Martin Aringer

Role of interleukin‐6 in stress, sleep, and fatigue

Chronic low‐grade inflammation, in particular increased concentrations of proinflammatory cytokines such as interleukin (IL)‐6 in the circulation, is observed with increasing age, but it is also as a consequence of various medical and psychological conditions, as well as life‐style choices. Since molecules such as IL‐6 have pleiotropic effects, consequences are wide ranging. This short review summarizes the evidence showing how IL‐6 elevations in the context of inflammatory disease affect the organism, with a focus on sleep‐related symptoms and fatigue; and conversely, how alterations in sleep duration and quality stimulate increased concentrations of IL‐6 in the circulation. Research showing that acute as well as chronic psychological stress also increase concentrations of IL‐6 supports the notion of a close link between an organisms response to physiological and psychological perturbations. The findings summarized here further underscore the particular importance of IL‐6 as a messenger molecule that connects peripheral regulatory processes with the CNS.

SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus

Tumor necrosis factor (TNF) is a proinflammatory cytokine and a B-cell growth factor. It has numerous possible effects on T lymphocytes and dendritic cells, and it influences apoptosis. These differential effects may in part explain why patients under TNF-blocker therapy can develop autoantibodies to nuclear antigens, and may shed some light on the finding that low TNF fosters autoimmune disease in some mouse strains. On the contrary, TNF is increased in the blood and in the inflamed kidneys of systemic lupus erythematosus patients. Several studies in lupus-prone mice other than the F1 generation of New Zealand Black mice crossed with New Zealand White mice suggest that TNF is highly proinflammatory in the efferent limb and is potentially detrimental in lupus organ disease. Therefore, TNF blockade probably constitutes an efficacious therapeutic option.

Cancer polyarthritis resembling rheumatoid arthritis as a first sign of hidden neoplasms. Report of two cases and review of the literature.

Recent onset arthritis reminiscent of rheumatoid arthritis (RA) may be an early manifestation of an occult malignancy. In this report, we present two patients with cancer-associated polyarthritis. Both suffered from symmetric polyarthritis when initially visiting their physicians and did not achieve relief when treated with non-steroidal anti-rheumatic drugs (NSAIDs). In both patients, subsequent work-up led to the diagnosis of an underlying malignancy. One patient suffered from small cell lung cancer (SCLC), while the other was diagnosed with adenocarcinoma of the colon. In both, the arthritis spontaneously disappeared after successful treatment of the malignancy, i.e. chemotherapy and tumor resection, respectively. We discuss these cases in view of the existing literature, since awareness of the entity of cancer polyarthritis is necessary for its timely treatment and may potentially be life-saving.Recent onset arthritis reminiscent of rheumatoid arthritis (RA) may be an early manifestation of an occult malignancy. In this report, we present two patients with cancer-associated polyarthritis. Both suffered from symmetric polyarthritis when initially visiting their physicians and did not achieve relief when treated with non-steroidal anti-rheumatic drugs (NSAIDs). In both patients, subsequent work-up led to the diagnosis of an underlying malignancy. One patient suffered from small cell lung cancer (SCLC), while the other was diagnosed with adenocarcinoma of the colon. In both, the arthritis spontaneously disappeared after successful treatment of the malignancy, i.e. chemotherapy and tumor resection, respectively. We discuss these cases in view of the existing literature, since awareness of the entity of cancer polyarthritis is necessary for its timely treatment and may potentially be life-saving.

Immunoadsorption (IAS) as a rescue therapy in SLE: considerations on safety and efficacy

SummaryOBJECTIVE: In systemic lupus erythematosus (SLE), extracorporeal procedures aiming at reduction of immunoglobulin (Ig) and immune complexes (IC) are used as a rescue therapy. Plasma exchange (PE) has not been proven overall effective in SLE, and long-term treatment in particular has been associated with severe bacterial and viral infections. Immunoadsorption (IAS), in contrast, selectively removes Ig and IC and may thus be safer. We therefore investigated the rate of infections in SLE patients who were undergoing long-term IAS. METHODS: 16 SLE patients were treated with ≥10 courses of IAS, and nine patients with highly active disease received pulse cyclophosphamide (IVCP) therapy in parallel. We retrospectively analysed the records of all these patients for the occurrence of infections. Patients receiving IAS therapy plus IVCP were compared with 25 patients with similarly active disease treated with standard IVCP therapy within the same observation period. Patients receiving IAS without additional IVCP were compared with patients with similarly moderate disease activity receiving neither IAS nor IVCP. RESULTS: No potentially life-threatening viral infection occurred in IAS-treated patients and episodes of herpes zoster were equally distributed. No severe infection was observed during IAS without concomitant cyclophosphamide. As expected, more patients with highly active disease receiving IVCP experienced infections than those with less active disease (16 of 34 [47%] vs. 2 of 22 [9%], p < 0.04). On comparing the two groups with highly active disease, infections were similar (IAS plus IVCP, 3 of 9 patients [33%]; IVCP only, 5 of 25 [20%]), but one patient receiving IAS plus IVCP died of septicaemia. Disease activity significantly decreased in both groups treated with IAS. CONCLUSION: IAS has an acceptable safety profile with regard to severe infections and appears safe with regard to severe viral disease. Highly active disease and IVCP therapy increase the risk of severe infections in SLE.

Engineering Anticancer T Cells for Extended Functional Longevity

Abstract: Like other somatic cells, human T lymphocytes have a finite replicative capacity in vitro, and, by implication and consistent with the limited data available, in vivo as well. An accumulation of dysfunctional T cells may be detrimental under conditions of chronic antigenic stress (chronic infection, cancer, autoimmunity). Using T cells from young donors to model the process of T cell clonal expansion in vitro under these conditions reveals age‐associated increasing levels of oxidative DNA damage and microsatellite instability (MSI), coupled with decreasing DNA repair capacity, telomerase induction and telomere length, decreased levels of expression of the T cell costimulator CD28 and consequently reduced secretion of the T cell growth factor interleukin‐2 (IL‐2). However, data from similar experiments using T cell clones (TCCs) derived from extremely healthy very elderly donors (“successfully aged”) indicate that DNA repair is better maintained, MSI less prevalent, and (already short) telomere lengths are maintained. Nonetheless, oxidative DNA damage is seen to the same extent, and clonal longevity is also similar in these clones. DNA damage levels are reduced by culture in 5% oxygen, but longevity is not improved. This may be because of the requirement for intermittent reactivation via receptor pathways dependent on free radical production in T cells. These recent findings from our international immunosenescence research consortium suggest that strategies other than telomere maintenance, better protection against free radicals, or improved DNA repair will be required for functional longevity extension of human TCCs. To obtain sufficient cells for adoptive immunotherapy of cancer, alternative avenues need exploration; currently, these include enforced expression of certain heat shock proteins and proteasome components, and interference with the expression of negative regulatory receptors expressed by T cells.

Functional and molecular aspects of transient T cell unresponsiveness: role of selective interleukin-2 deficiency

Defects of T cell (Tc) proliferation have been demonstrated in several autoimmune diseases. Detailed mechanisms governing activation and proliferation of Tc are still not completely known. Here we show that under certain conditions human peripheral blood lymphocytes, once activated by anti‐CD3, fail to respond to a subsequent restimulation via the Tc‐receptor. Peripheral blood mononuclear cells (PBMC) were preactivated by anti‐CD3 for 96 h following restimulation by anti‐CD3, interleukin (IL)‐2 and other mitogens. In control experiments unstimulated PBMC were incubated in medium alone. Immunophenotypes were analysed by flow cytometry. Cytokine production was determined by reverse transcription‐polymerase chain reaction and intracellular signalling protein contents of Tc were compared by Western blotting. Furthermore, apoptosis was detected by terminal deoxyribose transferase‐mediated deoxyuridine triphosphate nick end labelling assay. Unstimulated PBMC proliferate well after subsequent stimulation with anti‐CD3, whereas IL‐2 induces only limited proliferation. In contrast, preactivated cells respond only minimally to restimulation with anti‐CD3, but IL‐2 induces a marked proliferation. Both preactivated and unstimulated Tc respond well to restimulation by phytohaemagglutinin (PHA). In contrast, preactivated Tc show only a weak response to concanavalin A. Interestingly, when cells have been allowed to rest for 168 h, the responsiveness of preactivated Tc is restored. Immunoblots reveal that preactivated cells have a higher intracellular content of ζ‐chain and p56lck. No differences are found concerning apoptosis after restimulation with anti‐CD3 or the expression of ERK 1/2. The unresponsiveness to restimulation is due to an impairment of the transcription of the IL‐2 gene and this defect is temporary. Despite the lack of proliferation, preactivated Tc phenotypically maintain an intermediate stage of activation. These data show how the same cell population can change its functional phenotype into a non‐responder state.

Impaired T-cell rsponse to subsequent TCR-stimulation after anti-CD3 induced proliferation

Defects of T-cell (TC) proliferation and in TC-receptor (TCR) signaling have been demonstrated in several autoimmune diseases. The detailed mechanisms governing activation and proliferation of activated TC, however, are still not completely known. Here, we will show that under certain conditions human peripheral blood (PB) TC, once activated by anti-CD3 monoclonal antibody (mab) in vitro, fail to respond to a subsequent re-stimulation via the TCR. This unresponsiveness is caused at the transcriptional level by an impaired production of IL-2, and this defect is temporary.