Our results suggest that the evaluation of this gene is important to clarify its role in the OCD development. More comprehensive polymorphism coverage within the TNFA using high-throughput sequence of the entire gene is warranted.
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Moreover, differences in association of the TNFA polymorphism and OCD, found in different investigations, could be clarified by the analysis of larger case-control studies, additional family-based studies, and especially linkage disequilibrium mapping of TNFA, which should be considered a high-priority gene given its potentially important influence on the risk for OCD. We thank Juliana B. The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry ; A review and meta-analysis of the genetic epidemiology of anxiety disorders.
Am J Psychiatry ; Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev ; Elevated serum interleukin-6 IL-6 and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events.
Biol Psychiatry ; Plasma levels of tumor necrosis factor-alpha and interleukin-6 in obsessive compulsive disorder. Mediators Inflamm ; Immune modulation of the hypothalamic-pituitary-adrenal HPA axis during viral infection. Viral Immunol ; The catecholamine cytokine balance: interaction between the brain and the immune system.get link
Neuroimmune-Mediated Obsessive Compulsive Disorder - A Monograph (Paperback)
Ann N Y Acad Sci ; Vassalli P. The pathophysiology of tumor necrosis factors. Ann Rev Immunol ; Licinio J, Wong ML. The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry ; TNF-alpha polymorphisms are associated with obsessive-compulsive disorder.
Neurosci Lett ; Rev Bras Psiquiatr ; The Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders: recruitment, assessment instruments, methods for the development of multicenter collaborative studies and preliminary results. Association of polymorphisms within the promoter region of the tumor necrosis factor-alpha with clinical outcomes of rheumatic fever. Mol Immunol ; PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet ; J Leukoc Biol ; J Autoimmun ; J Inflamm ; Genetic influence on cytokine production in meningococcal disease.
Lancet ; Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens ; Enhancers and transcription factors controlling the inducibility of the tumor necrosis factor-alpha promoter in primary macrophages. J Immunol ; Evidence points increasingly toward a role for infection and immune factors in at least a subset of TS. The majority of immunologic investigations in patients with TS show a strong skew toward risk for the development of autoimmune phenomena and increased inflammatory markers Martino et al.
A wide range of viral and bacterial agents has been implicated in the generation of cross-reactive antibodies, hypothesized most commonly to occur through a process of molecular mimicry Allen et al. In molecular mimicry, similarities between the antigens on the proteins that make up a microorganism and the self-antigens on the proteins of the host allow for the antimicrobial antibodies and T cells generated by the host to also react against self-antigens i. As the direct effects of an actual infection in an animal host often differ greatly from those in humans, we restrict our focus here to the microbial agents most commonly implicated in induction of autoimmunity.
One of the earliest appearances in the literature suggesting a connection between infection and tic disorders came from Laurence Selling in , published as a case series of three boys presenting with tics that were ameliorated upon surgical correction of their sinusitis Selling, A common theme among the many subsequent reports of infectious triggers in TS that began to surface in the late s was a relationship to GAS infection; the publication of working diagnostic criteria for PANDAS by Swedo in consolidated the focus on GAS as a model for autoimmune neuropsychiatric disorder Swedo et al.
Streptococcal infection has figured prominently among the microbial agents considered as potential TS risk factors. Similarities in some motor manifestations of TS with those of SC, a post-streptococcal autoimmune movement and neuropsychiatric disorder primarily targeting the BG, and the high rate of obsessive-compulsive features in both TS and SC Murphy et al.
An association between GAS infections and onset or exacerbations of a subset of individuals with TS, tic disorders and OCD is also supported by numerous case-control Church et al.
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Some longitudinal studies fail to confirm one of the essential criteria for establishing a diagnosis of PANDAS, that of a temporal relationship between new GAS infections and clinical exacerbations Leckman et al. Additional support for a role for GAS in triggering TS came from demonstrations of the presence of high anti-streptococcal antibody titers and anti-neuronal antibodies targeting the caudate nucleus Kiessling et al. In some studies, higher levels of anti-neuronal antibodies to putamen Singer et al. Some studies find ASO and anti-DNase B antibodies to be significantly more common in TS, but not all studies differentiate TS subjects from controls on the basis of anti-streptococcal antibodies Kiessling et al.
One large, long term, population-based follow up study of children after GAS infection found a strong relationship with behavior and non tic-like motor changes but no association specifically with tics Murphy et al. Children with multiple GAS infections in the preceding month period had a fold increased risk for TS as compared with children who did not have multiple GAS infections Mell et al. In another case-control study of privately-insured children, streptococcal infection in the preceding 12 months was associated with an increased likelihood of a new diagnosis of OCD or of tic disorder, but not of TS Leslie et al.
This raised the possibility that other infectious stimuli or environmental factors may serve as inciting factors for autoimmunity. It also indicated that the autoimmune parameters identified in TS may only be a proxy for the actual pathogenic mechanisms involved in disease induction. The failure of other studies to find a temporal relationship of changes in anti-streptococcal or anti-neuronal antibody levels in TS patients with new-onset streptococcal infections Singer et al.
Discrepancies in the results across these studies cannot be easily resolved; potential explanations include differences in the specific characteristics, comorbidity and clinical status of study subjects and limitations of the assays employed to detect and quantitate anti-neuronal antibodies. It is possible that even if GAS infection is sufficient or necessary for the triggering of the initial onset of illness, other stimuli, including other infections or physical or psychosocial stressors, may be important.
We have yet to understand why certain circulating autoantibodies may become pathogenic in TS, as these are also detected with relatively high frequency in the sera of healthy controls Levin et al. Studies in animals afford the opportunity to define the relationship of autoantibody blood level, Ig isotype or subclass and circulating factors that affect BBB compromise to the timing or severity of episodes.
Other infectious agents, including Mycoplasma pneumoniae Muller et al. Acute onset movement and psychiatric disorders consisting of tics and obsessive-compulsive or other symptoms of anxiety are described following febrile illnesses of presumed but unknown infectious origin, with delay in the appearance of neuropsychiatric features ranging from a few days to a year Mink and Kurlan, Reports of improvement of TS with immunomodulatory therapies plasma exchange Allen et al.
Most of these reports, however, are based on small numbers of subjects selected largely on the basis of clinical features or history of recent infection with GAS or other pathogens, as opposed to laboratory criteria supporting the presence of anti-neuronal antibodies or other immune system disturbances. The risks associated with use of these treatment modalities, particularly in children, make it essential to intensify the search for immune markers predictive of response to these therapies. An increased prevalence of both adaptive and innate immune abnormalities is widely reported in certain TS subsets, including alterations in immune cell number or function, levels of cytokines and chemokines, presence and specificity of autoantibodies, and association with immune response gene mutations, polymorphisms or copy number variations CNV.
Animal studies directed at understanding pathogenesis and treatment response in immunologic subsets of TS provide an opportunity to discover and validate robust immune markers that reliably identify subjects with an immune diathesis who are more likely to benefit from an immunomodulatory therapy. A host of abnormalities in immune cell number and function have been reported in patients with TS. These include alterations in T, natural killer NK and B lymphocyte subsets. Reports of fewer regulatory T Treg cells in patients with moderate to severe TS as compared with age-matched healthy controls Kawikova et al.
The finding could be secondary to one of the core neurotransmitter disturbances described in TS, however. Decreased Treg number and function might be accounted for, in part, by the observation that dopamine can downregulate Tregs Kipnis et al. Studies in animals could be used to assess whether disturbances of dopamine transmission in peripheral immune cell subsets may drive autoantibody production in general, or lead specifically to the generation of antibodies directed against dopamine receptors. Augmented expression of CD19 or enhanced signaling along this pathway is associated with higher levels of autoantibody production and with autoimmune disease in both animal models and human studies Poe et al.
A key regulator of CD19 signaling pathways and thus of autoantibody generation is indoleamine 2,3-dioxygenase IDO Puccetti, , one of two enzymes known to activate the kynurenine tryptophan degradation pathway. The finding of higher levels of kynurenine pathway metabolites in two TS studies Dursun et al. Studies in animals models are consistent with a role for kynurenine pathway metabolites in induction of motor tics in TS Handley and Miskin, and will be reviewed below.
The relationship of immune cell subsets to CNS outcomes has not been examined in detail in animal models of TS.
NJCTS – Can Strep Infection Cause TS: is PANDAS Real?
Altered cytokine and chemokine levels have been reported in TS. In addition to the peripheral disturbances of immune function reported in several studies, markers of inflammation may be present in the brains of individuals with TS. Heightened expression of the genes coding for the T lymphocyte growth factor, IL-2, and monocyte chemotactic factor-1 MCP-1 , a marker of chronic inflammation, was reported in a post-mortem study of BG from adults patients diagnosed with TS Morer et al.
Animal model studies pertinent to TS have not generally examined immune cell subsets or their potential relationship to peripheral central cytokine expression. In contrast, one report based on two independent cross-sectional study samples noted that IgE serum levels tended to be decreased in one of the two samples, and also reported decreased levels of IgG3 and a trend toward a decrease in IgM levels Bos-Veneman et al.
In keeping with Landau et al. A trend toward an increase in IgG1 during tic exacerbations was found in a prospective analysis in the same study Bos-Veneman et al. IgA dysgammaglobulinemia has been reported in another study of children with TS. Whether these disturbances in Ig isotype and subclasses define a vulnerable phenotype in TS populations is unclear, as is their relationship to the detection or pathogenicity of autoantibodies within each of the different isotypes and subclasses. Studies in autoimmunity-dependent animal models may help elucidate the role of Ig of varying types and specificities in brain and behavioral outcomes.
Clinical similarity to SC, the prototypical autoantibody-mediated CNS disorder induced by GAS infection, has strengthened consideration that TS, tic disorders and OCD may also be manifestations of a post-streptococcal autoimmune process. In SC, a higher frequency of antibodies directed against BG or other targets is frequently reported, but anti-CNS antibodies are sometimes absent even in this hallmark autoimmune entity Brilot et al.
The mere presence of anti-CNS antibodies may also be insufficient to determine their pathogenic potential; anti-neuronal antibodies are highly common, even in apparently healthy individuals Levin et al. Whether anti-neuronal antibodies can be detected in subjects with TS and related disorders is a matter of some controversy Hoekstra et al. Commercial forms of these anti-glycolytic enzyme antibodies had effector function, as demonstrated by their capacity to induce apoptosis in primary rat cerebellar granule cells.
In further support of the presence of similar epitopes in GAS and these glycolytic enzymes, antibodies against pyruvate kinase were also shown to cross-react prominently with GAS proteins, supporting a probable post-streptococcal origin, and anti-streptococcal antibodies reacted with pyruvate kinase at the anticipated 60 kDa molecular weight Kansy et al.
Anti-neuronal antibody status appears to be related to TS comorbidity patterns but not to other phenotypic characteristics such as tic type and severity, duration of disease, self-injurious or aggressive behavior or family history of OCD or tics. Volumes of grey or white matter structures in frontostriatal circuits were the same in adults with TS whether anti-BG antibodies were present or absent Martino et al.
Closer dissection of the ontogeny of autoantibody development in animal models after exposure to relevant immunogens accompanied by careful delineation of antibody isotype, reactivity with the initial immunogen and with autoantigens present in CNS; and delineation of antibody binding patterns in brain circuits relevant to TS and OCD will help to address some of the apparent discrepancies of findings with the autoimmune hypothesis of TS. Detailed examination of behavioral consequences in motor, sensorimotor, and other domains relating to TS and OCD pathogenesis and determination of the potential correlation of these behaviors with the pattern of distribution of autoantibody deposits in key brain regions will provide clarification as to the mechanisms by which autoantibodies may contribute to disease.
A number of polymorphisms, CNV and mutations of genes with products affecting immune pathways have been reported in TS. Some, such as the strong association of TS with a polymorphism in IL-1RN, the gene encoding for IL-1 receptor antagonist IL-1Ra , lend support to the idea that cytokines and other immune molecules may contribute to TS pathogenesis separately from the influence of autoantibodies on the disease Chou et al. IL-1Ra, a component of the alternative type M2 macrophage response, appears to influence responses to GAS infection, as these are characterized by a combination of classical M1 macrophage type responses associated with secretion of proinflammatory cytokines TNF-a, IL-1 and IL-6 and M2 macrophage activation patterns Goldmann et al.
An increase in CNV affecting genes within histamine receptor signaling pathways that have also been shown to be involved in ASD was recently described in TS; in addition, a rare functional mutation has been described in the HDC gene that encodes the rate-limiting enzyme in histamine biosynthesis, L-histidine decarboxylase Ercan-Sencicek et al. Although these findings add support to reports of higher rates of allergic phenomena Chang et al. Animal models facilitate the evaluation of disease mechanisms and accelerate our ability to appraise the potential of therapeutic strategies.
They need not comprehensively represent every aspect of a disorder to derive this validity and value. In TS, gene-environment interplay during critical periods of brain development is thought to play a role in the pathogenesis of the disorder. Some models incorporate genetic polymorphisms or mutations implicated in the development of TS; other models focus on specific environmental factors supported by human epidemiologic or clinical studies. When the disease in question involves disordered behavior, emotion or cognition, as in the case of TS and other neuropsychiatric illnesses, assessing the suitability of an animal model becomes a more complex endeavor.
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