Stress, Inflammation and Pain: A Potential Role for Monocytes in Fibromyalgia-related Symptom Severity.

The possibility that immunological changes might contribute to symptom severity in fibromyalgia (FM) prompted this proof-of-concept study to determine whether differences in monocyte subpopulations might be present in persons with FM compared with healthy controls. Relationships were assessed by comparing specific symptoms in those with FM (n = 20) and patterns of monocyte subpopulations with healthy age-matched and gender-matched controls (n = 20). Within the same time frame, all participants provided a blood sample and completed measures related to pain, fatigue, sleep disturbances, perceived stress, positive and negative affect and depressed mood (and the Fibromyalgia Impact Questionnaire for those with FM). Monocyte subpopulations were assessed using flow cytometry. No differences were observed in total percentages of circulating monocytes between the groups; however, pain was inversely correlated with percentages of circulating classical (r = -0.568, p = 0.011) and intermediate (r = -0.511, p = 0.025) monocytes in the FM group. Stress and pain were highly correlated (r = 0.608, p = 0.004) in the FM group. The emerging pattern of changes in the percentages of circulating monocyte subpopulations concomitant with higher ratings of perceived pain and the correlation between stress and pain found in the FM group warrant further investigation. Copyright © 2015 John Wiley & Sons, Ltd.

BAFF regulates follicular helper t cells and affects their accumulation and interferon-γ production in autoimmunity.

OBJECTIVE: Follicular helper T (Tfh) cells are critical for the development of protective antibodies via germinal center (GC) B cell responses; however, uncontrolled Tfh cell expansion activates autoreactive B cells to produce antibodies that cause autoimmunity. The mechanisms that control Tfh cell homeostasis remain largely unknown. The aim of this study was to determine the contribution of BAFF to Tfh cell responses in autoimmunity. METHODS: We analyzed the properties of Tfh cells in lupus-prone mice sufficient or deficient in BCMA. Adoptive transfer studies and mixed bone marrow chimeras were used to test BCMA signaling in T cells. We assessed BAFF stimulation of Tfh cells through in vitro cell cocultures and in vivo depletion studies using flow cytometry. RESULTS: In Nba2 mice, Tfh cells expressed the BAFF receptors BCMA and B lymphocyte stimulator receptor 3 (BR-3) and accumulated in the spleen when BCMA was absent. BCMA deficiency in T cells promoted the expansion of Tfh cells, GC formation, autoantibody production, and interferon-γ (IFNγ) production by Tfh cells through BR-3. IFNγ-producing Tfh cells increased BAFF expression in dendritic cells. Blocking BAFF or IFNγ in vivo reduced Tfh cell accumulation and reduced autoimmunity in BCMA-deficient animals. Moreover, circulating Tfh-like cells that expressed BR-3 (but not BCMA) were elevated in patients with systemic lupus erythematosus, and this correlated with serum BAFF and IFNγ levels. CONCLUSION: In Nba2 mice, BCMA negatively regulates Tfh cell expansion, while BAFF signaling through BR-3 promotes Tfh cell accumulation. Our findings suggest that the balance between BCMA and BR-3 signaling in Tfh cells serves as a checkpoint of immune tolerance.

Diagnostic approach in patients with suspected vasculitis.

Vasculitides are a heterogeneous group of disorders that share the common feature of inflammation of the blood vessel wall. Vasculitis can be a systemic or localized process and depending on the disorder can affect large, medium, or small vessels. Vascular physicians including interventional radiologists often may be involved early in these cases before the establishment of a diagnosis as these patients may present with manifestations attributable to occlusive vascular syndromes. In this article, we discuss the presenting signs and symptoms of patients with vasculitis as well as laboratory and imaging studies required to further evaluate these disorders and treatment options, which include interventional as well as noninterventional options.

Cranial electrical stimulation improves symptoms and functional status in individuals with fibromyalgia.

To investigate the effects of microcurrent cranial electrical stimulation (CES) therapy on reducing pain and its associated symptoms in fibromyalgia (FM), we conducted a randomized, controlled, three-group (active CES device, sham device, and usual care alone [UC]), double-blind study to determine the potential benefit of CES therapy for symptom management in FM. Those individuals using the active CES device had a greater decrease in average pain (p = .023), fatigue (p = .071), and sleep disturbance (p = .001) than individuals using the sham device or those receiving usual care alone over time. Additionally, individuals using the active CES device had improved functional status versus the sham device and UC groups over time (p = .028).

Autoimmunity, end organ damage, and the origin of autoantibodies and autoreactive T cells in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmunity affecting many systems. Both antibodies and autoreactive T cells play significant roles in its pathogenesis. Experimental data and clinical observations indicate that autoimmunity and end organ damage are under separate genetic controls and that there are significant interactions between these two pathways. Experimental evidence has been obtained to support the hypothesis that autoantibodies and autoreactive T effector cells may be initiated by environmental factors through molecular mimicry and the inherent polyreactive nature of antigen receptors. A unified hypothesis has been postulated for the pathogenesis of SLE that has practical implications.

A randomized, controlled, double-blind pilot study of the effects of cranial electrical stimulation on activity in brain pain processing regions in individuals with fibromyalgia.

OBJECTIVE: To investigate the effects of microcurrent cranial electrical stimulation (CES) therapy on activity in pain processing brain regions. DESIGN: A randomized, controlled, three-group, double-blind pilot study. PARTICIPANTS: Persons with physician-diagnosed fibromyalgia. INTERVENTION: Active CES device, sham device, and usual care alone. RESULTS: Those individuals using the active device had a greater decrease in average pain (P = .023) than individuals using the sham device or receiving usual care alone over time. Preliminary analyses of the functional magnetic resonance imaging data on a subset of six participants from each of the two device groups show that individuals using an active CES device had a decrease in activation in the pain processing regions of the brain compared to those using a sham device. CONCLUSIONS: The observed decrease in activation in the pain processing regions may indicate a decrease in neural activity in these regions that may be related to decreased pain. This is the first randomized, controlled trial of CES in patients diagnosed with fibromyalgia to report functional magnetic resonance imaging data.

Neonatal autoimmune disease: influence of CD4+ CD25+ regulatory T cells.

Although previous studies have emphasized the tolerogenic property of murine neonatal immune system, recent studies indicate that neonatal mice are prone to autoimmune disease. This chapter will summarize the evidence for neonatal propensity to autoimmune ovarian disease (AOD) and describe the new finding that autoantibody can trigger a T cell-dependent autoimmune disease in neonatal but not adult mice. Based on depletion or addition of the CD4+ CD25+ T cells, disease resistance of older mice is explicable by the emergence of CD4+ CD25+ regulatory T-cell function after day 5, whereas disease susceptibility is associated with resistance to regulation by CD4+ CD25+ T cells.

Mechanisms of autoantibody diversification to SLE-related autoantigens.

Systemic lupus erythematosus is a prototype of systemic autoimmunity with autoantibodies (autoAbs) to ribonucleoproteins such as Ro/La, snRNP, dsDNA, and other cellular constituents. A/J mice were used to explore the mechanism of autoAb diversification with recombinant proteins and synthetic peptides. Previous studies showed that Ro60(316-335) induced Abs to Ro60, La, and snRNP proteins. Specific Abs to determinants outside Ro60(316-335) were detected. Absorption experiments showed that Abs to La and snRNP proteins were due to the induction of anti-Ro60 Abs cross-reactive with these peptides. With snRNP proteins, SmD, SmB, and A-RNP as immunogens, specific patterns of intermolecular spreading were obtained in addition to Abs to the immunogens. With SmD-immunized mice, specific Abs to A-RNP and SmB were detected. With SmB as the immunogen, specific Abs to A-RNP were detected in the majority of the mice. Only in a rare incident, specific Abs to SmD were induced. In A-RNP-immunized mice, only Abs to the 70-kD U1-RNP were seen. In all cases, Abs capable of precipitating snRNP particles were detected. Thus, the intermolecular epitope spreading is immunogen-dependent. Evidence for the presence of cross-reactive T cells to more than one autoAg was obtained. The Ag-dependent unique patterns of Ab diversification will facilitate analyses of patients' sera. These results have implications regarding the nature of the Ag-driven autoimmune process.