Ilijas Jelcic

Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

The inhibitory Fc-γ receptor FcγRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcγRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower FcγRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcγRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare −386C/−120A FcγRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcγRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcγRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcγRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.

EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2

Symptomatic primary Epstein-Barr virus (EBV) infection and elevated humoral immune responses to EBV are associated with an increased risk of developing multiple sclerosis (MS). We explored mechanisms leading to this change in EBV-specific immunity in untreated patients with MS and healthy virus carriers matched for MS-associated HLA alleles. MS patients showed selective increase of T cell responses to the EBV nuclear antigen 1 (EBNA1), the most consistently recognized EBV-derived CD4+ T cell antigen in healthy virus carriers, but not to other EBV-encoded proteins. In contrast, influenza and human cytomegalovirus–specific immune control was unchanged in MS. The enhanced response to EBNA1 was mediated by an expanded reservoir of EBNA1-specific central memory CD4+ T helper 1 (Th1) precursors and Th1 (but not Th17) polarized effector memory cells. In addition, EBNA1-specific T cells recognized myelin antigens more frequently than other autoantigens that are not associated with MS. Myelin cross-reactive T cells produced IFN-γ, but differed from EBNA1-monospecific cells in their capability to produce interleukin-2, indicative of a polyfunctional phenotype as found in controlled chronic viral infections. Our data support the concept that clonally expanded EBNA1-specific CD4+ T cells potentially contribute to the development of MS by cross-recognition of myelin antigens.

Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome.

Progressive multi-focal leucoencephalopathy and progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are caused by infection of the central nervous system with the JC polyoma virus. Both are complications of monoclonal antibody therapy in multiple sclerosis and other autoimmune diseases. Progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome can obscure the diagnosis of progressive multi-focal leucoencephalopathy and lead to severe clinical disability and possibly death. Different from progressive multi-focal leucoencephalopathy, in which demyelination results from oligodendrocyte lysis by JC virus in the absence of an immune response, tissue destruction in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome is caused by a vigorous immune response within the brain. The cells and mediators that are involved in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are as yet poorly understood. We examined two patients with multiple sclerosis, who developed progressive multi-focal leucoencephalopathy and later progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome under natalizumab therapy. Due to initially negative JC viral deoxyribonucleic acid testing in the cerebrospinal fluid, a diagnostic brain biopsy was performed in one patient. Histopathology revealed brain inflammation characterized by a prominent T cell infiltrate (CD4(+)> CD8(+) T cells), but also B/plasma cells and monocytes. Despite very low JC viral load, both patients showed high intrathecal anti-JC virus antibodies. Brain-infiltrating CD4(+) T cells were studied regarding antigen specificity and function. CD4(+) T cells were highly specific for peptides from several JC virus proteins, particularly the major capsid protein VP1. T cell phenotyping revealed CD4(+) Th1 and bifunctional Th1-2 cells. The latter secrete large amounts of interferon-γ and interleukin-4 explaining the strong brain inflammation, presence of plasma cells and secretion of intrathecal anti-VP1 antibodies. The functional phenotype of brain-infiltrating JC virus-specific CD4(+) T cells was confirmed and extended by examining brain-derived JC virus-specific CD4(+) T cell clones. Our data provide novel insight into the pathogenesis of progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome and indicate that JC virus-specific CD4(+) T cells play an important role in both eliminating JC virus from the brain, but also in causing the massive inflammation with often fatal outcome.

Treating Progressive Multifocal Leukoencephalopathy With Interleukin 7 and Vaccination With JC Virus Capsid Protein VP1

Progressive multifocal leukoencephalopathy is a currently untreatable infection of the brain. Here, we demonstrate in 2 patients that treatment with interleukin 7, JC polyomavirus (JCV) capsid protein VP1, and a Toll-like receptor 7 agonist used as adjuvant, was well tolerated, and showed a very favorable safety profile and unexpected efficacy that warrant further investigation.

Broadly neutralizing human monoclonal JC polyomavirus VP1–specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy

Human monoclonal antibodies broadly neutralize multiple PML-causing JC polyomavirus variants. Opportunity knocks for JC polyomavirus therapy JC polyomavirus (JCPyV) can be found in the urinary tract in most adults, resulting in a persistent but asymptomatic infection. However, in immunocompromised individuals, JCPyV opportunistically infects the brain, resulting in the debilitating and frequently fatal disease progressive multifocal leukoencephalopathy (PML). No treatments are currently available for PML, but two papers now identify and exploit a gap in the immune response to JCPyV. Ray et al. report that JCPyV strains found in the cerebrospinal fluid of PML patients have mutations that prevent antibody neutralization and that these blind spots can be overcome with vaccination. Jelcic et al. suggest that broadly neutralizing antibodies derived from a patient who recovered from PML may fill this gap. In immunocompromised individuals, JC polyomavirus (JCPyV) may mutate and gain access to the central nervous system resulting in progressive multifocal leukoencephalopathy (PML), an often fatal opportunistic infection for which no treatments are currently available. Despite recent progress, the contribution of JCPyV-specific humoral immunity to controlling asymptomatic infection throughout life and to eliminating JCPyV from the brain is poorly understood. We examined antibody responses against JCPyV major capsid protein VP1 (viral protein 1) variants in the serum and cerebrospinal fluid (CSF) of healthy donors (HDs), JCPyV-positive multiple sclerosis patients treated with the anti–VLA-4 monoclonal antibody natalizumab (NAT), and patients with NAT-associated PML. Before and during PML, CSF antibody responses against JCPyV VP1 variants show “recognition holes”; however, upon immune reconstitution, CSF antibody titers rise, then recognize PML-associated JCPyV VP1 variants, and may be involved in elimination of the virus. We therefore reasoned that the memory B cell repertoire of individuals who recovered from PML could be a source for the molecular cloning of broadly neutralizing antibodies for passive immunization. We generated a series of memory B cell–derived JCPyV VP1–specific human monoclonal antibodies from HDs and a patient with NAT-associated PML–immune reconstitution inflammatory syndrome (IRIS). These antibodies exhibited diverse binding affinity, cross-reactivity with the closely related BK polyomavirus, recognition of PML-causing VP1 variants, and JCPyV neutralization. Almost all antibodies with exquisite specificity for JCPyV, neutralizing activity, recognition of all tested JCPyV PML variants, and high affinity were derived from one patient who had recovered from PML. These antibodies are promising drug candidates for the development of a treatment of PML.

Reactivation of herpesvirus under fingolimod: A case of severe herpes simplex encephalitis

Fingolimod (FTY720, Gilenya, Novartis Pharma AG, Basel, Switzerland) is a sphingosin-1-phosphate (S1P) receptor modulator with immunomodulatory properties that traps naive and central memory T cells in lymph nodes, leading to reduced numbers of peripheral blood lymphocytes, and is the first licensed oral drug for multiple sclerosis (MS).1,2 We report a case of a near fatal herpes simplex virus 1 (HSV-1) encephalitis under the licensed dose of fingolimod in a patient with MS.

Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant

Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long‐term persistence of JCV and delayed clinical improvement despite inflammation.

Sustained efficacy of natalizumab in the treatment of relapsing-remitting multiple sclerosis independent of disease activity and disability at baseline: real-life data from a Swiss cohort.

ObjectivesTherapy for relapsing-remitting multiple sclerosis with natalizumab (Tysabri; Biogen Idec) has been shown to be effective in the reduction of the clinical relapse rate and disability progression. However, real-life longitudinal data, including years before baseline, are rare. MethodsAn observational single-center study was carried out. We analyzed data from 64 consecutive patients with multiple sclerosis. ResultsAfter 1 year of treatment (n = 64), score on the Expanded Disability Status Scale (EDSS) decreased by 0.47 points (P = 0.047) and the annualized relapse rate (ARR) decreased by 82% (P < 0.001). After 2 years (n = 41), EDSS score was still reduced by 0.28 (not significant) and ARR was reduced by 69% (P < 0.001). After 3 years (n = 23), EDSS score was reduced by 0.26 (not significant), and ARR was reduced by 77% (P < 0.001). Reduction of EDSS score and ARR did not depend on baseline ARR (1–2 vs >2) or EDSS score and was not biased by exceptional high disease activity or relapses around baseline. ConclusionsThese real-life data reinforce that natalizumab is effective over years, reduces ARR, and stabilizes EDSS score independent of baseline ARR, baseline EDSS score, or baseline treatment.

Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions.

Multiple sclerosis (MS) is a disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Based on infiltrating immune cells, deposition of humoral factors and loss of oligodendrocytes and/or myelin proteins, four lesion patterns have been described. Pattern II is characterized by antibody and complement deposition in addition to T‐cell infiltration. MS is considered a T‐cell‐mediated disease, but until now the study of pathogenic T cells has encountered major challenges, most importantly the limited access of brain‐infiltrating T cells. Our objective was to identify, isolate, and characterize brain‐infiltrating clonally expanded T cells in pattern II MS lesions.

T Cell Epitope Mapping of JC Polyoma Virus-Encoded Proteome Reveals Reduced T Cell Responses in HLA-DRB1*04:01+ Donors

ABSTRACT JC polyomavirus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. It is only during immunocompromise and especially impaired CD4+ T cell function in the brain, as seen in AIDS patients or natalizumab-treated multiple sclerosis patients, that JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4+ T cells likely play an important role in controlling JCV infection, we here describe the T cell response to JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. We identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. We observed positive JCV-specific T cell responses in 28.6% to 77.6%, humoral immune response in 42.6% to 89.4%, and urinary viral shedding in 36.4% to 45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01+, DRB1*07+, DRB1*11+, DRB1*13+, DRB1*15+, and DRB1*03+ individuals. We show for the first time that JCV-specific T cell responses may be directed not only against JCV VP1 and large T antigen but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01+ individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV.