Pulmonary eosinophilia associated to treatment with natalizumab

Natalizumab (Tysabri(®)) is a leukocytes chemotaxis inhibitor that decreases the leukocytes passage through the hematoencephalic barrier and it is currently used in relapsing-remitting forms of multiple sclerosis (MS). We present a patient with allergic rhinoconjunctivitis diagnosed with MS who started treatment with natalizumab. She began to show mild asthmatic symptoms until she needed admission to the hospital due to respiratory insufficiency. Blood tests showed peripheral eosinophilia and the thoracic computed tomography scan demonstrated pulmonary infiltrates. The bronchoscopy with the bronchoalveolar lavage resulted in eosinophilic alveolitis. No evidence of bacterial, fungal and parasitic infection, connective tissue disease, or vasculitis were observed. After discontinuation of natalizumab, the patient improved without other treatments. As MS is a prevalent disease and the use of natalizumab is increasing, we consider important to point out that this drug can be associated with pulmonary eosinophilia, especially in patients with allergic rhinoconjunctivitis or asthma

Pulmonary eosinophilia associated to treatment with natalizumab

Natalizumab (Tysabri®) is a leukocytes chemotaxis inhibitor that decreases the leukocytes passage through the hematoencephalic barrier and it is currently used in relapsing-remitting forms of multiple sclerosis (MS). We present a patient with allergic rhinoconjunctivitis diagnosed with MS who started treatment with natalizumab. She began to show mild asthmatic symptoms until she needed admission to the hospital due to respiratory insufficiency. Blood tests showed peripheral eosinophilia and the thoracic computed tomography scan demonstrated pulmonary infiltrates. The bronchoscopy with the bronchoalveolar lavage resulted in eosinophilic alveolitis. No evidence of bacterial, fungal and parasitic infection, connective tissue disease, or vasculitis were observed. After discontinuation of natalizumab, the patient improved without other treatments. As MS is a prevalent disease and the use of natalizumab is increasing, we consider important to point out that this drug can be associated with pulmonary eosinophilia, especially in patients with allergic rhinoconjunctivitis or asthma

Pulmonary eosinophilia associated to treatment with natalizumab

Natalizumab (Tysabri ®) is a leukocytes chemotaxis inhibitor that decreases the leukocytes passage through the hematoencephalic barrier and it is currently used in relapsing-remitting forms of multiple sclerosis (MS). We present a patient with allergic rhinoconjunctivitis diagnosed with MS who started treatment with natalizumab. She began to show mild asthmatic symptoms until she needed admission to the hospital due to respiratory insufficiency. Blood tests showed peripheral eosinophilia and the thoracic computed tomography scan demonstrated pulmonary infiltrates. The bronchoscopy with the bronchoalveolar lavage resulted in eosinophilic alveolitis. No evidence of bacterial, fungal and parasitic infection, connective tissue disease, or vasculitis were observed. After discontinuation of natalizumab, the patient improved without other treatments. As MS is a prevalent disease and the use of natalizumab is increasing, we consider important to point out that this drug can be associated with pulmonary eosinophilia, especially in patients with allergic rhinoconjunctivitis or asthma

Pulmonary eosinophilia associated to treatment with natalizumab

Natalizumab (Tysabri ®) is a leukocytes chemotaxis inhibitor that decreases the leukocytes passage through the hematoencephalic barrier and it is currently used in relapsing-remitting forms of multiple sclerosis (MS). We present a patient with allergic rhinoconjunctivitis diagnosed with MS who started treatment with natalizumab. She began to show mild asthmatic symptoms until she needed admission to the hospital due to respiratory insufficiency. Blood tests showed peripheral eosinophilia and the thoracic computed tomography scan demonstrated pulmonary infiltrates. The bronchoscopy with the bronchoalveolar lavage resulted in eosinophilic alveolitis. No evidence of bacterial, fungal and parasitic infection, connective tissue disease, or vasculitis were observed. After discontinuation of natalizumab, the patient improved without other treatments. As MS is a prevalent disease and the use of natalizumab is increasing, we consider important to point out that this drug can be associated with pulmonary eosinophilia, especially in patients with allergic rhinoconjunctivitis or asthma

Delayed B cell repopulation after rituximab treatment in multiple sclerosis patients with expanded adaptive natural killer cells

Background and purpose: The aim was to evaluate whether adaptive NKG2C+ natural killer (NK) cells, characterized by enhanced antibody-dependent cell cytotoxicity (ADCC), may influence time to B cell repopulation after rituximab treatment in multiple sclerosis (MS) patients. Methods: This was a prospective observational study of MS patients treated with rituximab monitoring peripheral B cells for repeated doses. B cell repopulation was defined as CD19+ cells above 2% of total lymphocytes, classifying cases according to the median time of B cell repopulation as early or late (≤9 months, >9 months, respectively). Basal NK cell immunophenotype and in vitro ADCC responses induced by rituximab were assessed by flow cytometry. Results: B cell repopulation in 38 patients (24 relapsing-remitting MS [RRMS]; 14 progressive MS) was classified as early (≤9 months, n = 19) or late (>9 months, n = 19). RRMS patients with late B cell repopulation had higher proportions of NKG2C+ NK cells compared to those with early repopulation (24.7% ± 16.2% vs. 11.3% ± 10.4%, p < 0.05), and a direct correlation between time to B cell repopulation and percentage of NKG2C+ NK cells (R 0.45, p < 0.05) was observed. RRMS cases with late repopulation compared with early repopulation had a higher secretion of tumor necrosis factor α and interferon γ by NK cells after rituximab-dependent NK cell activation. The NK cell immunophenotype appeared unrelated to B cell repopulation in progressive MS patients. Conclusions: Adaptive NKG2C+ NK cells in RRMS may be associated with delayed B cell repopulation after rituximab, a finding probably related to enhanced depletion of B cells exerted by NK-cell-mediated ADCC, pointing to the use of personalized regimens with anti-CD20 monoclonal antibody therapy in some patients

Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the 'hygiene hypothesis'?

BACKGROUND AND PURPOSE: Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. METHODS: Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. RESULTS: Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. CONCLUSIONS: Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease.This work was supported by grants FIS/PI14/00177,FIS/PI17/00254 and SAF 2013-49063-C2-1-R (SpanishMinistry of Economy and Competitiveness and FEDER), the EU FP7-MINECO Infect-ERA Pro-gram (PCIN-2015-191-C02-01) and Red Española de Esclerosis Múltiple from the Instituto de Salud CarlosIII, European Regional Development Fund (grant RD16/0015/0011) and Spanish Ministry of Economyand Competitiveness

Th1Th17 CM lymphocyte subpopulation as a predictive biomarker of disease activity in multiple sclerosis patients under dimethyl fumarate or fingolimod treatment

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n = 22) or fingolimod (n = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60 ± 4.17%vs. nonrelapsed: 9.25 ± 3.17%, p 11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells < 11.48% whose relapse-free survival was 88% (p = 0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%vs. no MRI activity: 9.82 ± 4.06%, p < 0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment

Adaptive features of natural killer cells in multiple sclerosis

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(-), and PLZF(-) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(-) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(-) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-β therapy was associated with lower proportions of FcRγ(-) CD56dim NK cells in HCMV(+) and increased PLZF(-) CD56bright NK cells in HCMV(-) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(-) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS.This work was supported by grants FIS/PI17/00254, SAF 2016-80363-C2-1-R (Spanish Ministry of Economy and Competitiveness and FEDER), the EU FP7-MINECO Infect-ERA Program (PCIN-2015-191-C02-01), and Red Española de Esclerosis Múltiple (REEM) from the Instituto de Salud Carlos III, the European Regional Development Fund (Grant RD16/0015/0011), and the Spanish Ministry of Economy and Competitiveness

Influence of the LILRA3 Deletion on Multiple Sclerosis Risk: Original Data and Meta-Analysis.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. OBJECTIVES: In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. RESULTS AND CONCLUSION: Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15:01 risk allele.Financial support for the study was provided by: Fondo de Investigación Sanitaria (FIS)- Instituto de Salud Carlos III (ISCIII)-Fondos Europeos de Desarrollo Regional (FEDER) (grant numbers PI12/00555 to FM; PI13/01527 to AA; PI13/01466 to GI; PI13/0879 to EU and RETICS-REEM RD12/0032/ ) and Junta de Andalucía (JA)- Fondos Europeos de Desarrollo Regional (FEDER) (grant number CTS2704 to FM