The role of IL-17 in systemic lupus erythematosus and its potential as a therapeutic target

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies production and immune complex deposition with systemic clinical manifestations. Interleukin (IL)-17-producing cells play a crucial role in disease pathogenesis and represent an attractive therapeutic target.

Areas covered: This review provides an update on the possibility of targeting IL-17 in SLE. The rational for this approach as well as currently available and future targets are discussed.

Expert opinion: Although human expression studies and animal models indicate that IL-17 blocking may be a promising therapeutic strategy for SLE, direct evidence for IL-17 inhibition in SLE patients is unavailable. Biologic therapies and small-molecule drugs that target IL-17 production are required for the achievement of a favorable clinical effect in SLE patients.     

Suppression of cell attachment and protein adsorption onto amphiphilic polylactide-grafted dextran films

To develop novel biodegradable biomedical materials, polylactide-grafted dextrans (Dex-g-PLA)s having various lengths, numbers of graft chains and sugar units were synthesized using the trimethylsilyl (TMS) protection method. To explore the possibility of using Dex-g-PLA as a biomedical soft-material, the contact angle, cell attachment and protein adsorption properties of the films prepared from these biodegradable and amphiphilic graft co-polymers were investigated. The poly-L-lactide (PLLA) film did not absorb water at all because of its high hydrophobicity, while the graft co-polymer films started immediately to swell after immersion in PBS. The percentage of water absorption at equilibrium increased with increasing sugar unit content. The receding contact angle of the Dex-g-PLA films against water was smaller than that of the PLLA film. The receding contact angle of Dex-g-PLA films against water decreased with increasing the sugar unit content. The top surface of the Dex-g-PLA film was suggested to be covered with hydrophilic Dex segments by means of annealing in water and to afford the wettable surface. Such a wettable surface led to the suppression of cell attachment and protein adsorption onto the film.     

Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3

1Alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been shown to modulate the production of various cytokines or the expression of certain differentiation markers in human T cells or monocytes. Its effects on neutrophils, however, are poorly understood. In this paper, we show several lines of evidence indicating that neutrophils express functional vitamin D receptors (VDR). Sort-purified neutrophils from human peripheral blood expressed VDR mRNA at a level comparable to that of monocytes. As reported to occur in monocytes, protein expression of CD14 on the cell surface of neutrophils was augmented when the cells were incubated with 1,25(OH)2D3. To investigate the physiological roles for VDR in neutrophils, we investigated possible modulating effects of 1,25(OH)2D3 on the expression of several genes in lipopolysaccharide-stimulated neutrophils by using differential display analysis. Of the genes we identified, trappin-2/elafin/SKALP, which was originally reported to be an inhibitor of elastase, was induced in neutrophils by lipopolysaccharide, but was suppressed significantly in the presence of 1,25(OH)2D3. Under the same conditions, interleukin-1beta expression was also inhibited. These findings suggest that 1,25(OH)2D3 has a potential to affect the inflammatory process by modulating the expression of neutrophil genes.     

Increase of IgA specific helper T alpha cells in patients with IgA nephropathy.

Patients with IgA nephropathy show an emergence of IgA dominant circulating immune complexes (CIC) as well as increased levels of serum IgA and/or IgA bearing peripheral blood lymphocytes. In order to elucidate immunological aberrations responsible for the increased IgA synthesis in such patients, quantitative and qualitative analysis was performed on T alpha cells which have been recently identified as possessing IgA specific helper activity on human B cells. Three different methods were employed to quantitate T alpha cells. These methods included a rosette formation of T cells with either bovine red cells coated with the IgA fraction of anti-bovine red cell antiserum or those coated with TNP and anti-TNP IgA antibody, and an analysis of T cells combined with fluorescein conjugated human IgA myeloma protein. T alpha cells were sorted by a fluorescence activated cell sorter and co-cultured with a B cell rich fraction to evaluate whether there is a qualitative difference in IgA specific helper activity between patients and healthy adults. T alpha cells were significantly increased in patients with IgA nephropathy while there were no significant changes in patients with chronic proliferative glomerulonephritis without mesangial deposition of IgA. There was no qualitative difference in IgA specific helper activity of T alpha cells between patients and healthy adults. It is suggested that increased levels of T alpha cells in patients with IgA nephropathy may be responsible for increased synthesis of IgA in such patients.     

Enhancement of immunoglobulin G responses in mice against hepatitis B virus surface antigen, influenza virus hemagglutinin vaccine, and tetanus toxoid by 6-O-acylated muramyl dipeptides.

The adjuvant activity of chemically synthesized 6-O-acylated muramyl dipeptides (MDP) was tested in aqueous form. The activity was assessed by determining immunoglobulin G (IgG) titers in sera of mice immunized with hepatitis B virus surface antigen, influenza virus hemagglutinin (HA) vaccine, or tetanus toxoid with an enzyme-linked immunosorbent assay. Administration of 6-O-acyl-MDP analogs with antigens induced marked enhancement of primary and secondary IgG antibody responses and maintained high antibody levels for at least 7 weeks. Among the analogs tested, an MDP methyl ester carrying a 6-O-3-hexadecanoyl-oxytetradecanoyl group (compound 309) exhibited the most intensive adjuvant activity. Its activity was stronger than that of 6-O-2-tetradecylhexadecanoyl (B3O)-MDP used as a positive control. However, accumulation of peritoneal cells and activation of peritoneal macrophages by compound 309 was weaker than that by 6-O-B30-MDP, suggesting that 309 as an immunoadjuvant is more suitable for vaccination in terms of its stronger enhancement of antibody formation and lower induction of inflammatory response than 6-O-B30-MDP.     

Evaluation of the staining findings of immunofluorescence in unfixed or fixed renal biopsy specimens from patients with IgA nephropathy and membranous nephropathy

A study on the evaluation of staining findings of immunofluorescence in unfixed or fixed renal biopsy specimens is described. Renal biopsy specimens obtained from ten patients with IgA nephropathy and membranous nephropathy were embedded in gelatin or paraffin matrix. Renal biopsy specimens embedded in paraffin matrix were digested with 0.05% protease. The specimens were stained with FITC-conjugated anti-human IgA, IgG, IgM or C3 antisera at 4 degrees C overnight. IgA, IgG or IgM were markedly observed in glomeruli using unfixed materials embedded in gelatin matrix or 10% neutral buffered formalin fixed materials embedded in paraffin matrix from patients with IgA nephropathy and membranous nephropathy. There was no significant difference in the intensity or distribution of IgA, IgG or IgM deposition among the two different conditions of immunofluorescence in patients with such diseases. Although the deposition of IgA using unfixed materials embedded in gelatin matrix was prominently coarse granular or lumpy in glomeruli from patients with IgA nephropathy, that of IgA using 10% formalin fixed materials embedded in paraffin matrix was fine granular and/or interrupted linear in glomeruli. It was suggested that the immunofluorescence in renal biopsy specimens embedded in paraffin matrix after digestion with protease is useful for the evaluation of immunoglobulins in glomeruli from patients with IgA nephropathy or membranous nephropathy.     

A novel translocation involving chromosomes 2, 9, 14, and 22 in chronic myeloid leukemia

A 46-year-old man with chronic myelogenous leukemia was found to have a new complex translocation. In chronic phase, all of the bone marrow cells had a rearrangement of a t(2;9;14;22) (p21;q34;q32;q11). Southern blot analysis of leukocyte DNA revealed rearrangement of the breakpoint cluster region (bcr) within the 5.8-Kb bcr. The patient eventually died in blast crisis 28 months later. The cytogenetic findings of bone marrow cells showed a 46,XY,t(2;9;14;22)(p21;q34;q32;qll),add(lp),del(3q) karyotype in blast crisis.     

Enhanced resistance against Listeria monocytogenes achieved by pretreatment with granulocyte colony-stimulating factor.

Phagocytosis, H2O2 production, Mac-1 expression, and in vivo elimination of Listeria monocytogenes were enhanced in granulocyte colony-stimulating factor (G-CSF)-treated mice. Transfer of polymorphonuclear leukocytes prolonged survival of mice infected with a lethal dose of L. monocytogenes. G-CSF augments the functions of polymorphonuclear leukocytes and thus plays a role in protection.     

Protective immunity to Listeria monocytogenes in neonatally thymectomized (NTx) mice: involvement of T cells distinct from those in sham-thymectomized mice.

Neonatally thymectomized (NTx) mice, whose ability to mount antigen-specific cell-mediated immunity is reported to be generally defective, were found to be capable of mounting a normal level of acquired cellular resistance (ACR) and delayed footpad reaction (DFR) to Listeria monocytogenes. The present study was done in order to determine the functional differences of T cells contributing to the protection against L. monocytogenes between NTx and sham-operated mice. In mice immunized with viable L. monocytogenes, the absolute number of splenic T cells was significantly lower in NTx mice compared with sham-operated mice. When the ability of immune T cells to transfer ACR and DFR was examined by passive transfer, lymphocytes from immune NTx mice conferred a higher level of ACR and DFR on naive recipient mice, despite the marked difference in total number of T cells compared with immune Sham mice. Antigen-specific proliferation and interleukin-2 (IL-2) production by splenic T cells from immune NTx mice were significantly lower than in those from immune Sham mice. The proliferative response of T cells to exogenous IL-2 was also lower in NTx group. These results suggest that the requirement for the IL-2-driven T-cell proliferation system is basically low in the generation of effector T cells specific for L. monocytogenes.     

Gamma interferon-mediated increase in the number of Ia-bearing macrophages during infection with Listeria monocytogenes.

The role of gamma interferon (IFN-gamma) in an increase in Ia-bearing macrophages during Listeria monocytogenes infection was studied. The peritoneal macrophages from L. monocytogenes-infected mice contained a high proportion of Ia. Intraperitoneal injection of the supernatant from a culture of spleen cells from L. monocytogenes-infected mice induced Ia-rich exudates in normal mice. The Ia-inducing activity in the culture supernatant was abrogated by the pretreatment of spleen cells with anti-Thy-1.2 antibody plus complement. Immunoadsorption of the culture supernatant with anti-recombinant IFN-gamma antibody and protein A-Sepharose CL-4B completely abrogated its Ia-inducing activity. These results suggested that an increase in Ia-bearing macrophages during L. monocytogenes infection was attributable to T-cell-derived IFN-gamma.