PANDAS - PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS ASSOCIATED WITH STREPTOCOCCUS

WHAT IS THE ROLE OF PRO-INFLAMMATORY CYTOKINE GENE EXPRESSIONS?

Brain Sci. 2018 Aug 9;8(8). pii: E149. doi: 10.3390/brainsci8080149.

Individualized Immunological Data for Precise Classification of OCD Patients.

 

Cytokines

Cytokines are molecules that allow communication between immune cells, or between immune cells and non-immune cells. Studying cytokines can help us understand the mechanism and pathways of potential immunological disruption in OCD. The first studies on cytokine variations in OCD patients included very few patients and were negative except for a positive and significant correlation between IL-6 (interleukin-6) or soluble IL-6 receptor plasma levels and severity of compulsive behaviors. Further studies found decreased IL-1β levels and decreased TNFα (tumor necrosis factor α) levels in non-depressed OCD patients (but not in OCD patients with possible comorbid depression), and increased IL-6 levels in adult medication-free OCD patients (but not in OCD children with possible medication use) compared to controls. More recently, discrepancies were found with this previous meta-analysis concerning TNF-α with increased levels in OCD patients. Despite these discrepancies, the increased IL-6 levels seem a consistent result as they were replicated in a recent study.

 

Cytokine studies.

 * The fact that IL-6 levels are higher in autoimmune diseases (e.g., rheumatoid arthritis) raises the hypothesis that increased IL-6 levels in OCD could favor the existence of an autoimmune etiological factor. It is known also that both IL-6 and TNFα can be involved in asthma pathophysiology and allergic diseases, and allergic diseases would appear to be more frequent in OCD patients, giving weight to elevated IL-6 and TNFα levels in some OCD cases.

 * TNFα, IL-1β, and IL-6 are inflammatory cytokines . TNFα is produced by a wide range of cells including T- or B-cells and monocytes (including microglia), and it targets all nucleated cells. TNFα has a complex role, being both pro-inflammatory and immunosuppressive.

In the brain, TNFα could be involved in synapses scaling with high levels of TNFα favoring LTP (long term potentiation) and low levels of TNFα favoring LTD (long term depression). Progranulin mutations were found to be associated with hyperexcitability of nucleus accumbens spiny neurons in mice, in line with hyperactivity of cortico-striatal loops in OCD, and elevated TNFα levels and hyperactivation of microglia. With the progranulin gene restored, OCD-like behavior disappeared in mice. Frontoparietal dementia patients showing mutations of progranulin presented OCD [46].

 * IL-1β is also produced by microglia and targets T-cells or endothelial and epithelial cells [42].

 * IL-6 is produced by both astrocytes and microglia, and IL-6 exposure could increase synaptic activity (for an excellent review on IL-6 central nervous system (CNS) effects, see Reference [47]).

 

Antibodies

Most studies concerning antibodies in OCD concern pediatric autoimmune neuropsychological disorders associated with streptococcal (PANDAS) infections.

Studies found that a subset of patients suffering from OCD showed high levels of anti-basal ganglia antibodies (ABGAs) and anti-streptolysin O antibodies (ASO) in the blood or corticospinal fluid (CSF). These studies strongly support the existence of an autoimmune etiological factor in OCD. Furthermore, it was shown that patients suffering from rheumatic fever—a disorder linked with PANDAS—show a higher proportion of a specific B-lymphocyte alloantigen detected with monoclonal antibodies D8/D17.

 

White Blood Cells

As with cytokines, very contrasting results were found for white blood cells. Some studies found a higher number of CD8+ (cluster of differentiation) lymphocytes and a lower number of CD4+ lymphocytes in OCD patients, whereas others did not.

Infections and OCD

Streptococcal Infection

Streptococcus pyogenes is a bacterial group that can lead to several pathologies such as pharyngitis, scarlet fever, or erysipelas. Among these diseases, rheumatic fever is the one we were interested in. This disease is characterized by elevated ASO (anti-streptolysin O) or anti-DNAse B antibody levels, and it affects the heart, skin, bone joints, and CNS.

 * The Jones criteria are usually used to make the diagnosis. They consist of carditis, arthritis, chorea, erythema marginatum, and subcutaneous nodules with evidence of S. pyogenes infection [108,109]. 

 ** S. pyogenes can, thus, affect the nervous system through choreic movements. This chorea, called Sydenham’s chorea, is characterized by involuntary movements which are irregular, rapid, and transient, and which are typically manifested in the extremities. Sydenham’s chorea is characterized by antibodies found in the basal ganglia that react with N-acetyl-beta-d-glucosamine of S. pyogenes, and with lysoganglioside and tubulin of the brain.  In summary, antibodies that originally target S. pyogenes may also attack the patient’s brain.

Toxoplasma gondii

Toxoplasma gondii is an intracellular parasite that is linked to several psychiatric disorders including schizophrenia and bipolar disorder. 

T. gondii is also linked to OCD. In a 1991 study, Strittmatter and colleagues showed that the CNS areas most affected by T. gondii were the cerebral hemispheres (91%) and the basal ganglia (78%) which are implicated in OCD neurobiology.

 * T. gondii can invade monocytes in the peripheral blood supply and then reach the brain. Once in the brain and in microglia, these monocytes become activated and show increased migratory activity.

 ** T. gondii infection leads to IFN-γ (interferon) production, and then, to the induction of IDO (indolamine-2,3-dioxygenase), mainly produced by microglia and one of the main enzymes of kynurenine pathway. This induction of IDO by T. gondii occurs firstly in parallel with the T. gondii-induced microglia activation and can secondly lead to a tryptophan depletion (since the kynurenine pathway is part of tryptophan catabolism). As tryptophan is the essential amino acid for serotonin synthesis, tryptophan depletion could interfere with OCD physiological pathways since OCD symptoms are improved with specific serotonin reuptake inhibitors (SSRIs). Nonetheless, we have to keep in mind that this causal tryptophan depletion hypothesis is still a matter of debate in MDD (major depressive disorder); thus, the putative T. gondii role in OCD is unclear [159].

5. Alternative Treatments for OCD

The above distinct etiological factors in OCD could be taken into account to develop specific treatments. Tricyclic or SSRI antidepressants are the usual treatment for OCD [165]. For refractory and severe OCD, deep brain stimulation can also be used [6]. Other treatments were also developed for specific etiological factors.

 

Specific Treatment in the PANS/PANDAS Context

Several specific treatments were studied for PANS/PANDAS patients. Intravenous immunoglobulin (IVIG) could be an effective treatment however, its effectiveness remains to be confirmed. The effects of antibiotic treatment in PANDAS were also studied. Four studies without control groups found that antibiotics could be effective, although a study comparing azithromycin vs. placebo as a treatment for PANS over four weeks failed to find an effect of azithromycin on OCD symptoms as measured with the Children’s Yale–Brown Obsessive Compulsive Scale (CY-BOCS). However, if streptococcal infection is still present during acute episodes of PANDAS, antibiotics are considered as the best treatment. Finally, corticosteroid and nonsteroidal anti-inflammatory drugs (NSAIDs) do appear to be effective.

Specific Treatment in the “Classical” OCD Context

In addition to PANS/PANDAS, immunological treatments were also tested in “classical” OCD, that is to say, with no clearly identified etiological factor. NSAIDs show contrasting results [135,136,170] (Table 5). However, in the general context of OCD with no specific etiological factors, anti-inflammatory treatment seems to have a place in the treatment strategy, which could be more precisely defined if OCD etiologies were better known. Minocycline, a specific antibiotic, is particularly interesting because of its action on microglia (see below).

 * Minocycline was studied as a potential new pharmacological treatment for OCD, and the results were mixed: one study found that minocycline could be a good adjunctive treatment to classical OCD treatment with SSRIs

 * N-acetylcysteine (NAC), an antioxidant which has a neuroprotective role against oxidative stress, produced divergent results.

 * Low-dose naltrexone (LDN) – inhibits microglial activation “Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/

Hyperbaric Oxygen Therapy combined with Cytokine modulation targets the cell mitochondria function.

Ann Lab Med. 2018 Sep;38(5):395-401. doi: 10.3343/alm.2018.38.5.395.

Rejuvenating Aged Hematopoietic Stem Cells Through Improvement of Mitochondrial Function.

Mitochondria are the powerhouses of the cell as well as the primary site of hematopoiesis, which also occurs in the cytoplasm. Hematopoietic stem cells (HSCs) are characterized by a very high turnover rate, and are thus considered to be relatively free from the age-related insults generated by mitochondria. However, HSCs are also subject to these age-related insults, including the incidence of myeloid proliferative diseases, marrow failure, hematopoietic neoplasms, and deterioration of the adaptive human immune system.

 * Recently, NAD⁺ dietary supplements, known as Niacin or vitamin B₃, including tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD⁺ precursor nicotinamide riboside, have been shown to play a role in restoring adult stem cell function through the amelioration of mitochondrial dysfunction.

This insight motivated a study that focused on reversing aging-related cellular dysfunction in adult mouse muscle stem cells by supplementing their diet with nicotinamide riboside. The remedial effect of nicotinamide riboside enhanced mitochondrial function in these muscle stem cells in a SIRT1-dependent manner, affecting cellular respiration, membrane potential, and production of ATP. Accordingly, numerous studies have demonstrated that sirtuins, under nuclear/mitochondrial control, have age-specific effects in determining HSC phenotypes. Based on the evidence accumulated thus far, we propose a clinical intervention for the restoration of aged HSC function by improving mitochondrial function through NAD⁺ precursor B3 supplementation.

Brain Sci. 2018 Aug 9;8(8). pii: E149. doi: 10.3390/brainsci8080149.

Individualized Immunological Data for Precise Classification of OCD Patients.

Lamothe H1,2,3, Baleyte JM4,5, Smith P6, Pelissolo A7,8,9, Mallet L10,11,12,13.

Abstract

Obsessive⁻compulsive disorder (OCD) affects about 2% of the general population, for which several etiological factors were identified. Important among these is immunological dysfunction. This review aims to show how immunology can inform specific etiological factors, and how distinguishing between these etiologies is important from a personalized treatment perspective. We found discrepancies concerning cytokines, raising the hypothesis of specific immunological etiological factors. Antibody studies support the existence of a potential autoimmune etiological factor. Infections may also provoke OCD symptoms, and therefore, could be considered as specific etiological factors with specific immunological impairments. Finally, we underline the importance of distinguishing between different etiological factors since some specific treatments already exist in the context of immunological factors for the improvement of classic treatments.

Psychoneuroendocrinology. 2018 Jul;93:39-44. doi: 10.1016/j.psyneuen.2018.04.013. Epub 2018 Apr 13.

Immune system and obsessive-compulsive disorder.

Marazziti D1, Mucci F2, Fontenelle LF3.

Abstract

BACKGROUND:

Recently, much attention has been devoted to the possible alterations of the immune system in obsessive-compulsive disorder (OCD). Therefore, the aim of this paper was to review the current literature on the relationships between OCD and immune system.

METHODS:

A PubMed and Google Scholar search was performed with specific keywords.

RESULTS:

In the childhood, much emphasis has been given to the relationship between group A Streptococcus (GAS) infection and the development of a group of clinical syndromes characterized by neuropsychiatric symptoms known as "pediatric autoimmune neuropsychiatric disorders associated with streptococcus" (PANDAS). However, more recently, PANDAS has been reconsidered and evolved towards pediatric acute-onset neuropsychiatric syndrome (PANS) and/or Childhood Acute Neuropsychiatric Syndrome (CANS) all characterized by the presence of typical of OCD symptoms and tics. In adult OCD patients, different immunological parameters have been described to differ from those of healthy control subjects, although a few numbers of studies were carried out and most of them performed in small samples.

CONCLUSIONS:

Although the exact relationships between OCD and immune processes are still unclear, available literature supports their role in the pathophysiology of OCD, while providing a fascinating hint for possible immunotherapeutic treatments in OCD.

Int J Pediatr Otorhinolaryngol. 2016 Jan;80:49-52. doi: 10.1016/j.ijporl.2015.11.020. Epub 2015 Nov 24.

Characterization of B-Cells in tonsils of patients diagnosed with pediatric autoimmune neuropsychiatric disorder associated streptococcus.

Walls A1, Dermody S2, Kumaran R3, Krishnan N2, Harley EH2.

Abstract

OBJECTIVE:

To determine if Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) patients demonstrate a significantly different number of B-Cells or markers of activity when compared to recurrent Group A Streptococcus or Obstructive Sleep Apnea patients.

STUDY DESIGN:

Prospective Cohort Study.

STUDY SETTING:

Academic University Hospital.

METHODS:

Tonsil tissue was collected from twenty-two patients in the operating room and organized into three groups. Ten clinically diagnosed PANDAS, six Group A Streptococcus and six Obstructive Sleep Apnea patients were included in this study. Each tissue sample was extracted with MSD Tris Lysis Buffer and protein lysates were analyzed for CD 19, B-Cell Activating Factor and B-Cell Activating Receptor by western blot methods.

RESULTS:

Based on ANOVA analysis, there was no significant difference in the expression of B-Cell Activating Factor, B-Cell Activating Receptor or CD 19 when comparing the three study groups by western blot analysis methods.

CONCLUSIONS:

In this prospective cohort study, it appears that PANDAS patients do not demonstrate increased number of B-Cells, expression of B-Cell Activating Factor or B-Cell Activating Receptor when compared to Group A Streptococcus or Obstructive Sleep Apnea cohorts. As a result, further evaluation of the cell-mediated immune system is warranted to provide further insight into the pathophysiology of PANDAS. In addition, we must investigate if PANDAS patients only demonstrate increased B-Cell number or activity when undergoing an acute Tic/OCD exacerbation.

Journal of Immunology Research Volume 2016, Article ID 8606057, 8 pages http://dx.doi.org/10.1155/2016/8606057

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

Luciana Frick1,2 and Christopher Pittenger1,2,3,4,5

Abstract

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain’s resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues.

Curr Psychiatry Rep. 2012 Jun; 14(3): 220–228.

Systematic Review of Proinflammatory Cytokines in Obsessive-Compulsive Disorder

Simon M. Gray and Michael H. Bloch

Abstract

Several studies have examined levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. This meta-analysis was conducted to examine the association between obsessive-compulsive disorder (OCD) and plasma serum levels of proinflammatory cytokines. Twelve studies met inclusion criteria. The meta-analysis demonstrated a significant reduction in IL-1β levels in OCD. No significant difference in plasma levels of IL-6 or TNF-α was demonstrated. Stratified subgroup analysis revealed possible moderating effects of age and medication use on IL-6 levels. Studies including children on psychotropic medication had lower plasma IL-6 levels. Stratified subgroup analysis revealed a moderating effect of comorbid depression on TNF-α levels. Elevated TNF-α levels were reported in studies that included individuals with comorbid depression. Future studies examining immune function in OCD should adjust for potential confounding due to medication use and comorbid depression. Further studies assessing cerebrospinal fluid cytokine levels in OCD are also needed.

 * In summary, this meta-analysis showed that overall plasma levels of IL-1β are reduced in OCD patients relative to controls, while there is no overall difference in TNF-α and IL-6 plasma levels. Additionally, moderating effects of age, mood, and medication appear to have an effect on the plasma levels of TNF-α and IL-6. Finally, the relatively few number of studies of CSF cytokine levels and ex vivo lymphocyte production of cytokines prevented us from performing a meta-analysis in the area. These limited studies suggested that IL-6 production may be decreased ex vivo in OCD, while TNF-α and IL-1β remain unchanged. Future research evaluating immune function in OCD should control for potential confounding of comorbid depression and medication use, involve larger sample sizes, and involve multiple sample collections from subjects to adjust for within-subject variation.