Purine nucleoside phosphorylase inhibition is an effective approach for the treatment of chemical hemorrhagic cystitis.

Hemorrhagic cystitis may be induced by infection, radiation therapy, or medications or may be idiopathic. Along with hemorrhagic features, symptoms include urinary urgency and frequency, dysuria (painful urination), and visceral pain. Cystitis-induced visceral pain is one of the most challenging types of pain to treat, and an effective treatment would address a major unmet medical need. We assessed the efficacy of a purine nucleoside phosphorylase inhibitor, 8-aminoguanine (8-AG), for the treatment of hemorrhagic/ulcerative cystitis. Lower urinary tract (LUT) function and structure were assessed in adult Sprague-Dawley rats, treated chronically with cyclophosphamide (CYP; sacrificed day 8) and randomized to daily oral treatment with 8-AG (begun 14 days prior to CYP induction) or its vehicle. CYP-treated rats exhibited multiple abnormalities, including increased urinary frequency and neural mechanosensitivity, reduced bladder levels of inosine, urothelial inflammation/damage, and activation of spinal cord microglia, which is associated with pain hypersensitivity. 8-AG treatment of CYP-treated rats normalized all observed histological, structural, biochemical, and physiological abnormalities. In cystitis 8-AG improved function and reduced both pain and inflammation likely by increasing inosine, a tissue-protective purine metabolite. These findings demonstrate that 8-AG has translational potential for reducing pain and preventing bladder damage in cystitis-associated LUT dysfunctions.

Post-vaccination SARS-Cov-2 T-cell receptor repertoires in patients with multiple sclerosis and related disorders.

BACKGROUND: Attenuation in post-vaccination SARS-CoV-2 humoral responses has been demonstrated in people treated with either anti-CD20 therapies or sphingosine-1-phosphate (S1P) receptor modulators. In the setting of disease modifying therapy (DMT) use, humoral response may not correlate with effective immunity, and analysis of vaccine-mediated SARS-CoV-2-specific memory T-cell responses is crucial. While vaccination in patients treated with anti-CD20 agents leads to deficient antibody production, emerging data from live cell assays suggests intact T-cell responses to vaccination. We evaluated post-vaccination SARS-CoV-2 T-cell receptor (TCR) repertoires in DMT-treated patients using the ImmunoSeqR assay, an assay that does not require live cells. METHODS: Adults 18-80 years old without prior COVID-19, with neuroimmune conditions, who had been vaccinated with two doses of Pfizer-BioNTech or Moderna mRNA vaccines at least 3 weeks and up to 6 months prior, were recruited. Whole blood was obtained for immunosequencing, and matched serum was obtained for humoral analysis. Immunosequencing of the CDR3 regions of human TCRß chains was completed using the immunoSEQR Assay (Adaptive Biotechnologies). TCR sequences were mapped across a set of TCR sequences reactive to SARS-CoV-2. Clonal diversity (breadth) and frequency (depth) of TCRs specific to SARS-CoV-2 spike protein were calculated and relationships with clinical variables were assessed. RESULTS: Forty patients were recruited into the study, aged 25-77, and 27 female. 37 had MS, 2 had neuromyelitis optica spectrum disorder (NMOSD), and 1 had hypophysitis. Subjects treated with anti-CD20 agents and S1P receptor modulators had severely attenuated humoral responses, but SARS-CoV-2-spike-specific TCR clonal depth and breadth were robust across all treatment classes except S1P modulators. No spike-specific or non-spike-specific SARS-CoV-2-associated TCRs were found in those treated with S1P modulators (p = 0.002 for both breadth and depth). Subjects treated with fumarates exhibited somewhat lower spike TCR breadth than subjects treated with other or no DMTs (median 2.27 × 10^-5 for fumarates and 4.96 × 10^-5 for all others, p = 0.008), but no statistically significant difference was demonstrated with spike TCR depth. No other significant associations with DMT type were found. We found no significant correlations between depth or breadth and age, duration of treatment, type of vaccination, or time interval since vaccination. CONCLUSION: This is the first study to characterize post-vaccination SARS-CoV-2 TCR repertoires in DMT-treated individuals. We demonstrated a dichotomous response to SARS-CoV-2 vaccination in anti-CD20-treated patients, with severely attenuated humoral response but intact TCR depth and breadth. It is unclear to what degree each arm of the adaptive immune system impacts post-vaccine immunity, both from the standpoint of incidence of post-vaccine infections and that of infection severity, and further clinical studies are necessary. S1P modulator-treated subjects exhibited both severely attenuated humoral responses and absent spike-specific TCR depth and breadth, information which is crucial for counseling of patients on these agents. Our methodology can be used in larger studies to determine the benefit of repeated vaccination doses, including those that are modified to better target modern or seasonal variants, without the use of live cell assays.

Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.

Immune cell profiles of patients with interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder characterized by bladder pain upon filling which severely affects quality of life. Clinical presentation can vary. Local inflammatory events typify the clinical presentation of IC/BPS patients with Hunner lesions (IC/BPS-HL). It has previously been proposed that B cells are more prevalent in HL, but understanding their exact role in this environment requires a more complete immunological profile of HL. We characterized immunological dysfunction specifically in HL using immunohistochemistry. We detected significantly more plasma cells (50× increase, p < 0.0001), B cells (28× increase, p < 0.0001), T cells (3× increase, p < 0.0001), monocytes/macrophages (6× increase, p < 0.0001), granulocytes (4× increase, p < 0.0001), and natural killer cells (2× increase, p = 0.0249) in IC/BPS patients with HL than in unaffected controls (UC). Patients with IC/BPS-HL also had significantly elevated urinary levels of IL-6 (p = 0.0054), TNF-α (p = 0.0064) and IL-13 (p = 0.0304) compared to patients with IC/BPS without HL (IC/BPS-NHL). In contrast, IL-12p70 levels were significantly lower in the patients with HL than in those without these lesions (p = 0.0422). Different cytokines were elevated in the urine of IC/BPS patients with and without HL, indicating that different disease processes are active in IC/BPS patients with and without HL. Elevated levels of CD138+, CD20+, and CD3+ cells in HL are consistent B and T-cell involvement in disease processes within HL.

Dietary factors in experimental autoimmune encephalomyelitis and multiple sclerosis: A comprehensive review.

BACKGROUND: Dietary intervention in multiple sclerosis carries potential therapeutic implications. While studies utilizing animal models of multiple sclerosis (MS) have demonstrated intriguing findings, well-designed clinical trials are few in number. OBJECTIVE: The objective of this study is to review the animal model and clinical literature regarding dietary factors in experimental autoimmune encephalitis (EAE) and MS. METHODS: This manuscript provides a comprehensive review of current animal model and clinical knowledge related to dietary factors in MS. RESULTS: While there is currently little data for any specific diet in MS, there is growing evidence that certain dietary factors may influence the disease. CONCLUSIONS: Definitive information regarding dietary factors as a modifiable risk factor in MS will require larger randomized clinical trials.

Steroid-Peptide Immunoconjugates for Attenuating T Cell Responses in an Experimental Autoimmune Encephalomyelitis Murine Model of Multiple Sclerosis.

Diseases of immunity, including autoimmune diseases such as multiple sclerosis, transplantation graft rejection, allergy, and asthma, are prevalent and increasing in prevalence. They contribute to significant morbidity and mortality; however, few if any curative therapies exist, and those that are available lack either potency or specificity. Dendritic cells (DCs) are sentinels of the immune system that connect the innate and adaptive immune system and are critical regulators of both immunity and tolerance. We posited that the tolerogenic potential of DC could be harnessed to develop more specific and potent therapies for diseases of immunity by delivering autoantigen to a sufficient number of tolerogenic DCs in situ that could then inhibit pathogenic effector T cell responses. Specifically, we hypothesized that the steroid dexamethasone covalently coupled to a peptide antigen could be processed by DCs, induce tolerogenic DCs, and attenuate antigen-specific pathogenic T cell responses. To test this hypothesis, we synthesized a series of dexamethasone-peptide immunoconjugates by standard solid-phase peptide synthesis. The antigenic portion of the immunoconjugate could be presented by DCs, and the immunoconjugate induced a tolerogenic phenotype in DCs that then inhibited antigen-specific T cell proliferation in vitro. When the immunoconjugate was administered prophylactically in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis, disease was attenuated compared to dexamethasone and peptide delivered as uncoupled components. Together, this work demonstrates the utility of immunoconjugates for inducing tolerance while establishing the foundation for future studies exploring methods to enrich and target DCs for tolerogenic therapies.

Defining the role of T lymphocytes in the immunopathogenesis of neuromyelitis optica spectrum disorder.

Auto-reactive T cells are fundamental to many autoimmune processes, including neuromyelitis optica spectrum disorder (NMOSD). Several lines of evidence indicate that an antibody against aquaporin-4 (AQP4) is present in NMOSD patients. Further, this AQP4 antibody is pathogenic and can cause profound neurological damage. T cells are fundamental to many autoimmune processes, including NMOSD. Here we review work from animal models to discuss mechanisms by which auto-reactive T cells modulate the process by which antibodies cross the blood-brain barrier and orchestrate the local inflammatory milieu underlying NMOSD pathophysiology. We also examine clinical studies that document the presence of AQP4-specific T cells and the unique cytokine profile of NMOSD patients. This work encourages a renewed and broadened attention to the fundamental role of T cells in neuroautoimmune conditions which will hopefully lead to new therapies and better patients' outcomes.

Utilization of high-fidelity simulation to address challenges with the basic science immunology education of preclinical medical students.

BACKGROUND: Immune function and dysfunction are highly complex basic science concepts introduced in the preclinical medical school curriculum. A challenge for early learners is connecting the intricate details and concepts in immunology with clinical manifestations. This impedes relevance and applicability. The impetus in medical education reform is promoting consolidation of basic science and clinical medicine during the first two years of medical school. Simulation is an innovation now widely employed in medical schools to enhance clinical learning. Its use in basic science curriculums is largely deficient. The authors piloted simulation as a novel curricular approach to enhance fundamental immunology knowledge and clinical integration. METHODS: The authors introduced a Primary Immunodeficiency Disease (PIDD) simulation during a basic science immunology course for second-year medical students at the Zucker School of Medicine at Hofstra/Northwell. The simulation tasked small groups of students with evaluating, diagnosing and managing an infant with previously undiagnosed immunodeficiency. Joint facilitation by clinical and science faculty during terminal debriefings engaged students in Socratic discussion. Debriefing aimed to immerse basic science content in the context of the clinical case. Students completed a post-simulation Likert survey, assessing utility in reinforcing clinical reasoning, integration of basic science and clinical immunology, enhanced knowledge and understanding of immunodeficiency, and enhanced learning. A summative Immunodeficiency Objective Structured Clinical Examination (OSCE) question was created by faculty to assess students' recognition of a PIDD and clinical reasoning. RESULTS: The simulation was well received by students with > 90% endorsing each of the objectives on the post-simulation survey. The authors also determined a statistically significant score variance on the summative OSCE question. Higher scores were achieved by the cohort of students completing the OSCE post-simulation versus the cohort completing the OSCE pre-simulation. CONCLUSIONS: The innovative use of simulation in a highly complex basic science immunology course provides relevance and consolidation for preclinical learners. Additional data will be collected to continuously assess application of concepts and proficiency stemming from this novel curricular intervention. The authors advocate the initiation and/or expansion of simulation in non-clinical basic science courses such as immunology to bridge the gap between theory and practice.

Targeting DEC-205-DCIR2+ dendritic cells promotes immunological tolerance in proteolipid protein-induced experimental autoimmune encephalomyelitis.

BACKGROUND: Dendritic cells (DC) induce adaptive responses against foreign antigens, and play an essential role in maintaining peripheral tolerance to self-antigens. Therefore they are involved in preventing fatal autoimmunity. Selective delivery of antigens to immature DC via the endocytic DEC-205 receptor on their surface promotes antigen-specific T cell tolerance, both by recessive and dominant mechanisms. We provide evidence that the induction of antigen-specific T cell tolerance is not a unique property of CD11c+CD8+DEC-205+ DCs. METHODS: We employed a fusion between αDCIR2 antibodies and the highly encephalitogenic peptide 139-151 of myelin-derived proteolipid protein (PLP139-151), to target CD11c +CD8- DCs with a DEC-205-DCIR2+ phenotype in vivo, and to substantially improve clinical symptoms in the PLP139-151-induced model of experimental autoimmune encephalomyelitis (EAE). RESULTS: Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by αDCIR2-PLP139-151 fusion antibody (Ab) depended on an immature state of targeted DCIR2+ DCs. The mechanism of αDCIR2-PLP139-151 mAb function included the deletion of IL-17- and IFN-γ-producing pathogenic T cells, as well as the enhancement of regulatory T (Treg) cell activity. In contrast to the effect of αDEC-205+ fusion antibodies, which involves extrathymic induction of a Foxp3+ Treg cell phenotype in naïve CD4+Foxp3- T cells, treatment of animals with DCIR2+ fusion antibodies resulted in antigen-specific activation and proliferative expansion of natural Foxp3+ Treg cells. CONCLUSIONS: These results suggest that multiple mechanisms can lead to the expansion of the Treg population, depending on the DC subset and receptor targeted.

Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal.

Neurons of the medullary reticular nucleus gigantocellularis (NGC) and their targets have recently been a focus of research on mechanisms supporting generalized CNS arousal (GA) required for proper cognitive functions. Using the retro-TRAP method, we characterized transcripts enriched in NGC neurons which have projections to the thalamus. The unique expression and activation of the endothelial nitric oxide (eNOS) signaling pathway in these cells and their intimate connections with blood vessels indicate that these neurons exert direct neurovascular coupling. Production of nitric oxide (NO) within eNOS-positive NGC neurons increases after environmental perturbations, indicating a role for eNOS/NO in modulating environmentally appropriate levels of GA. Inhibition of NO production causes dysregulated behavioral arousal after exposure to environmental perturbation. Further, our findings suggest interpretations for associations between psychiatric disorders and mutations in the eNOS locus.

Crosstalk between the immune system and neural pathways in interstitial cystitis/bladder pain syndrome.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition causing intense pelvic pain and urinary symptoms. While it is thought to affect millions of people and significantly impair quality of life, difficulty with diagnosis and a lack of reliably effective treatment options leave much progress to be made in managing this condition. We describe what is currently known about the immunological and neurological basis of this disease, focusing on the interactions between the immune and nervous system. Evidence for immune involvement in IC/BPS comes from its high co-occurrence with known autoimmune diseases, altered cytokine profiles, and immune cell infiltration in patients. These cytokines have the ability to cross-talk with the nervous system via NGF signaling, resulting in hyper-sensitization of pain receptors, causing them to release substance P and creating a positive feedback loop of neuroinflammation. While it seems that the crosstalk between the immune and nervous system in IC is understood, much of the information comes from studying other diseases or from animal models, and it remains to be confirmed in patients with the disease. Identifying biomarkers and confirming the mechanism of IC/BPS are ultimately important for selecting drug targets and for improving the lives of patients with this disease.

Endoscopic Injection of Low Dose Triamcinolone: A Simple, Minimally Invasive, and Effective Therapy for Interstitial Cystitis With Hunner Lesions.

OBJECTIVE: To investigate the efficacy of low dose triamcinolone injection for effectiveness and durability in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) with Hunner lesions (HL). MATERIALS AND METHODS: Clinical data from patients with HL who underwent endoscopic submucosal injection of triamcinolone were reviewed. Demographics, pre- and postoperative pain and nocturia scores, and long-term clinical outcomes were assessed. Duration of response was estimated by time to repeat procedure. Kaplan-Meier estimator was used to evaluate time to repeat procedure. RESULTS: A total of 36 patients who received injections of triamcinolone between 2011 and 2015 were included. Median age ± standard deviation of patients was 61.5 ± 12.0 years; 28 (77.8%) were female patients and 8 (22.2%) were male patients. Twenty six patients (72.2%) received only 1 set of injections, 8 (22.2%) received 2 sets of injections, and 2 (5.56%) received 3 or more sets of injections. Average time between injections in those receiving more than 1 set of injections was 344.9 days (median: 313.5, range: 77-714). Preprocedural pain scores were 8.3 ± 1.2 (mean ± standard deviation) on Likert pain scale (0-10), and mean postprocedural pain scores at approximately 1 month were 3.8 ± 2.2, P <.001. Mean preprocedural nocturia bother scores was 7.5 ± 2.0 and mean postprocedural nocturia bother scores was 5.1 ± 2.5, P <.001. CONCLUSION: Endoscopic submucosal injection of low dose triamcinolone in patients with IC/BPS with HL is an effective and durable adjunct to existing treatment modalities. This approach is associated with low morbidity and can be performed on an outpatient basis.

Integration of leadership training into a problem/case-based learning program for first- and second-year medical students.

PURPOSE: The evolution of health care systems in response to societal and financial pressures has changed care delivery models, which presents new challenges for physicians. Leadership training is increasingly being recognized as an essential component of medical education training to prepare physicians to meet these needs. Unfortunately, most medical schools do not include leadership training. It has been suggested that a longitudinal and integrated approach to leadership training should be sought. We hypothesized that integration of leadership training into our hybrid problem-based learning (PBL)/case-based learning (CBL) program, Patient-Centered Explorations in Active Reasoning, Learning and Synthesis (PEARLS), would be an effective way for medical students to develop leadership skills without the addition of curricular time. METHODS: We designed a unique leadership program in PEARLS in which 98 medical students participated during each of their six courses throughout the first 2 years of school. A program director and trained faculty facilitators educated students and coached them on leadership development throughout this time. Students were assessed by their facilitator at the end of every course on development of leadership skills related to teamwork, meaningful self-assessment, process improvement, and thinking outside the box. RESULTS: Students consistently improved their performance from the first to the final course in all four leadership parameters evaluated. The skills that demonstrated the greatest change were those pertaining to thinking outside the box and process improvement. CONCLUSION: Incorporation of a longitudinal and integrated approach to leadership training into an existing PBL/CBL program is an effective way for medical students to improve their leadership skills without the addition of curricular time. These results offer a new, time-efficient option for leadership development in schools with existing PBL/CBL programs.

Understanding the Antibody Repertoire in Neuropsychiatric Systemic Lupus Erythematosus and Neuromyelitis Optica Spectrum Disorder: Do They Share Common Targets?

OBJECTIVE: IgG anti-DWEYS antibodies cross-reactive with DNA and the N-methyl-d-aspartate receptor subunits GluN2A and GluN2B are known to be associated with neuropsychiatric systemic lupus erythematosus (NPSLE). IgG anti-DWEYS have not been investigated in demyelinating NPSLE or in another demyelinating disorder, neuromyelitis optica spectrum disorder (NMOSD), which is a disease also found mainly in young women and associated with aquaporin 4 (AQP-4) or myelin oligodendrocyte glycoprotein (MOG) antibodies. This study was undertaken to investigate the frequency of all of these brain-reactive antibodies in patients with NPSLE, those with demyelinating NPSLE, and those with NMOSD. METHODS: Serum samples from patients with NPSLE (n = 108), patients with SLE without neuropsychiatric manifestations (n = 38), patients with NMOSD (n = 33), and healthy controls (n = 106) were assessed for the frequency of IgG anti-brain antibodies as well as IgG antibodies to AQP-4, MOG, GluN2A/GluN2B, and double-stranded DNA (dsDNA). RESULTS: Sera were positive for IgG anti-AQP-4 antibodies in 27 (82%) of 33 patients with NMOSD and 3 (27%) of 11 patients with demyelinating NPSLE, whereas all sera from patients with non-demyelinating NPSLE, patients with SLE, and healthy controls were negative for IgG anti-AQP-4. IgG anti-MOG were detected at high titers in 3 (50%) of 6 patients with NMOSD who were negative for IgG anti-AQP-4, and at low titers in 2 (18%) of 11 patients with demyelinating NPSLE and 1 (1%) of 97 patients with non-demyelinating NPSLE. IgG antibodies to dsDNA were present in 11 (33%) of 33 patients with NMOSD. Only 4 (12%) of 33 patients with NMOSD were positive for IgG anti-DWEYS, compared to 11 (29%) of 38 patients with SLE and 59 (55%) of 108 patients with NPSLE. IgG anti-DWEYS antibodies were present in 56 (58%) of 97 patients with non-demyelinating NPSLE and 3 (27%) of 11 patients with demyelinating NPSLE. Serum IgG brain-reactive antibodies were present at a similar frequency in patients with non-demyelinating NPSLE (72 [75%] of 96), those with demyelinating NPSLE (9 [82%] of 11), and those with SLE (32 [84%] of 38), but were less frequent in patients with NMOSD (20 [61%] of 33). CONCLUSION: Patients with demyelinating NPSLE should be tested for IgG antibodies to AQP-4, MOG, and DWEYS. IgG anti-AQP-4 can be considered diagnostic for NMOSD, whereas none of these antibodies appear to be diagnostic for demyelinating NPSLE. Moreover, IgG anti-dsDNA are present in patients with NMOSD but are not cross-reactive with IgG anti-DWEYS, indicating that the antigenic stimulus and mechanisms of tissue damage are potentially different between demyelinating NPSLE and NMOSD.

Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence.

Schizophrenia is a psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction. It is a pathoetiologically heterogeneous disorder involving complex interrelated mechanisms that include oxidative stress and neuroinflammation. Neurovascular endothelial dysfunction and blood-brain barrier (BBB) hyperpermeability are established mechanisms in neurological disorders with comorbid psychiatric symptoms such as epilepsy, traumatic brain injury, and Alzheimer's disease. Schizophrenia is frequently comorbid with medical conditions associated with peripheral vascular endothelial dysfunction, such as metabolic syndrome, cardiovascular disease, and diabetes mellitus. However, the existence and etiological relevance of neurovascular endothelial dysfunction and BBB hyperpermeability in schizophrenia are still not well recognized. Here, we review the growing clinical and experimental evidence, indicating that neurovascular endotheliopathy and BBB hyperpermeability occur in schizophrenia patients. We present a theoretical integration of human and animal data linking oxidative stress and neuroinflammation to neurovascular endotheliopathy and BBB breakdown in schizophrenia. These abnormalities may contribute to the cognitive and behavioral symptoms of schizophrenia via several mechanisms involving reduced cerebral perfusion and impaired homeostatic processes of cerebral microenvironment. Furthermore, BBB disruption can facilitate interactions between brain innate and peripheral adaptive immunity, thereby perpetuating harmful neuroimmune signals and toxic neuroinflammatory responses, which can also contribute to the symptoms of schizophrenia. Taken together, these findings support the "mild encephalitis" hypothesis of schizophrenia. If neurovascular abnormalities prove to be etiologically relevant to the neurobiology of schizophrenia, then targeting these abnormalities may represent a promising therapeutic strategy.

The role of B cells in multiple sclerosis: more than antibodies.

Multiple sclerosis (MS) is a multicomponent disease that is marked by continual inflammation, demyelination and irreparable damage to the central nervous system. While it was long thought to be mediated by T cells, B cells are now understood to be a central component of MS pathology. Dysfunction and aberrant activity of antigen presenting cells, T cells and B cells are all part of the pathophysiology of the disease. B cells and plasma cells contribute to disease progression through multiple mechanisms, including cytokine secretion, antibody production and antigen presentation. More recent evidence suggests that B cells may play a larger role than previously thought in driving acute episodes of MS. In this review we explore the classical understanding of MS, the evidence and current understanding of B cells in the central nervous system in health and disease, and the interactions present between B cells in the central nervous system and the peripheral nervous system. Lastly, we explore targeted immunological treatments which affect B cells and how this has informed our understanding of MS.

High levels of anti-tuberculin (IgG) antibodies correlate with the blocking of T-cell proliferation in individuals with high exposure to Mycobacterium tuberculosis.

OBJECTIVES: To determine the effect of anti-tuberculin antibodies in the T-cell proliferation in response to tuberculin and Candida antigens in individuals with different levels of tuberculosis (TB) risk. METHODS: Sixteen high-risk TB individuals, 30 with an intermediate TB risk (group A), and 45 with a low TB risk (group B), as well as 49 control individuals, were studied. Tuberculin skin test (TST) results were analyzed and serum levels of antibodies (IgG and IgM) against purified protein derivative (PPD) were measured by ELISA. Tuberculin and Candida antigens were used to stimulate T-cell proliferation in the presence of human AB serum or autologous serum. RESULTS: High levels of anti-tuberculin IgG antibodies were found to be significantly associated with the blocking of T-cell proliferation responses in cultures stimulated with tuberculin but not with Candida antigens in the presence of autologous serum. This phenomenon was particularly frequent in high-risk individuals with high levels of anti-tuberculin IgG antibodies in the autologous serum when compared to the other risk groups, which exhibited lower levels of anti-tuberculin antibodies. CONCLUSIONS: Although cellular immunity plays a central role in the protection against TB, humoral immunity is critical in the control of Mycobacterium tuberculosis infection in high-risk individuals with latent TB infection.

Advancing drug delivery systems for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.