Immunophenotypic characterization of CSF B cells in virus-associated neuroinflammatory diseases

Enose-Akahata, Yoshimi; Azodi, Shila; Smith, Bryan; Billioux, Bridgette Jeanne; Vellucci, A; Ngouth, Nyater; Tanaka, Yuetsu; Ohayon, Joan; Cortese, Irene; Nath, Avindra; Jacobson, Steven

doi:10.1371/journal.ppat.1007042

Cited by 32 publications

(44 citation statements)

References 65 publications

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“…Although CD4+/CD25+ Tregs can be infected by HTLV-1 and HAM/TSP patients have been shown to have a high number of CD4+/CD25+ Tregs with impaired function and higher HBZ mRNA levels (Araya et al, 2011; Enose-Akahata et al, 2018), the results presented here indicate that in HAM/TSP patients, HBZ protein can be detected in CD4+ T cells not displaying the classical phenotype of Treg cells. Thus, the possible uncoupling of HBZ mRNA and protein expression in CD4+CD25+ Tregs as well as in other CD4+ T cell subpopulations in both AC and HAM/TSP patients (Yamano et al, 2009; Leal et al, 2013; Araya et al, 2014; Billman et al, 2017) certainly requires further investigation.…”

Section: Discussionmentioning

confidence: 52%

HTLV-1 HBZ Protein Resides Exclusively in the Cytoplasm of Infected Cells in Asymptomatic Carriers and HAM/TSP Patients

et al. 2019

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Human T cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. Two viral proteins, Tax-1 and HTLV-1 basic leucine zipper factor (HBZ), play important roles in the pathogenesis of both diseases. We recently demonstrated that HBZ, previously considered a nuclear protein, is exclusively localized in the cytoplasm of peripheral blood mononuclear cells (PBMCs) of HAM/TSP patients. Here, the analysis of a larger panel of HAM/TSP cases confirmed that HBZ is a cytoplasmic protein, while Tax-1 preferentially localized in the cytoplasm with fewer speckle-like dots in the nucleus. More importantly, here we report for the first time that HBZ, when expressed in asymptomatic carriers (AC), is also confined in the cytoplasm. Similarly, Tax-1 was preferentially expressed in the cytoplasm in a significant proportion of AC. Interestingly, in both HAM/TSP and AC patients, the expression of HBZ and Tax-1 was rarely found in the same cell. We observed only few cases coexpressing the two oncoprotein in a very limited number of cells. In representative AC and HAM/TSP patients, cells expressing cytoplasmic HBZ were almost exclusively found in the CD4+ T cell compartment and very rarely in CD8+ T cells. Interestingly, at least in the cases analyzed, the expression of thymocite-expressed molecule involved in selection (THEMIS) is dispensable for the cytoplasmic localization of HBZ in both AC and HAM/TSP. The study of an HTLV-1-immortalized cell line established from an HAM/TSP patient confirmed HBZ as a resident cytoplasmic protein not shuttling between the cytoplasm and nucleus. These results extend our previous observation on the dichotomy of HBZ localization between HAM/TSP and ATL, pointing to the exclusive either cytoplasmic or nuclear localization in the two diseased states, respectively. Moreover, they show a rather selective expression in distinct cells of either HBZ or Tax-1. The unprecedented observation that HBZ is expressed only in the cytoplasm in AC strongly suggests a progressive modification of HBZ localization during the disease states associated to HTLV-1 infection. Future studies will clarify whether the distinct HBZ intracellular localization is a marker or a causative event of disease evolution.

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Section: Discussionmentioning

confidence: 52%

HTLV-1 HBZ Protein Resides Exclusively in the Cytoplasm of Infected Cells in Asymptomatic Carriers and HAM/TSP Patients

et al. 2019

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“…The ability of cross-reactive autoantibodies to access the CSF and brain is a critical effector component to the pathogenesis of autoimmune encephalitis. There is increasing evidence that the components of the peripheral immune system are able to cross the BBB and enter the central nervous system (CNS) (52,(56)(57)(58)(59)(60) when permeability of the BBB is compromised by infectious or non-infectious factors (57,58). Bacteria, including group A streptococci, can impair BBB function in neurological niches like the olfactory bulb leading to loss of function, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The upregulation of certain adhesion molecules such as VCAM-1, ICAM-1, and ICAM-2 on CNS vessels during inflammation can promote the trafficking of lymphocytes into the CNS. Antibody-secreting B cells are found in the brain and CSF in infectious neurological diseases as well as in demyelinating diseases ( 59 ). One study suggested short-term sleep deprivation led to an influx of B cells across the BBB through a mechanism involving CXCR5 ( 60 ), a chemokine linked to BBB permeability ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Autoantibody Biomarkers for Basal Ganglia Encephalitis in Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections

et al. 2020

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sera of PANDAS subjects, who had 76-89% positive association with elevated individual autoantibody titers and positive CaMKII activity. At 6 months follow-up, symptoms improved for more than 80% of PANDAS subjects, and serum autoantibody titers also significantly decreased. Results reported herein and previously published studies in our laboratory suggest the antibody biomarkers may be a useful adjunct to clinical diagnosis of SC, PANDAS, and related disorders and are the first known group of autoantibodies detecting dopamine receptor-mediated encephalitis in children.

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“…However, subsequent analysis reported that the presence of hnRNPA1-specific antibodies in the CSF was not specific to this disease (Yukitake et al., 2008). Recent analysis shows intrathecal HTLV-1 specific antibody is significantly elevated in HAM/TSP patients compared to ACs, which is significantly correlated with antibody secreting B cells (ASCs) (Enose-Akahata et al., 2018). These results suggest that elevated ASCs may contribute to antibody production in the CSF and importance of the B cell compartment in the pathogenesis of developing of HAM/TSP.…”

Section: Host Immune Responese To Htlv-1mentioning

confidence: 99%

Neuroimmunology of Human T-Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis

Nozuma

Jacobson

2019

Front. Microbiol.

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Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of both adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is clinically characterized by chronic progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. Given its well-characterized clinical presentation and pathophysiology, which is similar to the progressive forms of multiple sclerosis (MS), HAM/TSP is an ideal system to better understand other neuroimmunological disorders such as MS. Since the discovery of HAM/TSP, large numbers of clinical, virological, molecular, and immunological studies have been published. The host-virus interaction and host immune response play an important role for the development with HAM/TSP. HTLV-1-infected circulating T-cells invade the central nervous system (CNS) and cause an immunopathogenic response against virus and possibly components of the CNS. Neural damage and subsequent degeneration can cause severe disability in patients with HAM/TSP. Little progress has been made in the discovery of objective biomarkers for grading stages and predicting progression of disease and the development of molecular targeted therapy based on the underlying pathological mechanisms. We review the recent understanding of immunopathological mechanism of HAM/TSP and discuss the unmet need for research on this disease.

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Immunophenotypic characterization of CSF B cells in virus-associated neuroinflammatory diseases

Cited by 32 publications

References 65 publications

HTLV-1 HBZ Protein Resides Exclusively in the Cytoplasm of Infected Cells in Asymptomatic Carriers and HAM/TSP Patients

HTLV-1 HBZ Protein Resides Exclusively in the Cytoplasm of Infected Cells in Asymptomatic Carriers and HAM/TSP Patients

Autoantibody Biomarkers for Basal Ganglia Encephalitis in Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections

Neuroimmunology of Human T-Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis

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