scholarly journals Differential expression of multiple kallikreins in a viral model of multiple sclerosis points to unique roles in the innate and adaptive immune response

2014 ◽  
Vol 395 (9) ◽  
pp. 1063-1073 ◽  
Author(s):  
Michael Panos ◽  
George P. Christophi ◽  
Moses Rodriguez ◽  
Isobel A. Scarisbrick
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Immune Response ◽  
Demyelinating Disease ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Axon Degeneration ◽  
Functional Link ◽  
The Brain

Abstract Recent studies provide a functional link between kallikrein 6 (Klk6) and the development and progression of disease in patients with multiple sclerosis (MS) and in its murine models. To evaluate the involvement of additional kallikrein family members, we compared Klk6 expression with four other kallikreins (Klk1, Klk7, Klk8, and Klk10) in the brain and spinal cord of mice infected with Theiler’s murine encephalomyelitis virus, an experimental model of progressive MS. The robust upregulation of Klk6 and Klk8 in the brain during the acute phase of viral encephalitis and in the spinal cord during disease development and progression points to their participation in inflammation, demyelination, and progressive axon degeneration. More limited changes in Klk1, Klk7, and Klk10 were also observed. In addition, Klk1, Klk6, and Klk10 were dynamically regulated in T cells in vitro as a recall response to viral antigen and in activated monocytes, pointing to their activities in the development of adaptive and innate immune function. Together, these results point to overlapping and unique roles for multiple kallikreins in the development and progression of virus-mediated central nervous system inflammatory demyelinating disease, including activities in the development of the adaptive and innate immune response, in demyelination, and in progressive axon degeneration.

scholarly journals The discovery of natalizumab, a potent therapeutic for multiple sclerosis

2012 ◽  
Vol 199 (3) ◽  
pp. 413-416 ◽  
Author(s):  
Lawrence Steinman
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Immune Cells ◽  
Strong Evidence ◽  
Demyelinating Disease ◽  
Critical Component ◽  
The Central Nervous System ◽  
The Brain

Multiple sclerosis (MS) is the major inflammatory demyelinating disease of the central nervous system. There is strong evidence that an immune response in the brain is a critical component of the disease. In 1992, in a collaboration between academia and biotechnology, my colleagues and I showed that α4 integrin was the critical molecule involved in the homing of immune cells into the inflamed brain. Was it sheer luck that these results led to the development of a drug for MS?

scholarly journals Innate Immune Responses and Viral-Induced Neurologic Disease

2018 ◽  
Vol 8 (1) ◽  
pp. 3 ◽  
Author(s):  
Yuting Cheng ◽  
Dominic Skinner ◽  
Thomas Lane
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Demyelinating Disease ◽  
Association Studies ◽  
Adaptive Immune Response ◽  
Neutrophil Infiltration ◽  
Innate Immune ◽  
Clinical Relapse ◽  
Genome Wide Association Studies ◽  
Neurologic Disease

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by chronic neuroinflammation, axonal damage, and demyelination. Cellular components of the adaptive immune response are viewed as important in initiating formation of demyelinating lesions in MS patients. This notion is supported by preclinical animal models, genome-wide association studies (GWAS), as well as approved disease modifying therapies (DMTs) that suppress clinical relapse and are designed to impede infiltration of activated lymphocytes into the CNS. Nonetheless, emerging evidence demonstrates that the innate immune response e.g., neutrophils can amplify white matter damage through a variety of different mechanisms. Indeed, using a model of coronavirus-induced neurologic disease, we have demonstrated that sustained neutrophil infiltration into the CNS of infected animals correlates with increased demyelination. This brief review highlights recent evidence arguing that targeting the innate immune response may offer new therapeutic avenues for treatment of demyelinating disease including MS.

scholarly journals Effects of antibiotics on acquired immunity in vivo – current state of knowledge

2012 ◽  
Vol 15 (3) ◽  
pp. 583-588 ◽  
Author(s):  
M. Pomorska-Mól ◽  
Z. Pejsak
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Ex Vivo ◽  
Animal Experiments ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Antimicrobial Drugs

AbstractAntibiotics are widely used in the therapy of infections. Besides the respective interactions between antibiotics and pathogens it seems that antibiotics also directly interact with the immune system. Some commonly used antibiotics are currently known to have effects on the innate immune response, as shown byin vitro, ex vivoand alsoin vivoanimal experiments and clinical studies. Most of the experimental papers published to date, as well as most reviews, relate to how antibiotics affect the innate immune response or non-specific monocyte or lymphocyte proliferation. However the effects of antibiotics on the adaptive immune response are still not well characterized. This review of the literature considering differentin vivoexperiments indicate the real importance of interrelations existing between acquired immune responses and antibiotics, however, the mechanism of immunomodulatory effects of antibiotics are still poorly understood. Currently, data on the immunomodulating effects of antibiotics often remain heterogeneous, contradictory or insufficient, but most results published to date revealed the immunosuppressive effect of antibiotics on the antigen- specific immune responsein vivo. In pigs as well as in poultry herds, it is not uncommon practice to add antibiotics to drinking water or feed at the time of vaccination. Information on the effects of such practices on the immune system of animals is restricted and morein vivostudies are needed to investigate the effects of antimicrobial drugs on the immune system, especially in the field conditions.

scholarly journals THE PATHOLOGIC EFFECTS OF STREPTOCOCCI FROM CASES OF POLIOMYELITIS AND OTHER SOURCES

1917 ◽  
Vol 25 (4) ◽  
pp. 557-580 ◽  
Author(s):  
Carroll G. Bull
Keyword(s):  
Spinal Cord ◽  
Guinea Pigs ◽  
The Other ◽  
Laboratory Animals ◽  
Histological Changes ◽  
Other Hand ◽  
Brain And Spinal Cord ◽  
The Brain

Streptococci cultivated from the tonsils of thirty-two cases of poliomyelitis were used to inoculate various laboratory animals. In no case was a condition induced resembling poliomyelitis clinically or pathologically in guinea pigs, dogs, cats, rabbits, or monkeys. On the other hand, a considerable percentage of the rabbits and a smaller percentage of some of the other animals developed lesions due to streptococci. These lesions consisted of meningitis, meningo-encephalitis, abscess of the brain, arthritis, tenosynovitis, myositis, abscess of the kidney, endocarditis, pericarditis, and neuritis. No distinction in the character or frequency of the lesions could be determined between the streptococci derived from poliomyelitic patients and from other sources. Streptococci isolated from the poliomyelitic brain and spinal cord of monkeys which succumbed to inoculation with the filtered virus failed to induce in monkeys any paralysis or the characteristic histological changes of poliomyelitis. These streptococci are regarded as secondary bacterial invaders of the nervous organs. Monkeys which have recovered from infection with streptococci derived from cases of poliomyelitis are not protected from infection with the filtered virus, and their blood does not neutralize the filtered virus in vitro. We have failed to detect any etiologic or pathologic relationship between streptococci and epidemic poliomyelitis in man or true experimental poliomyelitis in the monkey.

High content screening and computational prediction reveal viral genes that suppress innate immune response

2021 ◽  
Author(s):  
Tai L Ng ◽  
Erika J Olson ◽  
Tae Yeon Yoo ◽  
H. Sloane Weiss ◽  
Yukiye Koide ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Nuclear Transport ◽  
Computational Prediction ◽  
Viral Proteins ◽  
Innate Immune ◽  
Type I ◽  
Viral Genes ◽  
Genes Encoding

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single virus/gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human viral genes. We find that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-kB and IRF3. We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins.

Torticollis as an Initial Manifestation of a Seronegative Demyelinating Disorder in a Child: A Case Report

2021 ◽  
Author(s):  
Sandesh Kini ◽  
Yellanthoor Ramesh Bhat ◽  
Lakshmikanth Halegubbi Karegowda
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Case Report ◽  
Demyelinating Disease ◽  
Oligoclonal Bands ◽  
Initial Manifestation ◽  
Demyelinating Disorder ◽  
The Brain

AbstractTorticollis refers to a condition in which the head is persistently tilted to one side, sometimes associated with pain. Torticollis in a child can be congenital or acquired. Torticollis as an initial manifestation of an underlying demyelinating syndrome is quite rare in children. Here, we report a 7-year-old girl who presented with persistent torticollis. Neuroimaging of the brain revealed features of a demyelinating disease. Further studies did not show any evidence of multiple sclerosis. Cerebrospinal fluid was negative for antiaquaporin-4 antibodies, antimyelin oligodendrocyte glycoprotein antibodies, and oligoclonal bands. A seronegative demyelinating disorder was considered. She was treated with pulsed methylprednisolone therapy. She responded well to steroids with no progression of illness during follow-up. Torticollis was partially improved.

scholarly journals The Hepatitis C Virus-Induced Membranous Web in Liver Tissue

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 191
Author(s):  
Emmanuelle Blanchard ◽  
Philippe Roingeard
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Innate Immune Response ◽  
Liver Tissue ◽  
Hepatoma Cell ◽  
Membrane Vesicles ◽  
Innate Immune ◽  
Host Cell Membrane

Host cell membrane rearrangements induced by the hepatitis C virus (HCV) have been exclusively studied in vitro. These studies have shown that HCV induces double-membrane vesicles (DMVs), which probably serve to separate replication sites from the cytoplasmic sensors of the innate immune response. We report for the first time the observation of HCV-induced membrane rearrangements in liver biopsy specimens from patients chronically infected with HCV. Unlike observations performed in vitro, the membranous web detected in liver tissue seems essentially made of clusters of single-membrane vesicles derived from the endoplasmic reticulum and close to lipid droplets. This suggests that the DMVs could be a hallmark of laboratory-adapted HCV strains, possibly due to their ability to achieve a high level of replication. Alternatively, the concealment of viral RNA in DMVs may be part of innate immune response mechanisms particularly developed in hepatoma cell lines cultured in vitro. In any case, this constitutes the first report showing the differences in the membranous web established by HCV in vitro and in vivo.

scholarly journals The induced dose of experimental autoimmune encephalomyelitis was not determinant and proportional to histopathological findings

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
Maiara Carolina Perussolo ◽  
Bassam Felipe Mogharbel ◽  
Lucia de Noronha ◽  
Katherine Athayde Teixeira de Carvalho
Keyword(s):  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Demyelinating Disease ◽  
Clinical Signs ◽  
Signs And Symptoms ◽  
Control Group ◽  
Autoimmune Encephalomyelitis ◽  
Histopathological Findings ◽  
The Brain ◽  
Experimental Autoimmune

Abstract Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized as an inflammatory demyelinating disease. It presents a diversity of neurologic signs and symptoms as well the incapacities. Since the need for advances in MS treatment, many studies are for new therapeutic technologies, mainly through using preclinical models as experimental autoimmune encephalomyelitis (EAE). This study aimed to observe and analyze the development in Lewis rats-induced model of EAE. Methods It was used 23 females of Rattus norvegicus, from 6 to 8 weeks, weighing around 170 g. Of 23 rats, 19 underwent EAE induction distributed in six groups to establish the evolution of clinical signs. B. pertussis toxin (PTX) doses were 200, 250, 300, 350–400 ng, and four animals as the control group. The animals had weight and scores analyzed daily, starting seven and ending 24 days after induction. Then, all animals were euthanized, and the brain and spinal cord were collected for histopathological analyses. Results The results showed that the dose of 250 ng of PTX induced de higher score and weight reduction. All groups who received the PTX demonstrated histopathological findings. Those characterized as leukocyte infiltration, activation of microglia and astrocytes, and demyelinated plaques in the brain. In the spinal cord, the loosening of the myelinated fibers was observed by increasing the axonal space in all tested doses of PTX. Conclusions EAE was not dose-dependent. Histopathological findings do not proportionally related to clinical signs, as in human patients with MS.

scholarly journals An In Vitro Assessment of Immunostimulatory Responses to Ten Model Innate Immune Response Modulating Impurities (IIRMIs) and Peptide Drug Product, Teriparatide

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7461
Author(s):  
Claire K. Holley ◽  
Edward Cedrone ◽  
Duncan Donohue ◽  
Barry W. Neun ◽  
Daniela Verthelyi ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Cytokine Secretion ◽  
Poly I:C ◽  
In Vitro Assays ◽  
Innate Immune Responses ◽  
Vitro Assay

Understanding, predicting, and minimizing the immunogenicity of peptide-based therapeutics are of paramount importance for ensuring the safety and efficacy of these products. The so-called anti-drug antibodies (ADA) may have various clinical consequences, including but not limited to the alteration in the product’s distribution, biological activity, and clearance profiles. The immunogenicity of biotherapeutics can be influenced by immunostimulation triggered by the presence of innate immune response modulating impurities (IIRMIs) inadvertently introduced during the manufacturing process. Herein, we evaluate the applicability of several in vitro assays (i.e., complement activation, leukocyte proliferation, and cytokine secretion) for the screening of innate immune responses induced by ten common IIRMIs (Bacillus subtilis flagellin, FSL-1, zymosan, ODN2006, poly(I:C) HMW, poly(I:C) LMW, CLO75, MDP, ODN2216, and Escherichia coli O111:B4 LPS), and a model biotherapeutic Forteo™ (teriparatide). Our study identifies cytokine secretion from healthy human donor peripheral blood mononuclear cells (PBMC) as a sensitive method for the in vitro monitoring of innate immune responses to individual IIRMIs and teriparatide (TP). We identify signature cytokines, evaluate both broad and narrow multiplex cytokine panels, and discuss how the assay logistics influence the performance of this in vitro assay.

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