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1.  Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity 
The Journal of Clinical Investigation  2012;122(4):1393-1402.
The B cell–depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti–myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell–depleting therapies for autoimmune diseases.
doi:10.1172/JCI58743
PMCID: PMC3314454  PMID: 22426210
2.  Persistence of Epstein-Barr Virus in Self-Reactive Memory B Cells 
Journal of Virology  2012;86(22):12330-12340.
Epstein-Barr virus infection has been epidemiologically associated with the development of multiple autoimmune diseases, particularly systemic lupus erythematosus and multiple sclerosis. Currently, there is no known mechanism that can account for these associations. The germinal-center (GC) model of EBV infection and persistence proposes that EBV gains access to the memory B cell compartment via GC reactions by driving infected cells to differentiate using the virus-encoded LMP1 and LMP2a proteins, which act as functional homologues of CD40 and the B cell receptor, respectively. The ability of LMP2a, when expressed in mice, to allow escape of autoreactive B cells suggests that it could perform a similar role in infected GC B cells, permitting the survival of potentially pathogenic autoreactive B cells. To test this hypothesis, we cloned and expressed antibodies from EBV+ and EBV− memory B cells present during acute infection and profiled their self- and polyreactivity. We find that EBV does persist within self- and polyreactive B cells but find no evidence that it favors the survival of pathogenic autoreactive B cells. On the contrary, EBV+ memory B cells express lower levels of self-reactive and especially polyreactive antibodies than their uninfected counterparts do. Our work suggests that EBV has only a modest effect on the GC process, which allows it to access and persist within a subtly unique niche of the memory compartment characterized by relatively low levels of self- and polyreactivity. We suggest that this might reflect an active process where EBV and its human host have coevolved so as to minimize the virus's potential to contribute to autoimmune disease.
doi:10.1128/JVI.01699-12
PMCID: PMC3486485  PMID: 22951828
3.  Impaired IFN-γ production and proliferation of NK cells in Multiple Sclerosis 
International Immunology  2011;23(2):139-148.
NK cells are multicompetent lymphocytes of the innate immune system with a central role in host defense and immune regulation. Studies in experimental animal models of multiple sclerosis (MS) provided evidence for both pathologic and protective effects of NK cells. Humans harbor two functionally distinct NK-cell subsets exerting either predominantly cytotoxic (CD56dimCD16+) or immunoregulatory (CD56brightCD16−) functions. We analyzed these two subsets and their functions in the peripheral blood of untreated patients with relapsing-remitting MS compared with healthy blood donors. While ex vivo frequencies of CD56brightCD16− and CD56dimCD16+ NK cells were similar in patients and controls, we found that cytokine-driven in vitro accumulation and IFN-γ production of CD56brightCD16− NK cells but not of their CD56dimCD16+ counterparts were substantially diminished in MS. Impaired expansion of CD56brightCD16− NK cells was cell intrinsic because the observed effects could be reproduced with purified NK cells in an independent cohort of patients and controls. In contrast, cytolytic NK-cell activity toward the human erythromyeloblastoid leukemia cell line K562, the allogeneic CD4+ T cell line CEM and allogeneic primary CD4+ T-cell blasts was unchanged. Thus, characteristic functions of CD56brightCD16− NK cells, namely cytokine-induced NK cell expansion and IFN-γ production, are compromised in the NK cell compartment of MS patients.
doi:10.1093/intimm/dxq463
PMCID: PMC3030728  PMID: 21212154
NK cell; multiple sclerosis; autoimmunity
4.  Elevated EBNA1 Immune Responses Predict Conversion to Multiple Sclerosis 
Annals of neurology  2010;67(2):159-169.
Objective
The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CIS), and to evaluate their potential value in predicting conversion to MS.
Methods
Immune responses to Epstein-Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls.
Results
Compared to controls, CIS patients showed increased humoral (p<0.0001) and cellular (p=0.007) immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to other EBV-derived proteins. IgG responses to other virus antigens and frequencies of T cells specific for HCMV and influenza virus gene products were unchanged in CIS patients. EBNA1 was the only viral antigen towards which immune responses correlated with number of T2 lesions (p=0.006) and number of Barkhof criteria (p=0.001) at baseline, and with number of T2 lesions (p=0.012 both at 1 and 5 years), presence of new T2 lesions (p=0.003 and p=0.028 at 1 and 5 years), and EDSS (p=0.015 and p=0.010 at 1 and 5 years) during follow-up. In a univariate Cox regression model, increased EBNA1-specific IgG responses predicted conversion to MS based on McDonald criteria [hazard ratio (95% confidence interval), 2.2 (1.2–4.3); p=0.003].
Interpretation
Our results indicate that elevated immune responses towards EBNA1 are selectively increased in CIS patients and suggest that EBNA1-specific IgG titers could be used as a prognostic marker for disease conversion and disability progression.
doi:10.1002/ana.21886
PMCID: PMC2848293  PMID: 20225269
5.  Antiviral immune responses: triggers of or triggered by autoimmunity? 
Nature reviews. Immunology  2009;9(4):246-258.
Several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and multiple sclerosis, are genetically linked to distinct human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins as well as geographical distribution of disease risk point towards environmental factors in the genesis of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. In this review, we outline mechanisms by which pathogens can trigger autoimmune disease, and also pathways by which infection and immune control of infectious disease might be dysregulated during autoimmunity.
doi:10.1038/nri2527
PMCID: PMC2854652  PMID: 19319143
6.  Human NK cells kill resting but not activated microglia via NKG2D and NKp46 mediated recognition 
Microglia are resident macrophage-like antigen presenting cells of the central nervous system (CNS). To avoid escalation of inflammatory processes and bystander damage within the CNS, microglia-driven inflammatory responses need to be tightly regulated and both spatially and temporally restricted. Following traumatic, infectious and autoimmune-mediated brain injury, natural killer (NK) cells have been found in the CNS, but the functional significance of NK cell recruitment and their mechanisms of action during brain inflammation are not well understood. Here, we investigated whether and by which mechanisms human NK cells might edit resting and activated human microglial cells via cytotoxicity. IL-2 activated NK cells efficiently killed both resting allogeneic and autologous microglia in a cell-contact dependent manner. In addition they produced IFN-γ upon microglia recognition. Activated NK cells rapidly formed synapses with human microglial cells, polarizing perforin to the cellular interface. Antibody-mediated NKG2D and NKp46, but not DNAM-1 and NKp30 blockade decreased killing of human microglia by activated NK cells. Up-regulation of MHC class I surface expression by TLR4 stimulation protected microglia from NK cell mediated cytotoxicity These data suggest that brain-infiltrating NK cells might restrict innate and adaptive immune responses within the human CNS via elimination of resting microglia.
PMCID: PMC2596922  PMID: 18941207
Human; Cytotoxicity; Microglia; Natural Killer cells
7.  Regulatory NK-Cell Functions in Inflammation and Autoimmunity 
Molecular Medicine  2009;15(9-10):352-358.
Natural killer (NK) cells were viewed traditionally as cytotoxic effector cells whose rapid killing of infected and transformed cells without preactivation provides a first line of defense prior to the initiation of an adaptive immune response against infection and tumor development. However, it has become clear that NK cells interact with various components of the immune system, and therefore have the potential to function as regulatory cells. While NK cells can assist in dendritic cell (DC) maturation and T-cell polarization, increasing evidence indicates that NK cells can also prevent and limit adaptive (auto) immune responses via killing of autologous myeloid and lymphoid cells. Investigating immunoregulatory NK-cell functions might generate exciting insights into the reciprocal regulation between NK-cell–mediated innate immunity and adaptive immune responses, improve our capacity to monitor these cells as surrogate markers for disease activity and treatment responses in autoimmune diseases, and, perhaps, provide new prospects for NK cell-directed therapies.
doi:10.2119/molmed.2009.00035
PMCID: PMC2710290  PMID: 19603102
8.  Increased Frequency of EBV-Specific Effector Memory CD8+ T Cells Correlates with Higher Viral Load in Rheumatoid Arthritis1 
EBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8+ T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8+ T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4+ T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.
PMCID: PMC2570434  PMID: 18606650
9.  EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2 
The Journal of Experimental Medicine  2008;205(8):1763-1773.
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.
doi:10.1084/jem.20072397
PMCID: PMC2525578  PMID: 18663124
10.  Epstein-Barr Virus: Environmental Trigger of Multiple Sclerosis?▿  
Journal of Virology  2007;81(13):6777-6784.
doi:10.1128/JVI.00153-07
PMCID: PMC1933281  PMID: 17459939
11.  Cerebrospinal Fluid-Infiltrating CD4+ T Cells Recognize Borrelia burgdorferi Lysine-Enriched Protein Domains and Central Nervous System Autoantigens in Early Lyme Encephalitis▿  
Infection and Immunity  2006;75(1):243-251.
Neurological manifestations of Lyme disease are usually accompanied by inflammatory changes in the cerebrospinal fluid (CSF) and the recruitment of activated T cells into the CSF compartment. In order to characterize the phenotype and identify target antigens of CSF-infiltrating T cells in early neuroborreliosis with central nervous system (CNS) involvement, we combined T-cell cloning, functional testing of T-cell responses with positional scanning synthetic combinatorial peptide libraries, and biometric data analysis. We demonstrate that CD4+ gamma interferon-producing T cells specifically responding to Borrelia burgdorferi lysate were present in the CSF of a patient with acute Lyme encephalitis. Some T-cell clones recognized previously uncharacterized B. burgdorferi epitopes which show a specific enrichment for lysine, such as the heat shock-induced chaperone HSP90. Degenerate T-cell recognition that included T-cell responses to borrelia-specific and CNS-specific autoantigens derived from the myelin protein 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) could be demonstrated for one representative clone. Our results show that spirochetal antigen-specific and Th1-polarized CD4+ lymphocytes infiltrate the CSF during monophasic CNS symptoms of Lyme disease and demonstrate that cross-recognition of CNS antigens by B. burgdorferi-specific T cells is not restricted to chronic and treatment-resistant manifestations.
doi:10.1128/IAI.01110-06
PMCID: PMC1828376  PMID: 17060473
13.  Rapid Typing of Borrelia burgdorferi Sensu Lato Species in Specimens from Patients with Different Manifestations of Lyme Borreliosis 
Journal of Clinical Microbiology  2001;39(3):1130-1133.
To further investigate the pathogenic potential of different Borrelia burgdorferi genospecies, specimens from 27 patients with different manifestations of Lyme borreliosis were analyzed by PCR and reverse line blotting (RLB). In samples from Lyme arthritis patients, B. burgdorferi sensu stricto was predominantly identified, while in patients with neuroborreliosis or acrodermatitis, Borrelia garinii and Borrelia afzelii, respectively, were exclusively detected. The results demonstrate that PCR-RLB is a valuable tool for epidemiological and pathogenetic studies of Lyme borreliosis.
doi:10.1128/JCM.39.3.1130-1133.2001
PMCID: PMC87886  PMID: 11230440

Results 1-13 (13)