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PubMedDate not supplied

The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS).

Interleukin-10 (IL-10) is an immunoregulatory cytokine that plays a crucial role in inflammatory and immune reactions. It has potent anti-inflammatory and immunosuppressive activities on myeloid cell functions which forms a solid basis for its use in acute and chronic inflammatory diseases. Here, we discuss the role of IL-10 in autoimmune diseases and examine its beneficial effects in cellular-based autoimmune diseases such as multiple sclerosis (MS) or its involvement in humoral-based autoimmune diseases such as systemic lupus erythematosus (SLE). Inhibition of the immune stimulatory activities of IL-10 may provide novel approaches in the treatment of humoral autoimmune diseases, infectious diseases and cancer.

Animals↗

PubMed2001

An etiopathogenic role for the type I IFN system in SLE.

The type I interferon (IFN) system plays a pivotal role in the etiopathogenesis of systemic lupus erythematosus (SLE). The initial appearance of autoantibody-producing B cells can be precipitated by infection-induced type I IFNs, but the further, significant generation of autoimmune T and B cells is caused by the prolonged production of IFN-alpha, which is maintained by a vicious circle mechanism. This involves the activation of immature dendritic cells, known as natural IFN-producing cells, by continuously formed endogenous IFN-alpha inducers. These IFN-alpha inducers consist of complexes of autoantibodies with nucleic-acid-containing autoantigens derived from apoptotic cells.

Autoimmunity↗

PubMed2001

The regulation of FasL expression--a distinquishing feature between monocytes and T lymphocytes/NK cells with possible implications for SLE.

Monocytes and lymphocytes from patients with systemic lupus erythematosus (SLE) had a higher cell surface expression of FasL than the corresponding cells from healthy individuals. Inhibitors of metalloproteases upregulated the surface expression of FasL in peripheral blood lymphocytes (PBL), indicating that a metalloprotease is responsible for the cleavage of FasL. The level of sFasL in serum was slightly increased in the patient group compared to the controls. Therefore, the possible contribution of various mononuclear cell types to the release of FasL was analyzed. Isolated NK cells and T lymphocytes released FasL into the medium and the release was prevented by inhibitors of metalloproteases. In contrast, isolated monocytes did not release FasL. FasR expression was elevated in patients with inverted CD4/CD8 ratio, while FasL expression showed no relationship to CD4/CD8 ratio. The absence of FasL release by isolated cells and a high level of surface expression of FasL distinguish monocytes and T lymphocytes/NK cells.

Adult↗

PubMed1997

Autonomic nervous dysfunction in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA): possible pathogenic role of autoantibodies to autonomic nervous structures.

Autonomic nervous dysfunction has been previously reported in SLE, RA and systemic sclerosis, but the pathogenesis of such a complication is poorly understood. In the present study, four standard cardiovascular autonomic function tests were performed in 34 female patients with connective tissue diseases and in 25 healthy control subjects, and results expressed as cardiovascular (CV) test scores. Moreover, in each subject the presence of circulating complement-fixing autoantibodies directed against sympathetic and parasympathetic nervous structures, represented by superior cervical ganglia and vagus nerve, respectively, was simultaneously assessed by an indirect immunofluorescent complement-fixation technique, using rabbit tissue as substrate. None of the patients reported autonomic symptoms. However, an abnormal CV test score (> or = 5) was detected in 15% of the patients and in none of the healthy control subjects, approaching statistical significance (P = 0.07). No correlation was found between CV test results and disease duration, type of therapy or presence of conventional autoantibodies. One or two autoantibodies to autonomic nervous structures were detected in six patients (18%) and not in the control subjects (P < 0.05). Values of deep breathing test were significantly lower in autoantibody-positive patients compared with those amongst the control subjects (P < 0.05), and an abnormal CV test score was significantly associated with the presence of autoantibodies to autonomic nervous structures (P < 0.05). In conclusion, we confirm that autonomic nervous function can be impaired in patients with connective tissue diseases, and suggest that autoantibodies directed against autonomic nervous system structures may play a role in the pathogenesis of the autonomic dysfunction.

Adolescent↗

PubMed2001

Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives.

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.

Adolescent↗

PubMed1996

SLE autoantibodies recognize spermine induced Z-conformation of native calf thymus DNA.

The binding specificity of naturally occurring anti-DNA antibodies with spermine modified DNA was analyzed by direct binding and competition ELISA. The binding was visualised by band shift assay. The SLE anti-DNA antibodies appreciably recognized the spermine induced Z-conformation of native DNA. The degree of binding of these antibodies to the Z-conformer was almost similar to their binding with native DNA. The spermine-DNA complex was found to be thermodynamically more stable than native DNA.

Animals↗

PubMed1998

Dissection of the effects of tumor necrosis factor-alpha and class II gene polymorphisms within the MHC on murine systemic lupus erythematosus (SLE).

Gene(s) in the MHC of the NZW strain (H-2z) up-regulate(s) systemic lupus erythematosus (SLE) in (NZB x NZW) F1 mice. So far, two plausible mechanisms have been implicated: (i) unique mixed haplotype class II molecules formed in the F1 mice act as a restriction element for self-reactive T cells and (ii) a unique polymorphism in the H-2-linked NZW tumor necrosis factor (TNF)-alpha allele which down-regulates TNF-alpha is contributory. Because of the difficulty in dissecting these alleles within the H-2 complex, it has not been determined which is indeed the case. We addressed this issue by establishing three different H-2-congenic (NZB x NZW) F1 mice bearing distinct haplotypes at class II and TNF-alpha regions, i.e. (NZB x NZW) F1 (H-2d/z:A(d/u)E(d/u)TNF(d/z)), (NZB x NZW.PL) F1 (H-2(d/u):A(d/u)E(d/u)TNF(d/d)) and (NZB x NZW.H-2d) F1 (H-2(d/d):A(d/d)E(d/d)TNF(d/d)). Among these, only (NZB x NZW) F1 produced a markedly lower level of TNF-alpha, due to the unique NZW TNF-alpha allele (TNF(z)). Studies of anti-DNA antibodies and lupus nephritis revealed that, compared to (NZB x NZW) F1, the disease of (NZB x NZW.H-2d) F1 was markedly reduced. In (NZB x NZW.PL) F1, the onset of renal disease was significantly delayed, while the extent of proteinuria and renal histopathology in individuals that had developed the disease was comparable to that seen in (NZB x NZW) F1. It seems likely that both class II and TNF-alpha gene polymorphisms are functioning as H-2-linked predisposing genetic elements, and that the TNF-alpha polymorphism acts to modulate an initial process of the renal disease.

Animals↗

PubMed1988

A comparison of autoantibodies and common DNA antibody idiotypes in SLE patients and their spouses.

In order to determine whether environmental influence per se might influence autoantibody production, sera from the spouses of 20 SLE patients were examined. No antibodies to cardiolipin, poly (ADP-ribose), or ENA were detected and none had detectable rheumatoid factor. One weakly positive ANA reaction was noted, one had anti-DNA antibodies (by RIA and ELISA) and in two sera the common DNA antibody idiotype 16/6 was found. The idiotype was not, however, present on either anti-DNA or anti-K30 antibodies. Although long-term analyses are required, it is evident that sharing the same environment with patients who commonly express a wide range of autoantibodies and common idiotypes rarely leads to their expression in non-autoimmune subjects.

Antibodies, Antinuclear↗

PubMed2005

Complement and its breakdown products in SLE.

The complement system has important protective functions in both the innate and the adaptive immune systems but can also, when inappropriately activated, cause tissue damage. Complement deficiency predisposes to infection and also to development of autoimmune disease, especially SLE, and complement is at the same time involved in the pathogenesis of this disease. In this review, various aspects of this dualism are discussed. An overview of activation pathways and activation products is given, together with a description of autoimmunity against complement and the potential of complement regulation in future therapeutics.

Autoantibodies↗

PubMed1981

Immune complexes, complement, and anti-DNA in exacerbations of systemic lupus erythematosus (SLE).

The usefulness of serological parameters in assessing clinical exacerbations of SLE was examined. Patients with active renal disease tend to have lower levels of CH50 and C3 and highest levels of immune complexes detected by C1qBA than those patients with extrarenal manifestations only. Patients with a combination of both active extrarenal and renal disease are more likely to demonstrate the lowest levels of CH50, C4, and C3. However, immune complex levels are not higher than levels detected in patients with only active nephritis. A normal C3 level argues against active nephritis. Low complement levels without appreciably elevated levels of C1qBA suggest that significant renal disease is unlikely. The serial measurements that best reflect evolving clinical activity and which may serve as markers of impending exacerbation are, in decreasing order of usefulness: C4, CH50, C1qBA, C4, C3 and ADA. However, a combination of CH50, C4, C3 and C1qBA appeared to be the most useful. Given various serologic changes, guidelines for following patients are offered.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1982

Preleukemic syndrome simulating SLE. A case report.

A 70-year-old man presented with symmetrical arthritis and arthralgias, Raynaud's phenomenon, pleurisy, fever, maculopapular erythema, leuko- and thrombocytopenia, anemia, antinuclear antibodies and hypocomplementemia. His bone marrow morphology was normal. During therapy with corticosteroids he developed pulmonary tuberculosis which responded well to tuberculostatic treatment. Approximately one year after onset of his initial symptoms, myeloblasts were seen in the blood and a few weeks later the bone marrow showed a myeloblastic leukemia. The patient did not respond to cytostatic treatment and died six weeks later. Although this patient presented symptoms suggesting the diagnosis of SLE, in retrospect his condition probably represented an unusual type of preleukemic syndrome.

Aged↗

PubMed1989

Cutaneous mucinosis associated with SLE--a case provoked by PUVA.

A patient with SLE which was complicated by a characteristic cutaneous mucinosis is reported. The skin lesions were composed of intradermal soft nodules, purple-red plaques, and alopecia of the scalp. Acid mucopolysaccharides accumulated in each lesion. PUVA provoked an infiltrated skin lesion in which acid mucopolysaccharides were deposited in the dermis. Deposition of immunoglobulins and complements were also observed at the dermo-epidermal junction and on the vascular walls. Some immunological processes which may stimulate the synthesis of acid mucopolysaccharides in the dermis were suggested.

Adult↗

PubMed1992

Naturally occurring SLE anti-DNA antibodies recognize unique conformation on DNA-lysine photoadduct.

Native calf thymus DNA has been covalently modified with lysine under UV-A light. Human autoantibodies on purification through affinity column of native DNA linked to polylysyl-Sepharose 4B showed almost equal recognition of DNA and photoadduct. The recognition of DNA-lysine photoadduct by the affinity-purified autoantibodies might be helpful in understanding their origin in SLE vis-à-vis the role of positively charged amino acids in the pathogenesis of autoimmune diseases.

Animals↗

PubMed1986

Concurrent multiple morphea and neonatal lupus erythematosus in an infant boy born to a mother with SLE.

An infant boy born to a mother with systemic lupus erythematosus developed multiple morphea and annular erythematous lesions. The annular lesions appeared on his face, back, chest and extremities one month after birth and faded within 7 months. The sclerotic lesions progressed until the age of 6 months and remain on his back, chest, right cheek, the nape of the neck and left shoulder at the age of 3 years. Histological findings in the sclerotic lesions were consistent with scleroderma. Serological tests, performed at 14 months of age, were within normal limits. The mother developed acute SLE and died of cardio-renal failure 8 months after the delivery. It is highly probable that maternal factors transferred through the placenta caused the sclerotic lesions in the infant.

Humans↗

PubMed1985

Thrombocytopenia in SLE and related autoimmune disorders: association with anticardiolipin antibody.

Anticardiolipin antibody levels were determined in 116 patients with systemic lupus erythematosus and related autoimmune disorders. Forty-three of these patients had a history of thrombocytopenia--36 of whom had SLE, three primary Sjögren's syndrome, two rheumatoid arthritis and two mixed connective tissue disease. IgG anticardiolipin antibody levels were raised in 31 (72%) of the 43 patients and IgM anticardiolipin antibody levels were raised in 19 (44%). There was a strong statistical correlation between thrombocytopenia and raised anticardiolipin antibody levels of both the IgG (P less than 0.001) and IgM (P less than 0.01) immunoglobulin classes. Of the 20 patients with the highest IgG anticardiolipin antibody levels 16 had a history of thrombocytopenia. We suggest that anticardiolipin antibodies may play a direct role in mediating platelet destruction in autoimmune disorders.

Antibodies↗

PubMed1990

Heterogeneity of binding reactivity to different phospholipids of antibodies from patients with systemic lupus erythematosus (SLE) and with syphilis.

The binding specificities were investigated of anti-phospholipid antibodies derived from sera from 55 patients with SLE and related diseases, and from 33 patients with syphilis. Antibodies from both these groups of patients bind strongly to cardiolipin in solid-phase immunoassays, but only antiphospholipid antibodies from patients with autoimmune diseases are associated with thrombotic complications and recurrent spontaneous abortions. IgG anti-phospholipid antibodies from both groups of patients cross-reacted with a range of negatively charged phospholipids, but binding to neutral phospholipids was largely restricted to sera from patients with syphilis. A monoclonal IgM lambda anti-cardiolipin antibody, derived from a patient with autoimmunity, was used to inhibit binding of anti-phospholipid antibodies to cardiolipin and to phosphatidic acid. This antibody inhibited the binding of autoimmune sera to cardiolipin more strongly than sera from syphilis patients, but the converse pattern of inhibition of binding to phosphatidic acid was observed. The VDRL titre correlated with anti-phospholipid antibody activity in sera from syphilis patients, but not from those with autoimmunity. Lupus anti-coagulant activity correlated weakly with IgG antibody levels to each of the negatively charged phospholipids among the patients with autoimmunity. Lupus anticoagulant activity did not correlate uniquely with any anti-phospholipid antibody specificity. These results provide further documentation of the great heterogeneity of anti-phospholipid antibodies associated with autoimmune disease and syphilis.

Antibody Specificity↗

PubMed1991

Autoimmunity to a 28-30 kD cell membrane DNA binding protein: occurrence in selected sera from patients with SLE and mixed connective tissue disease (MCTD).

Previous experiments have established the presence of a 30-kD DNA binding protein on the surface of human leukocytes. Herein we report that selected sera from patients with systemic lupus erythematosus (SLE) and MCTD are reactive with a 28-30 kD protein on immunoblots of peripheral blood mononuclear cells (PBMC) cell membrane preparations; the reactivity is abolished by prior incubation of the blot with DNA. Antibodies eluted from the 28-30 kD strip inhibited the binding of 3H. DNA to human PBMC. An immunomatrix of 28-30 kD reactive immunoglobulins was able to extract a 29-kD DNA binding protein from a PBMC cell membrane preparation. Flow cytometry experiments confirmed the cell surface IgG reactivity of sera with T lymphocytes. Additional experiments indicated that cell surface IgG binding was not due to antibodies binding to cell surface DNA, DNA anti-DNA immune complexes reacting with a DNA binding protein, anti-histone antibodies or anti-Sm antibodies. It is hypothesized that this autoimmune response could be one component of an idiotypic network involving anti-DNA antibodies.

Autoantibodies↗

PubMed1992

Combined total deficiency of C7 and C4B with systemic lupus erythematosus (SLE).

The first inherited combined total deficiency of C7 and C4B complement components associated with SLE is described in a young female. Functional C7 assays showed a homozygous C7 deficiency in the propositus and her sister, and an heterozygous one in their parents. C4 molecular analyses showed that both the propositus and her mother had two HLA haplotypes carrying only C4A-specific DNA sequences and a normal C4 gene number. Thus, only C4A proteins could be expressed, with resultant normal C4 serum levels. The coexistence of a combined complete C7 and C4B deficiency may therefore abrogate essential functions of the complement cascade presumably related to immune complex handling and solubilization despite an excess of circulating C4A. These findings challenge the putative pathophysiological roles of C4A and C4B and stress the need to perform both functional assays and C4 allotyping in patients with autoimmune pathology and low haemolytic activity without low serum levels of a classical pathway complement component.

Adult↗