Janet E. Lewis

Ro60 peptides induce antibodies to similar epitopes shared among lupus-related autoantigens.

The coexistence of autoantibodies to ribonucleoproteins (RNP) in sera of patients with systemic lupus erythematosus has been attributed to intermolecular determinant spreading among physically associated proteins. Recently, we showed that murine Ab responses to rRo60 or Ro60 peptides were diversified unexpectedly to small nuclear RNP. In this investigation, the mechanisms for this autoantibody diversification were examined. Intramolecular determinant spreading was demonstrated in mice immunized with human or mouse Ro60316–335. Immune sera depleted of anti-peptide Ab immunoprecipitated Ro60-associated mY1 and mY3 RNA and remained reactive to a determinant on Ro60128–285. Absorption with the immunogen depleted the immune sera completely of anti-Golgi complex Ab (inducible only with human Ro60316–335) and anti-La Ab, and reduced substantially Ab to SmD and 70-kDa U1RNP. Mouse rRo60 completely inhibited the immune sera reactivity to La, SmD, and 70-kDa U1RNP. However, La, SmD, and 70-kDa U1RNP preferentially inhibited the antiserum reactivities to these Ags, respectively. Affinity-purified anti-La Ab were reactive with Ro60, La, SmD, and 70-kDa U1RNP. These results provide evidence that a population of the induced autoantibodies recognized determinants shared by these autoantigens. Lack of sequence homology between Ro60316–335 and La, SmD, or 70-kDa U1RNP suggests that these determinants are conformational. Interestingly, similar cross-reactive autoantibodies were found in NZB/NZW F1 sera. Thus, a single molecular mimic may generate Ab to multiple RNP Ags. Furthermore, cross-reactive determinants shared between antigenic systems that are not associated physically (Ro/La RNP and small nuclear RNP) may be important in the generation of autoantibody diversity in systemic lupus erythematosus.

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

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.

Autoimmune ovarian disease in day 3-thymectomized mice: the neonatal time window, antigen specificity of disease suppression, and genetic control.

Discovery of the CD4+CD25+ T cells has stemmed from investigation of the AOD in the d3tx mice. Besides CD4+CD25+ T cell depletion, d3tx disease induction requires effector T cell activation prompted by lymphopenia. This is supported by other neonatal AOD models in which T cell-mediated injury has been found to be triggered by immune complex or Ag immunization. In addition, there is growing evidence that support a state of neonatal propensity to autoimmunity, which depends on concomitant endogenous antigenic stimulation, concomitant nematode infection, resistance to CD4+CD25+ T cell regulation, and participation of the neonatal innate system. The suppression of d3tx disease by polyclonal CD4+CD25+ T cells appears to be dependent on endogenous Ag and the persistence of regulatory T cells. Thus, suppression of AOD occurs in the ovarian LN, and AOD emerges upon ablation of the input regulatory T cells; and in AIP, the hormone-induced expression of prostate Ag in the CD4+CD25+ T cell donors rapidly enhances the capacity to suppress disease over Ag negative donors. Finally, genetic analysis of AOD and its component phenotypes has uncovered seven Aod loci. As the general themes that emerged, significant epistatic interactions among the loci play a role in controlling disease susceptibility, the majority of the Aod loci are linked to susceptibility loci of other autoimmune diseases, and the genetic intervals encompass candidate genes that are differentially expressed between CD4+CD25+ T cells and other T cells. The candidate genes include Pdcd1, TNFR superfamily genes, H2, Il2, Tgfb, Nalp5 or Mater, an oocyte autoAg that reacts with autoantibody in sera of d3tx mice.

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.

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

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.

Restorative Yoga for Symptom Management in Fibromyalgia: Results of an 8-week Intervention

Objective: The aim of this study was to determine the feasibility of an 8-week restorative yoga intervention and to collect preliminary data on its effects on the fibromyalgia-related symptoms of chronic widespread pain, sleep disturbance, and fatigue, and health-related quality of life. In a mixed methods, single-arm, feasibility study, participants completed pre- and post-intervention semi-structured interviews and self-report assessments at baseline, weeks 4 and 8, and at a 1-month follow-up telephone interview. Results: In this group of participants (N = 12), recruitment, retention, and adherence rates were comparable to those of other fibromyalgia yoga studies: recruitment 57.14%; retention 75%; adherence to group class 87.5%; and home practice adherence 93.33%. A ratio of 1:2 yoga instructor to participants was required for the five-posture 90-minute class sequence as compared with a ratio of 1-2:10-25 yoga instructors to study participants reported in other fibromyalgia yoga studies. Statistically significant trends and minimal clinically important differences were found at week 8 when comparing participant baseline to week 8 self-report questionnaire scores for the Revised Fibromyalgia Impact Questionnaire total score (p = 0.01; 18.51%), the Pain Numeric Rating Scale for the subscales pain now (p = 0.04; 36.36%) and average pain over the past week (p = 0.04; 19.61%), the General Sleep Disturbance Scale total score (p = 0.04; 17.40%), and the Pittsburgh Sleep Quality Index total score (p = 0.02; 27.06%). Conclusion: Although the 8-week, five-posture, 90-minute restorative yoga group class was found not to be feasible as a symptom self-management strategy in this study, the findings support the need for further investigation of the home practice format. Future longitudinal, randomized, controlled trials of a restorative yoga home practice format to establish intervention efficacy and symptom-self management potential as well as those examining restorative yoga intervention resource utilization in persons with fibromyalgia are recommended

Protocol for a Feasibility Study of Restorative Yoga for Symptom Management in Fibromyalgia

Objective: Increasingly, yoga is among the therapies included in recommended multimodal treatment approaches for persons with fibromyalgia. Given the numerous yoga lineages, styles, practice components, and the relatively scant empirical evidence of the effectiveness of yoga therapy for persons diagnosed with fibromyalgia, rigorous studies are needed to support these recommendations. The development of sound methodological designs and protocols to ensure study rigor, enhance replication potential, and synthesize results across studies for establishing evidence-based best practices is needed. Thus, this article presents the design and protocol used in an 8-week intervention study aimed at determining the feasibility of restorative yoga as an appropriate intervention for persons diagnosed with fibromyalgia. A secondary aim was to collect preliminary data on the perceived effects of restorative yoga to inform future fibromyalgia yoga therapy research. Method: Using a prospective, mixed-methods, single-arm design, the investigators assessed the feasibility of an 8-week restorative yoga intervention for persons diagnosed with fibromyalgia. Twelve (12) persons with physiciandiagnosed fibromyalgia took part in twice weekly, 90-minute restorative yoga group classes and a 20-minute home practice on the five non-class evenings. The Theory of Planned Behavior informed the study design. Quantitative findings for feasibility included recruitment, study completion, and adherence rates during the 8-week intervention and at a 1-month follow-up. These findings were corroborated by qualitative findings from semi-structured pre- and post-intervention interviews. Data regarding the perceived effects of restorative yoga were collected using self-report questionnaires at intervention baseline and at weeks 4 and 8. Discussion: The study protocol provides a template for future feasibility studies of restorative yoga for persons diagnosed with musculoskeletal conditions, and one that can inform future yoga intervention studies aimed at identifying the most efficacious and feasible yoga style(s) for persons diagnosed with fibromyalgia.

BAFF regulates T follicular helper cells and affects accumulation and IFNγ production in autoimmunity

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.