ObjectivesOur objectives were to investigate the characteristics of people living with HIV who pr... more ObjectivesOur objectives were to investigate the characteristics of people living with HIV who presented with new or recurrent symptoms in the context of re‐emergence of cerebrospinal fluid HIV RNA escape after antiretroviral therapy (ART) modification (termed relapse of CSF HIV RNA escape).MethodsPeople living with HIV‐1 with known CSF HIV RNA escape were identified, with clinical and laboratory data obtained from records in a tertiary centre. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in the presence of unquantifiable plasma HIV‐RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV‐RNA was quantifiable. Relapse was defined as a re‐emergence of CSF HIV RNA escape with new symptoms after ART therapy intensification post‐initial CSF HIV RNA escape.ResultsAmong 40 people living with HIV who presented with neurosymptomatic CSF HIV RNA, eight (20%) presented with a relapse of CSF HIV RNA escape. Symptoms on relapse included confusion (n = 2), cognitive decline (n = 2), cerebellar dysfunction (n = 2) and worsening of pre‐existing seizures (n = 1). Prior to their relapse, three people underwent drug therapy modification, with two people stopping raltegravir intensification, and one person switched from tenofovir alafenamide, emtricitabine and raltegravir for a new regimen.ConclusionsPeople with a relapse of CSF HIV RNA escape within this cohort presented with varied symptoms similar to their initial CSF HIV RNA escape. Clinicians should be vigilant of relapse of symptoms, particularly when simplifying ART regimens in people with CSF HIV RNA escape.
ObjectiveThe antigen‐presenting lectin‐like receptor complex (APLEC) was recently identified as a... more ObjectiveThe antigen‐presenting lectin‐like receptor complex (APLEC) was recently identified as a genetic determinant for arthritis susceptibility. We undertook this study to define mechanisms underlying the impact of APLEC on arthritis, to determine whether sex effects occur, and to determine whether APLEC influences different types of arthritis and phenotypes other than susceptibility.MethodsArthritis‐susceptible DA rats were compared with sex‐matched congenic rats in which APLEC alleles were substituted with alleles from arthritis‐resistant PVG rats. Six different arthritogenic agents were injected at the base of the tail: Freund's incomplete adjuvant, pristane, squalene, killed mycobacteria, yeast β‐glucan, or rat type II collagen (CII). Arthritis was visually scored, body weight was measured, and anti‐CII IgG and cytokine messenger RNA (mRNA) levels were determined by enzyme‐linked immunosorbent assay and reverse transcription–polymerase chain reaction, respectively.ResultsIn 5 models of rheumatoid arthritis (RA), congenic rats deviated profoundly from DA rats by having reduced arthritis susceptibility, delayed onset, decreased severity, and/or reduced body weight loss. Paradoxical opposite genetic effects were noted, including a more severe disease course in congenic males in pristane‐induced arthritis and decreased clinical signs in collagen‐induced arthritis despite increased autoantibody levels. Interestingly, the anti‐CII IgG isotype profile was skewed in congenic rats, and markedly reduced lymph node mRNA levels for interleukin‐17 suggested that the cytokine profile of autoreactive T helper cells was also skewed in a less pathogenic direction.ConclusionRat APLEC regulates autoimmunity and multiple phenotypes in several types of arthritis. However, delineating the genetic impact may require stratification for sex or mode of arthritis induction. This pathogenetic complexity should be considered when evaluating APLEC in inflammatory and autoimmune diseases, including RA.
Multiple sclerosis (MS) is the most common inflammatory demyelinating and degenerative disease of... more Multiple sclerosis (MS) is the most common inflammatory demyelinating and degenerative disease of the CNS. The cause of MS is unknown but environmental risk factors are implicated in MS. Several viruses have been proposed as a trigger for MS, and lately Epstein-Barr virus (EBV) has become the leading candidate. An infectious aetiology fits with a number of epidemiological observations in addition to the immunopathological features of the disease. In this review we will summarize the emerging evidence, which demonstrates a strong association between EBV infection and MS. The conundrum remains as to whether EBV is directly involved in the pathophysiology of MS, or alternatively if the immunopathology of MS somehow affects the regulation of EBV infection.
Multiple sclerosis and related disorders, Nov 1, 2021
BACKGROUND Antigen-specific tolerance in auto-immune diseases is the goal for effective treatment... more BACKGROUND Antigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFNβ1a) develop neutralizing antibodies to IFNβ1a that do not disappear in repeated tests over years. METHODS One PwMS was recruited, as part of a planned phase IIa trial (n = 15), who had developed neutralizing antibodies to subcutaneous IFNβ1a. Mitoxantrone (12 mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88 μg/day + three 132 μg/day) intravenous IFNβ1a. Subcutaneous IFNβ1a three times a week was maintained during follow-up. IFNβ1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months. FINDINGS One participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased. INTERPRETATION The data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted. FUNDING The study was supported by an unrestricted research grant from Merck-Serono.
Cns & Neurological Disorders-drug Targets, Jun 1, 2012
The term &amp... more The term "disease modifying drugs" (DMD) is taken from rheumatologists who coined it after the use of immunosuppressive drugs and, more recently, the association of "biological drugs" that changed the degenerative course of rheumatic disease. In the treatment of multiple sclerosis (MS), the advent of interferon (IFN)-β, which caused a reduction in the number of relapses and possibly improvement in disability outcomes, was the first strategy to prevent inflammatory damage in the central nervous system (CNS). Soon after, glatiramer acetate showed similar results. It would be more than a decade before natalizumab was licensed, showing a much better efficiency in relapse reduction than was seen after first-line therapies failed. The pipeline is now much larger with several drugs on the horizon. Overall, the anti-inflammatory strategy has been mostly successful but drugs that have protection and repair mechanisms are still missing.
ObjectivesOur objectives were to investigate the characteristics of people living with HIV who pr... more ObjectivesOur objectives were to investigate the characteristics of people living with HIV who presented with new or recurrent symptoms in the context of re‐emergence of cerebrospinal fluid HIV RNA escape after antiretroviral therapy (ART) modification (termed relapse of CSF HIV RNA escape).MethodsPeople living with HIV‐1 with known CSF HIV RNA escape were identified, with clinical and laboratory data obtained from records in a tertiary centre. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in the presence of unquantifiable plasma HIV‐RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV‐RNA was quantifiable. Relapse was defined as a re‐emergence of CSF HIV RNA escape with new symptoms after ART therapy intensification post‐initial CSF HIV RNA escape.ResultsAmong 40 people living with HIV who presented with neurosymptomatic CSF HIV RNA, eight (20%) presented with a relapse of CSF HIV RNA escape. Symptoms on relapse included confusion (n = 2), cognitive decline (n = 2), cerebellar dysfunction (n = 2) and worsening of pre‐existing seizures (n = 1). Prior to their relapse, three people underwent drug therapy modification, with two people stopping raltegravir intensification, and one person switched from tenofovir alafenamide, emtricitabine and raltegravir for a new regimen.ConclusionsPeople with a relapse of CSF HIV RNA escape within this cohort presented with varied symptoms similar to their initial CSF HIV RNA escape. Clinicians should be vigilant of relapse of symptoms, particularly when simplifying ART regimens in people with CSF HIV RNA escape.
ObjectiveThe antigen‐presenting lectin‐like receptor complex (APLEC) was recently identified as a... more ObjectiveThe antigen‐presenting lectin‐like receptor complex (APLEC) was recently identified as a genetic determinant for arthritis susceptibility. We undertook this study to define mechanisms underlying the impact of APLEC on arthritis, to determine whether sex effects occur, and to determine whether APLEC influences different types of arthritis and phenotypes other than susceptibility.MethodsArthritis‐susceptible DA rats were compared with sex‐matched congenic rats in which APLEC alleles were substituted with alleles from arthritis‐resistant PVG rats. Six different arthritogenic agents were injected at the base of the tail: Freund's incomplete adjuvant, pristane, squalene, killed mycobacteria, yeast β‐glucan, or rat type II collagen (CII). Arthritis was visually scored, body weight was measured, and anti‐CII IgG and cytokine messenger RNA (mRNA) levels were determined by enzyme‐linked immunosorbent assay and reverse transcription–polymerase chain reaction, respectively.ResultsIn 5 models of rheumatoid arthritis (RA), congenic rats deviated profoundly from DA rats by having reduced arthritis susceptibility, delayed onset, decreased severity, and/or reduced body weight loss. Paradoxical opposite genetic effects were noted, including a more severe disease course in congenic males in pristane‐induced arthritis and decreased clinical signs in collagen‐induced arthritis despite increased autoantibody levels. Interestingly, the anti‐CII IgG isotype profile was skewed in congenic rats, and markedly reduced lymph node mRNA levels for interleukin‐17 suggested that the cytokine profile of autoreactive T helper cells was also skewed in a less pathogenic direction.ConclusionRat APLEC regulates autoimmunity and multiple phenotypes in several types of arthritis. However, delineating the genetic impact may require stratification for sex or mode of arthritis induction. This pathogenetic complexity should be considered when evaluating APLEC in inflammatory and autoimmune diseases, including RA.
Multiple sclerosis (MS) is the most common inflammatory demyelinating and degenerative disease of... more Multiple sclerosis (MS) is the most common inflammatory demyelinating and degenerative disease of the CNS. The cause of MS is unknown but environmental risk factors are implicated in MS. Several viruses have been proposed as a trigger for MS, and lately Epstein-Barr virus (EBV) has become the leading candidate. An infectious aetiology fits with a number of epidemiological observations in addition to the immunopathological features of the disease. In this review we will summarize the emerging evidence, which demonstrates a strong association between EBV infection and MS. The conundrum remains as to whether EBV is directly involved in the pathophysiology of MS, or alternatively if the immunopathology of MS somehow affects the regulation of EBV infection.
Multiple sclerosis and related disorders, Nov 1, 2021
BACKGROUND Antigen-specific tolerance in auto-immune diseases is the goal for effective treatment... more BACKGROUND Antigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFNβ1a) develop neutralizing antibodies to IFNβ1a that do not disappear in repeated tests over years. METHODS One PwMS was recruited, as part of a planned phase IIa trial (n = 15), who had developed neutralizing antibodies to subcutaneous IFNβ1a. Mitoxantrone (12 mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88 μg/day + three 132 μg/day) intravenous IFNβ1a. Subcutaneous IFNβ1a three times a week was maintained during follow-up. IFNβ1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months. FINDINGS One participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased. INTERPRETATION The data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted. FUNDING The study was supported by an unrestricted research grant from Merck-Serono.
Cns & Neurological Disorders-drug Targets, Jun 1, 2012
The term &amp... more The term "disease modifying drugs" (DMD) is taken from rheumatologists who coined it after the use of immunosuppressive drugs and, more recently, the association of "biological drugs" that changed the degenerative course of rheumatic disease. In the treatment of multiple sclerosis (MS), the advent of interferon (IFN)-β, which caused a reduction in the number of relapses and possibly improvement in disability outcomes, was the first strategy to prevent inflammatory damage in the central nervous system (CNS). Soon after, glatiramer acetate showed similar results. It would be more than a decade before natalizumab was licensed, showing a much better efficiency in relapse reduction than was seen after first-line therapies failed. The pipeline is now much larger with several drugs on the horizon. Overall, the anti-inflammatory strategy has been mostly successful but drugs that have protection and repair mechanisms are still missing.
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