The relation between infections and autoimmune diseases has been extensively investigated. Multiple studies suggest a causal relation between these two entities with molecular mimicry, ...hyperstimulation and dysregulation of the immune system as plausible mechanisms. The recent pandemic with a new virus, i.e., SARS-CoV-2, has resulted in numerous studies addressing the potential of this virus to induce autoimmunity and, eventually, autoimmune disease. In addition, it has also revealed that pre-existing auto-immunity (auto-Abs neutralizing type I IFNs) could cause life-threatening disease. Therefore, the topic of the 15th Dresden Symposium on Autoantibodies was focused on autoimmunity in the SARS-CoV-2 era. This report is a collection and distillation of the topics presented at this meeting.
Characterization of liver-specific autoantigens has given a fresh impetus to research in the pathogenesis of autoimmune liver diseases, viral-triggered and drug-induced autoimmunity affecting the ...liver. Intriguing is the fact that most of the liver-specific autoantigens are enzymes of key importance for cells homeostasis. Detection of autoantibodies against the respective antigens is carried out for diagnostic and research purposes using indirect immunofluorescence, immunoblotting, enzyme-linked immunosorbent assays, radioimmunoassay, immunoprecipitation or assays determining inhibition of enzyme activity. In patients with autoimmune hepatitis, a liver disorder of unknown etiology and pathogenesis, disease-specific autoantibodies are frequently directed against drug metabolizing enzymes of phase 1, namely cytochrome P450 2D6 (CYP2D6). The same and other members of these families of enzymes (CYPs) have also been described as targets of liver-specific autoimmunity in chronic hepatitis C virus (HCV)-infected patients, patients with autoimmune hepatitis as part of the autoimmune polyglandular syndrome type-1 (APS-1) and drug-induced autoimmunity. How these enzymes become 'self targets' is not yet established. An antigen release following hepatocyte injury could provide the stimulus for an immune response towards epitopes on these enzymes but the highly-specific, antigenrestricted initiation of the observed autoimmune response is against such an explanation. Accordingly, in this review we will focus on the pathogenic role -if any- of autoimmune responses against liver-related CYPs in autoimmune hepatitis, HCV infection, APS-1 and drug-induced autoimmunity. Learning more about the specificity of antibody responses against these enzymes may help us better understand the mechanisms underlying liver autoimmunity and may facilitate the development of therapeutic and preventive interventions.
Medical nutrition therapy (MNT) is an indisputable component of the multidisciplinary therapeutic approach in rheumatoid arthritis (RA). Previous research has suggested that in chronic disease where ...nutrition is an important effector of prognosis, healthy dietary choices might take an unhealthy turn, with patients developing disordered eating in the form of orthorexia nervosa (ON). ON is characterized by a pathological preoccupation with "healthy", "pure" eating, associated with restrictive dietary patterns, nutrient deficiencies and worsening disease outcomes. The aim of the present cross-sectional study was to evaluate ON tendencies in a sample of adult patients with RA. A total of 133 patients with RA were recruited, and completed the ORTO-15 questionnaire for the assessment of ON tendencies. Most of the patients were overweight/obese (53.4%). The results revealed ON tendencies in the sample, with the median ORTO-15 score reaching 36 (IQR: 33-39). Greater ON tendencies were associated with the female gender, and lowered ON tendencies with increasing age and body mass index. The present findings highlight the need for health professional awareness regarding the problem of ON in patients with RA and the importance of screening patients.
Background: Antinuclear antibodies (ANA) giving a rim-like/membranous (RL/M) or a multiple nuclear dot (MND) pattern are highly specific for primary biliary cirrhosis (PBC). Aim and subjects: To ...assess the prevalence of PBC specific ANAs, their Ig isotype, and their clinical significance in 90 PBC patients from Greece and Spain. Twenty eight patients with chronic hepatitis C, 23 patients with systemic lupus erythematosus, and 17 healthy subjects were studied as controls. Methods: PBC specific ANA reactivity was tested by indirect immunofluorescence using HEp2 cells as substrate and individual Ig class (IgG, IgA, IgM) and IgG subclass (IgG1, IgG2, IgG3, IgG4) specific antisera as revealing reagents. Results: Fourteen of 90 (15.6%) PBC patients had PBC specific ANA reactivity when an anti-IgG (total) antiserum was used as the revealing reagent while 58 (64.4%) were positive when specific antisera to each of the four IgG isotypes were used. The prevailing isotype was IgG3 for MND and IgG1 for RL/M. PBC patients with specific ANA, in particular of the IgG3 isotype, had significantly more severe biochemical and histological disease compared with those who were seronegative. None of the controls was positive. Conclusions: Disease specific ANA are present in the majority of patients with PBC when investigated at the level of immunoglobulin isotype. PBC specific ANA, in particular of the IgG3 isotype, are associated with a more severe disease course, possibly reflecting the peculiar ability of this isotype to engage mediators of damage.
Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic stroke. In this review, the epidemiology and pathophysiology of stroke in cancer patients is discussed, ...while providing vital information on the diagnosis and management of patients with cancer and stroke. Cancer may mediate stroke pathophysiology either directly or via coagulation disorders that establish a state of hypercoagulation, as well as via infections. Cancer treatment options, such as chemotherapy, radiotherapy and surgery have all been shown to aggravate the risk of stroke as well. The clinical manifestation varies greatly depending upon the underlying cause; however, in general, cancer-associated strokes tend to appear as multifocal in neuroimaging. Furthermore, several serum markers have been identified, such as high D-Dimer levels and fibrin degradation products. Managing cancer patients with stroke is a delicate matter. The cancer should not be considered a contraindication in applying thrombolysis and recombinant tissue plasminogen activator (rTPA) administration, since the risk of hemorrhage in cancer patients has not been reported to be higher than that in the general population. Anticoagulation, on the contrary, should be carefully examined. Clinicians should weigh the benefits and risks of anticoagulation treatment for each patient individually; the new oral anticoagulants appear promising; however, low-molecular-weight heparin remains the first choice. On the whole, stroke is a serious and not a rare complication of malignancy. Clinicians should be adequately trained to handle these patients efficiently.
Summary
Background
Anti‐C1q autoantibodies (autoAbs) are associated with systemic lupus erythematosus (SLE), but their presence in other rheumatic diseases has not been adequately investigated.
...Objectives
We aimed to assess anti‐C1q autoAbs and circulating immune complexes (CICs) in systemic sclerosis (SSc).
Methods
In total 124 patients with SSc were studied; 106 were female and the median age was 59·4 years (range 25–81·4). Overall 75 (60·5%) had limited cutaneous SSc and 49 (39·5%) had diffuse cutaneous SSc. Also included were 25 patients with Sjögren syndrome (SjS), 29 with rheumatoid arthritis (RA), 38 with SLE and 53 healthy controls. Enzyme‐linked immunosorbent assays with high‐ and low‐salt buffers were used to measure anti‐C1q antibodies and CICs. The former allows only anti‐C1q antibody binding to C1q and the latter also allows IgG Fc to bind to C1q.
Results
Anti‐C1q antibodies were present in 20 of 124 (16·1%) patients with SSc: five had high levels (> 80 RU mL−1) and 10 (50%) had moderate levels (40–80 RU mL−1). Anti‐C1q antibodies were also present in one of 25 (4%) patients with SjS, one of 29 (3%) with RA (P < 0·05 for both) and three of 53 (6%) healthy controls (P < 0·01). Anti‐C1q antibodies were detected in 13 of 38 (34%) patients with SLEs. Anti‐C1q antibodies were more frequent in male than female patients with SSc (P = 0·005); this association remained after multivariate regression analysis. Anti‐C1q antibody level was the most important factor in predicting the presence of pulmonary fibrosis, and the second most important in predicting pulmonary arterial hypertension. Fourteen patients with SSc (11·3%) had CICs.
Conclusions
Anti‐C1q autoAbs were frequently detected in patients with SSc, and their high levels predict the co‐occurrence of pulmonary fibrosis or pulmonary arterial hypertension.
What's already known about this topic?
In patients with systemic sclerosis (SSc) many autoantibodies are detected.
Some autoantibodies in SSc are likely to be involved in the pathogenesis of the disease.
Studies have reported complement activation in SSc.
Studies investigating antibodies against C1q, which are frequently detected in systemic lupus erythematosus, have not been performed in SSc.
What does this study add?
Anti‐C1q antibodies are frequently detected in patients with SSc.
Anti‐C1q antibody level is the most important risk factor for the presence of lung fibrosis.
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Autoimmune rheumatic diseases (AIRDs) constitute a set of connective tissue disorders and dysfunctions with akin clinical manifestations and autoantibody responses. AIRD treatment is based on a ...comprehensive approach, with the primary aim being achieving and attaining disease remission, through the control of inflammation. AIRD therapies have a low target specificity, and this usually propels metabolic disturbances, dyslipidemias and increased cardiovascular risk. Ceramides are implicated in inflammation through several different pathways, many of which sometimes intersect. They serve as signaling molecules for apoptosis, altering immune response and driving endothelial dysfunction and as regulators in the production of other molecules, including sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P). With lipid metabolism being severely altered in AIRD pathology, several studies show that the concentration and variety of ceramides in human tissues is altered in patients with rheumatic diseases compared to controls. As a result, many in vitro and some in vivo (animal) studies research the potential use of ceramides as therapeutic targets in rheumatoid arthritis (RA), ankylosing spondylitis, systemic lupus erythematosus, fibromyalgia syndrome, primary Sjögren's syndrome, systemic sclerosis, myositis, systemic vasculitis and psoriatic arthritis. Furthermore, the majority of ceramide synthesis is diet-centric and, as a result, dietary interventions may alter ceramide concentrations in the blood and affect health. Subsequently, more recently several clinical trials evaluated the possibility of distinct dietary patterns and nutrients to act as anti-ceramide regimes in humans. With nutrition being an important component of AIRD-related complications, the present review details the evidence regarding ceramide levels in patients with AIRDs, the results of anti-ceramide treatments and discusses the possibility of using medical nutritional therapy as a complementary anti-ceramide treatment in rheumatic disease.
CD4 T lymphocytes constitutively expressing the IL-2-receptor α-chain (CD25) (T-regs) are central to self-tolerance maintenance, preventing the proliferation and effector function of autoreactive ...T-cells. In autoimmune hepatitis T-regs are defective in number but maintain the ability to suppress IFNγ production by CD4+CD25− T-cells. We have studied the ability of CD4+CD25+ (T-regs) to regulate proliferation and cytokine production by CD8 T-cells in patients with autoimmune hepatitis at diagnosis and during remission.
Twenty-five patients were studied. T-regs were purified from PBMCs by CD4 negative selection followed by CD25 positive selection, using immunomagnetic beads. The ability of T-regs to suppress CD8 T-cell proliferation was assessed by
3H-thymidine incorporation; their ability to regulate cytokine production by intracellular cytokine staining.
We found that T-regs are unable to regulate CD8 T-cell proliferation and cytokine production in patients studied at diagnosis, while they suppress CD8 T-cell proliferation and induce an elevation of IL-4 producing CD8 T-cells in patients during drug-induced remission.
Inability of T-regs to regulate CD8 T-cell function at diagnosis may contribute to the initiation of autoimmune liver damage. The ability of T-regs to regulate CD8 proliferation and IL-4 production during drug-induced remission suggests a role for immunosuppressive treatment at reconstituting T-regs function.
CD4+ lymphocytes constitutively expressing the IL-2-receptor α-chain (CD25) regulate the activation of CD4 and CD8 autoreactive T-cells by suppressing their proliferation and effector function. The ...aim of this study is to: (1) measure the percentage of CD4+CD25+ T-cells (T-regs) in patients with autoimmune liver disease at presentation and during remission, (2) correlate their frequency with disease activity, (3) determine their ability to expand and (4) to inhibit interferon-gamma (IFNγ) production by CD4+CD25− T-cells.
41 patients were studied. Percentage of T-regs was determined on peripheral blood mononuclear cells (PBMCs) by triple-colour flow cytometry; their ability to expand by exposing PBMCs to a T-cell expander (CD3/CD28 Dynabeads); their immunoregulatory function by measuring their ability to suppress IFNγ production by CD4+CD25− T-cells.
T-regs were significantly less in patients than in controls, and at diagnosis than during remission. Their percentage was inversely correlated with titres of anti-liver kidney microsomal and soluble liver antigen autoantibodies. T-regs ability to expand was significantly lower in patients than in controls, but that to suppress IFNγ production by CD4+CD25− T-cells was maintained.
Decreased T-regs numbers and ability to expand may favour the emergence of liver-targeted autoimmunity, despite preserved suppressor function. Treatment should aim at increasing T-regs number.
Background: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic disease characterized by the presence of antibodies directed predominantly against the E2 subunit of the pyruvate ...dehydrogenase complex (PDC-E2). What provokes tolerance breakdown in PBC remains to be established, though there is evidence to indicate that microbes may induce anti-mitochondrial antibodies (AMA) through a mechanism of molecular mimicry. Methods: Having found that urease beta (UREB)
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antigen of Helicobacter pylori (HELPY) shares extensive (87%) similarity with PDC-E2
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, the major mitochondrial autoepitope, it was hypothesized that this would also lead to cross-reactivity. The UREB PDC-E2 mimics were thus constructed and tested by ELISA in 112 PBC patients and 114 controls. Results: Reactivity to PDC-E2
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was found in 104 patients but to UREB
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in only 2. In these two patients, the double reactivity was not cross-reactive. The lack of surface antibody accessibility to UREB
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, as demonstrated through three-dimensional model prediction analysis, may explain this unexpected finding. There was some speculation on whether HELPY UREB
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might act as a cross-reactive CD4 T-cell epitope. All seven PBC patients, tested in a standard proliferation assay against PDC-E2
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, gave a positive response. All seven were unresponsive to HELPY UREB
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. The pattern of reactivity to HELPY antigens by immunoblot was similar between anti-PDC-E2-positive and negative PBC cases, as well as between PBC patients and controls. Conclusion: Contrary to common belief, extensive sequence homology (molecular mimicry) between self and microbe does not necessarily result in cross-reactivity. It is therefore likely that, when present, cross-reactivity between self and microbes is of biological importance.
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