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Ipilimumab is a monoclonal antibody that prolongs survival in patients with metastatic melanoma.1 It targets the coinhibitory receptor cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 signaling induces a state of T-cell unresponsiveness, which facilitates tumor escape from immune surveillance. Blockade of CTLA-4 is believed to shift the immune status from T-cell exhaustion to a functional antitumor response. Anti-CTLA-4 therapy is associated with immune-related adverse events in 64% of patients. Autoimmunity involving the nervous system has a low incidence and manifests predominantly as peripheral inflammatory neuropathy.2 We report new-onset inflammatory CNS demyelination in an ipilimumab-treated melanoma patient (figure), confirmed by histology and associated with enhanced responses of myelin-reactive CD4+ T cells.

Objective: We set out to characterize the clinical impact and functional consequences of rs1800693 G , the multiple sclerosis (MS) susceptibility allele found in the TNFRSF1A locus. Methods: We analyzed prospectively collected data on patients with MS to assess the role of the TNFRSF1A locus on disease course and treatment response. Using archival serum samples and freshly isolated monocytes from patients with MS and healthy subjects, we evaluated the effects of rs1800693 G and a second risk allele, R92Q, on immune function. Results: In 772 patients with MS, we see no evidence that rs1800693 G strongly influences clinical or radiographic indices of disease course and treatment response; thus, rs1800693 G appears to be primarily involved in the onset of MS. At the molecular level, this validated susceptibility allele generates an RNA isoform, TNFRSF1A Δ6, that lacks the transmembrane and cytoplasmic domains. While there was no measurable effect on serum levels of soluble TNFRSF1A, rs1800693 G appears to alter the state of monocytes, which demonstrate a more robust transcriptional response of CXCL10 and other genes in response to tumor necrosis factor (TNF)–α. We also report that activation of the TNF-α pathway results in altered expression of 6 other MS susceptibility genes, including T-cell activation rho GTPase activating protein ( TAGAP ) and regulator of G-protein signaling 1 ( RGS1 ), which are not previously known to be responsive to TNF-α. Conclusions: The MS rs1800693 G susceptibility allele affects the magnitude of monocyte responses to TNF-α stimulation, and the TNF pathway may be one network in which the effect of multiple MS genes becomes integrated.

Objective: In addition to the main multiple sclerosis (MS) major histocompatibility complex (MHC) risk allele ( HLA DRB1*1501 ), investigations of the MHC have implicated several class I MHC loci ( HLA A, HLA B, and HLA C ) as potential independent MS susceptibility loci. Here, we evaluate the role of 3 putative protective alleles in MS: HLA A*02 , HLA B*44 , and HLA C*05 . Methods: Subjects include a clinic-based patient sample with a diagnosis of either MS or a clinically isolated syndrome (n = 532), compared to subjects in a bone marrow donor registry (n = 776). All subjects have 2-digit HLA data. Logistic regression was used to determine the independence of each allele9s effect. We used linear regression and an additive model to test for correlation between an allele and MRI and clinical measures of disease course. Results: After accounting for the effect of HLA DRB1*1501 , both HLA A*02 and HLA B*44 are validated as susceptibility alleles ( p A*02 0.00039 and p B*44 0.00092) and remain significantly associated with MS susceptibility in the presence of the other allele. Although A*02 is not associated with MS outcome measures, HLA B*44 demonstrates association with a better radiologic outcome both in terms of brain parenchymal fraction and T2 hyperintense lesion volume ( p = 0.03 for each outcome). Conclusion: The MHC class I alleles HLA A*02 and HLA B*44 independently reduce susceptibility to MS, but only HLA B*44 appears to influence disease course, preserving brain volume and reducing the burden of T2 hyperintense lesions in subjects with MS.

Background: Individuals with high levels of antibodies to the Epstein–Barr virus nuclear antigen 1 (EBNA-1) have an increased risk of developing multiple sclerosis (MS), but this association could be confounded by genetic susceptibility. Methods: We conducted a nested case-control study including 148 women with MS (18 with blood collected before disease onset) and 296 age-matched healthy women to determine whether the human leukocyte antigen (HLA) DRB1*1501 allele (DR15) and anti-Epstein–Barr virus (anti-EBV) antibody titers are independent risk factors for MS. Results: The association between anti-EBNA-1 antibody titers and MS risk was not affected by adjustment for DR15 and was similar in DR15-positive and DR15-negative women. The relative risk of MS among DR15-positive women with elevated (>1:320) anti-EBNA-1 titers was ninefold higher than that of DR15-negative women with low ( Conclusions: Anti-Epstein–Barr virus nuclear antigen 1 (anti-EBNA-1) antibody titers are a risk factor for multiple sclerosis (MS), independently from the DR15 allele. Carriers of the DR15 allele with elevated anti-EBNA-1 antibody titers may have a markedly increased risk of MS. GLOSSARY: CMV = cytomegalovirus; EBV = Epstein–Barr virus; HLA = human leukocyte antigen; MS = multiple sclerosis; NHS = Nurses9 Health Study; RR = relative risk.

The authors compared the functional activation state and cytokine secretion profile of CD8+ T cells in patients with relapsing-remitting and secondary progressive (SP) MS to those in normal controls. In addition, they examined cytokine secretion in relationship to single nucleotide polymorphism (SNP) analysis of cytokine genes. A significant increase in lymphotoxin secretion from anti-CD3-stimulated CD8+ T cells was observed in patients with SPMS as compared to normal controls. The authors found no significant differences in SNP frequency or in secretion of other cytokines.

MS is an idiopathic, chronic inflammatory syndrome of CNS white matter. Cellular and humoral immune elements occur at zones of ongoing white matter destruction, although their prevalence varies.1 In this issue of Neurology , Wandinger et al.2 use sophisticated serologic and genetic methods to study an association between Epstein–Barr virus (EBV) infections and the diagnosis and symptoms of MS. Can common pathogens trigger demyelination? If so, clarifying the etiology (etiologies) of the MS syndrome might lead to specific therapies. There have been two parallel hypotheses for the pathogenesis of MS: 1) autoimmune, with immune injury to an essentially normal CNS; and 2) infectious, with chronic or reactivated latent infection provoking the immune injury. Recently, these hypotheses have been fused into a third: a common pathogen drives or initiates autoimmunity, whether or not the pathogen resides in the CNS. Inflammatory diseases resembling MS can be autoimmune or infectious (or parainfectious). There are noninfectious experimental models of acute and chronic CNS demyelination, but these models rely on lymphocytes derived in a milieu similar to infection-powerful adjuvants and brain peptides. However, there are numerous naturally occurring mammalian diseases similar to MS, each caused by an interaction between a neurotropic virus …

Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97.(ABSTRACT TRUNCATED AT 250 WORDS)

Twelve patients with progressive MS were treated with a murine IgM pan-T-cell monoclonal antibody reactive against T12, a determinant present on most post-thymic T-cells. Circulating T12 + cells could not be detected from days 1 to 7, although T3 + Til + T12 - cells appeared by day 3. Human anti-mouse antibodies were detected in 78% of patients by day 7 and correlated with a decrease in anti-T12 M Ab blood levels and the reappearance of T12 + cells in the blood. Although there were high levels of anti-T12 MAb in the serum, there were only barely detectable levels in the CSF and no decrease in the proportion of T12+ cells in the CSF with treatment. Immunologic studies demonstrated a decrease of in vitro pokeweed mitogen-driven Ig synthesis on day 3 with an increase on day 10 that consisted in part of human anti-mouse antibodies. Eleven of 12 patients completed therapy. Prednisone was administered with the treatment after mild allergic reactions occurred in the first two patients. Because this was an open phase one study and patients were treated with prednisone, the effect of treatment on the progression of disease is difficult to assess, and no definitive conclusions concerning clinical effects can be made.

Immunoblot analysis was performed on the serum from 29 patients with polyneuropathy and monoclonal gammopathy. Nine patients had IgM spikes, and six of the nine had reactivity against myelin-associated glycoprotein (MAG) associated with a slowly progressive, predominantly sensory neuropathy. In contrast, 23 patients who lacked anti-MAG reactivity had more severe sensory motor neuropathy. Thus, IgM monoclonal gammopathy with reactivity against MAG may define a distinct clinical entity.

A man with a grade II astrocytoma in the medial frontal lobe exhibited complex partial seizures, with the aura being a feeling of extreme embarrassment. This previously unreported ictus suggests that an electric discharge in the prefrontal cortex may produce the opposite effect of prefrontal lesions, in which there is a lack of insight and an absence of the capacity for embarrassment.