Barbara Mittleman

T Helper Cell Dysfunction in Systemic Lupus Erythematosus (SLE): Relation to Disease Activity

Patients with systemic lupus erythematosus (SLE) are known to have defects in both humoral and cellular immunity. The significance of defective T cell-mediated immunity and its relationship to disease activity have not been clearly established. We studiedin vitro T helper cell (Th) function in 150 SLE outpatients and correlated Th function with validated measures of disease activity. Interleukin 2 (IL-2) production by peripheral blood mononuclear cells (PBMC) was measured after stimulation with the recall antigens influenza A virus (FLU) and tetanus toxoid (TET), irradiated allogeneic peripheral blood mononuclear cells (ALLO), and phytohemagglutinin (PHA). We observed three patterns of Th response: (1) 76 of 150 (50%) of patients responded to the recall antigens FLU and/or TET, ALLO, and PHA; (2) 62 of 150 (42%) of patients did not respond to recall antigens but responded to ALLO and PHA; and (3) 12 of 150 (8%) of patients did not respond to either recall antigens or ALLO antigens. This diminished T cell function was correlated with higher disease activity as measured by four scales of clinical activity, such that individuals who exhibited morein vitro immune dysfunction presented with significant increases in their clinical activity indicies. The alterations in T cell function could not be accounted for by medication doses alone. Thus, SLE patients have multiple distinct defects at the level of the Th cell which are associated with clinical measures of disease activity.

Elevated Serum and Cerebrospinal Fluid Levels of Soluble Human Herpesvirus Type 6 Cellular Receptor, Membrane Cofactor Protein, in Patients with Multiple Sclerosis

Membrane cofactor protein (CD46) is a member of a family of glycoproteins that are regulators of complement and prevent activation of complement on autologous cells. Recently, CD46 has been identified as the cellular receptor for human herpesvirus Type 6 (HHV‐6). Elevated levels of soluble CD46 have been described in several autoimmune disorders and may be implicated in the pathogenesis of these diseases. As several reports have supported an association of HHV‐6 and multiple sclerosis, it was of interest to compare levels of soluble CD46 in the sera of MS patients to that of healthy controls, other neurological disease controls, and other inflammatory disease controls. Using an immunoaffinity column comprised of immobilized monoclonal antibodies to CD46, serum levels of soluble CD46 were found to be significantly elevated in multiple sclerosis patients compared with healthy and other neurological disease controls. Moreover, multiple sclerosis patients who tested positive for HHV‐6 DNA in serum had significantly elevated levels of soluble CD46 in their serum compared with those who were negative for HHV‐6 DNA. A significant increase in soluble CD46 was also found in the serum of other inflammatory disease controls tested compared with healthy controls. Additionally, a significant correlation was demonstrated between levels of soluble CD46 in the serum and cerebrospinal fluid of multiple sclerosis patients. Collectively, these data suggest that elevated levels of soluble CD46 may contribute to the pathogenesis of inflammatory diseases, including MS.

Public-private partnerships as driving forces in the quest for innovative medicines

BackgroundDespite progress in translational research, we are still falling short in developing the innovative medicines required to address major public health needs. Furthermore, the failure rate, time, and cost required for registration of a new drug are pushing the economics of the industry to the breaking point. New models of drug development based on collaborative endeavours are badly needed to improve this dire situation.FindingsIn 2004, the US Food and Drug Administration (FDA) introduced the Critical Path Initiative with the intent of modernizing drug development by implementing public-private partnerships (PPP) to share data, expertise, and resources. In response to FDA’s initiative, in the following year the non-profit Critical Path Institute (C-Path) was formed. At the same time, the National Institutes of Health (NIH) Public-Private Partnership program was established. In Europe, the Innovative Medicines Initiative (IMI) supported jointly by the European Union and the European Federation of Pharmaceutical Industries and Associations was launched in 2008. These independent efforts have a common long-term objective, namely to facilitate the emergence of innovative medicines by developing new tools for drug discovery, new indicators for drug efficacy or safety, and new approaches for patient stratification. Herein, we present evidence that PPP already exert a positive impact on the drug development process.ConclusionsPublic-private partnerships represent attractive means to leverage resources dispersed across industry, academia, and voluntary health organizations in order to address multiple challenges of drug development in an era of constrained resources and increased regulatory pressure.

HLA antigens in childhood onset schizophrenia

Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.

Cytokine networks in Sydenham's chorea and PANDAS.

Sydenham’s chorea (SC) is a manifestation of post-streptococcal autoimmunity. Following infection of a susceptible individual with an appropriate strain of Group A beta-hemolytic streptococcus (GABHS), anti-strep antibodies are generated. SC is presumably due to the recognition by certain anti-strep antibodies of autoantigens present in the basal ganglia, and subsequent antibody-antigen binding1. The production of antibodies is a complex cascade of events which involve T cells; antigen presenting cells (APC) of various sorts; B cells; and a variety of soluble mediators which regulate cellular function and influence isotype and subclass of the antibodies produced2. We have sought to examine the role of T cell and APC derived cytokines in SC.

A pilot study of yoga as self-care for arthritis in minority communities

BackgroundWhile arthritis is the most common cause of disability, non-Hispanic blacks and Hispanics experience worse arthritis impact despite having the same or lower prevalence of arthritis compared to non-Hispanic whites. People with arthritis who exercise regularly have less pain, more energy, and improved sleep, yet arthritis is one of the most common reasons for limiting physical activity. Mind-body interventions, such as yoga, that teach stress management along with physical activity may be well suited for investigation in both osteoarthritis and rheumatoid arthritis. Yoga users are predominantly white, female, and college educated. There are few studies that examine yoga in minority populations; none address arthritis. This paper presents a study protocol examining the feasibility and acceptability of providing yoga to an urban, minority population with arthritis.Methods/designIn this ongoing pilot study, a convenience sample of 20 minority adults diagnosed with either osteoarthritis or rheumatoid arthritis undergo an 8-week program of yoga classes. It is believed that by attending yoga classes designed for patients with arthritis, with racially concordant instructors; acceptability of yoga as an adjunct to standard arthritis treatment and self-care will be enhanced. Self-care is defined as adopting behaviors that improve physical and mental well-being. This concept is quantified through collecting patient-reported outcome measures related to spiritual growth, health responsibility, interpersonal relations, and stress management. Additional measures collected during this study include: physical function, anxiety/depression, fatigue, sleep disturbance, social roles, and pain; as well as baseline demographic and clinical data. Field notes, quantitative and qualitative data regarding feasibility and acceptability are also collected. Acceptability is determined by response/retention rates, positive qualitative data, and continuing yoga practice after three months.DiscussionThere are a number of challenges in recruiting and retaining participants from a community clinic serving minority populations. Adopting behaviors that improve well-being and quality of life include those that integrate mental health (mind) and physical health (body). Few studies have examined offering integrative modalities to this population. This pilot was undertaken to quantify measures of feasibility and acceptability that will be useful when evaluating future plans for expanding the study of yoga in urban, minority populations with arthritis.Trial registrationClinicalTrials.gov: NCT01617421

Precompetitive consortia in biomedicine--how are we doing?

Too few precompetitive consortia are being formed to mitigate lost opportunities and deliver on other potential mutual gains for public and private stakeholders in drug development.

Patients' and Community Leaders' Perceptions Regarding Conducting Health Behavior Research in a Diverse, Urban Clinic Specializing in Rheumatic Diseases

Background: Disparities in the incidence, prevalence, severity, care, and outcomes for rheumatic diseases exist among racial and ethnic groups compared with White Americans. Objective: This paper describes a community-based participatory research (CBPR) approach engaging researchers, community leaders, and patients in purposeful dialogues related to the implementation of health behavior research in an urban rheumatic disease clinic. Methods: Seven focused discussions were led in either English or Spanish. Discussions were audiotaped and transcribed verbatim. Results: Six community leaders and nine patients participated in the seven scheduled focused discussions. Transcripts uncovered five major themes that assisted with study design: trust, patient–provider relationship, study implementation suggestions, decreased functional capacity, and access to healthcare. Conclusions: Engaging community partners and patients in informal and formal discussions from early phases of research design through implementation, followed by systematic application of these insights, may serve to accelerate the potential for translation from findings into improved clinical practice and optimal outcomes.

Amelioration of experimental systemic lupus erythematosus (SLE) by retrovirus infection

Experimental SLE can be induced in susceptible 129/J mice by immunization with a human anti-DNA antibody bearing a common idiotype designated 16/6 Id. Immunized mice develop autoantibodies, leukopenia, proteinuria, and immune complex deposits in renal glomeruli. Case reports have described clinical improvement in SLE in individuals becoming infected with HIV-1. Because 129/J mice are susceptible to experimental SLE and to infection with the BM5def murine leukemia virus (MuLV) mixture but do not develop the lymphoproliferative/immunodeficiency disorder known as murine AIDS (MAIDS), we superimposed this infection on immunization with the 16/6 Id. Multiple effects were observed. First, we noted an amelioration in the course of experimental SLE. Second, both in experimental SLE and in BM5def MuLV infection, immunoreactivity to HIV-1 gp120 was demonstrated, although gp120 is not present in the BM5def MuLV viruses. Third, production of autoantibodies characteristically found in SLE, e.g., anti-DNA, anti-RNP, and anti-SSA, was seen in BM5def MuLV-infected mice, demonstrating that an immune response as a consequence of infection had occurred despite the absence of MAIDS induction. We conclude that (1) retrovirus inoculation may ameliorate the course of experimental SLE; and (2) retrovirus inoculation, even in the absence of MAIDS induction, induces an immunologic response which promotes the production of potentially pathogenic autoantibodies.