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Mathieu Chappuy,1– 3 Fadi Meroueh,4 Benoit Trojak,5,6 Jérôme Bachellier,7 Patrick Bendimerad,8 Margaux Kosim,9,10 Peter Hjelmström,11 Philippe Nubukpo,12,13 Georges Brousse,14,15 Benjamin Rolland1,2,16 1Service Universitaire d’Addictologie de Lyon (SUAL), CH Le Vinatier, Bron, 69500, France; 2Service d’Addictologie, Groupement Hospitalier Centre, Hospices Civils de Lyon, Lyon, France; 3CSAPA, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France; 4UCSA, CHU Lapeyronie, Montpellier, France; 5Service Hospitalo-Universitaire d’Addictologie, CHU de Dijon, Dijon, France; 6INSERM U1093, UFR Staps, Université de Bourgogne Franche Comté, Dijon, France; 7Service Universitaire d’Addictologie de Tours, CHU Bretonneau, Tours, France; 8Service d’Addictologie, Groupe Hospitalier de La Rochelle-Ré-Aunis, La Rochelle, France; 9Consultations de Médecine-Alcoologie PASS, Groupe Hospitalier Pitié Salpêtrière, Paris, France; 10Camurus SAS, Paris, France; 11Camurus AB, Ideon Science Park, Lund, Sweden; 12Service d’Addictologie, Centre Hospitalier Esquirol, Limoges, France; 13INSERM UMR 1094, Université de Limoges, Limoges, France; 14Service de Psychiatrie B et d’Addictologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France; 15Équipe d’Accueil 7280, Université Clermont Auvergne, Clermont-Ferrand, France; 16INSERM U1028, CNRS UMR 5292, CRNL, Université de Lyon, UCBL1, Bron, FranceCorrespondence: Benjamin RollandService Universitaire d’Addictologie, CH Le Vinatier, Pôle MOPHA, 95 Bd Pinel, Bron, 69500, FranceTel +33 437 915 555Fax +33 437 915 556Email benjrolland@gmail.comPurpose: Extended-release buprenorphine (XR-BUP) covers a range of formulations of buprenorphine-based treatments for opioid use disorder (OUD) that release the medication over a period of one week, one month, or six months. OUD is particularly prevalent among incarcerated populations, and previous findings have shown that incarcerated subjects were not less interested in XR-BUP than non-incarcerated subjects. However, no study has ever investigated whether the factors of interest in XR-BUP were similar in incarcerated and non-incarcerated populations.Patients and Methods: We carried out post-hoc analyses using data from the “AMBRE” survey, which was conducted among 366 individuals with OUD, that were recruited in 68 French addiction settings, including six prison medical centers. The reasons for interest in XR-BUP were compared between incarcerated and non-incarcerated interviewees, using logistic regressions models, which provided raw and adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Adjustment variables were gender, age category, level of education, and type of current medication for OUD, respectively.Results: Data from 317 participants (ie, 221 non-incarcerated, and 96 incarcerated individuals) were included in the analyses. Adjusted comparisons found that “no longer taking a daily treatment” (aOR= 2.91; 95% CI= 1.21– 6.98) and “having a more discreet medication” (aOR= 1.76; 95% CI= 1.01– 3.10) were reasons that appealed more to incarcerated participants than to non-incarcerated ones. On the other hand, the potential reduction of withdrawal symptoms (aOR= 0.54; 95% CI= 0.29– 0.99) or the risk of misuse (aOR= 0.56; 95% CI= 0.34– 0.94) associated with XR-BUP treatment were considered more important by non-incarcerated individuals than by incarcerated ones.Conclusion: Incarcerated interviewees were interested in XR-BUP for different reasons than those outside prison. In particular, incarcerated patients were more interested in practicability and discretion features, and less in improving recovery or reducing misuse than non-incarcerated patients.Keywords: prison, opioid use disorder, buprenorphine, preferences

Takayasu's arteritis (TA) is a chronic large vessel vasculitis with a predilection for the aortic arch and its branches. T lymphocytes may be important in the pathogenesis as they have been found to initiate the vascular lesions. To elucidate further the role of T cells in thc disease, we studied circulating CD4+ and CD8+ T cells, expression of the activation marker (HLA-DR). marker for naive (CD45RA) and primed (CD45RO) cells and the different variable α/β (AV/BV) gene segments on them. The TCR AV/BV repertoire was studied using a panel of 15 T cell receptor (TCR) V-specific MoAbs by flow cytometry in 18 patients and 23 age- and sex-matched controls. Patients had a higher percentage of AV12S1 (P<0.05), BV6S7 (P<0.05) and BV9 (P<0.05)-bearing CD4+ cells. Patients also had a higher frequency of expansions, i.e. of T cell populations with an abnormally high TCR AV/BV gene usage. In patients' CD4+ subset of cells, there were 22 expansions out of 231 analyses (9.5%), whereas in controls, four were expanded out of 310 analyses (1%) (P<0.01). For CD8+ cells, the frequency of expansions was 32 in 231 analyses (14%) in patients and nine out of 304 analyses in controls (3%) (P<001). In addition, there was a correlation between CD4+ expansions and disease activity; nine out of 10 patients with active disease in comparison with two out of eight patients with inactive disease (P<0.01) had an expansion. Some of the expanded populations in patients were phenotypically characterized and observed to be HLA-DR+, CD28+, CD45RA+ and CD45RO+, with a greater proportion being CD45RO+. Patients had a higher percentage of expression of KLA-DR on both CD4+ and CD8+ T cells (P < 0.01). The percentages of naive and primed CD4+ and CD8+ T cells, γδ+ T cells and natural killer cells were comparable to those in the control group. [ABSTRACT FROM AUTHOR]

Discusses the use of a roentgen stereophotogrammetric procedure of recording variations in the volume of organs in living animals. Differences in the coordinate computations in a variety of x-ray photographs; Method of obtaining volume changes at small additions in the coordinates; Percental magnitude of the approximation error.

Aim: To identify and characterize oxycodone related deaths in Sweden from 2006 to 2018 and to compare them to other opioid-related deaths., Methods: To assess the factors contributing to the deaths, we used multinomial logistic regression to compare oxycodone-related deaths extracted from all forensic autopsy examinations and toxicology cases in the age groups 15-34 (reference group), 35-54 and 55-74 with regard to sex, presence of benzodiazepines and alcohol at the time of death, prescription of oxycodone, benzodiazepines and antidepressants, previous substance use-related (SUD) treatment, and manner of death. The oxycodone related deaths were compared with deaths with presence of other opioids., Result: We identified 575 oxycodone-related deaths, and the rate increased during the study period from 0.10 to 1.12 per 100,000 in parallel with an increase of oxycodone prescriptions from 3.17 to 30.33 per 1000. Oxycodone-related deaths amounted to 10.0% of all opioid-related deaths. The deaths occurred mainly in older patients previously being prescribed oxycodone. Benzodiazepines were present at the time of death in 403 (70%) and alcohol in 259 (45%). Prescriptions of any opioid for pain (61%), oxycodone (50%), benzodiazepines (67%) and antidepressants (55%) were common. Only 15% had received treatment for SUD during the last year., Conclusion: Oxycodone-related deaths increased in Sweden between 2006 and 2018 in parallel to an increase in oxycodone prescriptions. The increase occurred mainly in older patients being prescribed oxycodone for pain. There might be specific interventions needed to avoid oxycodone-related deaths compared to other opioid-related deaths associated with illicit opioid use., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To explore the factors determining the interest in extended-release buprenorphine (XR-BUP) injections among patients receiving opioid agonist treatment (OAT) in France., Methods: 366 patients receiving OAT for opioid use disorder, recruited in 66 French centers, were interviewed from 12/2018 to 05/2019. A structured questionnaire assessed their interest in XR-BUP using a [1-10] Likert scale. 'More' vs. 'less' interested groups were defined using the median score of interest, and their characteristics were explored using adjusted odds ratios (aORs) and 95 % confidence interval (95 %CI). Independent variables were as follows: sociodemographic characteristics, OAT-related features (e.g., type of OAT and prescriber, dosing, or duration of treatment), OAT representations, and personal objectives of treatment., Results: The median interest in XR-BUP was 7 (interquartile range: 3-9) out of 10. The participants who were 'more interested' (i.e. those scoring ≥7) showed no substantial difference in sociodemographic characteristics, relative to the 'less interested' participants. However, they more frequently reported forgetting to take their OAT (OR = 1.81; CI95 % = 1.06-3.10) or reported experiencing situations where taking their OAT was impractical (aOR = 1.69; CI95 % = 1.05-2.73). Their treatment objective was more focused on stopping illicit drugs (aOR = 1.67; 95 %CI = 1.02-2.70), reducing health risks (aOR = 3.57; 95 %CI = 1.67-7.69) and craving (aOR = 2.38; 95 %CI = 1.39-4.02) or improving family (aOR = 1.81; 95 %CI = 1.03-3.13) or professional (aOR = 2.22; 95 %CI = 1.43-3.85) recovery., Conclusions: In France, where the access to OAT is relatively unrestricted, the majority of participants were interested in XR-BUP formulations. Being interested was associated with treatment objectives focused on abstinence and recovery, and with experiencing constraints in taking a daily oral OAT., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: To identify methadone-related deaths and determine the prevalence among youth and young adults in Sweden 2006-15., Design, Setting and Participants: National retrospective registry study comparing data from all forensic autopsy examinations and toxicology cases involving methadone during 2006-15 in individuals aged 15-29 years with police records, previous pharmaceutical prescriptions and health-care episodes., Measurements: Multinomial logistic regression. To assess the factors contributing to the deaths, we compared individuals with and without previous substance use treatment and opioid use-related diagnoses with regard to previous opioid agonist treatment (OAT), psychiatric care and previous pain medication. To assess the circumstances of deaths, we analyzed the presence of other drugs and other factors at time of death., Findings: We identified 269 methadone-related deaths, and the rate increased during the study period. Seventy-two (27%) cases had not previously received substance use treatment, 112 (42%) had received treatment but had no opioid use-related diagnosis and 85 (32%) had received treatment and had an opioid use-related diagnosis. In total, only 10 individuals had been prescribed methadone during the year before death. Prescriptions of benzodiazepines (60%), antidepressants (62%) and opioids for pain (22%) the year before death were common. Most deaths occurred during sleep with a time lag from ingestion of methadone., Conclusion: Prescription opioid- and methadone-related deaths increased in the group aged 15-29 years in Sweden between 2006 and 2015. Exposure to non-prescribed methadone and prescribed benzodiazepines, antidepressants and opioids for pain appears to be common in drug-related deaths in youth and young adults in Sweden., (© 2020 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Context: There is currently no consensus regarding optimal dose or dose-range of buprenorphine (BUP) for treatment of opioid use disorder (OUD). Objective: To elucidate the relationship between BUP dose and opioid receptor blockade, retention in treatment and illicit opioid drug use. Methods: Systematic review of the scientific literature through searches in the databases MEDLINE and PubMed. Results: The review of the opioid receptor blockade studies did not find evidence that a daily sublingual (SL) BUP tablet dose higher than 16 mg confers added blockade benefit, while doses under 8 mg are insufficient to produce opioid receptor blockade. The data are inconclusive regarding the relative effectiveness of an 8 mg SL BUP tablet dose versus a 16 mg SL BUP tablet dose in terms of opioid receptor blockade. The review did not establish any clear relationship between BUP dose and treatment retention or illicit opioid use. Conclusions: The BUP dose in treatment of OUD should be individualized based on a continuous clinical benefit-risk assessment. Further research is needed to better understand the relationship between dose and efficacy over time in patients with this complex disorder.

This prospective, randomized, active-controlled, non-inferiority study evaluated the efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet (Zubsolv ® ; buprenorphine/naloxone rapidly dissolving tablet) versus generic buprenorphine for induction of opioid maintenance among dependent adults. The study, conducted at 13 sites from June 2013 to January 2014, included a 2-day blinded induction phase and a 27-day open-label stabilization/maintenance phase. During the blinded induction, patients received fixed doses of buprenorphine/naloxone rapidly dissolving tablets or generic buprenorphine. During open-label stabilization/early maintenance, all patients received buprenorphine/naloxone rapidly dissolving tablets. The primary efficacy assessment was treatment retention at day 3; buprenorphine/naloxone rapidly dissolving tablets were considered non-inferior to generic buprenorphine if the lower limit of the 95% confidence interval for the difference between the treatments was ≥-10% in patients retained on day 3. Secondary assessments included opioid withdrawal symptoms and cravings as measured using the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the opioid cravings visual analogue scale. Safety was also assessed. A total of 313 patients were randomly assigned to induction with generic buprenorphine or buprenorphine/naloxone rapidly dissolving tablets. The mean age was 38.4 years, and the mean duration of opioid dependence was 12.4 years. For the primary efficacy assessment, 235 of 256 patients (91.8%) were retained at day 3 and continued to the maintenance phase. The lower limit of the 95% confidence interval was -13.7; thus, buprenorphine/naloxone rapidly dissolving tablets did not demonstrate non-inferiority to generic buprenorphine, and significantly more patients who received induction with generic buprenorphine (122/128 [95.3%]) were retained at day 3 compared with those who received induction with buprenorphine/naloxone rapidly dissolving tablets (113/128 [88.3%]; 95% confidence interval: -13.7, -0.4; p = 0.040). The rates of clinical response, as measured by the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the visual analogue scale, were comparable among patients regardless of the induction medication. Treatment with buprenorphine/naloxone rapidly dissolving tablets was generally safe and reduced the severity of withdrawal symptoms and cravings.

Purpose: Sublingual buprenorphine and combination buprenorphine/naloxone (BNX) are effective options for the treatment of opioid dependence. A BNX sublingual tablet approved by the US Food and Drug Administration for the induction and maintenance treatment of opioid-dependence in adults was developed as a higher-bioavailability formulation, allowing for a 30% lesser dose of buprenorphine with bioequivalent systemic exposure compared with another BNX sublingual tablet formulation. No data were previously available comparing the higher-bioavailability BNX sublingual tablet to generic buprenorphine or BNX sublingual film; we therefore evaluated treatment retention during induction and stabilization with the higher-bioavailability BNX sublingual tablet versus generic buprenorphine or BNX sublingual film., Methods: This multicenter, prospective, randomized, parallel-group noninferiority trial was conducted at 43 centers in the United States. Eligible patients were adults aged 18 to 65 years who met the criteria for opioid dependence and had at least mild withdrawal symptoms. On days 1 and 2, patients received blinded, fixed-dose induction with the higher-bioavailability BNX sublingual tablet or generic buprenorphine. On days 3 to 14, patients induced with BNX received open-label, titrated doses of the BNX tablet for stabilization; patients induced with buprenorphine received sublingual BNX film. Co-primary end points were treatment retention on days 3 and 15; noninferiority was concluded if the lower limit of the 95% CI of the between-group difference in treatment retention was ≥-10%. Tolerability was assessed throughout the study period., Findings: A total of 758 opioid-dependent patients were included in the study (BNX sublingual tablet, 383 patients; generic buprenorphine, 375). Day-3 retention rates were 93.9% (309/329) and 92.6% (302/326) with the BNX tablet and buprenorphine, respectively (between-group difference 95% CI, -2.6 to 5.1). Day-15 retention rates were 83.0% (273/329) and 82.5% (269/326) with the BNX tablet and BNX film, respectively (between-group difference 95% CI, -5.3 to 6.3). No unexpected tolerability issues were identified; the safety profile of the BNX sublingual tablet was similar to those of generic buprenorphine and BNX film., Implications: Based on the findings from this study in patients with opioid dependence, the higher-bioavailability BNX sublingual tablet formulation was noninferior to both generic buprenorphine (induction) and BNX film (stabilization). These findings suggest that BNX sublingual tablets are an efficacious and well-tolerated option for induction and early stabilization treatment of opioid dependence. ClinicalTrials.gov identifier: NCT01908842., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery., Objective: To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability., Methods: Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4 mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2 mg)., Results: Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively., Conclusions: A sublingual tablet formulation with an improved acceptability has been successfully developed.

A T-cell-mediated autoimmune process against central nervous system myelin is believed to underlie the pathogenesis of multiple sclerosis (MS). Formation of immunological memory is based on the differentiation of naïve T cells to memory T cells after exposure to antigens and specific cytokines. The aim of this study was to analyse peripheral blood mononuclear cells in patients with MS for different T-cell subsets including naïve and memory T cells. Flow cytometry and enzyme-linked immunosorbent assay were used to analyse memory T-cell subsets and plasma concentration of interleukin-15 (IL-15) in peripheral blood of MS patients, patients with other neurological disorders and healthy controls. MS patients had a skewed distribution of T cells with an increased level of CD8+/CCR7+/CD45RA - central memory T cells (TCM) compared to healthy controls. In addition, MS patients showed significantly higher levels of plasma IL-15 than healthy controls did. Upregulated CD8+ TCM in MS patients may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. This derangement may be important for maintaining chronic inflammation in MS.

The role of B cells and antibodies in the pathogenesis of multiple sclerosis (MS) is controversial. We investigated the expression of B-cell-activating factor of the tumor necrosis factor family (BAFF), a protein indispensable for B-cell survival, and of its three receptors in MS patients and controls. BAFF mRNA levels in monocytes, and BAFF-receptor mRNA in B and T cells, were higher in patients than in healthy controls; yet, BAFF protein levels in cerebrospinal fluid and plasma were similar in patients and headache controls. In addition, each MS disease course was associated with a unique expression pattern for all four molecules.

The attraction of leukocytes to tissues is essential for inflammation and the initiation of the autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytokines. We investigated whether human chemokine receptor gene polymorphisms, namely CCR5-Delta32 and CCR2-64I, are associated with susceptibility to autoimmune Addison's disease. Genotyping was performed in 56 patients and 127 healthy controls by a new method using pyrosequencing for CCR2-64I and by polymerase chain reaction and detecting gel for CCR5-Delta32. None of the CCR2 or CCR5 alleles was found to be associated, either positively or negatively, with disease risk. Our results indicate that the CCR2-64I and CCR5-Delta32 gene polymorphisms do not play a major role in conferring genetic risk for, and/or protection against, autoimmune Addison's disease.

Objective: To investigate functional properties of the germinal center (GC)-like structures observed in salivary glands of patients with Sjögren's syndrome (SS) and to determine the frequency with which such structures develop., Methods: Hematoxylin and eosin-stained sections from 165 minor salivary gland biopsy samples were screened for GC-like structures. Expression of markers for GCs (CD3, CD20, Ki-67, CD35, CD31), adhesion molecules (intercellular adhesion molecule 1, lymphocyte function-associated antigen 1, vascular cell adhesion molecule 1, very late activation antigen 4), chemokines (CXCL13, CCL21, CXCL12), and production of autoantibodies (anti-Ro/SSA and anti-La/SSB) was investigated by immunohistochemistry. Apoptosis was investigated by TUNEL staining., Results: GC-like structures were observed in 28 of 165 patients (17%). When GCs were defined as T and B cell aggregates with proliferating cells with a network of follicular dendritic cells and activated endothelial cells, such microenvironments were found in all patients in whom structures with GC-like morphology were observed. The defined microenvironments were not found in patients without apparent GC-like structures. The GCs formed within the target tissue showed functional features with production of autoantibodies (anti-Ro/SSA and anti-La/SSB) and apoptotic events (by TUNEL staining), and the local production of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly increased (P = 0.04) in patients with GC development., Conclusion: Lymphoid neogenesis and functional ectopic GC formation take place in salivary glands of a subset of patients with SS. Our data suggest that the ectopic secondary lymphoid follicles contain all elements needed for driving the autoimmune response. Our findings underscore a key role for the target organ in recruitment of inflammatory cells and propagation of the disease process.

The aim of this study was to examine the association of human autoimmune myasthenia gravis (MG) with two DNA polymorphisms of the chemokine receptors CCR5-Delta 32 and CCR2-64I. CCR2 and CCR5 interact primarily with the human CC family ligands CCL2 (formerly called monocyte chemoattractant protein; MCP-1), CCL3 and CCL4 (macrophage inflammatory protein-1 alpha and -1 beta; MIP-1 alpha/beta), and their main function is to recruit leukocytes from circulation into the tissues, thus playing an important role in human inflammatory disorders. A PCR-based genotyping method was used to determine the genetic variation at the CCR5 gene and an automated real-time Pyrosequencing technology was employed for the analysis of G right curved arrow A point mutation at the CCR2 gene. Results obtained from 158 patients and 272 healthy controls demonstrate no evidence of association between genetic variants of CCR2 and CCR5 with MG and its clinical manifestations. CCR2-64I and CCR5-Delta 32 genotypes are thus unlikely to be involved in protection or predisposition to MG.

It is well known that type 1 diabetes mellitus (T1DM) is a complex genetic disease resulting from the autoimmune destruction of pancreatic beta cells. Several genes have been associated with susceptibility and/or protection for T1DM, but the disease risk is mostly influenced by genes located in the class II region of the major histocompatibility complex. The attraction of leukocytes to tissues is essential for inflammation and the beginning of autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytolines. Some studies have shown that CCR2-64I and CCR5-Delta 32 might be important for protection of susceptibility to some immunologically-mediated disorders. In the present study, we demonstrate the lack of association between CCR2-64I and CCR5-Delta 32 gene polymorphism and TIDM and we describe a new method for a simple and more precise genotyping of the CCR2 gene.

Inflammation is a serious medical problem that causes suffering in many common diseases such as rheumatoid arthritis and asthma. Despite the fact that the clinical signs of inflammation--rubor, tumor, calor and dolor--have been known for almost two thousand years, our knowledge of the molecular pathways that mediate inflammation is still limited. Today's anti-inflammatory drugs are non-specific and have many undesirable side effects. The discovery of chemokines as small specific regulatory proteins of the immune system has increased our understanding of the inflammatory process. We have reason to believe that chemokines and their receptors are going to be targets for a new kind of anti-inflammatory therapy.

Chronic inflammation is a complex pathophysiological process with accumulation of mononuclear cells seen in response to invading pathogens, neoplastic transformation, or autoimmune recognition of self-antigens. The inflammatory process has evolved to facilitate effective elimination of pathogens and tumors and it is normally transient and turned off when the causative stimulus has been eliminated. Occasionally, however, the process is sustained for a long time and can lead to severe tissue damage. This is seen in organ-specific autoimmune diseases such as rheumatoid arthritis, Sjögren's syndrome, and Hashimoto's thyroiditis, but also in infectious diseases such as Helicobacter pylori-induced gastritis. Disturbingly, many of these chronic inflammatory diseases are associated with an increased risk for neoplastic transformation and development of lymphomas. This review summarizes experimental evidence suggesting that chronic inflammation involves ectopic de novo formation of organized lymphoid tissue and that this lymphoid neogenesis is regulated by expression of homing chemokines.

A complete prevention of clinical experimental autoimmune myasthenia gravis (EAMG) was observed in lymphotoxin (LT)-alpha deficient (LT-alpha(-/-)) mice compared to LT-alpha(+/+) mice when immunized with acetylcholine receptor. However, only a partial prevention of clinical EAMG incidence was observed in LT-beta(-/-) mice compared to LT-beta(+/+) mice. LT-alpha(-/-)and LT-beta(-/-) mice had lower mean titers of total IgG, IgG(1), IgG(2a) and IgG(2b) and higher or equal mean titers of IgM anti-AChR antibodies compared to controls. Therefore, LT-alpha(-/-)and LT-beta(-/-) AChR immunized mice are capable of mounting a primary (IgM) humoral immune response to AChR, but are less capable of switching to the pathogenic anti-AChR IgG isotypes. LT could play a significant role in the pathogenesis of myasthenia gravis.

HLA genes have been shown to be associated with cervical intraepithelial neoplasia (CIN), a precursor of cervical cancer. The human papillomaviruses (HPV) types 16 and 18 are the major environmental cause of this disease. Because the immune system plays an important role in the control of HPV infection, the association of polymorphic HLA could lead to a different immune response to control the development of cervical cancer. The aim of this study was to analyze the association between CIN and a microsatellite polymorphism of tumor necrosis factor (TNFa) taking HPV exposure and CIN-associated HLA haplotypes into account. In a nested case-control study in northern Sweden, 64 patients and 147 controls matched for age and sex and derived from the same population-based cohort were typed for TNFA, HLA-DR, and DQ and assayed for antibodies to HPV types 16 and 18. TNFa polymorphism was not associated with CIN per se. However, there was a significant increase in the frequency of TNFa-11 among HPV16-positive and HLA DR15-DQ6 (B*0602) patients compared with HPV16- and HLA-DQ6-negative patients (odds ratios, 5.4 and 9.3, respectively). The relative risk for CIN conferred by the combination of TNFa-11, HLA-DQ6, and HPV 16 positivity was 15. Our study suggests that the TNFa-11 allele is associated with HPV16 infection and associated with CIN in combination with HLA-DQ6 but not by itself.

Tetrodotoxin-resistant sodium currents contribute to the somal and axonal sodium currents of small diameter primary sensory neurons, many of which are nociceptive. NaN is a recently described tetrodotoxin-resistant sodium channel expressed preferentially in IB4-labeled dorsal root ganglion (DRG) neurons. We employed an antibody raised to a NaN specific peptide to show that NaN is preferentially localized along axons of IB4-positive unmyelinated fibers in the sciatic nerve and in axon terminals in the cornea. NaN immunoreactivity was also found at some nodes of Ranvier of thinly myelinated axons of the sciatic nerve, where it was juxtaposed to Kv1.2 potassium channel immunoreactivity. This distribution of NaN is consistent with a role for NaN sodium channels in nociceptive transmission.

Experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2b) mice is characterized by early (day 12) acute paralysis, followed by a sustained chronic clinical course that gradually stabilizes. Extensive inflammation and demyelination coincide with clinical signs of disease. To identify the mechanisms of these processes, individual proinflammatory and anti-inflammatory cytokines and chemokines were studied. Sensitive single-cell assays were utilized to determine the cellular origin and kinetics of cytokine production in the CNS. Immunization with MOG35-55 peptide resulted in priming of both Th1 (lymphotoxin, IFN-gamma, and TNF-alpha) and Th2 (IL-4) cells in the spleen. However, only Th1 cells were apparent in the CNS. CD4 T cells that produced IFN-gamma or TNF-alpha were present in the CNS by day 7 after immunization with MOG35-55, peaked at day 20, and then waned. TNF-alpha was also produced in the CNS by Mac-1+ cells. On days 7 and 10 after immunization, the TNF-alpha-producing Mac1+ cells were predominantly microglia. By day 14, a switch occurred in that the Mac1+ TNF-alpha-producing cells had the phenotype of infiltrating macrophages. RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA were detected in the CNS by day 8 after immunization. The early presence of monocyte chemotactic protein 1 (MCP-1) in the CNS provides a mechanism for the recruitment of macrophages. These data implicate TNF-alpha production by a continuum of T cells, microglia, and macrophages at various times during the course of disease. The importance of Th1 cytokines is highlighted, with little evidence for a role of Th2 cytokines.

Cervical intraepithelial neoplasia (CIN) is associated with human papillomaviruses (HPV) and the HLA genes. The MICA (MHC class I chain-related gene A) is expressed by keratinocytes and epithelial cells and interacts with gamma delta T cells. It is therefore possible that MICA might influence the pathogenesis of CIN and cervical cancer through presentation of viral or tumor antigens. To investigate this, we determined the MICA transmembrane allele frequencies in a prospective population-based cohort study from the Västerbotten County in northern Sweden. 74 women developed CIN. 153 control women who remained healthy during follow up were matched for age. Five polymorphic microsatellite alleles of MICA were identified by a polymerase chain reaction-based (PCR) technique using fluorescent-labeled primers. MICA A5 and A5.1 were the most common alleles in this population. None of the alleles of MICA were associated with disease. The frequency of MICA allele A5 was higher among HPV 18 seropositive than HPV 18 seronegative patients but this difference was not significant after the correction of p value. In conclusion, microsatellite allele polymorphism of MICA transmembrane part is not associated with cervical intraepithelial neoplasia.

Myelin oligodendrocyte glycoprotein (MOG) induced experimental allergic encephalomyelitis (EAE) is an animal model for the central nervous system disease multiple sclerosis (MS). The roles of individual components of the immune system have not been completely defined in the mouse model, and to determine the role of B cells and Abs in the induction of EAE and demyelination, B cell-deficient muMT (H-2b) mice were immunized with MOG peptide 35-55. The muMT mice were susceptible to MOG-induced EAE and developed a chronic sustained disease, with inflammatory lesions and primary demyelination in the spinal cord, brain, and optic nerves, similar to that seen in wild-type C57BL/6 mice. The inflammatory cells in the central nervous system of muMT mice included both activated and memory T cells and macrophages. The data suggest that B cells and Abs are not necessary for primary demyelination in MOG-induced EAE in mice.