The induction and effects of Substance P and its receptor in human immune cells and neurons: potential relevance in multiple sclerosis

INTRODUCTION: Substance P (SP) has well-established roles in neurogenic inflammation and pain transmission, however recently, a number of SP immunomodulatory effects have been shown. In this thesis SP and its neurokinin-1-receptor (NK1R) role in autoimmune inflammation was investigated with an applicability to multiple sclerosis (MS). In the four experimental chapters the role of SP and its receptor was studied in human immune cells and neurons with a focus on the relationship with Th17 and Th1 pathways as the main pro-inflammatory arms in autoimmune pathology. AIMS: To quantify the effects of SP on inflammatory cytokine induction in peripheral blood mononuclear cells (PBMC); to measure Th17 and Th1 pathway effects on SP and NK1R expression in T cells and NT2 neurons; to compare NK1R expression and relevant parameters in peripheral immune cells of relapsing-remitting MS patients and healthy controls. METHODS: Real-time PCR, flow cytometry, ELISA, Western blotting and promoter studies were used to measure the expression of target genes under different stimulation conditions. Cells were isolated from consented healthy controls, relapsing-remitting MS patients, or differentiated as specified. RESULTS: In PBMC, treatment with SP significantly increased the relative quantity of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA showing that SP can signal induction of IL-12 and IL-23. As part of the reciprocal mechanism in T cells, NK1R and SP expression was strongly upregulated by Th17 cytokines and significantly less by Th1 cytokines. These effects for NK1R were confirmed at promoter and protein levels. The Th17 effects were prevalent at earlier stages compared to the Th1 effects. As a novel finding, IL-17 (IL-17A) had direct effects on neurons via its functionally expressed receptor. Neuronal NK1R mRNA-level expression was subject to regulation by IL-17, whereas SP precursor was considerably less upregulated by IL-17. In MS patients in a relapse NK1R mRNA in peripheral immune cells was strongly downregulated as compared to controls. This finding is likely associated with the inflammatory activity in an acute MS relapse. CONCLUSIONS: Mutual interactions exist between SP and Th17, Th1 responses with SP showing involvement in Th17 and less in Th1 pathway effects. This supports NK1R role in mediating autoimmune activity as occurs in an acute MS relapse. The results also show direct neuronal involvement in immune interactions involving SP and Th17 pathway

The induction and effects of Substance P and its receptor in human immune cells and neurons: potential relevance in multiple sclerosis

INTRODUCTION: Substance P (SP) has well-established roles in neurogenic inflammation and pain transmission, however recently, a number of SP immunomodulatory effects have been shown. In this thesis SP and its neurokinin-1-receptor (NK1R) role in autoimmune inflammation was investigated with an applicability to multiple sclerosis (MS). In the four experimental chapters the role of SP and its receptor was studied in human immune cells and neurons with a focus on the relationship with Th17 and Th1 pathways as the main pro-inflammatory arms in autoimmune pathology. AIMS: To quantify the effects of SP on inflammatory cytokine induction in peripheral blood mononuclear cells (PBMC); to measure Th17 and Th1 pathway effects on SP and NK1R expression in T cells and NT2 neurons; to compare NK1R expression and relevant parameters in peripheral immune cells of relapsing-remitting MS patients and healthy controls. METHODS: Real-time PCR, flow cytometry, ELISA, Western blotting and promoter studies were used to measure the expression of target genes under different stimulation conditions. Cells were isolated from consented healthy controls, relapsing-remitting MS patients, or differentiated as specified. RESULTS: In PBMC, treatment with SP significantly increased the relative quantity of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA showing that SP can signal induction of IL-12 and IL-23. As part of the reciprocal mechanism in T cells, NK1R and SP expression was strongly upregulated by Th17 cytokines and significantly less by Th1 cytokines. These effects for NK1R were confirmed at promoter and protein levels. The Th17 effects were prevalent at earlier stages compared to the Th1 effects. As a novel finding, IL-17 (IL-17A) had direct effects on neurons via its functionally expressed receptor. Neuronal NK1R mRNA-level expression was subject to regulation by IL-17, whereas SP precursor was considerably less upregulated by IL-17. In MS patients in a relapse NK1R mRNA in peripheral immune cells was strongly downregulated as compared to controls. This finding is likely associated with the inflammatory activity in an acute MS relapse. CONCLUSIONS: Mutual interactions exist between SP and Th17, Th1 responses with SP showing involvement in Th17 and less in Th1 pathway effects. This supports NK1R role in mediating autoimmune activity as occurs in an acute MS relapse. The results also show direct neuronal involvement in immune interactions involving SP and Th17 pathway

The induction and effects of Substance P and its receptor in human immune cells and neurons: potential relevance in multiple sclerosis

INTRODUCTION: Substance P (SP) has well-established roles in neurogenic inflammation and pain transmission, however recently, a number of SP immunomodulatory effects have been shown. In this thesis SP and its neurokinin-1-receptor (NK1R) role in autoimmune inflammation was investigated with an applicability to multiple sclerosis (MS). In the four experimental chapters the role of SP and its receptor was studied in human immune cells and neurons with a focus on the relationship with Th17 and Th1 pathways as the main pro-inflammatory arms in autoimmune pathology. AIMS: To quantify the effects of SP on inflammatory cytokine induction in peripheral blood mononuclear cells (PBMC); to measure Th17 and Th1 pathway effects on SP and NK1R expression in T cells and NT2 neurons; to compare NK1R expression and relevant parameters in peripheral immune cells of relapsing-remitting MS patients and healthy controls. METHODS: Real-time PCR, flow cytometry, ELISA, Western blotting and promoter studies were used to measure the expression of target genes under different stimulation conditions. Cells were isolated from consented healthy controls, relapsing-remitting MS patients, or differentiated as specified. RESULTS: In PBMC, treatment with SP significantly increased the relative quantity of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA showing that SP can signal induction of IL-12 and IL-23. As part of the reciprocal mechanism in T cells, NK1R and SP expression was strongly upregulated by Th17 cytokines and significantly less by Th1 cytokines. These effects for NK1R were confirmed at promoter and protein levels. The Th17 effects were prevalent at earlier stages compared to the Th1 effects. As a novel finding, IL-17 (IL-17A) had direct effects on neurons via its functionally expressed receptor. Neuronal NK1R mRNA-level expression was subject to regulation by IL-17, whereas SP precursor was considerably less upregulated by IL-17. In MS patients in a relapse NK1R mRNA in peripheral immune cells was strongly downregulated as compared to controls. This finding is likely associated with the inflammatory activity in an acute MS relapse. CONCLUSIONS: Mutual interactions exist between SP and Th17, Th1 responses with SP showing involvement in Th17 and less in Th1 pathway effects. This supports NK1R role in mediating autoimmune activity as occurs in an acute MS relapse. The results also show direct neuronal involvement in immune interactions involving SP and Th17 pathway

PRNP geeni mutatsiooniga perekondliku Creutzfeldti-Jakobi tõve haigusjuht

Creutzfeldti­Jakobi tõvesse (CJT) haigestumus on keskmiselt üks juht miljoni inimese kohta aastas. Inimestel esineva CJT põhiliste vormidena eristatakse sporaadilist (85%), pärilikku (15%) ja variantset CJTd (< 1%). Hiljuti avaldati ajakirjas Eesti Arst artikkel sporaadilise CJT juhu kohta, käesolevas artiklis on keskendutud päriliku CJT geneetikale TÜ Kliinikumis diagnoositud haigusjuhu näitel. Artiklis on käsitletud 28 aasta vanuse naise haigusjuhtu progresseeruva kognitiivse häire ja ekstrapüramidaalse sündroomiga. Patsiendile tehtud mitmed CJT­le viitavad diagnostilised uuringud olid negatiivsed. Päriliku CJT korral võib haigus kesta aastaid, magnetresonantstomograafiline, elektroentsefalograafiline ega liikvori leid ei pruugi haigusele viidata. Geneetiliselt kinnitati haigusseoseline muutus prioonvalku kodeerivas PRNP geenis inserteerunud 6 oktapeptiidse järjestusega ja modifitseeriva tegurina 129. koodonis Met/Met homosügootsus, mis iseloomustab haiguse varast avaldumist

Reetina periflebiit ja selle patogeneetilised seosed hulgiskleroosiga

Artiklis on antud ülevaade reetina periflebiidist (RP) hulgiskleroosi ehk multiipelskleroosi (MS) korral. Kuigi RP esinemist osal MSi-haigetel on täheldatud aastakümneid, on nende seisundite patogeneetiline seos kirjanduses vähe kajastamist leidnud. Siiani ei ole suuresti teada, millised põletikulised mehhanismid põhjustavad RPd. MS on heterogeense immuunmehhanismiga kesknärvisüsteemi demüeliniseeriv haigus, mille kolded arenevad tüüpiliselt veenide ümber. MSi korral esinev põletikuline protsess on vahendatud nii rakulise kui ka humoraalse immuunsuse poolt, mis erinevatel haigetel võivad olla erineva osakaaluga. Arvestades uuemaid teadmisi, võib RP osutuda kliiniliseks markeriks, mis kirjeldab MSi-patsientide ühe alarühma immuunpatoloogilist fenotüüpi ning võib tulevikus abistada ravivalikute tegemisel

The lack of association between angiotensin-converting enzyme gene insertion/deletion polymorphism and nicotine dependence in multiple sclerosis

Blood-borne angiotensin II is generated from angiotensinogen via cleavage by renin and angiotensin-converting enzyme (ACE), an enzymatic cascade known as the renin–angiotensin system (RAS). Several lines of evidence indicate that ACE, beyond its classical role of mediating blood pressure regulation, might contribute to the etiology of substance addictions by influencing dopaminergic signaling. A functional insertion/deletion (I/D) polymorphism of the ACE gene was associated with risk for being a smoker among individuals with depression and with smoking severity in studies comprising patients with depression and healthy controls. Several reports have described significantly increased ACE activity in cerebrospinal fluid and serum among MS patients. Furthermore, in our previous work with MS patients from Croatian and Slovenian populations, we demonstrated that the ACE-I/D polymorphism contributes to an elevated MS risk among male patients. Here we investigated whether the ACE-I/D polymorphism might influence smoking behavior among patients with MS. Patients and Methods Genotyping was performed in 521 patients (males/females: 139/382) using polymerase chain reaction. Results We revealed no significant differences in ACE genotype and allele frequencies between smokers and nonsmokers and no significant association between the ACE-I/D polymorphism and either pack-year smoking history or number of cigarettes smoked daily (p > .05, respectively). Conclusion The ACE-I/D polymorphism does not contribute either to risk for nicotine dependence or to smoking severity among MS patients. In the context of reports on the ACE-I/D polymorphism and nicotine dependence among healthy controls and patients with depression, we may speculate that the mechanism by which this polymorphism influences nicotine dependence risk differs in MS compared to depression, although not compared to a healthy population. In addition to angiotensin II, other potential ACE substrates, such as substance P and neurotensin, which also influence dopaminergic neurotransmission (and are proposed to be associated with MS), may deserve study in future

De la violence comme symptôme de la violence symbolique dans le sport

A partir de l'expérience du travail psychologique avec des sportifs, identification des différents niveaux de violence présents dans la pratique sportive compétitive (illustrations cliniques) et mise en évidence de la violence symbolique du système sportif, la violence apparaissant comme indissociable du sport, car omniprésente dans les représentations psychiques que se font les entraîneurs et le monde sportif des principes fondamentaux de l'entraînement et de la performanc

New Onset Generalized Myasthenia Gravis Evolving Following SARS-CoV-2 Infection

During the SARS-CoV-2 (COVID-19) pandemic, the immunogenicity of the virus for various autoimmune complications has been observed. To date, a few reports have been published that raise the possibility of new onset myasthenia gravis (MG) associated with COVID-19 infection. We report a case of a 65-year-old male who developed his initial myasthenic presentation with mild dysarthria 14 days after COVID-19 infection symptomatic onset. His bulbar symptoms, diplopia, and ptosis progressed considerably over the next 1.5 months before he was diagnosed with non-thymomatous MG. Serological tests showed a high concentration of anti-acetylcholine receptor and anti-titin antibodies. He responded well to treatment with pyridostigmine and intravenous immunoglobulin. Reasonable latency from COVID-19 infection and gradual evolvement of myasthenic symptoms makes the causative association probable in this case. To our knowledge, this is the first report of anti-titin antibodies in new-onset MG associated with COVID-19 infection. In the article, we analyze the previously reported cases and summarize the information published to date. We discuss the possible immunological mechanisms behind new onset autoimmune disease following a viral infection and the associated features that raise the suspicion for such a possibility. We also hint at structural homologies between SARS-CoV-2 spike glycoprotein and titin epitopes