Immunophenotypical Characterization of a Brazilian POIS (Post-Orgasmic Illness Syndrome) Patient: Adding More Pieces to Puzzle.

Post-orgasmic illness syndrome (POIS) is a rare condition characterized by post-ejaculatory symptoms. Here is reported the first Brazilian POIS patient. Immunological investigation did not confirm the previous hypothesis of a hypersensitivity reaction. Cell immunophenotyping comparing healthy individuals produced evidence of abnormalities not associated to clinical manifestations. The patient was submitted to specific immunotherapy with transient clinical response and was referred to a psychologist but did not demonstrate clinical improvement of symptoms. Therefore, etiology of POIS remains unclear.

Stability of Cellular Immune Parameters over 12 Weeks in Patients with Major Depression or Somatoform Disorder and in Healthy Controls.

OBJECTIVE: Cellular immune status in major depression (MD) patients differs from that in somatoform disorder (SFD) patients and healthy controls (HC). It is still questionable whether the patterns of immune parameters remain stable over time. Therefore, we studied lymphocyte and monocyte cell counts and neopterin levels in peripheral blood of MD and SFD patients and HC over 12 weeks and tested for correlations between biochemical and psychometric parameters. METHODS: Thirty-nine patients with MD, 27 with SFD, and 51 HC were recruited. Peripheral blood was drawn at four visits, at 4-week intervals. We assessed the total cell count of B lymphocytes, natural killer (NK) cells, T lymphocyte subpopu-lations, and monocytes by flow cytometry, and neopterin serum levels by ELISA. Psychometric parameters were measured with questionnaires. RESULTS: Counts of lymphocytes, monocytes, and neopterin were stable in the SFD and HC groups. In the MD group, total CD3+, CD3+CD8+, NK cells, and CD3+CD25+ T cells showed inhomogeneous variances in Friedman tests, particularly in females. Neopterin correlated with depressed mood in MD patients, and with body mass index in HC. CONCLUSIONS: Cellular immune parameters are stable in HC and SFD. Our results may indicate influences of MD and gender on some cellular immune parameters. This may need to be considered in future immunological studies.

Somatoform and neurocognitive syndromes after HPV immunization are not associated to cell-mediated hypersensitivity to aluminum.

Vaccines against human papilloma virus (HPV) have been demonstrated to be very effective to prevent infection-related neoplasms. However, several reports describing heterogeneous post-vaccination phenomena have been published in last few years. The spectrum of these disorders includes both immune-mediated neurological diseases and neuropsychiatric functional disorders. Some researchers speculated about a genetic predisposition, but others hypothesized a role of adjuvants, including some metals and, particularly, aluminum. Here, we tested sixteen young girls developing somatoform and neurocognitive syndromes after the HPV immunization, through MELISA® test, detecting cell-mediated hypersensitivity to several metals. We found no association between these neurocognitive disorders and the results provided by this test; importantly, no patients showed hypersensitivity to aluminum, which is the inorganic adjuvant included in HPV vaccines. Thus, if aluminum played a role in the pathophysiology of musculoskeletal and neurocognitive disturbances occurring in some young girls after HPV immunization, that should recognize other mechanisms than the activation of aluminum-specific lymphocytes.

Defensas, emociones y estrés: la ciencia de la psiconeuroinmunología / No disponible

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Immunological aspects of botulinum toxin therapy.

INTRODUCTION: Botulinum toxin (BT) is used in many medical specialties to treat muscle hyperactivity, exocrine gland hyperactivity and pain disorders. BT drugs consist of botulinum neurotoxin (BNT), complexing proteins (CP) and excipients. Antibodies can be formed against BNT and CP. When they are formed against BNT (BTAB) they can block BT's therapeutic efficacy thus producing antibody induced therapy failure (ABTF). Areas covered: BT applied and BTAB are in a functional balance within the body. ABTF is rare, but influences the treatment algorithms of BT therapy considerably. ABTF risk factors include BT doses given, interinjection intervals, booster injections and immunological quality of the BT drug. Testing for BTAB and interpretation of ABTF is complicated. As management of ABTF is frustrating, prevention of ABTF is of major importance. Improved antigenicity of new BT drugs may improve treatment algorithms of BT therapy, substandard antigenicity may very likely be their end. Expert commentary: Concern about ABTF has influenced the treatment algorithms of BT therapy considerably. Better understanding of ABTF may improve them and, thus, the outcome of BT therapy. New BT drugs may have further improved antigenicity, especially when their CP are removed. They may, however, fail because of antigenicity problems.

High Immunoglobulin A Levels Mediate the Association Between High Anger Expression and Low Somatic Symptoms in Intimate Partner Violence Perpetrators.

It has been hypothesized that anger expression may be associated with increased salivary immunoglobulin A (sIgA) levels, which is associated with decreased somatic symptoms, and therefore anger expression may be associated with reduced somatic symptoms in intimate partner violence (IPV) perpetrators. This study tested the potential mediating effect of sIgA levels on the relationship between anger expression and respiratory and gastrointestinal symptoms in IPV perpetrators and non-violent controls. The sample consisted of IPV perpetrators (n = 19) and controls (n = 21). Saliva samples were collected for assessing sIgA levels. The State-Trait Anger Expression Inventory-2 was used to assess anger expression and the Revised version of the Somatic Symptoms Scale developed by Sandín and Chorot to measure somatic symptoms. High anger expression was associated with low levels of respiratory and gastrointestinal symptoms in IPV perpetrators mediated through high sIgA levels but the same was not true for non-violent controls. This finding supports the hypothesis that for IPV perpetrators, anger expression may be physiologically and psychologically rewarding. Future research examining other immunological parameters is needed to further test this hypothesis. Such effort may illuminate why some IPV perpetrators continue to use violence against their partners.

Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome.

OBJECTIVE: Somatization is a symptom cluster characterized by 'psychosomatic' symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of 'psychosomatic' symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms. METHOD: This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune (CMI). RESULTS: The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc. CONCLUSION: Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.

Pro-inflammatory cytokine associated with somatic and pain symptoms in depression.

BACKGROUND: More than two-thirds of depressed patients complain of somatic and pain symptoms, which are frequently regarded as a psychological reaction. Although there is a growing body of evidence showing that depression is related to immune abnormalities, few studies have investigated the association between inflammatory cytokines and somatic/pain symptoms. METHOD: Patients with depressive disorder but without any medical disorders, and age/gender/body mass index (BMI)-matched healthy subjects were enrolled. All the subjects completed the self-rating scales of the Beck Depression Inventory-II and the Depression and Somatic Symptoms Scale, which was comprised of depressive, somatic, and pain subscales. Pro-inflammatory cytokines, including C-reactive protein (CRP), interleukin-2 receptor (sIL-2R), soluble interleukin 6 receptor (sIL-6R), soluble TNF-receptors (sTNF-R), soluble P-selectin (sP-selectin), monocyte chemotactic protein-1 (MCP-1), and adiponectin, were assessed by enzyme-linked immunosorbent assays. RESULTS: In all, 109 patients with depressive disorder and 126 normal controls were enrolled. The patients with depressive disorder had significantly more severe depression, somatic and pain symptoms (all p<0.001), and higher levels of sIL-2R (p<0.0001), sTNF-R (p<0.001), and sP-selectin (p=0.005) than the normal control group. Using multivariate regression analysis with controlling of age, gender, BMI, and other pro-inflammatory cytokines, sIL-2R was the most significant predictor for depressive symptoms (p<0.0001); with further controlling of severity of depressive symptom, sP-selectin was the only predictor for somatic (p=0.002) and pain (p=0.059) symptoms. CONCLUSION: The elevated sP-selectin associated with somatic symptoms in depression, may indicate early micro-vascular changes occur subtly, and provide neurobiological evidence for somatic and pain symptom in depression.

A hypothesis regarding the cause of the functional somatic syndrome and suggestions in regard to its validation.

This hypothesis states that if the lymphocytes from some patients diagnosed as having the functional somatic syndrome were observed in the scanning electron microscope as they reacted with brain cells thought to be involved with the somatic syndrome, that unique changes in the anatomy of the T-cells would be observed.

Functional somatic symptoms in childhood and adolescence.

PURPOSE OF REVIEW: Functional somatic symptoms (FSS) are common in children and adolescents, but explanatory models that synthesize research findings are lacking. This article reviews the studies published from January 2012 to March 2013 that investigate the neurophysiological mechanisms that may underlie FSS. RECENT FINDINGS: Studies from diverse medical disciplines suggest that FSS are associated with functional differences in hypothalamic-pituitary-adrenal function, imbalances in vagal-sympathetic tone, upregulation of immune-inflammatory function, and primed cognitive-emotional responses that serve to amplify reactivity to threatening stimuli, thereby contributing to the subjective experience of somatic symptoms. SUMMARY: FSS appear to reflect dysregulations of the stress system. When seemingly disparate research findings are interpreted together within an overarching 'stress-system' framework, a coherent explanatory model begins to emerge.

Vulnerability to somatic symptoms of depression during interferon-alpha therapy for hepatitis C: a 16-week prospective study.

OBJECTIVE: This study evaluated the distinctive clinical and biological manifestations of depressive symptom subtypes (i.e., cognitive-affective and somatic) in Veterans with hepatitis C viral infection (HCV) before and during interferon-alpha (IFN) based antiviral therapy. METHODS: Thirty-two Veterans with HCV and no prior history of IFN therapy were followed prospectively during the first 16weeks of therapy to evaluate depressive symptoms and to determine if baseline cytokine and serotonin levels predicted subsequent changes in depressive scores. RESULTS: IFN therapy resulted in a significant increase in total depressive symptoms from baseline (week 0) to week 16, with neurovegetative and somatic symptoms of depression including loss of appetite, fatigue and irritability increasing within the first two weeks of therapy and continuing to increase throughout IFN therapy. When depressive symptoms were evaluated using a two-factor (i.e., Cognitive-Affective and Somatic) model, the Cognitive-Affective factor score did not change significantly following IFN therapy initiation, while the Somatic factor score showed a significant increase from week 0 to week 16. Veterans with the largest increases in somatic symptoms from week 0 to week 2 had significantly higher levels of tumor necrosis factor-alpha (TNF-α) and lower levels of serotonin at baseline, as compared to Veterans with minimal or no increase in somatic symptoms. CONCLUSION: Somatic symptoms of depression can be significantly exacerbated during IFN therapy and may be predicted by higher TNF-α levels and lower serotonin levels at baseline.

Relationship between neural activity and immunity in patients with undifferentiated somatoform disorder.

It has been suggested that somatoform disorders are related to both the brain and the immune system, and that immune functions may be influenced by cerebral asymmetry. However, few studies have examined the relationship between brain activity and immune function in somatoform disorders. Thirty-two patients with non-medicated undifferentiated somatoform disorder were enrolled in this study. Blastogenic responses to phytohemagglutinin (PHA) were used to measure immunity. Regional cerebral perfusion was measured by 99m-Tc-ethyl cysteinate dimer single photon emission computed tomography (SPECT). Significant hypoperfusion was found at the left inferior parietal lobule and the left supramarginal gyrus in the more immune-suppressed (MIS) subgroup compared with the less immune-suppressed (LIS) subgroup. However, no regions of significant hyperperfusion were found in the MIS subgroup compared with the LIS subgroup. Decreased cerebral blood flow in the left inferior parietal lobule and the left supramarginal gyrus in the patient group was also significantly associated with reduced blastogenic responses to PHA regardless of sex and age. These results suggest that the left inferior parietal lobule and the left supramarginal gyrus might play an immunomodulating role in patients with undifferentiated somatoform disorder. In addition, these results suggest the role of cerebral asymmetry in altered immunity in the patients.

Generalized anxiety and C-reactive protein levels: a prospective, longitudinal analysis.

BACKGROUND: Generalized anxiety disorder (GAD) is highly co-morbid with depression. Depression is associated with elevated levels of the inflammation marker C-reactive protein (CRP), cross-sectionally and over time. To date, no studies have looked at the association between CRP and GAD. METHOD: A total of nine waves of data from the prospective population-based Great Smoky Mountains Study (n=1420) were used, covering children in the community aged 9-16, 19 and 21 years old. Structured interviews were used at each assessment to assess GAD symptoms, diagnosis and cumulative episodes. Blood spots were collected and assayed for high-sensitivity CRP levels. RESULTS: GAD was associated with increased levels of CRP in bivariate cross-sectional analyses. These bivariate associations, however, were attenuated after accounting for demographic, substance-use and health-related covariates. In longitudinal models, there was little evidence that CRP predicted later GAD. Associations from GAD to later CRP were attenuated in models adjusted for health-related coavariates and there was evidence that the GAD-CRP association was mediated by body mass index (BMI) and medication use. CONCLUSIONS: Similar to depression, GAD was associated with elevated levels of CRP, but the effect of GAD on CRP levels was explained by the effect of GAD on health-related behaviors such as BMI and medication use. This study suggests differences in the association between inflammation and depression and GAD.

Thyroid peroxidase antibody positivity is associated with symptomatic distress in patients with Hashimoto's thyroiditis.

Previous studies suggest impairments of physical, mental, and psychic well-being in patients with Hashimoto's thyroiditis (HT), but these impairments have been shown to be independent of thyroid dysfunction. In 64 euthyroid patients with HT, symptomatic distress was assessed with the Symptom Checklist-90-Revised (SCL-90-R), a 90-item multidimensional self-report symptom inventory using a 5-point rating scale. In a subgroup of patients, endocrine testing 3 years prior to the current investigation was available. Anti-thyroid peroxidase antibodies (TPO-Abs) were associated with the three SCL-90-R global indices Global Severity Index (GSI), Positive Symptom Distress Index (PSDI), and Positive Symptom Total (PST) as well as with somatization and obsessive-compulsive symptoms after adjustment for age, gender, and thyroid function as assessed by TSH levels (all p<0.05). HT patients positive for TPO-Abs showed poorer results in the three SCL-90-R global indices as well as in the three domains: somatization, obsessive-compulsive symptoms, and depression (all p≤0.02), though the aforementioned associations did not withstand sequential Bonferroni correction for multiple testing. In contrast, TPO-Abs positivity, defined as TPO-Abs >100 IU/l, significantly predicted poorer psychosocial well-being in all of the three SCL-90-R global indices after three years, even after correction (all p≤0.02). In conclusion, high TPO-Abs are associated with poor physical and psychological well-being and appear to predict future health perception in HT patients.

Psychobiological differences between depression and somatization.

BACKGROUND: Comorbidity studies have shown that depression and somatization (multiple somatoform symptoms) often overlap. Therefore it has been suggested to classify at least some patients with somatization syndromes under the category of depressive disorders. We wanted to investigate whether psychobiological investigations confirm the lumping of somatization and depression, or whether psychobiological pathways favor distinguishing these disorders. METHOD: An overview is presented summarizing psychobiological studies including patients with depression and/or somatization-associated syndromes. We focus on the following topics: heritability, polymorphisms in special candidate genes, immune activation, hypothalamic-pituitary-adrenal (HPA) axis reactivity, serotonergic pathways, monoamino acids, and fatty acid concentrations. RESULTS: Immunological activation seems to be associated with specific features of somatoform disorders, namely, sickness behavior and pain thresholds. Genetic factors can also contribute to somatic complaints, e.g., via serotonergic pathways, HPA-axis response, immune activation, and other biological systems that contribute to the self-description of not being healthy. Some results indicate that psychobiological aspects of depression and somatization overlap in part (e.g., the relevance of serotonergic pathways), but there is clearly more evidence for discrepancies of psychobiological pathways in depression and somatization (e.g., the relevance of proinflammatory immune processes; HPA-axis activity; monoamino acid availability; omega-3-concentration; the role of triallelic subtypes of 5-HTTLPR). CONCLUSION: Many psychobiological pathways act differently in depression and somatization. These differences in psychobiology favor the distinction of these syndromes in classification approaches.

Useful biomarkers in pediatric eosinophilic duodenitis and their existence: a case-control, single-blind, observational pilot study.

OBJECTIVES: The aim of this study was to determine whether screening for food hypersensitivity could be a clinically useful biomarker for eosinophilic duodenitis in the pediatric population. PATIENTS AND METHODS: Twenty-two patients with functional dyspepsia and 19 controls with no significant history of gastrointestinal or allergic disorders were enrolled. Participants underwent skin prick, atopy patch, and serum-specific (S)-IgE, -IgG, and -IgG4 testing to corn, wheat, soy, peanut, milk, and egg. Participants in the patient group also underwent endoscopy with biopsies as part of standard care. RESULTS: Three participants in the patient group did not exhibit duodenal eosinophilia on biopsy and were excluded from data analyses. The patient group consisted of 13 females and 6 males, 8 to 17 years of age. The control group consisted of 10 females and 9 males, 8 to 17 years of age. Seven patients had at least 1 positive reaction to food by skin prick, atopy patch, or SIgE testing compared with 7 controls; odds ratio 1; 95% confidence interval 0.3 to 3.7. Receiver operating characteristics curves showed SIgG and SIgG4 performed poorly or no better than chance for predicting group assignment. CONCLUSIONS: Allergy screening for the foods tested was not useful as a biomarker for eosinophilic duodenitis in this small study. A higher rate of positive reactions to patch testing was observed in the control group than previous studies have reported. The incidence of a positive food patch test in nonselected subjects needs further investigation. Method standardization and establishment of reference intervals are needed for atopy patch tests, SIgG, and SIgG4 to better evaluate the clinical value of these measures.

Depression, traumatic stress and interleukin-6.

BACKGROUND: Recent evidence indicates that various types of interactions between nervous and immune system are important in pathogenesis of depression. These findings show that a significant role in developing depression play pro-inflammatory cytokines that may mediate its psychological, and neurobiological manifestations. Great importance among these cytokine molecules plays interleukin-6 (IL-6). There is growing evidence that this inflammatory process related to depression may be influenced by psychological stress as well as organic inflammatory conditions. These findings suggest that specific influences related to traumatic stress and dissociation could be found in close relationship to increased level of cytokine IL-6. METHODS: In the present study we have performed psychometric measurement of depression (BDI-II), traumatic stress symptoms (TSC-40) and dissociation (DES, SDQ-20), and immunochemical measure of serum IL-6 in 40 inpatients with unipolar depression (mean age 42.3+/-6.8). RESULTS: The results show that IL-6 is significantly correlated to BDI-II (Spearman R=0.47, p<0.01), TSC-40 (Spearman R=0.32, p<0.05), SDQ-20 (Spearman R=0.34, p<0.05) but not to DES (Spearman R=0.25, p=0.11). CONCLUSION: The findings of the present study indicate that increased level of IL-6 in depression could be directly related to symptoms of traumatic stress and somatoform dissociation.

Is high-sensitive C-reactive protein a biomarker for functional somatic symptoms? A population-based study.

Functional somatic symptoms (FSS) are symptoms unexplained in terms of underlying organic pathology. Alterations in the immune system function may be associated with FSS via induction of sickness behavior. We aimed to investigate whether low-grade immune system activation is positively associated with FSS in a population-based cohort of 881 adults (46% male, mean age 53.0, SD 11.4). Participants completed the somatization section of the Composite International Diagnostic Interview surveying the presence of 43 FSS. Innate immune function was assessed by measuring high-sensitive C-reactive protein (hs-CRP). Follow-up measurements of hs-CRP and FSS were performed approximately 2years later. Regression analyses, with adjustments for gender, age, body mass index, anxiety, depression, smoking, alcohol use, and frequency of exercise, did not reveal a cross-sectional association (beta=0.01, t=0.40, p=0.693) or longitudinal association (beta=-0.03, t=-0.93, p=0.352) between hs-CRP and the total number of FSS. When examining different bodily clusters of FSS, hs-CRP was not associated with the gastrointestinal FSS cluster, but the association approached statistical significance for the general FSS cluster (OR 1.08, 95% CI 0.98-1.18) and musculoskeletal FSS cluster (OR 1.08, 95% CI 0.99-1.17). For the latter association, exploratory analyses revealed that mainly the pure musculoskeletal complaints were responsible (OR 1.12, 95% CI 1.03-1.21). We conclude that the level of hs-CRP is not a biomarker for the total number of FSS in the general population. The association between hs-CRP and musculoskeletal and general FSS needs further study.

Alexithymia and interleukin variations in somatoform disorder.

OBJECTIVE: The aim of the present study was to investigate if somatoform disorders (SFD) are associated with changes in the normal serum levels of important interleukins, and further, to establish if these changes are related to the presence and severity of alexithymia in patients with SFD. METHODS: Twenty-four unmedicated patients who met the International Classification of Diseases (ICD-10) diagnostic criteria for SFD completed the psychological questionnaire to assess alexithymia (Toronto Alexithymia Scale), symptom reporting (SCL-90-R) and diagnostic criteria for SFD (Screening for Somatoform Symptoms scale). Serum concentrations of soluble interleukin 2 receptor alpha (sIL-2 Ralpha), IL-4, IL-6, IL-10 and IL-12 were determined in patients with SFD and in 9 healthy subjects. RESULTS: In patients with SFD, serum levels of IL-6 (p < 0.001), IL-10 (p = 0.047) and immunoglobulin E (p = 0.045) were significantly increased in comparison with healthy controls. Additionally, a negative correlation was observed between the level of alexithymia ('total' Toronto Alexithymia Scale score) and the serum levels of sIL-2 Ralpha (r = -0.538) in SFD. CONCLUSIONS: Taken together, these results suggest that SFD, with clinically significant alexithymia, are associated with a reduction in Th1-mediated immune function and an increase in the activation of the Th2 immune function, indicated by the augmented serum levels of IL-6 and IL-10 and elevated immunoglobulin E.