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F Hiepe

Publications and source records attributed to F Hiepe.

At least 19 recordsLinked to original sources
PubMed2007

[Revision of the recommendations of the Commission on Pharmacotherapy of the German Society for Rheumatology. Comment on the use of mycophenolic acid for systemic lupus erythematosus].

According to the NIH scheme, the "evidence based medicine" standard in the treatment of severe proliferative lupus-nephritis is cyclophosphamide in combination with steroids. Undesired effects, therapy resistance, and deficient long-term effects underscore the necessity for the development of alternative therapies for the treatment of organ involvement. Mycophenolate mofetil (MMF) possesses the potential to decisively improve the therapeutic possibilities for systemic lupus erythematosus (SLE). On the basis of the available data, MMF represents an alternative to the current standard therapies for severe lupus-nephritises and shows less toxicity. MMF is also effective in patients with other manifestations refractory to conventional therapy. Questions remain unanswered on the optimal dosage and possible reduction in cases of remission. In addition, the duration of maintenance therapy is unclear. Therefore, large, prospective, randomized clinical studies in the treatment of lupus-nephritis with a sufficiently long follow-up phase are underway.

Drug Therapy, Combination↗
PubMed2006

The systemic and SmD183-119-autoantigen-specific cytokine memory of Th cells in SLE patients.

OBJECTIVES: The aim of the study was to analyse the cytokine memory of T-cells derived from systemic lupus erythematosus (SLE) patients and healthy donors enriched for autoantigen-specific T-cells by in vitro stimulation with SmD1(83-119), a common autoantigen in SLE. METHODS: Autoreactive CD3+ T-cells derived from 37 SLE patients and 14 healthy donors were enriched by repetitive ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with SmD1(83-119). For control, PBMCs were stimulated only with interleukin-2 (IL-2). After two rounds of antigenic stimulation, cultures were stimulated with PMA/ionomycin to probe the cytokine memory by intracellular cytokine staining. Frequencies of cytokine-expressing T-cells were analysed and, in SLE patients, compared with disease activities and autoantibody levels. RESULTS: Comparing the cytokine memory in the cultures, SLE patients displayed higher frequencies of tumour necrosis factor-alpha (TNF-alpha)+ T-cells than healthy donors and the frequencies correlated with disease activity. Frequencies of SmD1(83-119)-specific TNF-alpha+ T-cells and of memory T-cells expressing interferon-gamma (IFN-gamma) correlated with serum anti-dsDNA antibody levels. The frequencies of IL-10 expressing SmD1(83-119)-specific T-cells were lower among PBMCs of SLE patients. Relatively higher frequencies of IL-10+ T-cells in SLE patients correlated with low disease activities, and low anti-dsDNA and anti-SmD1(83-119) antibody concentrations in culture supernatants. CONCLUSIONS: The memory of autoreactive SmD1(83-119)-specific and unspecific stimulated peripheral Th cells for re-expression of cytokines is shifted towards more cells expressing TNF-alpha and less IL-10+ cells, when compared SLE patients with normal donors. This shift towards proinflammatory memory effector Th cells correlates with disease severity and humoral autoimmunity.

Antibodies, Antinuclear↗
PubMed2006

Immunological memory stabilizing autoreactivity.

The etiopathologies of autoimmune diseases are complex. A broad variety of cell types and gene products are involved. However, clinical and experimental evidence suggests that the importance of an individual factor changes during the course of the disease. Factors and cell types that induce acute autoreactivity and initiate an autoimmune disease could be distinct from those that drive a chronic course of that disease. Autoreactive immunological memory, in particular B cell and plasma cell memory, contributes to chronicity through several mechanisms. Formation of autoreactive memory B cells leads to an increase in the numbers of autoreactive cells. In comparison to naive B cells, these memory B cells show a decreased threshold for activation. Additionally, a fraction of memory B cells express the chemokine receptor CXCR3, which supports their accumulation within chronically inflamed tissues. This may allow their escape from mechanisms for induction of peripheral tolerance. Within the inflamed tissue, inflammatory cytokines and autoantigens provide activation signals that promote plasma cell differentiation and survival. The autoantibodies produced locally by these plasma cells contribute to the severity of inflammation. Together, an autoreactive loop of autoantibody-induced inflammation is formed. Another integral part of immunological memory are long-lived plasma cells. These cells provide persistent humoral antibody memory. Though not all autoantibodies are produced by long-lived plasma cells, these cells have a special impact on immune pathology. Long-lived plasma cells are relatively resistant to existing therapies of immunosuppression and continuously secrete antibodies, without need for restimulation. Long-lived plasma cells provide titers of autoantibodies even during clinically quiescent phases and after immunosuppression. These persisting autoantibody titers, though often low and not causing acute clinical symptoms, are likely to maintain a low level of chronic inflammation and progressive tissue destruction, which reduces the threshold for another break of immunological tolerance.

Animals↗
PubMed2005

[Autoantibodies and antibody-secreting cells].

Autoantibodies are a hallmark of systemic and organ-specific autoimmune diseases. They contribute both directly and indirectly to the pathogenesis of these diseases. There is now a rising interest in cells that secrete (auto)antibodies. Antibody-secreting cells are plasma blasts and plasma cells that differentiate from B cells following antigen encounter. The view held by the immunology community for decades was that (auto)antibodies are produced by short-lived cells arising from chronic (auto)antigen-mediated B cell stimulation. However, it was recently shown that plasma cells can survive in niches in the bone marrow and inflamed tissues for months to years. These long-lived plasma cells continuously secrete (auto)antibodies without the need for any additional antigen stimulation. They are resistant to immuno-suppressants and are not eliminated by B-cell depleting therapies. Depending on which antibodies are secreted, this plasma cell memory may play an important role in maintaining protective humoral immunity or in the pathogenesis of autoimmune diseases. Consequently, strategies targeting long-lived autoreactive plasma cells may provide new therapeutic options in the treatment of autoimmune diseases.

Animals↗
PubMed2004

[Wegener's granulomatosis (WG) presented with hearing loss and without positive serologic ANCA].

BACKGROUND: Wegener's granulomatosis (WG) is a granulomatous inflammation involving the upper and lower respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels. In contrast to a generalised WG with glomerulonephritis initial or isolated forms of the upper respiratory tract may be a diagnostic challenge. PATIENT: We report the case of a 33 year old man with clinical signs of a limited WG exhibiting an imminent irreversible hearing loss, negative PR3-ANCA (anti neutrophil cytoplasmic antibodies with proteinase 3 as target) in serum and an ambiguous histology. CONCLUSION: In case of a chronic otitis media and rhinitis as well as signs of a labyrinthine deafness a limited form of a WG has to be taken into account, even with an ambiguous histology and negative PR3-ANCA. This diagnosis is supported by high inflammation parameters, e. g. ESR and CRP, exclusion of infectious cause and response to corticosteroids. A quick therapeutic intervention with corticosteroids and cyclophosphamide is required in order to interrupt the vasculitis of the inner ear with consequential deafness.

Adult↗
PubMed2004

Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry.

OBJECTIVE: To analyse the durability of the responses after haematopoietic stem cell transplantation (HSCT) for severe systemic sclerosis (SSc) and determine whether the high transplant related mortality (TRM) improved with experience. This EBMT/EULAR report describes the longer outcome of patients originally described in addition to newly recruited cases. METHODS: Only patients with SSc, treated by HSCT in European phase I-II studies from 1996 up to 2002, with more than 6 months of follow up were included. Transplant regimens were according to the international consensus statements. Repeated evaluations analysed complete, partial, or non-response and the probability of disease progression and survival after HSCT (Kaplan-Meier). RESULTS: Given as median (range). Among 57 patients aged 40 (9.1-68.7) years the skin scores improved at 6 (n = 37 patients), 12 (n = 30), 24 (n = 19), and 36 (n = 10) months after HSCT (p<0.005). After 22.9 (4.5-81.1) months, partial (n = 32) or complete response (n = 14) was seen in 92% and non-response in 8% (n = 4) of 50 observed cases. 35% of the patients with initial partial (n = 13/32) or complete response (n = 3/14) relapsed within 10 (2.2-48.7) months after HSCT. The TRM was 8.7% (n = 5/57). Deaths related to progression accounted for 14% (n = 8/57) of the 23% (n = 13/57) total mortality rate. At 5 years, progression probability was 48% (95% CI 28 to 68) and the projected survival was 72% (95% CI 59 to 75). CONCLUSION: This EBMT/EULAR report showed that response in two thirds of the patients after HSCT was durable with an acceptable TRM. Based on these results prospective, randomised trials are proceeding.

Adolescent↗
PubMed2003

Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus.

OBJECTIVE: To investigate the distribution of peripheral B cell subpopulations of children with active and inactive systemic lupus erythematosus (SLE) compared with healthy controls. METHODS: Peripheral B cell subpopulations of 11 children with SLE (6 with active and 5 with inactive disease) and 14 age matched normal healthy children were analysed. Active disease was diagnosed in children with a flare of SLE, who received treatment by i.v. cyclophosphamide or i.v. methylprednisolone pulse to control the disease. Additionally, the peripheral B cells of the children with SLE were compared with those of 13 consecutive patients with adult onset SLE. RESULTS: No major difference was found in the frequency and total number of CD27(-)/CD19(+) naïve B cells and CD27(+)/CD19(+) memory B cells between patients with active and inactive lupus and healthy controls, but there was a significant increase in CD27(high) expressing plasma blasts in patients with active SLE. These cells coexpress CD38(+), HLA-DR(dim), surface Ig(low) and lack the expression of CD20 but are clearly positive for intracellular Ig, indicative of early plasma cells. Most CD138(+) cells coexpress CD27(high)/CD19(+). The enhanced frequency of peripheral plasma blasts in children with active SLE is consistent with previous findings in adult patients with SLE, whereas a relative predominance of CD27(+) memory B cells was only identified in the adult patients. CONCLUSIONS: Profound abnormalities in the distribution of B cell compartments are more pronounced in older patients with SLE, but an enhanced frequency and cell number of peripheral plasma blasts is characteristic of both diseases during active stages. Thus detection of CD27(high) plasma blasts significantly correlates with active lupus in both children and adults.

Adolescent↗
PubMed2002

Rapid detection of autoantibodies to dsDNA with the particle gel immunoassay (ID-PaGIA).

OBJECTIVE: To describe a new particle agglutination test for the detection of autoantibodies to double stranded DNA (dsDNA). PATIENTS AND METHODS: Serum samples were collected from 40 unselected healthy blood donors and 200 patients with systemic lupus erythematosus (SLE) or a positive antinuclear antibody screen, or both. The samples were tested in the presence of red high density polystyrene particles coated with purified human dsDNA using the gel technique (Micro Typing System, ID-PaGIA, particle gel immunoassay). The results were compared with those obtained by the two standard anti-dsDNA antibody detection methods, Crithidia luciliae immunofluorescence test (CLIF) and enzyme linked immunosorbent assay (ELISA). RESULTS: The three anti-dsDNA assays exhibited an overall agreement of 87% and significant correlation with each other (p<0.0001). In the SLE group (n=71), 45 patients (63%) were found to be positive by ID-PaGIA compared with only 11/129 (9%) patients in the non-SLE group. Thus the ID-PaGIA had a sensitivity of 63%, and a specificity of 92% for SLE. In comparison, the standard detection methods showed sensitivities of 62% (CLIF) and 70% (ELISA) and specificities of 99% (CLIF) and 84% (ELISA) for SLE. Anti-dsDNA reactivity in the agglutination assay correlated closely with the quantities of antibody obtained by CLIF (r=0.81, p<0.0001) and ELISA (r=0.73, p<0.0001). CONCLUSIONS: The new particle gel agglutination test is a sensitive and specific immunoassay. It is a simple test procedure that might be well suited as a rapid screening method.

Agglutination Tests↗
PubMed2002

T cell reactivity against the SmD1(83-119) C terminal peptide in patients with systemic lupus erythematosus.

BACKGROUND: The SmD1(83-119) peptide is a major target of the B cell response in patients with systemic lupus erythematosus (SLE). OBJECTIVE: To investigate the T cell response directed against this peptide, its disease specificity, and possible impact on SLE pathogenesis. METHODS: Peripheral blood mononuclear cells derived from 28 patients with SLE and 29 healthy and disease controls were stimulated by the SmD1(83-119) and the recombinant (r)SmD1 protein, and [3H]thymidine incorporation was measured. Patients with SLE were simultaneously tested for autoantibodies, disease activity, clinical symptoms, and medical treatments. RESULTS: T cell reactivity against the SmD1(83-119) peptide was detected in 11/28 (39%) patients with SLE and against the rSmD1 protein in 10/28 (36%) patients. In contrast, only 2/29 (7%) controls exhibited SmD1 reactivity. An analysis of proliferation kinetics showed that SmD1 reactive T cells are activated in vivo, as additionally confirmed by cytometric analysis. Addition of mammalian dsDNA to rSmD1 enhanced the rSmD1-specific T cell response. SmD1(83-119)-specific T cell reactivity was significantly more common in patients with cardiac and pulmonary symptoms. No correlation between T and B cell responses and disease activity was seen. CONCLUSION: SmD1(83-119) is a major T cell epitope of SmD1, commonly recognised by T cells from patients with SLE and much less commonly found by healthy or disease controls. This strong T cell reactivity as well as the high frequency and specificity of anti-SmD1(83-119) antibodies in SLE suggest a possible role in SLE pathogenesis, at least in a subset of patients.

Adult↗
PubMed2002

Shwartzman phenomenon in a patient with active systemic lupus erythematosus preceding fatal disseminated intravascular coagulation.

The recurrence of widespread and diverse vascular lesions is a hallmark of systemic lupus erythematosus (SLE). Inflammatory and thrombotic mechanisms almost invariably associated with circulating antiphospholipid antibodies play a role in the pathogenesis of SLE-related vascular disease. Both mechanisms can coexist in the same patient. Vasculitis is most commonly induced by the local deposition of immune complexes. However, some SLE patients have an inflammatory complement-mediated vascular injury in the absence of immune complex deposition. We report on a fatal case of disseminated intravascular coagulation (DIC) in a young woman with active SLE. Hemorrhagic lesions due to localized intravascular coagulation (Shwartzman phenomenon) preceded disseminated intravascular coagulation accompanied by disseminated cardiac necrosis. Immune complex 'independent' and other mechanisms of vascular injury and states of hypercoagulability will be discussed.

Adult↗
PubMed2002

Anti-DNA antibodies--overview of assays and clinical correlations.

Many authors have studied the links between levels of anti-dsDNA antibodies and disease activity in patients with SLE. Interpretation of these studies must take into account the facts that there are a range of possible assays for anti-dsDNA and a number of indices available for assessing disease activity. A recent study compared levels of various autoantibodies with organ specific disease activity assessed during the British Isles Lupus Assessment Group (BILAG) index. Anti-dsDNA and anti-heparan sulphate levels were more likely to be raised in patients with renal than non-renal disease. Some anti-DNA antibodies are actually anti-nucleosome antibodies, which lose DNA reactivity when purified under dissociating conditions. Patients with SLE have significantly increased levels of nucleosomes in their sera compared with healthy controls. In patients with SLE, reduced clearance of nucleosomes released from apoptotic cells may induce the formation of anti-nucleosome antibodies.

Antibodies, Antinuclear↗
PubMed2001

Inflamed kidneys of NZB / W mice are a major site for the homeostasis of plasma cells.

(NZB x NZW)F1 (NZB / W) mice develop a disease similar to human systemic lupus erythematosus (SLE), including autoantibody production, hypergammaglobulinaemia and inflammation of the kidneys. It is known that large numbers of lymphocytes infiltrate the kidneys of these mice. Here, we compare the roles of bone marrow, spleen and inflamed kidneys of NZB / W mice in the activation of B cells and the persistence of antibody-secreting cells (ASC). ASC are present in the kidneys of NZB / W mice with full-blown disease, as many as in the spleen and bone marrow. The specificity of the ASC in the inflamed kidneys is not restricted to self-antigens. After immunization of NZB / W mice with ovalbumin (OVA) the OVA-specific ASC are found initially in the spleen. Weeks later, OVA-specific ASC are found in high numbers in the bone marrow and the kidneys of these mice, but no longer in the spleen. As determined by FACS, B cells with a germinal center phenotype (B220(+) / PNA(+)) are found only in very low numbers in the kidneys, but in high numbers in the spleen of NZB / W mice. Germinal centers could not be detected in the kidneys, but in the spleen, and plasma cells appear to be scattered over the tissue. These data suggest that in autoimmune NZB / W mice, plasma cells generated in immune reactions of secondary lymphoid organs, later accumulate and persist in the inflamed kidneys, were they enhance the local concentrations of Ab and immunocomplexes. These experiments identify the inflamed kidneys of NZB / W mice as a site of prime relevance for the homeostasis of plasma cells, irrespective of their specificity.

Animals↗