No description available.

<p>  </p> <p>IL-9-producing CD4+ T helper (Th9) cells contribute to inflammatory responses during infection, anti-cancer responses and autoimmune disease. Thus, elucidating the signals that regulate their differentiation is critical for understanding the roles of Th9 cells in protective immunity and disease. Th9 cells differentiate in response to IL-4, TGF-β and IL-2, where IL-2 signaling through STAT5 is crucial for transactivating <em>Il9</em> locus. While the roles of IL-4 and TGF- β-mediated signaling are relatively well understood, how IL-2 signaling contributes to Th9 cell differentiation outside of directly inducing the <em>Il9</em> locus remains less clear. I found that human allergen-induced Th9 cells exhibited a strong signature of STAT5-mediated gene repression that was associated with inhibition of a Th17-like transcriptional signature. Likewise, blockade of IL-2/STAT5 signaling increased IL-17 and RORγt expression in murine Th9 cells <em>in vitro</em>. Interestingly, development of this Th17-like phenotype was independent of STAT3. While STAT3 was not required for IL-17 expression, it was required for their long-term persistence. These results suggest that IL-2/STAT5 signaling controls the balance between Th9 and Th17-like cell differentiation in vitro and during allergy. Additionally, I found that murine Th9 cells cultured in a low IL-2 environment had reduced IL-9 production and a diminished NF-kB-associated transcriptional signature, suggesting that IL-2 signaling is associated with NF-kB activation in Th9 cells. Interestingly, NF-kB activation via IL-1β stimulation enhanced Th9 differentiation under IL-2 limiting conditions and promoted their inflammatory potential in a mouse model of Lung inflammation. Mechanistically, we found that IL-2- limiting conditions enhanced IL-1β receptor expression and that IL-1β/NF-kB signaling increased the sensitivity to IL-2 and silenced the expression of the anti-Th9 transcription factor BCL6. Together, these findings indicate that IL-1β /NF-kB signaling can promote Th9 cell differentiation in IL-2-limiting conditions and that this pathway may be targeted to enhance Th9 differentiation and their inflammatory function.  Collectively, these data revealed two novel roles for the IL-2/STAT5 axis in Th9 cells.</p> <p>The Thymocyte associated High Mobility Group (HMG) box, known as TOX has been previously described to have paramount functions in the development of all the lineages of CD4+ T cells during thymic selection, during CD8+ T cell exhaustion and in Tfh cell differentiation and function. However, the role of TOX in non-Tfh CD4+ T cells in the periphery has not been addressed. In these studies, I found that CD4+ T cells express TOX in the steady state in secondary lymphoid organs like spleen, lymph nodes, and Peyer’s patches. Specifically, TOX was expressed remarkably in Tfh, Th1, Treg cells, and other non-Tfh unidentified Th cells, as well as Th2 cells in the lungs. Transcriptomics analyses using bulk RNA-seq revealed that TOX minimally alters s gene expression, however it revealed for the first time, that TOX induced genes associated with cell migration i.e., <em>Xcl1</em> <em>Ccl3</em>, <em>Ccl4</em> and also the inhibitory cytokine <em>Il10</em>. The induction of IL-10 and CCL3 was validated at the protein levels, and mechanistic studies revealed that the induction of these molecules required the transcription factor BATF, indicating for the first time a mechanism of TOX-mediated functions. Together, these data shed light in novel roles of TOX in CD4+ T cell function and opens the door for future functional and mechanistic studies that may be relevant during health and disease.</p>

O Diabetes Mellitus tipo 1 (DM1A) é uma doença autoimune caracterizada pela infiltração pancreática de linfócitos T e B, macrófagos e células dendríticas, levando à perda progressiva da capacidade de secreção de insulina pelas células beta pancreáticas. A homeostase das células T, ou seja, o desenvolvimento e manutenção apropriados dos números e funções das células T são essenciais para a integridade do sistema imune. Classicamente acreditava-se que as células T CD4+ poderiam se subdividir em duas populações efetoras distintas, T helper 1 e T helper 2. Recentemente, foram descritas duas novas vias de ativação de linfócitos T CD4+: a via Th17, que tem papel fundamental na autoimunidade; a via T regulatória, onde células T CD4+CD25+ high são essenciais na tolerância periférica e proteção contra autoimunidade. As Interleucinas (IL) de cadeia gama comum agem em várias etapas desta diferenciação linfocítica. A IL-21 é o membro mais recente desta família de citocinas, que inclui também: IL-2, IL-4, IL-7 , IL-9 e IL-15. A IL-21 atua através da interação com seu receptor, o IL-21R, apresentando ações pleiotrópicas e, como regra, pró-inflamatórias. Em estudos com modelos animais de diabetes autoimune verificou-se que a IL-21 e seu receptor são essenciais para o desenvolvimento da doença, porém ainda não há estudos sobre a ação desta interleucina no DM1 em humanos. O objetivo de nosso estudo foi avaliar o papel dos receptores das interleucinas de cadeia gama comum na patogênese do DM1A através da determinação da expressão da proteína de superfície e do RNA mensageiro destes receptores em pacientes com DM1A de início recente, em comparação com indivíduos controles normais, e da correlação destes valores com títulos de autoanticorpos pancreáticos. Estudamos a expressão da proteína de superfície do IL-21R, IL-2R (CD25), IL-2R (CD122), IL-4R (CD124) e IL-7R (CD127) em linfócitos T periféricos de 35 pacientes com DM1 e 25 controles sadios utilizando citometria de fluxo. O tempo médio de diagnóstico do DM1 foi de 3 meses, e todos os pacientes estavam em uso de insulina no momento da coleta de sangue. Auto-anticorpos pancreáticos (anti-GAD65 e anti-IA2) foram dosados através de radioimunoensaio. A expressão do RNAm de IL-21R, IL-2R e IL-2R foi quantificada por PCR em tempo real em 23 dos pacientes portadores de DM1A. Detectamos, pela primeira vez, diminuição significativa na expressão proporcional de IL-21R, CD25 e CD122 em linfócitos TCD3+ e TCD4+, além de diminuição na expressão de CD124 em linfócitos T CD4+ e CD127 em linfócitos T CD3+. Verificamos também redução significativa na quantidade de células TCD4+CD25+high (T regulatórias) nos pacientes DM1A. Não houve correlação entre expressão dos receptores de superfície das interleucinas de cadeia gama comum e títulos de autoanticorpos pancreáticos. Realizamos o PCR em tempo real para quantificar a expressão do RNA mensageiro (RNAm) dos receptores de interleucinas de cadeia gama comum, e avaliar se esta correspondia à expressão das proteínas de superfície obtida através de citometria de fluxo. Comparamos a expressão do RNAm de IL-21R, IL-2R e IL-2R nos pacientes DM1A dividindo-os em tercis de acordo com os valores de expressão de proteína de superfície obtidos por citometria de fluxo em linfócitos T CD3+, e verificamos que não houve diferença entre os 3 grupos na expressão relativa dos genes estudados. Portanto, em nossa casuística a redução da expressão da proteína de superfície dos receptores de interleucinas de cadeia gama comum possivelmente decorreu de alterações posteriores à transcrição do RNA mensageiro / Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic infiltration of T and B lymphocytes, macrophages and dendritic cells, leading to a progressive destruction of the insulin-producing -cells. Homeostasis of T cells can be defined as the ability of the immune system to maintain normal T-cell counts and to restore T-cell numbers following T-cell depletion or expansion. It was classically believed that the CD4+ T cells could be activated into two distinct effector populations, T helper1 and T helper2. It was recently described two new pathways of CD4+ T lymphocytes activation: the Th17 pathway, that plays a fundamental role in autoimmunity and the regulatory pathway (Treg), where CD4+CD25+high T cells are essential to maintain peripheral tolerance and therefore protect against autoimmunity. The common gamma chain cytokines interfere with several steps of the CD4+ T lymphocytes differentiation. Interleukin-21 (IL-21) is the most recent member of this family, that also includes IL-2, IL-4, IL-7, IL-9 and IL-15, and has pleiotropic effects on the immune system. Interleukin-21 acts through interaction with its receptor, the IL-21R, which is expressed in a great variety of immune cells. Various studies with animal models of autoimmune diabetes demonstrated that IL-21 and its receptor are essential for the development of the disease, but there are no studies evaluating the role of this interleukin and its receptor in T1DM in humans. The aim of our study was to assess the role of common gamma chain-dependent cytokine receptors in the pathogenesis of T1D, by determining the expression of the surface protein and mRNA of these receptors in recent-onset T1D patients and correlating these values with titles of pancreatic autoantibodies. We studied the surface protein expression of IL-21R, IL-2R (CD25), IL-2R (CD122), IL-4R (CD124) and IL-7R (CD127) in peripheral T lymphocytes of 35 patients with T1D and 25 healthy controls using flow cytometry. Mean T1D duration was 3 months and all patients were using insulin at the time of blood withdraw. Pancreatic autoantibodies (anti-GAD65 and anti-IA2) were assessed by radioimmunoassay. The mRNA expression of IL-21R, IL-2R and IL-2R was quantified by real time PCR in 23 of the T1D patients. We detected for the first time a statistically significant decrease in the proportional expression of IL-21R, CD25 and CD122 on CD3+ and CD4+ T lymphocytes, a decrease in the expression of CD124 on CD4+ T cells and CD127 on CD3+ T lymphocytes. We also observed a significant reduction in the amount of CD4+ CD25+high (T regulatory cells) in T1D patients. There was no correlation between the expression of the surface receptors of common gamma chain cytokines and titles of pancreatic autoantibodies. We performed real-time PCR to quantify RNA expression of common gamma-chain interleukin receptors, and evaluate if these values corresponded to those of surface proteins obtained using flow cytometry. We compared the mRNA expression of IL-21R, IL-2R and IL-2R in T1D patients by dividing them into tertiles according to the expression values of surface protein obtained by flow cytometry in CD3+T lymphocytes. We observed that there was no difference in the relative expression of mRNA among the 3 groups of patients. Therefore, in our study, the reduction of surface protein expression of common gamma chain cytokines receptors was possibly due to alterations that occurred after the transcription of mRNA

O Diabetes Mellitus tipo 1 (DM1A) é uma doença autoimune caracterizada pela infiltração pancreática de linfócitos T e B, macrófagos e células dendríticas, levando à perda progressiva da capacidade de secreção de insulina pelas células beta pancreáticas. A homeostase das células T, ou seja, o desenvolvimento e manutenção apropriados dos números e funções das células T são essenciais para a integridade do sistema imune. Classicamente acreditava-se que as células T CD4+ poderiam se subdividir em duas populações efetoras distintas, T helper 1 e T helper 2. Recentemente, foram descritas duas novas vias de ativação de linfócitos T CD4+: a via Th17, que tem papel fundamental na autoimunidade; a via T regulatória, onde células T CD4+CD25+ high são essenciais na tolerância periférica e proteção contra autoimunidade. As Interleucinas (IL) de cadeia gama comum agem em várias etapas desta diferenciação linfocítica. A IL-21 é o membro mais recente desta família de citocinas, que inclui também: IL-2, IL-4, IL-7 , IL-9 e IL-15. A IL-21 atua através da interação com seu receptor, o IL-21R, apresentando ações pleiotrópicas e, como regra, pró-inflamatórias. Em estudos com modelos animais de diabetes autoimune verificou-se que a IL-21 e seu receptor são essenciais para o desenvolvimento da doença, porém ainda não há estudos sobre a ação desta interleucina no DM1 em humanos. O objetivo de nosso estudo foi avaliar o papel dos receptores das interleucinas de cadeia gama comum na patogênese do DM1A através da determinação da expressão da proteína de superfície e do RNA mensageiro destes receptores em pacientes com DM1A de início recente, em comparação com indivíduos controles normais, e da correlação destes valores com títulos de autoanticorpos pancreáticos. Estudamos a expressão da proteína de superfície do IL-21R, IL-2R (CD25), IL-2R (CD122), IL-4R (CD124) e IL-7R (CD127) em linfócitos T periféricos de 35 pacientes com DM1 e 25 controles sadios utilizando citometria de fluxo. O tempo médio de diagnóstico do DM1 foi de 3 meses, e todos os pacientes estavam em uso de insulina no momento da coleta de sangue. Auto-anticorpos pancreáticos (anti-GAD65 e anti-IA2) foram dosados através de radioimunoensaio. A expressão do RNAm de IL-21R, IL-2R e IL-2R foi quantificada por PCR em tempo real em 23 dos pacientes portadores de DM1A. Detectamos, pela primeira vez, diminuição significativa na expressão proporcional de IL-21R, CD25 e CD122 em linfócitos TCD3+ e TCD4+, além de diminuição na expressão de CD124 em linfócitos T CD4+ e CD127 em linfócitos T CD3+. Verificamos também redução significativa na quantidade de células TCD4+CD25+high (T regulatórias) nos pacientes DM1A. Não houve correlação entre expressão dos receptores de superfície das interleucinas de cadeia gama comum e títulos de autoanticorpos pancreáticos. Realizamos o PCR em tempo real para quantificar a expressão do RNA mensageiro (RNAm) dos receptores de interleucinas de cadeia gama comum, e avaliar se esta correspondia à expressão das proteínas de superfície obtida através de citometria de fluxo. Comparamos a expressão do RNAm de IL-21R, IL-2R e IL-2R nos pacientes DM1A dividindo-os em tercis de acordo com os valores de expressão de proteína de superfície obtidos por citometria de fluxo em linfócitos T CD3+, e verificamos que não houve diferença entre os 3 grupos na expressão relativa dos genes estudados. Portanto, em nossa casuística a redução da expressão da proteína de superfície dos receptores de interleucinas de cadeia gama comum possivelmente decorreu de alterações posteriores à transcrição do RNA mensageiro / Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic infiltration of T and B lymphocytes, macrophages and dendritic cells, leading to a progressive destruction of the insulin-producing -cells. Homeostasis of T cells can be defined as the ability of the immune system to maintain normal T-cell counts and to restore T-cell numbers following T-cell depletion or expansion. It was classically believed that the CD4+ T cells could be activated into two distinct effector populations, T helper1 and T helper2. It was recently described two new pathways of CD4+ T lymphocytes activation: the Th17 pathway, that plays a fundamental role in autoimmunity and the regulatory pathway (Treg), where CD4+CD25+high T cells are essential to maintain peripheral tolerance and therefore protect against autoimmunity. The common gamma chain cytokines interfere with several steps of the CD4+ T lymphocytes differentiation. Interleukin-21 (IL-21) is the most recent member of this family, that also includes IL-2, IL-4, IL-7, IL-9 and IL-15, and has pleiotropic effects on the immune system. Interleukin-21 acts through interaction with its receptor, the IL-21R, which is expressed in a great variety of immune cells. Various studies with animal models of autoimmune diabetes demonstrated that IL-21 and its receptor are essential for the development of the disease, but there are no studies evaluating the role of this interleukin and its receptor in T1DM in humans. The aim of our study was to assess the role of common gamma chain-dependent cytokine receptors in the pathogenesis of T1D, by determining the expression of the surface protein and mRNA of these receptors in recent-onset T1D patients and correlating these values with titles of pancreatic autoantibodies. We studied the surface protein expression of IL-21R, IL-2R (CD25), IL-2R (CD122), IL-4R (CD124) and IL-7R (CD127) in peripheral T lymphocytes of 35 patients with T1D and 25 healthy controls using flow cytometry. Mean T1D duration was 3 months and all patients were using insulin at the time of blood withdraw. Pancreatic autoantibodies (anti-GAD65 and anti-IA2) were assessed by radioimmunoassay. The mRNA expression of IL-21R, IL-2R and IL-2R was quantified by real time PCR in 23 of the T1D patients. We detected for the first time a statistically significant decrease in the proportional expression of IL-21R, CD25 and CD122 on CD3+ and CD4+ T lymphocytes, a decrease in the expression of CD124 on CD4+ T cells and CD127 on CD3+ T lymphocytes. We also observed a significant reduction in the amount of CD4+ CD25+high (T regulatory cells) in T1D patients. There was no correlation between the expression of the surface receptors of common gamma chain cytokines and titles of pancreatic autoantibodies. We performed real-time PCR to quantify RNA expression of common gamma-chain interleukin receptors, and evaluate if these values corresponded to those of surface proteins obtained using flow cytometry. We compared the mRNA expression of IL-21R, IL-2R and IL-2R in T1D patients by dividing them into tertiles according to the expression values of surface protein obtained by flow cytometry in CD3+T lymphocytes. We observed that there was no difference in the relative expression of mRNA among the 3 groups of patients. Therefore, in our study, the reduction of surface protein expression of common gamma chain cytokines receptors was possibly due to alterations that occurred after the transcription of mRNA

5 Abstract Interleukin-2 possesses strong stimulatory activity for activated T and NK cells and thus it is an attractive molecule for immunotherapy. However, its unfavourable pharmacological properties, extremely short half-life and severe toxicities associated with high-dose IL-2 are the most serious and limiting drawbacks. Moreover, IL-2 has been also implicated in the homeostasis of T regulatory cells where it plays a decisive role as an essential growth factor of these cells. Several different approaches to improve the therapeutic potential of IL-2 have been studied. Recently described IL-2/anti-IL-2 mAb immunocomplexes which show much higher and selective biological activity in contrast with free IL-2 in vivo are probably the most promising of them. In this study, we compared the biological activity of free IL-2 with IL-2/anti-IL-2 mAb immunocomplexes in order to demonstrate their benefits over free IL-2. We also demonstrated that IL-2/anti-IL-2 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely EL4 T lymphoma and B16F10 melanoma, if administered early in tumor progression. Therefore, we justified potential use of IL-2/anti-IL-2 mAb immunocomplexes in tumor immunotherapy. We covalently conjugated IL-2 to synthetic semitelechelic polymeric carrier based...

A proposta principal deste estudo foi de avaliar o efeito da prática regular de atividade física por longos anos na imunossenescência, isto é, nas alterações que o sistema imune sofre com o envelhecimento. Para tal, comparou-se os resultados dos exames imunológicos de 20 idosos praticantes de corrida (idade média = 67 anos) aos de 20 idosos sedentários (idade média = 66 anos) e 10 jovens sedentários (idade média = 26 anos). Os idosos corredores eram praticantes da modalidade em média nos últimos 23 anos e vinham percorrendo uma distância semanal média de 39 quilômetros. O consumo máximo de oxigênio (VO2 max) deles foi 52% maior do que o dos idosos sedentários, atingindo valores similares aos dos jovens. Os parâmetros imunológicos analisados foram: contagem de linfócitos e seus subtipos, resposta proliferativa dos linfócitos T a mitógenos, atividade citotóxica das células natural killer e produção de citocinas (interleucinas 2, 3, 4, 6, 10 e 12). A dosagem das mesmas citocinas no soro também foi realizada, porém somente nos dois grupos de idosos. Os idosos corredores apresentaram resposta proliferativa dos linfócitos T a OKT-3 e produção de interleucina-2 significativamente maiores do que as dos idosos sedentários. Eles apresentaram também uma produção de interleucina-3 significativamente menor do que a dos seus pares sedentários. Por outro lado, não apresentaram diferença significativa destes parâmetros em relação aos jovens. Os níveis séricos das interleucinas 3, 6 e 12 dos idosos corredores foram significativamente menores do que os dos idosos sedentários. A influência da prática de atividade física regular sobre os níveis séricos do hormônio de crescimento, da testosterona e da dehidroepiandrosterona sulfato (DHEAS), que sofrem redução com o envelhecimento (\"endocrinossenescência\"), também foi estudada. Não houve diferença significativa entre os níveis séricos destes hormônios anabólicos dos idosos corredores e dos idosos sedentários. O efeito da atividade física regular sobre a beta-endorfina também foi avaliado. Os idosos corredores não apresentaram diferença significativa nos níveis séricos deste neuropeptídeo em relação aos idosos sedentários. Em virtude do possível envolvimento do sistema endócrino na imunossenescência, avaliou-se a correlação entre os hormônios anabólicos e as citocinas. Não se constatou correlação relevante entre eles, especialmente entre a DHEAS e a interleucina-6. Os resultados indicam que a prática regular de atividade física por longos anos tem o potencial de desacelerar a imunossenescência / The main objective of this study was to assess the effect of regular practice of physical activity on immunosenescence, that is, the changes that occur when the immune system is affected by aging. The results of immune tests conducted on 20 elderly runners (mean age = 67 years) were compared to those of 20 elderly sedentary individuals (mean age = 66 years) and to those of 10 young sedentary individuals (mean age = 26 years). On average, the elderly runners had practiced this activity for the last 23 years, running a mean weekly distance of 39 kilometers. Their maximum oxygen consumption (VO2 max) was 52% higher than that of sedentary elderly group, and similar to that of the group of younger individuals. The immune parameters studied were: lymphocyte and lymphocyte subtype counts, the proliferative response of T-lymphocytes to mitogens, cytotoxic activity of natural killer cells and production of cytokines (interleukins 2, 3, 4, 6, 10 and 12). The same cytokines were measured in serum, but only in the two groups of elderly people. Elderly runners presented a significantly higher proliferative response of T-lymphocytes to OKT-3 as well as interleukin-2 production than the sedentary group. The production of interleukin-3 was also significantly lower in the group of runners. On the other hand, the results of these parameters did not differ significantly from those of young subjects. Serum levels of interleukins 3, 6, and 12 were significantly lower in elderly runners than in sedentary individuals. The impact of regular physical activity on serum levels of growth hormone, testosterone, and dehydroepiandrosterone sulfate (DHEAS), which are affected by aging (\"endocrinosenescence\"), was also studied. The serum levels of these anabolic hormones did not differ significantly between the groups of elderly runners and the elderly sedentary individuals. When the impact of regular physical activity on beta-endorphin was studied, again no significant difference in the serum levels of this neuropeptide was found between the two elderly groups. Owing to the possible involvement of the endocrine system in immunosenescence, the correlation between anabolic hormones and cytokines was assessed. No relevant correlation was found, especially between DHEAS and interleukin-6. The results indicate that the regular practice of physical activity for several years may delay immunosenescence

A proposta principal deste estudo foi de avaliar o efeito da prática regular de atividade física por longos anos na imunossenescência, isto é, nas alterações que o sistema imune sofre com o envelhecimento. Para tal, comparou-se os resultados dos exames imunológicos de 20 idosos praticantes de corrida (idade média = 67 anos) aos de 20 idosos sedentários (idade média = 66 anos) e 10 jovens sedentários (idade média = 26 anos). Os idosos corredores eram praticantes da modalidade em média nos últimos 23 anos e vinham percorrendo uma distância semanal média de 39 quilômetros. O consumo máximo de oxigênio (VO2 max) deles foi 52% maior do que o dos idosos sedentários, atingindo valores similares aos dos jovens. Os parâmetros imunológicos analisados foram: contagem de linfócitos e seus subtipos, resposta proliferativa dos linfócitos T a mitógenos, atividade citotóxica das células natural killer e produção de citocinas (interleucinas 2, 3, 4, 6, 10 e 12). A dosagem das mesmas citocinas no soro também foi realizada, porém somente nos dois grupos de idosos. Os idosos corredores apresentaram resposta proliferativa dos linfócitos T a OKT-3 e produção de interleucina-2 significativamente maiores do que as dos idosos sedentários. Eles apresentaram também uma produção de interleucina-3 significativamente menor do que a dos seus pares sedentários. Por outro lado, não apresentaram diferença significativa destes parâmetros em relação aos jovens. Os níveis séricos das interleucinas 3, 6 e 12 dos idosos corredores foram significativamente menores do que os dos idosos sedentários. A influência da prática de atividade física regular sobre os níveis séricos do hormônio de crescimento, da testosterona e da dehidroepiandrosterona sulfato (DHEAS), que sofrem redução com o envelhecimento (\"endocrinossenescência\"), também foi estudada. Não houve diferença significativa entre os níveis séricos destes hormônios anabólicos dos idosos corredores e dos idosos sedentários. O efeito da atividade física regular sobre a beta-endorfina também foi avaliado. Os idosos corredores não apresentaram diferença significativa nos níveis séricos deste neuropeptídeo em relação aos idosos sedentários. Em virtude do possível envolvimento do sistema endócrino na imunossenescência, avaliou-se a correlação entre os hormônios anabólicos e as citocinas. Não se constatou correlação relevante entre eles, especialmente entre a DHEAS e a interleucina-6. Os resultados indicam que a prática regular de atividade física por longos anos tem o potencial de desacelerar a imunossenescência / The main objective of this study was to assess the effect of regular practice of physical activity on immunosenescence, that is, the changes that occur when the immune system is affected by aging. The results of immune tests conducted on 20 elderly runners (mean age = 67 years) were compared to those of 20 elderly sedentary individuals (mean age = 66 years) and to those of 10 young sedentary individuals (mean age = 26 years). On average, the elderly runners had practiced this activity for the last 23 years, running a mean weekly distance of 39 kilometers. Their maximum oxygen consumption (VO2 max) was 52% higher than that of sedentary elderly group, and similar to that of the group of younger individuals. The immune parameters studied were: lymphocyte and lymphocyte subtype counts, the proliferative response of T-lymphocytes to mitogens, cytotoxic activity of natural killer cells and production of cytokines (interleukins 2, 3, 4, 6, 10 and 12). The same cytokines were measured in serum, but only in the two groups of elderly people. Elderly runners presented a significantly higher proliferative response of T-lymphocytes to OKT-3 as well as interleukin-2 production than the sedentary group. The production of interleukin-3 was also significantly lower in the group of runners. On the other hand, the results of these parameters did not differ significantly from those of young subjects. Serum levels of interleukins 3, 6, and 12 were significantly lower in elderly runners than in sedentary individuals. The impact of regular physical activity on serum levels of growth hormone, testosterone, and dehydroepiandrosterone sulfate (DHEAS), which are affected by aging (\"endocrinosenescence\"), was also studied. The serum levels of these anabolic hormones did not differ significantly between the groups of elderly runners and the elderly sedentary individuals. When the impact of regular physical activity on beta-endorphin was studied, again no significant difference in the serum levels of this neuropeptide was found between the two elderly groups. Owing to the possible involvement of the endocrine system in immunosenescence, the correlation between anabolic hormones and cytokines was assessed. No relevant correlation was found, especially between DHEAS and interleukin-6. The results indicate that the regular practice of physical activity for several years may delay immunosenescence

Objectives: To assess the expression of the symptoms of jaw muscle pain and its association with alterations in biochemistry, other symptoms and the carriage of staphylococci. Methods: Three different study populations were assessed. The first was selected and examined by the author and consisted of 43 pain and 41 age and sex matched controls. The second was a study of CFS patients who were blinded to the author and the author subsequently examined the associations between jaw muscle symptom reporting and the standardised biochemistry measures. The third study was also blinded to the author but included an investigation of staphylococci and certain cytokine and biochemistry measures. Results: The three studies clearly establish an association between the carriage of toxicogenic coagulase negative staphylococci and the expression of jaw muscle pain in both males and females. These associations were homogeneous and were found whether the patients were selected on the basis of having jaw muscle pain or selected from within a population of patients selected on the basis of having Chronic Fatigue Syndrome. The studies associated the changes with variations in biochemistry and these were in turn associated with symptom expression within the jaw muscle pain patients. These biochemical alterations included the dysregulation of immune cell counts, cytokines, electrolyte and protein metabolism. These symptoms and biochemical changes were associated with pain severity and illness duration and staphylococcal toxin production. From the data a model was developed which shows the mechanisms involved in the development of chronic pain in the jaw muscles. Conclusions: The carriage of toxicogenic coagulase-negative staphylococci were found to be associated with the expression of jaw muscle pain and the alterations in biochemistry associated with these symptoms.

Objectives: To assess the expression of the symptoms of jaw muscle pain and its association with alterations in biochemistry, other symptoms and the carriage of staphylococci. Methods: Three different study populations were assessed. The first was selected and examined by the author and consisted of 43 pain and 41 age and sex matched controls. The second was a study of CFS patients who were blinded to the author and the author subsequently examined the associations between jaw muscle symptom reporting and the standardised biochemistry measures. The third study was also blinded to the author but included an investigation of staphylococci and certain cytokine and biochemistry measures. Results: The three studies clearly establish an association between the carriage of toxicogenic coagulase negative staphylococci and the expression of jaw muscle pain in both males and females. These associations were homogeneous and were found whether the patients were selected on the basis of having jaw muscle pain or selected from within a population of patients selected on the basis of having Chronic Fatigue Syndrome. The studies associated the changes with variations in biochemistry and these were in turn associated with symptom expression within the jaw muscle pain patients. These biochemical alterations included the dysregulation of immune cell counts, cytokines, electrolyte and protein metabolism. These symptoms and biochemical changes were associated with pain severity and illness duration and staphylococcal toxin production. From the data a model was developed which shows the mechanisms involved in the development of chronic pain in the jaw muscles. Conclusions: The carriage of toxicogenic coagulase-negative staphylococci were found to be associated with the expression of jaw muscle pain and the alterations in biochemistry associated with these symptoms.