Yassine Taoufik

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the brain caused by reactivation of the JC virus (JCV), a polyomavirus that infects at least 60% of the population but is asymptomatic or results in benign symptoms in most people. PML occurs as a secondary disease in a variety of disorders or as a serious adverse event from immunosuppressant agents, but is mainly found in three groups: HIV-infected patients, patients with hematological malignancies, or multiple sclerosis (MS) patients on the immunosuppressant therapy natalizumab. It is severely debilitating and is deadly in ~50% HIV cases, ~90% of hematological malignancy cases, and ~24% of MS-natalizumab cases. A PML risk prediction test would have clinical utility in all at risk patient groups but would be particularly beneficial in patients considering therapy with immunosuppressant agents known to cause PML, such as natalizumab, rituximab, and others. While a JC antibody test is currently used in the clinical decision process for natalizumab, it is suboptimal because of its low specificity and requirement to periodically retest patients for seroconversion or to assess if a patient's JCV index has increased. Whereas a high specificity genetic risk prediction test comprising host genetic risk variants (i.e., germline variants occurring at higher frequency in PML patients compared to the general population) could be administered one time to provide clinicians with additional risk prediction information that is independent of JCV serostatus. Prior PML case reports support the hypothesis that PML risk is greater in patients with a genetically caused immunodeficiency disorder. To identify germline PML risk variants, we performed exome sequencing on 185 PML cases (70 in a discovery cohort and 115 in a replication cohort) and used the gnomAD variant database for interpretation. Our study yielded 19 rare variants (maximum allele frequency of 0.02 in gnomAD ethnically matched populations) that impact 17 immune function genes (10 are known to cause inborn errors of immunity). Modeling of these variants in a PML genetic risk test for MS patients considering natalizumab treatment indicates that at least a quarter of PML cases may be preventable.

Recent works have suggested a possible link between interleukin (IL)-33 and B-cell biology. We aimed to study the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients in different cohorts with an accurate enzyme-linked immunosorbent assay (ELISA). Serum IL-33, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and high serum immunoglobulin (Ig)G levels were assessed in 111 RA patients receiving a first course of 2 g RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Univariate and multivariate analyses identified factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks. At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33.5% of the patients. In the combined cohorts, the presence of RF or anti-CCP (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.13–9.46; p = 0.03), high serum IgG (OR 2.32, 95% CI 1.01–5.33; p = 0.048), and detectable serum IL-33 (OR 2.40, 95% CI 1.01–5.72; p = 0.047) were all associated with RTX response in multivariate analysis. The combination of these three factors increased the likelihood of response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the three risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the three risk factors 29.61, 95% CI 1.30–674.79; p = 0.034). Detectable serum IL-33 may predict clinical response to RTX independently of, and synergistically with, auto-antibodies and serum IgG level. NCT01126541 ; 18 May 2010.

Antiretroviral combination therapy raises issues of long-term adherence and toxicity. Initial treatment simplification based on single-drug therapy was investigated in the MONARK trial, which compared first-line lopinavir/ritonavir monotherapy (arm A) with first-line lopinavir/ritonavir + zidovudine/lamivudine tritherapy (arm B). The MONARK trial is registered as a randomized trial at clinical trials.gov under identifier NCT 00234923. Immune recovery was compared in patients with undetectable plasma virus (n = 21; arm B, n = 13). The week 60 CD4 T cell count and CD4 T cell subset distribution did not differ significantly between the treatment arms. Memory CD4 T cell responses to HIV and recall antigens were better with triple therapy than with monotherapy. The frequencies of activated CD8 T cells and anti-HIV CD8 T cell effector responses were similar in the two arms. However, the repertoire of CD8 T cell effector responses was broader and persistent residual viraemia more frequent (by ultrasensitive PCR) in the monotherapy arm. While viral control can be achieved with first-line lopinavir/ritonavir monotherapy, the quality of immune recovery is inferior to that obtained with triple therapy, possibly owing to a higher level of residual viral replication. Thus, the benefits of first-line lopinavir/ritonavir monotherapy in terms of toxicity and adherence might be offset by an increased risk of residual viral replication, which may also fuel latent viral reservoirs.

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain. PML classically occurs in patients with severe immunodepression, and cases have recently been linked to therapeutic monoclonal antibodies such as natalizumab and also rituximab, which depletes B cells. B cells appear to play a complex role in the pathogenesis of PML. They may act as a viral reservoir and as a vector for viral dissemination in the CNS. Anti-JCV antibody responses appear to have a limited effect on JCV replication in the brain. However, accumulating evidence suggests that B cells may considerably influence T cell responses through their cytokine secretion. This immunomodulatory function of B cells may play an important role in the control of JCV infection and in the pathogenesis of PML, including rituximab-induced PML.

In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4⁺ T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (T_SCM) CD4⁺ T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the T_SCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.

In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

Progressive multifocal leukoencephalopathy (PML) is the main adverse effect of natalizumab. Detectable JC virus-specific effector memory T-cell (TEM) responses may indicate ongoing JCV replication. We detected JCV-specific TEM responses in blood of patients with multiple sclerosis (MS) treated with natalizumab, including 2 patients with PML. The frequency of detection of these responses increased with the time on natalizumab. Thus, a subset of MS patients exhibit immunological hallmarks of JCV replication during prolonged natalizumab therapy.

T cell immunity is characterized by striking tissue specialization. Tissue-specificity imprinting starts during priming by tissue-derived migratory dendritic cells in the non-random, specialized micro-anatomical area of the draining lymph node and is influenced by constitutive and induced cues from local environment. Besides tissue-specific effectors, memory cells also exhibit a tissue-specificity. Long-lived tissue-resident memory T cells likely play a considerable role in preventing pathogen invasion. Understanding of the mechanisms of tissue-specialization of T cells is of major importance for the design of optimal vaccination strategies and therapeutic interventions in tissue/organ-specific inflammatory diseases. The present review summarizes our current knowledge and hypothesis about tissue-specificity imprinting and tissue residency of T cells.

During the primary immune response, CD8 memory emerges from an environment of strong immune activation. The FoxP3⁺ regulatory CD4 T-cell subset (Treg) is known as a key suppressive component of the immune system. Here we report that Tregs are required for the generation of functional CD8 memory. In the absence of Tregs during priming, the resulting memory cells proliferate poorly and fail to differentiate into functional cytotoxic secondary effectors following antigen reactivation. We find that the Tregs act early, during the expansion phase of primary CD8 effectors, by fine tuning interleukin-2 exposure of CD8 memory precursors. This crucial new role of Tregs has implications for optimal vaccine development.

B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-γ play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-α triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-γ gene imprinting factors. IFN-α primed naive B-cells for IFN-γ production and increased IFN-γ gene responsiveness to IL-12. IFN-γ continues this polarization by re-inducing T-bet and up-regulating IL-12Rβ2 expression. IFN-α and IFN-γ therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-α, IFN-γ and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.