A controlled study of Tourette syndrome. II. Conduct.

To assess conduct in Tourette syndrome (TS), 47 controls, 246 TS patients, 17 attention-deficit-disorder (ADD), and 15 ADD patients with minor tics or a family history of TS (ADD 2(0) TS) were compared for the following behaviors: running away from home, lying, stealing, starting fires, vandalism, being in trouble with the law, fighting, shouting at parents or peers, attacking others, lack of respect for adults, short temper, hurting animals, feeling full of hate, being unable to stop fighting, and problems with drugs and alcohol. With the exception of running away from home and being in trouble with the law, TS patients were significantly different from controls in all other behaviors. When the components were combined for a total conduct score, only one (2.1%) of the controls had a score greater than 13, and he had TS. By contrast, 35% of the TS patients had scores greater than 13 (P less than .0005). The correlation coefficient between the total conduct score and ADD score was .48. Although the presence of ADD was an important factor in determining conduct in TS, other factors such as depression and compulsive behavior also played a contributing role. There was little correlation between the total conduct score and the number of tics. It is estimated that among non-economically disadvantaged children, 10%-30% of conduct disorder may be due to the presence of a TS gene.     

A controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems

Tourette syndrome (TS) is a common, hereditary, neurobehavioral disorder of childhood. To determine the frequency of various behavioral manifestations, we have compared 47 random normal controls to 246 patients with TS, 17 with attention-deficit disorder (ADD), and 15 with ADD secondary to a TS gene (ADD 2(0) TS). All subjects were examined prospectively with a 425-item questionnaire based on the Diagnostic Interview Schedule and the Diagnostic and Statistical Manual of Mental Disorders (DSM III). The TS patients were divided into grade 1 (too mild to treat [17.5%]), grade 2 (requiring treatment [58.9%]), and grade 3 (severe [23.6%]). Patients in all three grades of TS were significantly different from controls for DSM III symptoms of inattention, impulsivity, and hyperactivity. Sixty-two percent of TS patients had ADD, compared with 6.3% of controls; and 48.8% had ADD with hyperactivity (ADDH), compared with 4.2% of controls. In the majority of TS patients, the natural history of the disease was to start with ADDH and 2.4 years later develop motor and vocal tics. Among TS patients, 39% had previously received medication for ADDH or behavior problems, compared with 2% of the controls. Although stimulants can occasionally exacerbate tics, there was no evidence that stimulants cause TS and they are often a valuable adjunct to the treatment of TS. It is estimated that 10%-30% of ADDH is due to or associated with the presence of a TS gene. TS patients had a significantly increased frequency of (1) attending classes for the educationally handicapped, (2) placement in classes for the severely emotionally disturbed, (3) attending any special classes, (4) severe test anxiety, (5) stuttering, (6) letter, number, or word reversal, (7) reading very slowly, and (8) poor retention of material read. A reading-problem score (dyslexia) greater than or equal to 3 was present in 26.8% of TS patients, compared with 4.2% of controls. Number reversal, word reversal, and poor retention were significant even for the TS patients with tics too mild to treat. The multiple ways in which TS impacts school performance, as well as potential remedies, are discussed.     

A controlled study of Tourette syndrome. VI. Early development, sleep problems, allergies, and handedness.

Developmental milestones, problems with bladder and bowel control, sleep disturbances, allergies, and handedness were compared in 247 consecutive Tourette syndrome (TS) patients, 17 patients with attention-deficit disorder (ADD), 15 patients with ADD secondary to TS (ADD 2(0) TS), and 47 random controls. There were no significant differences in age of first talking or walking. By contrast, there were significant differences in problems with bladder and bowel control between TS patients and controls, as measured by age of first toilet training, age of last bed-wetting, frequency of enuresis, and age that bowel control was achieved. Sleep problems were pervasive in TS patients, with a significantly increased frequency of sleepwalking, night terrors, trouble getting to sleep, early awakening, and inability to take afternoon naps as a young child. In all diagnostic categories, including mild (grade 1) TS patients, a total sleep-problem score was significantly greater than that in controls. The sleep disorders and other TS symptoms are consistent with TS as a disorder of disinhibition of the limbic system. Allergies and left-handedness have been evoked as contributing to or being associated with ADD and learning disorders. There were no significant differences in the frequency of allergies or left-handedness in TS patients compared with that in controls. We conclude that when there is a clearly defined genetic cause of ADD and learning disorders, it is not associated with an increased frequency of allergies or left-handedness.     

A controlled study of Tourette syndrome. III. Phobias and panic attacks.

Comparison was made of the frequency of phobias and panic attacks in normal controls and in patients with Tourette syndrome (TS), attention-deficit disorder (ADD), and ADD secondary to a TS gene. For phobias the most significant difference between controls and TS patients was with respect to fear of public transportation (P = .002), followed by fear of being alone (P = .009), fear of being in a crowd (P = .01), fear of being in water (P = .025), fear of animals (P = .04), fear of public speaking (P = .05), and other fears (P = .05). Only 8.5% of controls had more than three simple phobias and none had more than five, whereas 26% of TS patients had more than three (P = .008) and some had as many as 13. As opposed to 19% of TS patients, none of the controls had phobias that interfered with their life (P = .001). Among female TS patients 55.1% had 3-13 phobias, compared with 8.7% of the female controls (P less than .0005). There was no correlation between the ADD score and the number of phobias (r = -.010) and little correlation with the total number of tics (r = .14). Panic attacks were present in 8.3% of the controls and 33% of the TS patients (P = .0008). This frequency increased to 55.2% (P less than .0005) for grade 3 (severe) TS patients. None of the controls, 15.9% of all TS patients (P = .002), and 31% of grade 3 TS patients (P less than .0005) had more than three panic attacks in 1 wk. Total panic-symptom score (12 possible symptoms) was significantly greater than that in the controls in all grades of TS. The presence or absence of ADD had little effect on the total panic-symptom score, but the presence of ADD resulted in a significantly lower average age at onset of panic attacks (8.8 years) compared with those TS patients without ADD (15.4 years) (P = .03). These observations indicate that phobias and panic attacks are a significant part of the symptomatology of TS and provide the first clear indication that phobias and panic attacks can be due to the presence of a major gene.     

A controlled study of Tourette syndrome. V. Depression and mania.

To evaluate the role of depression and mania in Tourette syndrome (TS), we have examined 246 TS patients, 17 attention-deficit disorder (ADD) patients, 15 patients with ADD associated with TS, and 47 controls, using (1) the standardized National Institutes of Mental Health Diagnostic Interview Schedule questions for a life history of major depression and/or mania and (2) a modified Beck depression score for evaluation of depression at the time of the examination. The results were combined into depression, Beck, and mania scores. Among the controls, 2.1% had a depression score greater than 9, and none had a score greater than 10. Among the TS patients, 22.9% had a score greater than 9 and the scores ranged up to the maximum of 18 (P less than .0005). None of the pure ADD patients had a score greater than 6, whereas 20% of the ADD-secondary-to-TS (ADD 2(0) TS) patients had scores greater than or equal to 9. Among grade 3 TS patients, 46.6% had scores greater than or equal to 9. There were no differences in the frequency of depression in the TS patients with or without ADD. Comparable results were obtained for the Beck depression score, except that the percent with a score greater than or equal to 8 was higher for the TS patients with ADD (23.7%) than for those without ADD (9.3%). There was a good correlation between the depression score and the Beck score (r = .63), but no correlation between the ADD-with-hyperactivity (ADDH) score and either the depression score (r = .086) or the Beck score (r = .077). Among the controls, none had a mania score greater than or equal to 4, compared with 19.1% of the total TS patients (P = less than .0005), 11.8% of the ADD patients (P = .002), and 26.6% of the ADD 2(0) TS patients (P = .0005). Although some of the mania questions would be expected to be answered positively by ADDH patients, the correlation coefficient between the ADDH scores and the mania scores was only moderate (r = .29), whereas the correlation with the depression score was much higher (r = .63). There was minimal correlation between the number of tics and either the depression score (r = .267) or the Beck score (r = .193). We conclude that depression and manic-depressive symptoms are common in TS patients and are an integral part of the disorder rather than being secondary to motor or vocal tics.     

A family study of Gilles de la Tourette syndrome.

Previous studies have demonstrated that Gilles de la Tourette syndrome (TS) is a familial disorder and that chronic tics (CT) and obsessive compulsive disorder (OCD) appear to be etiologically related to the syndrome. In the present study we report the results from a study of 338 biological relatives of 86 TS probands, 21 biologically unrelated relatives of adopted TS probands, and 22 relatives of normal subjects. The 43 first-degree relatives of the adopted TS and normal probands constituted a control sample. The rates of TS, CT, and OCD in the total sample of biological relatives of TS probands were significantly greater than in the relatives of controls. In addition, the morbid risks of TS, OCD, and CT were not significantly different in families of probands with OCD when compared to relatives of probands without OCD. These findings provide further evidence that OCD is etiologically related to TS.     

The brain mechanism of error detection: the P.E.T. study

In present research, the brain maintenance of the error detection mechanism was studied in resting condition and while subjects consciously implemented incorrect actions (i.e. deception). Assessment of the regional cerebral blood flow revealed involvement of anterior cingulated cortex in deception. The obtained data indicate that it is impossible to consciously control the activity of the error detection mechanism. PET study of patients with obsessive compulsive disorder in resting condition revealed a decrease of brain glucose metabolism in the anterior cingulated cortex in comparison with healthy subjects. These data pointed to malfunctioning of the error detection mechanism. The findings support the formerly proposed hypothesis about the impact of the error detection mechanism in formation and support of obsessive compulsive disorder.     

Oxytocin in obsessive compulsive disorder

A double-blind, placebo-controlled study with syntocinon (oxytocin) was carried out in 12 patients, nine females and three males with obsessive compulsive disorder (OCD). Patients were treated by intranasal administration of oxytocin spray (18 IU per day) or placebo. No reductions in the number of obsessions or compulsive behaviors were observed in either treatment group. To evaluate whether a higher dosage would exert more beneficial effects, two additional patients were treated with a threefold higher dosage of oxytocin using an open design. In one patient a slight reduction in the number of checking rituals was observed, whereas in the other patient virtually no effect was observed. The results of this study do not support the hypothesis that oxytocin might be a potential anticompulsive agent.     

Elevated CSF dynorphin A [1-8] in Tourette's syndrome

A recent neuropathological study has reported decreased levels of dynorphin A immunoreactivity in striato-pallidal fibers in the brain of a patient with severe Gilles de la Tourette's syndrome (TS). This observation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS. We report on the presence of elevated concentrations of dynorphin A [1-8] in the CSF of 7 TS patients, aged 20 to 45 years. The increase in CSF dynorphin was found to be associated with the severity of the obsessive compulsive symptoms but not with tic severity in these patients. Although CSF studies lack the precision necessary to address questions of selective involvement of neuronal system in specific CNS locations, these findings suggest that endogenous opioids are involved in the pathobiology of TS and related disorders. Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) (1). Once thought to be a rare condition, the prevalence of TS is now estimated to be one case per 1,000 boys and one case per 10,000 girls, and milder variants of the syndrome are likely to occur in a sizeable percentage of the population (2). Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consistent with an autosomal dominant form of inheritance (3,4). Neurobiologic and pharmacological data have implicated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and basal ganglia structures remain the prime candidates as the neuroanatomical origin for TS and related conditions (1). Endogenous opioids, including dynorphin and met-enkephalin are concentrated in structures of the basal ganglia (5), are known to interact with central dopaminergic neurons (6, 7), and may play an important role in the control of motor functions (8). Post-mortem brain studies have directly implicated opioids in the pathophysiology of Parkinson's disease (9), Huntington's disease (10), and most recently in TS (11). The neuropathological study of Haber et al. (11) reported decreased levels of dynorphin A [1-17] immunoreactivity in striatal fibers projecting to the globus pallidus in the brain of a patient with severe TS. This ovservation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS.(ABSTRACT TRUNCATED AT 400 WORDS)     

Getting a GRIP on liprins

Excessive grooming behaviors, cleansing rituals, and self-mutilation are important features of a range of neuropsychiatric diseases including obsessive compulsive (OC)-spectrum disorders. In this issue of Neuron, Greer and Capecchi (2002) report that Hoxb8 mutant mice exhibit this behavioral phenotype. These Hoxb8 mutants will be valuable in exploring the genetics and pathophysiology of OC-spectrum disorders as well as strategies for their treatment.     

Altered Brain Activity during Reward Anticipation in Pathological Gambling and Obsessive-Compulsive Disorder

Background

Pathological gambling (PG) and obsessive-compulsive disorder (OCD) are conceptualized as a behavioral addiction, with a dependency on repetitive gambling behavior and rewarding effects following compulsive behavior, respectively. However, no neuroimaging studies to date have examined reward circuitry during the anticipation phase of reward in PG compared with in OCD while considering repetitive gambling and compulsion as addictive behaviors.

Methods/Principal Findings

To elucidate the neural activities specific to the anticipation phase of reward, we performed event-related functional magnetic resonance imaging (fMRI) in young adults with PG and compared them with those in patients with OCD and healthy controls. Fifteen male patients with PG, 13 patients with OCD, and 15 healthy controls, group-matched for age, gender, and IQ, participated in a monetary incentive delay task during fMRI scanning. Neural activation in the ventromedial caudate nucleus during anticipation of both gain and loss decreased in patients with PG compared with that in patients with OCD and healthy controls. Additionally, reduced activation in the anterior insula during anticipation of loss was observed in patients with PG compared with that in patients with OCD which was intermediate between that in OCD and healthy controls (healthy controls < PG < OCD), and a significant positive correlation between activity in the anterior insula and South Oaks Gambling Screen score was found in patients with PG.

Conclusions

Decreased neural activity in the ventromedial caudate nucleus during anticipation may be a specific neurobiological feature for the pathophysiology of PG, distinguishing it from OCD and healthy controls. Correlation of anterior insular activity during loss anticipation with PG symptoms suggests that patients with PG fit the features of OCD associated with harm avoidance as PG symptoms deteriorate. Our findings have identified functional disparities and similarities between patients with PG and OCD related to the neural responses associated with reward anticipation.     

黄山雄性短尾猴的拥抱行为

拥抱是非人灵长类动物特殊且重要的问候方式,常用于修复冲突后的个体间关系,但拥抱行为的影响因素及其社会功能仍需进一步阐明。本研究以栖息于安徽黄山的野生雄性短尾猴为研究对象,通过系统描述拥抱行为的类型、年龄组分布,分析拥抱行为的主要影响因素,并进一步探讨该行为的社会功能。结果显示：短尾猴的拥抱行为可分为无触摸生殖器、触摸生殖器和舔生殖器3种类型,其中无触摸生殖器和触摸生殖器类型最常见;3种类型的拥抱行为主要发生在非冲突环境下;随着年龄增加,拥抱行为的无触摸生殖器类型减少,触摸生殖器类型增加;成年个体的顺位越高,则接受拥抱越多,顺位提升会使个体接受拥抱的频次显著增加,顺位接近的个体拥抱发生频繁;拥抱发起的频次也与社会联系强度有正相关关系。本研究结果证实雄性短尾猴的拥抱行为具有表达顺位认知和增强社会联系的功能。     

Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance.

To investigate the transmission of Tourette syndrome (TS) and associated disorders within families, complex segregation analysis was performed on family study data obtained from 53 independently ascertained children and adolescents with TS and their 154 first-degree relatives. The results suggest that the susceptibility for TS is conveyed by a major locus in combination with a multifactorial background. Other models of inheritance were definitively rejected, including strictly polygenic models, all single major locus models, and mixed models with dominant and recessive major loci. The frequency of the TS susceptibility allele was estimated to be .01. The major locus accounts for over half of the phenotypic variance for TS, whereas the multifactorial background accounts for approximately 40% of phenotypic variance. Penetrance estimates suggest that all individuals homozygous for the susceptibility allele at the major locus are affected, whereas only 2.2% of males and 0.3% of females heterozygous at the major locus are affected. Of individuals affected with TS, approximately 62% are heterozygous and approximately 38% are homozygous at the major locus. While none of the families had two parents affected with TS, 19% of families had two parents affected with the broader, phenotype, which includes TS, chronic tic disorder, or obsessive-compulsive disorder.     

Electroconvulsive therapy for manic state with mixed and psychotic features in a teenager with bipolar disorder and comorbid episodic obsessive–compulsive disorder: a case report

Background

Comorbidity of bipolar disorder and obsessive–compulsive disorder is common in adolescence. Obsessive–compulsive disorder symptoms may be episodic and secondary to alterations in mood, and display specific features. Management of pediatric bipolar disorder-obsessive–compulsive disorder is challenging, as pharmacotherapy of obsessive–compulsive disorder may induce or exacerbate manic episodes and there is limited evidence of treatment efficacy. Electroconvulsive therapy is sparsely used in children and adolescents, but is documented to be a safe and efficacious intervention in adults with bipolar disorder. In view of the severity of symptoms in juvenile mania, studies on treatment strategies are warranted. We report a case of an adolescent with bipolar disorder-obsessive–compulsive disorder who was successfully treated with electroconvulsive therapy during an episode of severe mania.

Case presentation

A 16-year-old girl of Middle East origin first presented to us with depressed mood, irritability, and increased obsessive–compulsive disorder symptoms, which were initially interpreted in the context of acute stress secondary to migration. She had been diagnosed with bipolar disorder and obsessive–compulsive disorder in her previous home country, but had difficulties in accounting for earlier psychiatric history. During hospitalization her mood switched to a manic state with mixed and psychotic features, at times showing aggression toward others. Interruption in her lithium treatment for a short period and possibly the introduction of an atypical antipsychotic could in part have been triggering factors. After 8 weeks of in-patient care and psychotropic drug trials, electroconvulsive therapy was initiated and administered every second or third day for 4 weeks, with marked positive response. No apparent side effects were reported.

Conclusions

This case demonstrates the need for a detailed medical history, taking special note of periodicity and character of obsessive–compulsive disorder symptoms, in adolescents with mood disorders. When treating culturally diverse patients, extra consideration should be taken. Special concerns in the pharmacological treatment to avoid the patient’s condition from worsening must be addressed, including giving priority to mood stabilization before obsessive–compulsive disorder symptoms. There are potential benefits in considering electroconvulsive therapy in young patients with severe mania where first-line treatment options have failed.

     

Brazilian psychiatric brain bank: a new contribution tool to network studies

There is an urgent need for expanding the number of brain banks serving psychiatric research. We describe here the Psychiatric Disorders arm of the Brain Bank of the Brazilian Aging Brain Study Group (Psy-BBBABSG), which is focused in bipolar disorder (BD) and obsessive compulsive disorder (OCD). Our protocol was designed to minimize limitations faced by previous initiatives, and to enable design-based neurostereological analyses. The Psy-BBBABSG first milestone is the collection of 10 brains each of BD and OCD patients, and matched controls. The brains are sourced from a population-based autopsy service. The clinical and psychiatric assessments were done by an expert team including psychiatrists, through an informant. One hemisphere was perfused-fixed to render an optimal fixation for conducting neurostereological studies. The other hemisphere was comprehensively dissected and frozen for molecular studies. In 20?months, we collected 36 brains. A final report was completed for 14 cases: 3 BDs, 4 major depressive disorders, 1 substance use disorder, 1 mood disorder NOS, 3 obsessive compulsive spectrum symptoms, 1 OCD and 1 schizophrenia. The majority were male (64%), and the average age at death was 67.2?±?9.0?years. The average postmortem interval was 16?h. Three matched controls were collected. The pilot stage confirmed that the protocols are well fitted to reach our goals. Our unique autopsy source makes possible to collect a fairly number of high quality cases in a short time. Such a collection offers an additional to the international research community to advance the understanding on neuropsychiatric diseases.     

Social development of stumptail macaques (Macaca arctoides): Momentary touching,play, and other interactions with aunts and immatures during the infants' first 60 days of life

Interactions of seven infant stumptail macaques with aunts and immatures were observed during the infants' first 60 days of life in colony groups. Data were collected using 14 interaction categories, including typical maternal behaviors, play, and five categories of momentary touching. Aunts and immatures rarely engaged in maternal behaviors such as clinging, carrying, or retrieving. Both aunts and immatures were recorded momentarily touching the infants; aunts groomed them and immatures began playing with them during the second month. Such play was primarily between age-mates and rarely between infants and yearlings. Adult males engaged in more maternal behavior than aunts during the infants' first two months of life.     

Alterations of Serum Zinc, Copper, Manganese, Iron, Calcium, and Magnesium Concentrations and the Complexity of Interelement Relations in Patients with Obsessive–Compulsive Disorder

The purpose of the present study was to evaluate the status of serum trace elements: zinc, copper, manganese, iron, calcium, and magnesium concentrations in obsessive-compulsive disorder patients. Forty-eight obsessive-compulsive disorder patients and 48 healthy volunteers were included in this study. Patients were recruited from Bangabandhu Sheikh Mujib Medical University by random sampling. Serum trace element concentrations were determined using flame atomic absorption spectroscopy (for zinc, copper, iron, calcium, and magnesium) as well as graphite furnace atomic absorption spectroscopy (for manganese). Data were analyzed using independent t test, Pearson's correlation analysis, regression analysis, and ANOVA. Statistical analysis of these data showed a definite pattern of variation among certain elements in patients with obsessive-compulsive disorder compared to controls. In patients' serum, zinc, iron, and magnesium concentrations decreased significantly (p<0.05) compared to the controls. Serum manganese and calcium concentrations were significantly higher (p<0.05) in patients compared to the controls. These data showed a definite imbalance in the interelement relations in obsessive-compulsive disorder patients compared to controls and therefore suggest a disturbance in the element homeostasis.     

Abnormal Spontaneous Neural Activity in Obsessive-Compulsive Disorder: A Resting-State Functional Magnetic Resonance Imaging Study

Neuroimaging studies of obsessive-compulsive disorder have found abnormalities in orbitofronto-striato-thalamic circuitry, including the orbitofrontal cortex, anterior cingulate cortex, caudate, and thalamus, but few studies have explored abnormal intrinsic or spontaneous brain activity in the resting state. We investigated both intra- and inter-regional synchronized activity in twenty patients with obsessive-compulsive disorder and 20 healthy controls using resting-state functional magnetic resonance imaging. Regional homogeneity (ReHo) and functional connectivity methods were used to analyze the intra- and inter-regional synchronized activity, respectively. Compared with healthy controls, patients with obsessive-compulsive disorder showed significantly increased ReHo in the orbitofrontal cortex, cerebellum, and insula, and decreased ReHo in the ventral anterior cingulate cortex, caudate, and inferior occipital cortex. Based on ReHo results, we determined functional connectivity differences between the orbitofrontal cortex and other brain regions in both patients with obsessive-compulsive disorder and controls. We found abnormal functional connectivity between the orbitofrontal cortex and ventral anterior cingulate cortex in patients with obsessive-compulsive disorder compared with healthy controls. Moreover, ReHo in the orbitofrontal cortex was correlated with the duration of obsessive-compulsive disorder. These findings suggest that increased intra- and inter-regional synchronized activity in the orbitofrontal cortex may have a key role in the pathology of obsessive-compulsive disorder. In addition to orbitofronto-striato-thalamic circuitry, brain regions such as the insula and cerebellum may also be involved in the pathophysiology of obsessive-compulsive disorder.     

Traitement psychopharmacologique du trouble obsessionnel compulsif de l’enfant et de l’adolescent

The present report review available literature on psychopharmacological treatment of obsessive compulsive disorder (OCD) in children and adolescents. There is now clear evidence that drugs that are potent serotonin reuptake inhibitors (clomipramine and SSRIs) induce a clinically substantial reduction of OC symptoms for most children and adolescents with the disorder. However, improvement is often incomplete, few patients become asymptomatic, and long-term maintenance treatment may be required. Cognitive behavioural treatment, based on graded exposure with response prevention, might have more durable benefits, and is considered as the first line treatment in mild non comorbid OCD. Because OCD frequently occurs in the context of other psychopathology and adaptative difficulties, additional individual and family psychotherapy, pharmacological associations and educational interventions are often necessary.     

CD4+FOXP3+ Regulatory T Cells Exhibit Impaired Ability to Suppress Effector T Cell Proliferation in Patients with Turner Syndrome

Objective

We investigated whether the frequency, phenotype, and suppressive function of CD4⁺FOXP3⁺ regulatory T cells (Tregs) are altered in young TS patients with the 45,X karyotype compared to age-matched controls.

Design and Methods

Peripheral blood mononuclear cells from young TS patients (n = 24, 17.4–35.9 years) and healthy controls (n = 16) were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (–) (n = 7) and TS (+) (n = 17). Tregs sorted for CD4⁺CD25^bright were co-cultured with autologous CD4⁺CD25⁻ target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function.

Results

Despite a lower frequency of CD4⁺ T cells in the TS (-) and TS (+) patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively), both groups exhibited a higher frequency of FOXP3⁺ Tregs among CD4⁺ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively). There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3⁺, and CCR4⁺CCR6⁺ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4⁺CD25⁻ T cells was significantly impaired in the TS (–) and TS (+) patients compared to controls (P = 0.003 and P = 0.041). Meanwhile, both the TS (–) and TS (+) groups had lower frequencies of naïve cells (P = 0.001 for both) but higher frequencies of effector memory cells (P = 0.004 and P = 0.002) than did the healthy control group.

Conclusions

The Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4⁺ T cells.