filters. High-dose intravenous immunoglobulins are an alternative treatment for these patients but are much more expensive. We reviewed medical records of 20 patients with severe neurological diseases requiring TPE or DFPP. We analyzed the indications, complications and efficacy of these procedures. After completing the procedures, neurological improvement was recorded in 80% of the patients, 5% had no improvement, and the mortality was 15%. The rate of neurological improvement was similar to other studies. None of the patients presented catheter related complications. Systemic complications were mild, transient and completely reversible.

Recognizing the Leaky Gut as a Trans-diagnostic Target for Neuroimmune Disorders Using Clinical Chemistry and Molecular Immunology Assays.

Increased intestinal permeability with heightened translocation of Gramnegative bacteria, also known as "leaky gut", is associated with the pathophysiology of neuroimmune disorders, such as Major Depressive Disorder (MDD), Chronic Fatigue Syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice. We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words "diagnosis" or "biomarkers" and "leaky gut", "bacterial translocation", and "intestinal permeability" and focused on papers describing tests that may aid in the clinical recognition of leaky gut. To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α- antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption. Here, we propose strategies to recognize "leaky gut" in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.

Protection by tyrosine kinase inhibitor, tyrphostin AG126, through the suppression of IL-17A, RORγt, and T-bet signaling, in the BTBR mouse model of autism

Autism spectrum disorder (ASD) is an extremely predominant neurodevelopmental disorder expressed as impairment in reciprocal social interaction along with repetitive, restricted, and stereotyped behaviors. The protein tyrosine kinase inhibitor, tyrphostin AG126 (AG126), regulates the expression of several genes that play an important role in the development of neuroinflammatory disorders. Here, we investigate the possible effects of AG126 (5 mg/kg daily through intraperitoneal injection) on self-grooming, marble burying, and hot plate test results in BTBR T + Itpr3tf/J mice (BTBR is a model of autism). We also explore the effects of AG126 administration on IL-17 A, RORγt, T-bet, and IFN-γ production in CD4+ T cells and on CCR6+ chemokine receptors in splenic cells. We further investigated the effect of AG126 administration on the mRNA and protein expression of IL-17 A, RORγt, T-bet, IFN-γ, and NF-κB in the brain tissue. Our results demonstrate that treatment of BTBR mice with AG126 reduced repetitive self-grooming scores and lowered hot plate sensitivity potentials. Furthermore, AG126 administration also caused a substantial reduction of IL-17 A, RORγt, T-bet, and IFN-γ production in CD4+ T cells and on CCR6+ chemokine receptors in splenic cells. BTBR mice treated with AG126 also show decreased mRNA and protein expression levels of IL-17 A, RORγt, T-bet, IFN-γ, and NF-κB activation in brain tissue. Our results indicate that treating BTBR mice with AG126 leads to protection against neuroimmune dysfunction/dysregulation through the inhibition of cytokines and transcription factor signaling. This mechanism may be useful in the development of future therapies for neuroimmune disorders.

The Effects of Tryptophan Catabolites on Negative Symptoms and Deficit Schizophrenia are Partly Mediated by Executive Impairments: Results of Partial Least Squares Path Modeling.

We recruited 80 schizophrenic patients and 40 healthy controls and assessed 10 key cognitive tests using the Cambridge Neuropsychological Test Automated Battery (CANTAB), IgA/IgM responses to tryptophan catabolites (TRYCATs), the Scale for the Assessment of Negative Symptoms (SANS) and Positive and Negative Syndrome Scale. Partial Least Squares path modeling shows that a large part of the variance in negative symptoms and the deficit phenotype (39-53%) is explained by executive impairments, TRYCAT levels and male sex and that 53.4% of the variance in executive impairments is explained by TRYCATs, lower education, age and a familial history of psychosis. Specific indirect effects of TRYCATs, age and education on negative symptoms are mediated by executive impairments. Nevertheless, sustained attention, memory and emotion recognition also mediate the effects of TRYCATS, lower education and male sex on negative symptoms. Deficit schizophrenia is accompanied by a broader spectrum of cognitive impairments than nondeficit schizophrenia, including executive functions, sustained attention, episodic and semantic memory and emotion recognition. Furthermore, neuro-immune disorders underpin executive impairments, whilst neuro-immune disorders coupled with executive and other cognitive impairments to a large extent determine negative symptoms and the deficit phenotype.