Viral load determines the B‐cell response in the cerebrospinal fluid during human immunodeficiency virus infection

Cepok, Sabine; Geldern, Gloria von; Nolting, Thorsten; Grummel, Verena; Srivastava, Rajneesh; Zhou, Dun; Hartung, Hans‐Peter; Adams, Ortwin; Arendt, Gabriele; Hemmer, Bernhard

doi:10.1002/ana.21195

Cited by 23 publications

(26 citation statements)

References 38 publications

(24 reference statements)

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“…We focused our analysis on CSF CD138+ cells because prior studies have demonstrated that this predominantly plasma blast population is the primary source of intrathecal Ig production in inflammatory and infectious CNS disease 11, 15, 16, 21. Consistent with the proposed role of AQP4 autoantibodies in NMO pathogenesis, our findings indicate that an intrathecal humoral immune response against AQP4 is evident at the onset of clinical disease.…”

Section: Discussionmentioning

confidence: 62%

Intrathecal pathogenic anti–aquaporin‐4 antibodies in early neuromyelitis optica

Bennett¹,

Lam²,

Kalluri³

et al. 2009

Annals of Neurology

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530

571

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Objective-The serum of most neuromyelitis optica (NMO) patients contains autoantibodies (NMO-IgGs) directed against the aquaporin-4 (AQP4) water channel located on astrocyte foot processes in the perivessel and subpial areas of the brain. Our objectives were to determine the source of central nervous system (CNS) NMO-IgGs and their role in disease pathogenesis.Methods-Fluorescence activated cell sorting and single-cell reverse transcriptase PCR were used to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the cerebrospinal fluid (CSF) of an NMO patient after a first clinical attack. Monoclonal recombinant antibodies (rAbs) were generated from the paired heavy and light chain sequences and tested for target specificity and Fc effector function. The effect of CSF rAbs on CNS immunopathology was investigated by delivering single rAbs to rats with experimental autoimmune encephalomyelitis (EAE).Results-Repertoire analysis revealed a dynamic, clonally expanded plasma cell population with features of an antigen-targeted response. Using multiple independent assays, 6 of 11 rAbs generated from CSF plasma cell clones specifically bound to AQP4. AQP4-specific rAbs recognized conformational epitopes and mediated both AQP4-directed antibody-dependent cellular cytotoxicity and complement-mediated lysis. When administered to rats with EAE, an AQP4-specific NMO CSF rAb induced NMO immunopathology: perivascular astrocyte depletion, myelinolysis and complement and Ig deposition.Interpretation-Molecular characterization of the CSF plasma cell repertoire in an early NMO patient demonstrates that AQP4-specfic Ig is synthesized intrathecally at disease onset and directly

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Section: Discussionmentioning

confidence: 62%

Intrathecal pathogenic anti–aquaporin‐4 antibodies in early neuromyelitis optica

Bennett¹,

Lam²,

Kalluri³

et al. 2009

Annals of Neurology

Self Cite

530

571

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“…Most of these cells die by apoptosis, while some traffic to bone marrow or inflamed tissue and become long-lived plasma cells that maintain continuous production of antibodies (reviewed in references 32 and 87). Plasmablasts are also increased during episodes of active systemic lupus erythematosus (59), infectious mononucleosis (49), and acute rotavirus infection (34) and appear at a higher frequency in the cerebrospinal fluid of HIV-infected patients compared to controls (21). We show here that in the setting of chronic HIV infection, plasmablast frequency in the blood is significantly higher in patients than in uninfected donors (1.6% versus 0.46%, P ϭ 0.001).…”

Section: Vol 83 2009 Frequency and Phenotype Of Hiv-specific B Cellmentioning

confidence: 63%

Frequency and Phenotype of Human Immunodeficiency Virus Envelope-Specific B Cells from Patients with Broadly Cross-Neutralizing Antibodies

Doria‐Rose¹,

Klein²,

Manion³

et al. 2009

J Virol

290

241

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Induction of broadly cross-reactive neutralizing antibodies (NAb) is an important goal for a prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine. Some HIV-infected patients make a NAb response that reacts with diverse strains of HIV-1, but most candidate vaccines have induced NAb only against a subset of highly sensitive isolates. To better understand the nature of broad NAb responses that arise during natural infection, we screened patients for sera able to neutralize diverse HIV strains and explored the frequency and phenotype of their peripheral Envelope-specific B cells. We screened 113 HIV-infected patients of various clinical statuses for the prevalence of broad NAb. Sera able to neutralize at least four of five viral isolates were found in over one-third of progressors and slow progressors, but much less frequently in aviremic long-term nonprogressors. Most Env-specific antibody-secreting B cells were CD27 hi CD38 hi plasmablasts, and the total plasmablast frequency was higher in HIV-infected patients than in uninfected donors. We found that 0.0031% of B cells and 0.047% of plasmablasts secreted Env-specific immunoglobulin G (IgG) in an enzyme-linked immunospot (ELISPOT) assay. We developed a novel staining protocol to label HIV-specific B cells with Env gp140 protein. A total of 0.09% of B cells were found to be Env-specific by this method, a frequency far higher than that indicated by ELISPOT assay. gp140-labeled B cells were predominantly CD27 ؉ and surface IgG ؉ . These data describe the breadth and titer of serum NAb and the frequency and phenotype of HIV-specific B cells in a cohort of patients with broad cross-neutralizing antibody responses that are potential goals for vaccines for HIV.

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“…We clearly showed the added value of CSF CXCL13 to CSF-RPR, and we also showed that HIV-infected patients benefited more from CSF CXCL13 as an added marker for diagnosis of neurosyphilis. Cepok et al showed that HIV infection triggers an early profound B cell response in CNS, which serves as the main virus-related B cell subset in the CSF (14), and B cells are the main source of CSF CXCL13 (8,13). However, Bremell et al showed that CSF CXCL13 was not increased in HIV-infected patients (15), and we did not observe elevated CSF CXCL13 concentrations in the HIV-and T. pallidum-coinfected control group with a negative CSF-RPR result.…”

Section: Discussionmentioning

confidence: 99%

Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

et al. 2015

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eIn patients with syphilis, central nervous system (CNS) involvement is often difficult to determine. In patients who also are infected with human immunodeficiency virus (HIV), this is even more challenging, as cerebrospinal fluid (CSF) pleocytosis can be attributed to HIV, syphilis, or both. Hence, this study investigated (i) CSF chemokine (C-X-C motif) ligand 13 (CXCL13) as a potential marker to diagnose neurosyphilis in HIV-infected individuals and (ii) the added value of CSF CXCL13 to conventional CSF biomarkers, such as the rapid plasma reagin test (RPR), in diagnosing neurosyphilis. We included 103 syphilis patients from two centers in The Netherlands: 47 non-HIV-infected patients and 56 HIV-infected patients. A positive CSF-RPR was regarded as the gold standard for neurosyphilis. CSF CXCL13 levels were significantly higher in neurosyphilis patients when neurosyphilis was diagnosed by CSF-RPR (P ‫؍‬ 0.0002) than in the syphilis control group. The sensitivity and specificity of CSF CXCL13 (cutoff of 76.3 pg/ml) to diagnose neurosyphilis by using positive CSF-RPR as the gold standard were 50% and 90%, respectively. CSF CXCL13 had an added value to CSF-RPR positivity in 70% of HIV-positive patients and in 33% of HIV-negative patients. Our data show that CSF CXCL13 might be a potential additional marker in neurosyphilis when other markers are not conclusive. The added value of CSF CXCL13 measurement to the current neurosyphilis gold standard appears to benefit HIV-positive patients more than HIV-negative patients. In 2007, the World Health Organization estimated an incidence of 12 million new infections with Treponema pallidum each year worldwide (1). Invasion of the central nervous system (CNS) by T. pallidum may occur during any disease stage of syphilis, leading to the development of neurosyphilis in some patients (2, 3). When dual infections with HIV and syphilis exist, the diagnostic challenge increases. A positive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory test (VDRL) is generally considered the gold standard for neurosyphilis (4); however, several studies have clearly shown that a positive CSF rapid plasma reagin test (RPR) is an alternative to CSF-VDRL (5, 6), and RPR is also recommended by 2014 European guidelines (IUSTI-2014) (7). When the CSF-RPR or CSF-VDRL is negative, the diagnosis relies on other markers, like CSF pleocytosis, the CSF T. pallidum particle agglutination (TPPA) index, and clinical signs and symptoms.As the laboratory diagnosis of neurosyphilis is difficult, new markers are needed, and CSF B cell chemoattractant chemokine (C-X-C motif) ligand 13 (CXCL13) is currently forwarded as an interesting marker. CXCL13 has been demonstrated to be elevated in B lymphocyte-rich CSF (8, 9). CSF CXCL13 has a higher sensitivity than the established diagnostic markers for neuroborreliosis, such as CSF pleocytosis and Borrelia-specific antibodies (10). High numbers of B lymphocytes have also been observed in CSF from patients with syphilitic meningitis (11). CXCL13 dictates homi...

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Viral load determines the B‐cell response in the cerebrospinal fluid during human immunodeficiency virus infection

Abstract: Our findings demonstrate that HIV infection of the CNS triggers an early profound B-cell response, with plasmablasts serving as the main virus-related B-cell subset in the CSF.

Cited by 23 publications

References 38 publications

Intrathecal pathogenic anti–aquaporin‐4 antibodies in early neuromyelitis optica

Intrathecal pathogenic anti–aquaporin‐4 antibodies in early neuromyelitis optica

Frequency and Phenotype of Human Immunodeficiency Virus Envelope-Specific B Cells from Patients with Broadly Cross-Neutralizing Antibodies

Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

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