Serum levels of interleukin-6 are not elevated in patients with Alzheimer's disease

Serum levels of interleukin-6 (IL-6) were determined in 97 patients with clinically diagnosed Alzheimer's disease and 79 age- and sex-matched control subject. Median serum levels of IL-6 did not differ significantly between Alzheimer patients (8.6 U/ml) and controls (8.2 U/ml). Median levels of serum IL-6 were similar for sporadic and familial patients. The concentration of IL-6 was not associated with the severity of the dementia or the duration of the disease since first symptoms. According to these observations there is no evidence for a significant elevation in serum IL-6 in Alzheimer's disease

Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor-á, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy

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Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside—a Comprehensive Review

Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions

Translating IL-6 biology into effective treatments

In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still’s disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases

Effector Functions of CD4+ T Cells at the Site of Local Autoimmune Inflammation—Lessons From Rheumatoid Arthritis

Infiltration of memory CD4+ T cells in synovial joints of Rheumatoid Arthritis (RA) patients has been reported since decades. Moreover, several genome wide association studies (GWAS) pinpointing a key genetic association between the HLA-DR locus and RA have led to the generally agreed hypothesis that CD4+ T cells are directly implicated in the disease. Still, RA is a heterogeneous disease and much effort has been made to understand its different facets. T cell differentiation is driven by mechanisms including antigen stimulation, co-stimulatory signals and cytokine milieu, all of which are abundant in the rheumatic joint, implying that any T cells migrating into the joint may be further affected locally. In parallel to the characterization and classification of T-cell subsets, the contribution of different effector T cells to RA has been investigated in numerous studies though sometimes with contradictory results. In particular, the frequency of Th1 and Th17 cells has been assessed in the synovial joints with various results that could, at least partly, be explained by the stage of the disease. For regulatory T cells, it is largely accepted that they accumulate in RA synovial fluid and that the equilibrium between regulatory T cells and effector cells is a key factor in controlling inflammation processes involved in RA. Recent phenotypic studies describe the possible implication of a novel subset of peripheral T helper cells (Tph) important for T-B cell cross talk and plasma cell differentiation in the RA joint of ACPA+ (autoantibodies against citrullinated proteins) RA patients. Finally, cytotoxic CD4+ T cells, historically described as increased in the peripheral blood of RA patients have attracted new attention in the last years. In view of the recently identified peripheral T-cell subsets, we will integrate immunological data as well as information on genetic variants and therapeutic strategy outcomes into our current understanding of the width of effector T cells. We will also integrate tissue-resident memory T cell aspects, and discuss similarities and differences with inflammatory conditions in skin (psoriasis) and mucosal organs (Crohn's disease)

Immunological aspects of polymyalgia rheumatica and giant cell arteritis

Forty four patients with PMR/GCA have been followed from presentation for a period of 2-4 years. Immunological investigations have been carried out in a search for useful tests to assist in the diagnosis of PMR/GCA and in assessing disease activity. This study has confirmed that ESR and CRP are useful investigations at presentation of PMR/GCA, although even at this stage these tests may not be elevated. During relapses of PMR/GCA both ESR and CRP remain in the normal range in the majority of patients so no reliance should be placed on these investigations to confirm a clinical diagnosis of relapse. Alpha-1-antichymotrypsin (ACT) has shown an interesting pattern of response, in that the raised levels at presentation (1.0g/l) did not fall rapidly on prednisolone treatment but fell gradually over 2-4 years reaching normal levels (0.6g/l) in those patients satisfactorily off prednisolone treatment. An ACT concentration of ≤0.8g/l at 12 months and ≤0.7g/l at 18 months indicated a reduced risk of subsequent relapse. Hence this investigation may be a useful tool in tailoring prednisolone reduction for the individual patient with PMR/GCA. Measurement of the cytokines IL1B, IL6 and soluble IL2 receptor, using ELISA methods, did not add any useful information to the assessment of the individual patient. However the fact that IL1≤ levels were raised at presentation and relapse (albeit to only 4pg/ml and 5pg/ml respectively) does illustrate that this mediator of inflammation is involved in PMR/GCA. The elevation of soluble IL2 receptor at presentation (476 U/ml) compared with controls (366 U/ml) also illustrates that there is immune system activation in PMR/GCA. IL6 levels were not significantly elevated in this study. This study did not find low CD8+ cells in PMR/GCA prior to treatment. %CD8+ cells were significantly reduced after prednisolone treatment commenced, and a study in volunteers confirmed that this was an effect of the prednisolone itself, particularly in the older volunteers

Mecanismos de ocorrência de dor

Physiopatology of nociception and supression of pain is very complex. Pain is the result of activation or sensitizationof the peripheral receptors by physical or chemical stimuli in the tissues. The excitation and sensitization of central nervous system units in the spinal cord and brain sensitive-discriminative, affective-motivacional and quantitative-evaluative dimensions is involved in the of pain. The discriminative afferences induces the synthesis and activation of suppressive neurotransmitters. Pain is the product of the disbalance between the excitatory and inhibitory systems.Vários mecanismos estão envolvidos na ativação e supressão das unidades nociceptivas. Traumatismos físicos e químicosambientais ativam e sensibilizam os nociceptores nos tecidos. Disto resulta liberação tecidual de neurotransmissores excitatórios que sensibilizam e ativam as vias nociceptivas no sistema nervoso periférico e central. No ístmo nervoso central, unidades envolvidas nos mecanismos sensitivo-discriminativos, afetivo-motivacionais e quantitativo-avaliativos da sensibilidade. Nas unidades nervosas periféricas, nos gânglios sensitivos e nas unidades neuronais da medula espinal e encefálica há mecanismos supressores de dor; são ativados pela liberação de neurotransmissores inibitórios quando da apresentação de estímulos discriminativos. Do balanço da atividade das vias excitatórias e da vias supressoras ocorre a dor

Mecanismos de ocorrência de dor

Physiopatology of nociception and supression of pain is very complex. Pain is the result of activation or sensitization of the peripheral receptors by physical or chemical stimuli in the tissues. The excitation and sensitization of central nervous system units in the spinal cord and brain is involved in the sensitive-discriminative, affective-motivacional and quantitative-evaluative dimensions of pain. The discriminative afferences induces thesynthesis and activation of suppressive neurotransmitters. Pain is the product of the disbalance between the excitatory and inhibitory systems.Vários mecanismos estão envolvidos na ativação e supressão das unidades nociceptivas. Traumatismos físicos e químicos ambientais ativam e sensibilizam os nociceptores nos tecidos. Disto resulta liberação tecidual de neurotransmissores excitatórios que sensibilizam e ativam as vias nociceptivas no sistema nervoso periférico e central. No sistema nervoso central das unidades envolvidas nos mecanismos sensitivo-discriminativos, afetivomotivacionais e quantitativo-avaliativos da sensibilidade. Nas unidades nervosas periféricas, nos gânglios sensitivos e nas unidades neuronais da medula espinal e encefálica há mecanismos supressores de dor; são ativados pela liberação de neurotransmissores inibitóriosquando da apresentação de estímulos discriminativos. Do desbalanço da atividade das vias excitatórias e da vias supressoras ocorre a dor.