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The presence of naturally occurring cytokine-specific autoantibodies (c-aAb) in humans is well established, as well as associations to selected pathologies. However, the overall influence of c-aAb on immunocompetence remains largely unknown. In this paper, we performed a large-scale investigation of c-aAb association with infection risk. A cohort of healthy Danish blood donors was screened for c-aAb against IL-1α, IL-6, IL-10, IFNα, and GM-CSF using a Luminex-based multiplex assay, and results were linked to data from the Danish National Prescription Registry. The filing of an antimicrobial prescription following c-aAb measurement was used as a proxy for impaired immunocompetence. We found that c-aAb against pro-inflammatory cytokines IFNα and GM-CSF tended to associate with increased risk of prescription filings in women, whereas antibodies against anti-inflammatory IL-10 were associated with a lower predicted risk of antimicrobial prescriptions, as well as higher self-perceived health scores. We also observed an association of cumulative c-aAb presence with prescription risk. Our data show that cytokine autoantibodies in healthy individuals associate with various proxies for immunomodulation, with the exact association dependent on the pattern of pro- or anti-inflammatory cytokines targeted. This suggests that c-aAb may express cytokine-modulatory properties in healthy individuals and may be critical to further investigate as biomarkers of immunodeficiency.

Aims/hypothesis: Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. Methods: IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells. Results: IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. Conclusions/interpretation: The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes., SCOPUS: ar.j, info:eu-repo/semantics/published

As an alternative treatment with allogeneic bone marrow transplantation, a possibility of autologous stem cell transplantation for chronic myelogenous leukemia (CML) was studied. The most critical problem in this study is how to purify normal stem cells from autologous bone marrow or peripheral blood cells. Although normal stem cells are present in these patients in chronic phase, absolute amount of these cells are very small and difficult to detect by regular chromosome analysis. Concerning to a previous report, appearance of Philadelphia chromosome (Ph) negative clones was observed after long-term marrow culture (LTMC) of CML patients. Our previous studies had shown that addition of interferon-α (IFNα) in LTMC preferentially decrease Ph cells. In the present study, we investigated the frequencies of leukemic clones in suspending-and adherent-fraction of LTMC by reverse transcriptional-polymerase chain reaction (RT-PCR) for bcr-abl, CML specific and chromosome analysis of a single progenitor derived colony. All colonies derived from suspending cells presented either bcr-abl and Ph chromosome in both cultures with and without IFNα. In all 11 colonies derived from adherent-fraction of LTMC without IFNα, bcr-abl was detectable, whereas 2/2 CFU-mix and 3/11 CFU-GM were negative for bcr-abl from the culture with IFNα. Results from chromosome analysis of single colony was similar to that by RT-PCR. These results indicate the possibility of application of LTMC with IFNα to eliminate leukemic clones from CML marrow cells, however, there remains a problem that stem cell number decreases during LTMC with IFNα. Our investigation of ex vivo expansion for human hematopoietic stem cells is still experimental, and more progression is necessary for clinical application.

The acute human immunodeficiency virus type 1 (HIV-1) infection of activated peripheral blood mononuclear cells (PBMCs) from normal donors results in inhibition of cell proliferation and generation of functional suppressive T cells. Cultured HIV-1 infected PBMCs but not uninfected PBMCs, following irradiation, can inhibit the proliferation of antigen-activated autologous T cells in a dose-dependent way. CD8' cell subpopulation is responsible for this inhibition. The presence of anti-alpha interferon (IFNα) and anti-Tat antibodies in the culture medium counteracts the HIV-1-induced immunosuppression and prevents the generation of suppressive T cells by these PBMCs. The reported data should have major implications for strategies of AIDS treatment which, in association with antiviral drugs, aim at targetting immune disorders., SCOPUS: ar.j, info:eu-repo/semantics/published