Immune alterations in subacute sclerosing panencephalitis reflect an incompetent response to eliminate the measles virus

In subacute sclerosing panencephalitis (SSPE) the persistence of measles virus (MeV) may be related to the altered immune response. In this study, cytokine responses of lymphocytes and monocytes were evaluated in SSPE compared to controls with non-inflammatory (NICON) and inflammatory (ICON) diseases. Patients with SSPE (n = 120), 78 patients with ICON and 63 patients with NICON were included in this study. Phenotypes of peripheral blood mononuclear cells (PBMC) have been analyzed by flow cytometry. CD3 and CD28, and S. aureus Cowan strain I (SAC) stimulated and unstimulated cells were cultured and IL-2, IL-10, IFN-γ, IL-12p40, IL-12p70 and IL-23 were detected in supernatants by ELISA. MeV peptides were used for MeV-specific stimulation and IFN-γ secretion of PBMC was measured by ELISPOT. Spontaneous and stimulated secretions of IL-10 were lower in SSPE compared to both control groups. T cell stimulation induced lower IFN-γ production than ICON group, but higher IL-2 than NICON group in SSPE. Stimulated PBMC produced lower IL-12p70 in SSPE and had decreased CD46 on the cell surface, suggesting the interaction with the virus. IFN-γ responses against MeV peptides were not prominent and similar to NICON patients. The immune response did not reveal an inflammatory activity to eliminate the virus in SSPE patients. Even IL-10 production was diminished implicating that the response is self-limited in controlling the disease.

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Immune Response to Infection withMycobacterium ulcerans

Infection and Immunity ◽

10.1128/iai.69.3.1704-1707.2001 ◽

2001 ◽

Vol 69 (3) ◽

pp. 1704-1707 ◽

Cited By ~ 78

Author(s):

Travis M. Gooding ◽

Paul D. R. Johnson ◽

Dianne E. Campbell ◽

John A. Hayman ◽

Elizabeth L. Hartland ◽

...

Keyword(s):

Immune Response ◽

Mononuclear Cells ◽

Tuberculin Test ◽

Acid Fast Bacillus ◽

Mycobacterium Ulcerans ◽

Cell Mediated Immunity ◽

Peripheral Blood Mononuclear ◽

T Cell Anergy ◽

Skin Ulcers ◽

Ifn Γ

ABSTRACT Mycobacterium ulcerans is a slow-growing, acid-fast bacillus that causes chronic necrotizing skin ulcers known as Buruli ulcers. Previously reported information on immunity to this mycobacterium is limited. We examined immune responses to M. ulcerans and M. bovis BCG in patients with M. ulcerans disease and in 20 healthy control subjects (10 tuberculin test positive and 10 tuberculin test negative). Cell-mediated immunity was assessed by stimulating peripheral blood mononuclear cells (PBMC) with whole mycobacteria and then measuring PBMC proliferation and the production of gamma interferon (IFN-γ). Humoral immunity was assessed by immunoblotting. PBMC from all subjects showed significantly greater proliferation and IFN-γ production in response to stimulation with living mycobacteria compared with killed cells. However, PBMC from subjects with past or current M. ulcerans disease showed significantly reduced proliferation and production of IFN-γ in response to stimulation with live M. ulcerans or M. bovis than PBMC from healthy, tuberculin test-positive subjects (P < 0.001) and showed results in these assays comparable to those of tuberculin test-negative subjects (P > 0.2). Serum from 9 of 11 patients with M. ulcerans disease, but no control subject, contained antibodies to M. ulcerans. The results indicate that patients with M. ulcerans infection mount an immune response to M. ulcerans as evidenced by antibody production, but they demonstrate profound systemic T-cell anergy to mycobacterial antigens. These findings may explain some of the distinct clinical and pathological features of M. ulcerans-induced disease.

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Cytokine Profiles of Patients Infected with Mycobacterium ulcerans and Unaffected Household Contacts

Infection and Immunity ◽

10.1128/iai.70.10.5562-5567.2002 ◽

2002 ◽

Vol 70 (10) ◽

pp. 5562-5567 ◽

Cited By ~ 64

Author(s):

Travis M. Gooding ◽

Paul D. R. Johnson ◽

May Smith ◽

Andrew S. Kemp ◽

Roy M. Robins-Browne

Keyword(s):

Immune Response ◽

Mononuclear Cells ◽

Buruli Ulcer ◽

Mycobacterium Ulcerans ◽

Interleukin 4 ◽

Peripheral Blood Mononuclear ◽

Household Contacts ◽

Control Subjects ◽

Cytokine Profiles ◽

Ifn Γ

ABSTRACT Mycobacterium ulcerans, the cause of Buruli ulcer, is an environmental mycobacterium with a distinct geographic distribution. The reasons why only some individuals who are exposed to M. ulcerans develop ulcers are not known but are likely to reflect individual differences in the immune response to infections with this bacterium. In this study, we investigated cytokine profiles of peripheral blood mononuclear cells (PBMC) from 23 Buruli ulcer patients and 25 household contacts in a region of Australia where Buruli ulcer is endemic. The results showed that following stimulation with M. ulcerans or Mycobacterium bovis BCG, PBMC from Buruli ulcer patients mounted a Th2-type response, which was manifested by the production of mRNA for interleukin 4 (IL-4), IL-5, IL-6, and IL-10, whereas unaffected contacts responded mainly with the Th1 cytokines gamma interferon (IFN-γ) and IL-12. For example, mRNA for IL-4 was detected in 18 of 23 patients but in only 3 of 25 control subjects (P < 0.0001). By contrast, PBMC from 21 of 25 unaffected individuals produced IFN-γ compared with 3 of 23 patients (P < 0.0001). IFN-γ release following stimulation with mycobacteria was markedly reduced in affected subjects. Frequencies of antibodies to M. ulcerans in serum samples from affected and unaffected subjects were similar, indicating that many of the control subjects had been exposed to this bacterium. Together, these findings suggest that a Th1-type immune response to M. ulcerans may prevent the development of Buruli ulcer in people exposed to M. ulcerans, but a Th-2 response does not.

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Immunization with Brucella VirB Proteins Reduces Organ Colonization in Mice through a Th1-Type Immune Response and Elicits a Similar Immune Response in Dogs

Clinical and Vaccine Immunology ◽

10.1128/cvi.00653-14 ◽

2014 ◽

Vol 22 (3) ◽

pp. 274-281 ◽

Cited By ~ 10

Author(s):

Cora N. Pollak ◽

María Magdalena Wanke ◽

Silvia M. Estein ◽

M. Victoria Delpino ◽

Norma E. Monachesi ◽

...

Keyword(s):

Immune Response ◽

Mononuclear Cells ◽

Interleukin 4 ◽

Delayed Type Hypersensitivity ◽

Peripheral Blood Mononuclear ◽

Content Type ◽

Type Iv ◽

Ifn Γ ◽

Organ Colonization

ABSTRACTVirB proteins fromBrucellaspp. constitute the type IV secretion system, a key virulence factor mediating the intracellular survival of these bacteria. Here, we assessed whether a Th1-type immune response against VirB proteins may protect mice fromBrucellainfection and whether this response can be induced in the dog, a natural host forBrucella. Splenocytes from mice immunized with VirB7 or VirB9 responded to their respective antigens with significant and specific production of gamma interferon (IFN-γ), whereas interleukin-4 (IL-4) was not detected. Thirty days after an intraperitoneal challenge with liveBrucella abortus, the spleen load of bacteria was almost 1 log lower in mice immunized with VirB proteins than in unvaccinated animals. As colonization reduction seemed to correlate with a Th1-type immune response against VirB proteins, we decided to assess whether such a response could be elicited in the dog. Peripheral blood mononuclear cells (PBMCs) from dogs immunized with VirB proteins (three subcutaneous doses in QuilA adjuvant) produced significantly higher levels of IFN-γ than cells from control animals uponin vitrostimulation with VirB proteins. A skin test to assess specific delayed-type hypersensitivity was positive in 4 out of 5 dogs immunized with either VirB7 or VirB9. As both proteins are predicted to locate in the outer membrane ofBrucellaorganisms, the ability of anti-VirB antibodies to mediate complement-dependent bacteriolysis ofB. caniswas assessedin vitro. Sera from dogs immunized with either VirB7 or VirB9, but not from those receiving phosphate-buffered saline (PBS), produced significant bacteriolysis. These results suggest that VirB-specific responses that reduce organ colonization byBrucellain mice can be also elicited in dogs.

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A ComparativeIn VitroStudy of the Effects of Separate and Combined Products ofCitrus e fructibusandCydonia e fructibuson Immunological Parameters of Seasonal Allergic Rhinitis

Mediators of Inflammation ◽

10.1155/2012/109829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

E. W. Baars ◽

M. C. Jong ◽

I. Boers ◽

A. F. M. Nierop ◽

H. F. J. Savelkoul

Keyword(s):

Allergic Rhinitis ◽

Seasonal Allergic Rhinitis ◽

Mononuclear Cells ◽

Immunological Parameters ◽

Peripheral Blood Mononuclear ◽

Tnf Α ◽

Ifn Γ ◽

Specific Stimulation

This paper examined the effects of the combined product,Citrus e fructibus/Cydonia e fructibus(Citrus/Cydonia; Citrus and Cydonia: each 0.01 g/mL), and separate products of Citrus (0.01 g/mL) and Cydonia (0.01 g/mL) on the immunological pathways involved in seasonal allergic rhinitis (SAR). Peripheral blood mononuclear cells (PBMCs) from five healthy and five grass pollen-allergic donors were isolated and analyzedin vitroafter polyclonal and allergen-specific stimulation of T cells in the presence of the three extracts. The analyses demonstrated acceptable cell survival with no signs of toxicity. Citrus mainly had a selective effect on reducing allergen-specific chronic inflammatory (TNF-α; Citrus compared to Cydonia and Citrus/Cydonia: −87.4 (P<0.001) and −68.0 (P<0.05), resp.) and Th2 pathway activity (IL-5; Citrus compared to Cydonia: −217.8 (P<0.01); while, both Cydonia and Citrus/Cydonia mainly affected the induction of the allergen-specific Th1 pathway (IFN-γ; Cydonia and Citrus/Cydonia compared to Citrus: 3.8 (P<0.01) and 3.0 (P<0.01), resp.). Citrus and Cydonia demonstrated different working mechanisms in the treatment of SAR and the combination product did not demonstrate larger effects than the separate preparations. Further effectiveness and efficacy studies comparing the effects of the products on SARin vivoare indicated.

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Modulation of Innate Cytokine Responses by Products of Helicobacter pylori

Infection and Immunity ◽

10.1128/iai.68.11.6265-6272.2000 ◽

2000 ◽

Vol 68 (11) ◽

pp. 6265-6272 ◽

Cited By ~ 59

Author(s):

Frank Meyer ◽

Keith T. Wilson ◽

Stephen P. James

Keyword(s):

Immune Response ◽

Helicobacter Pylori ◽

Lymphocyte Proliferation ◽

Mononuclear Cells ◽

Cytokine Production ◽

Peripheral Blood Mononuclear ◽

Cytokine Responses ◽

Ifn Γ ◽

H Pylori ◽

Th1 Polarization

ABSTRACT The gastric inflammatory and immune response in Helicobacter pylori infection may be due to the effect of different H. pylori products on innate immune mechanisms. The aim of this study was to determine whether bacterial components could modulate cytokine production in vitro and thus contribute to Th1 polarization of the gastric immune response observed in vivo. The effect of H. pylori recombinant urease, bacterial lysate, intact bacteria, and bacterial DNA on proliferation and cytokine production by peripheral blood mononuclear cells (PBMCs) from H. pylori-negative donors was examined as a model for innate cytokine responses. Each of the different H. pylori preparations induced gamma interferon (IFN-γ) and interleukin-12p40 (IL-12p40), but not IL-2 or IL-5, production, and all but H. pylori DNA stimulated release of IL-10. Addition of anti-IL-12 antibody to cultures partially inhibited IFN-γ production. In addition, each bacterial product inhibited mitogen-stimulated IL-2 production by PBMCs and Jurkat T cells. The inhibitory effect of bacterial products on IL-2 production correlated with inhibition of mitogen-stimulated lymphocyte proliferation, although urease inhibited IL-2 production without inhibiting proliferation, suggesting that inhibition of IL-2 production alone is not sufficient to inhibit lymphocyte proliferation. The results of these studies demonstrate that Th1 polarization of the gastric immune response may be due in part to the direct effects of multiple different H. pylori components that enhance IFN-γ and IL-12 production while inhibiting both IL-2 production and cell proliferation that may be necessary for Th2 responses.

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Immune Responses in Cutaneous Leishmaniasis: in vitro Thelper1/Thelper2 Cy-tokine Profiles Using Live Versus Killed Leishmania major

Journal of Arthropod-Borne Diseases ◽

10.18502/jad.v15i1.6491 ◽

2021 ◽

Author(s):

Akram Miramin-Mohammadi ◽

Amir Javadi ◽

Seyyed Ebrahim Eskandari ◽

Mahmood Nateghi-Rostami ◽

Ali Khamesipour

Keyword(s):

Immune Response ◽

Cutaneous Leishmaniasis ◽

Leishmania Major ◽

Mononuclear Cells ◽

Control Measure ◽

Peripheral Blood Mononuclear ◽

Significant Difference ◽

History Of ◽

Ifn Γ

Background: Recovery from cutaneous leishmaniasis (CL) leads to protection against further lesion development. In contrast, vaccination using killed parasites does not induce enough protection; the reason(s) is not currently known but might be related to different immune response induced against live versus killed parasites. In this study, Th1/Th2 cyto-kine profiles of CL patients were evaluated against live versus killed Leishmania major. Methods: In this study peripheral blood mononuclear cells (PBMC) of the volunteers with active CL lesion (CL), history of CL (HCL) and healthy volunteers were cultured and stimulated with live or killed Leishmania major, the superna-tants were collected and levels of IFN-γ, IL-5 and IL-10 were titrated using ELISA method. Results: The results showed that IFN-γ levels in CL patients (p< 0.001) and HCL volunteers (p< 0.005) are signifi-cantly higher when stimulated with live than stimulated with killed L. major. IFN-γ production in PBMC volunteers with CL and HCL stimulated with live or heat-killed L. major was significantly (p< 0.001) higher than in unstimulated ones. The level of IL-5 in CL patients (p< 0.005) and HCL volunteers (p< 0.001) are significantly lower when stimulated with live than killed L. major. There was no significant difference between the levels of IL-10 in PBMC stimulated with either live or killed L. major. Conclusion: It is concluded that using live Leishmania induces a stronger Th1 type of immune response which justify using leishmanization as a control measure against CL.

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Measles in children. Weren’t you waiting? What should a pediatrician know

Medical Council ◽

10.21518/2079-701x-2020-10-180-186 ◽

2020 ◽

pp. 180-186

Author(s):

I. N. Zakharova ◽

I. M. Osmanov ◽

I. V. Berezhnaya ◽

I. D. Maykova ◽

N. F. Dubovets ◽

...

Keyword(s):

Measles Virus ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Subacute Sclerosing Panencephalitis ◽

Immune Memory ◽

Interferon Α ◽

Peripheral Blood Mononuclear ◽

Recombinant Interferon ◽

Long Time ◽

Tract Infections

From a long time ago to the present day, measles remains one of the leading health problems in the world. The main reason for this is high mortality from measles – 1/500. Despite the availability of an effective and safe vaccine, which was discovered in 1963, there are still epidemic outbreaks of measles. According to WHO, there were 413,308 confirmed cases in 187 countries and 764 deaths during 2019. Most measles deaths are due to complications associated with the disease.Complications are most common in children under five or in adults over 30 years of age. The most serious complications include blindness, encephalitis leading to cerebral edema, severe diarrhoea and associated dehydration, purulent otitis and severe lower respiratory tract infections such as pneumonia. In a study from 2019, Michael J. Mina and colleagues showed that after measles in the group of unprivileged people, 11 to 73% of previous immune memory is “erased”. Currently, there is no specific etiotropic therapy for measles. One of the pathogenetic links in therapy is the use of interferon replacement therapy. According to the Federal Clinical Recommendations and WHO recommendations, the use of recombinant interferon α-2B and vitamin A is recommended. The effectiveness of interferonotherapy for measles was first shown in 1992 by the Leopardi R team. This study showed that the secretion of measles virus in human peripheral blood mononuclear cells was gradually reduced by increasing the concentrations and blocked at the concentration of interferon α-2B in 1000 units/ml. Moreover, at the XXIV World Congress of Neuroscientists (WCN) it was noted that the safest and most effective method of treatment of subacute sclerosing panencephalitis, one of the severe complications of measles, is recombinant human α-2B interferon.

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Identification and Characterization of Novel, Naturally Processed Measles Virus Class II HLA-DRB1 Peptides

Journal of Virology ◽

10.1128/jvi.78.1.42-51.2004 ◽

2004 ◽

Vol 78 (1) ◽

pp. 42-51 ◽

Cited By ~ 25

Author(s):

Inna G. Ovsyannikova ◽

Kenneth L. Johnson ◽

David C. Muddiman ◽

Robert A. Vierkant ◽

Gregory A. Poland

Keyword(s):

Amino Acid ◽

Measles Virus ◽

Mononuclear Cells ◽

Class Ii ◽

Hla Class Ii ◽

Interleukin 4 ◽

Design Strategies ◽

Peripheral Blood Mononuclear ◽

Amino Acid Peptide ◽

Ifn Γ

ABSTRACT Previously, we identified a naturally processed and presented measles virus (MV) 19-amino-acid peptide, ASDVETAEGGEIHELLRLQ (MV-P), derived from the phosphoprotein and eluted from the human leukocyte antigen (HLA) class II molecule by using mass spectrometry. We report here the identification of a 14-amino-acid peptide, SAGKVSSTLASELG, derived from the MV nucleoprotein (MV-N) bound to HLA-DRB1*0301. Peripheral blood mononuclear cells (PBMC) from 281 previously vaccinated measles-mumps-rubella II (MMR-II) subjects (HLA discordant) were studied for peptide recognition by T cells. Significant gamma interferon (IFN-γ) responses to MV-P and MV-N peptides were observed in 55.9 and 15.3% of subjects, respectively. MV-P- and MV-N-specific interleukin-4 (IL-4) responses were detected in 19.2 and 23.1%, respectively, of PBMC samples. Peptide-specific cytokine responses and HLA-DRB1 allele associations revealed that, for the MV-P peptide, the allele with the strongest association with both IFN-γ (P = 0.02) and IL-4 (P = 0.03) secretion was DRB1*0301. For MV-N, the allele with the strongest association with IFN-γ secretion was DRB1*1501 (P = 0.04), and the alleles with the strongest associations with IL-4 secretion were DRB1*1103 and DRB1*1303 (P = 0.01). These results indicate that HLA class II MV proteins can be processed, presented, and identified, and the ability to generate cell-mediated immune responses can be demonstrated. This information is promising for new vaccine design strategies with peptide-based vaccines.

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Role of the Th1 and Th17 Pathway in Subacute Sclerosing Panencephalitis

Journal of Child Neurology ◽

10.1177/0883073819860631 ◽

2019 ◽

Vol 34 (13) ◽

pp. 815-819

Author(s):

Dilara F. Kocacık Uygun ◽

Vedat Uygun ◽

Durmuş Burgucu ◽

Nilüfer Çiçek Ekinci ◽

Nilgün Sallakçı ◽

...

Keyword(s):

Measles Virus ◽

Mononuclear Cells ◽

Inflammatory Mediator ◽

Subacute Sclerosing Panencephalitis ◽

Enzyme Linked Immunosorbent Assay ◽

Inflammatory Mediator Production ◽

Healthy Donors ◽

New Strategy ◽

Ifn Γ

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal disease caused by reactivation of a mutated measles virus in brain tissue. The process of reactivation is yet to be elucidated. In this study, the possible roles of the Th1 (interleukin [IL]-12, interferon [IFN]-γ) and the Th17 axis (IL-23, IL-17, IL-22), particularly of IL-17, in the pathogenesis of SSPE were investigated. Briefly, mononuclear cells from SSPE patients were stimulated using measles virus peptide, and the release of IL-12, IL-23, IL-22, IFN-γ, and IL-17 cytokines was measured using enzyme-linked immunosorbent assay and/or enzyme-linked immunosorbent spot assay (ELISpot). We found that in comparison to the mononuclear cells obtained from healthy donors, cells from SSPE patients exhibited increased levels of IL-12, IL-23, IL-17, IL-22, and IFN-γ cytokines in response to measles virus stimulation. However, the same result was not obtained with cytomegalovirus and phytohemagglutinin. Using flow cytometry, mononuclear cells obtained from SSPE patients and healthy controls were also analyzed for the presence of intracellular IL-17 in response to measles virus stimulation. On stimulation, the number of IL-17-positive cells were found to be higher among mononuclear cells obtained from the patients. In addition, the numbers of IL-17- and IFN-γ-positive cells were significantly increased in SSPE patients. In conclusion, this study demonstrates that both the IL-12/IFN-γ and the IL-23/IL-17/IL-22 pathways are functionally abnormal in SSPE pathogenesis. Targeting these pathways and their specific pro-inflammatory mediator production may provide a new strategy to suppress SSPE development.

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Gene Expression Changes in Peripheral Blood Mononuclear Cells during Measles Virus Infection

Clinical and Vaccine Immunology ◽

10.1128/cvi.00031-07 ◽

2007 ◽

Vol 14 (7) ◽

pp. 918-923 ◽

Cited By ~ 41

Author(s):

Michael J. Zilliox ◽

William J. Moss ◽

Diane E. Griffin

Keyword(s):

Gene Expression ◽

Immune Response ◽

Virus Infection ◽

Measles Virus ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Necrosis Factor Alpha ◽

Surface Receptors ◽

Blood Mononuclear Cells ◽

Efficacious Vaccine

ABSTRACT Measles virus continues to cause morbidity and mortality despite the existence of a safe and efficacious vaccine. Measles is associated with induction of both a long-lived protective immune response and immunosuppression. To gain insight into immunological changes during measles virus infection, we examined gene expression in blood mononuclear cells from children with acute measles and children in the convalescent phase compared to uninfected control children. There were 13 significantly upregulated and 206 downregulated genes. Upregulated genes included the immune regulatory molecules interleukin 1β (IL-1β), CIAS-1, tumor necrosis factor alpha, PDE4B, PTGS2, IL-8, CXCL2, CCL4, ICAM-1, CD83, GOS-2, IER3 (IEX-1), and TNFAIP3 (A20). Plasma levels of IL-1β and IL-8 were elevated during measles virus infection. Downregulated genes mainly involved three gene ontology biological processes, transcription, signal transduction, and the immune response, and included IL-16 and cell surface receptors IL-4R, IL-6R, IL-7R, IL-27RA, CCR2, and CCR7. Most mRNAs had not returned to control values 1 month after discharge, consistent with prolonged immune response abnormalities during measles virus infection.

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