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Body fat has regulatory functions through producing cytokines and adipokines whose role in the pathogenesis of systemic sclerosis (SSc) is currently emerging. Changes in body mass, either over‐ or underweight, entail a dysregulation of the cytokine/adipokine network that may impact upon SSc disease activity. We evaluated serum levels of adipokines and cytokines in SSc patients and correlated them to clinical features and body mass index (BMI) categories. The study included 89 SSc patients and 26 healthy donors (HD). Serum levels of adiponectin, leptin, resistin, visfatin, tumor necrosis factor (TNF)‐α, interferon (IFN)‐γ, interleukin (IL)‐2, IL‐10 and IL‐17A were measured by multiplex immunoassay and correlated to BMI and disease‐specific features. Student’s t‐test or analysis of variance (ANOVA) were used for comparisons between groups. Spearman’s or Pearson’s tests were used for correlation analysis. Serum levels of TNF‐α, IL‐2, leptin and resistin were significantly higher in SSc than in HD. Leptin levels were significantly higher in interstitial lung disease (ILD)‐ and pulmonary arterial hypertension (PAH)‐SSc subgroups. The highest levels of IL‐17A, IL‐2, IL‐10, leptin and visfatin were detected in SSc patients with obesity (p, Adpokines and cytokines are regulated in Systemic Sclerosis across BMI categories. Leptin levels raise with BMI increase, but did not seem to be correlated with disease activity. Interestingly, TNFα levels were lowest in underweight patients suggesting its possible role in SSc associated sarcopenia.

Summary The objective of this study was to evaluate the predictive role of CD21low B cells as markers of new digital ulcers in systemic sclerosis patients. Peripheral blood B cell subpopulations and clinical assessments have been evaluated in 74 systemic sclerosis patients at baseline and after a 12‐month follow‐up. After a 12‐month follow‐up, 23 (31.1%) systemic sclerosis patients developed new digital ulcers. The median percentage of CD21low B cells was significantly higher in patients with than without new digital ulcers [10.1 (4.3–13.6) versus 4.8 (3.5–7.4); p, CD21low B cells are increased in SSc patients. CD21low B cells are higher in SSc patients with major vascular complications. CD21low B cells may be a possible predictive marker of new DUs.

Summary Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN‐stimulating pathways, but also from decreased activation of type I IFN‐inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR‐induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired FcγR‐mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR‐induced interleukin (IL)‐1β production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR‐mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL‐1β. This dysregulation may contribute to the development of nephritis in SLE patients., In healthy individuals, immune complexes stimulate FcγRIIa, which signals through two parallel pathways: an inhibitory pathway that suppresses type I IFN and is Syk‐independent, and an activating pathway which amplifies the production of proinflammatory cytokines such as IL‐1β and is Syk‐dependent. In lupus nephritis patients these pathways are dysregulated, leading to (over)activation of the Syk‐dependent pathway (resulting in more IL‐1β), while the Syk‐independent pathway is dysfunctional (resulting in higher type I IFN levels).

In this study, IgG‐autoantibodies associated with autoimmune hepatitis and primary biliary cholangitis (PBC) were found in a considerable proportion of well‐characterized patients diagnosed with primary Sjögren’s syndrome and systemic lupus erythematosus (SLE) but without known liver involvement or autoimmune liver disease (AILD). PBC‐associated autoantibodies have previously not been reported in a substantial percentage of cases with SLE. However, the association between autoantibody findings and AILD was poor as no significant difference in liver enzymes was observed between AILD‐associated autoantibody negative and positive patients., Summary Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjögren’s syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver–kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti‐nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD‐associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2·9%) and three pSS (2·6%) cases were diagnosed with AILD. Among SLE‐cases without known AILD (n = 272), 26 (9·6%) had PBC‐associated autoantibodies, 15 (5·5%) AIH‐associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC‐associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7·4%), while one fulfilled the diagnostic PBC‐criteria. AMA‐M2 detected by immunoblot was the most common PBC‐associated autoantibody in SLE (20 of 272, 7·4%). The prevalence of SMA (4·4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH‐criteria. The patient with combined AIH/PBC‐serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8·1%) had PBC‐associated, 12 (10·8%) AIH‐associated autoantibodies and two overlapped. PBC‐associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD‐associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody‐negative and ‐positive patients.

Anti‐phospholipid syndrome (APS) is a systemic autoimmune disorder defined by the simultaneous presence of vascular clinical events, pregnancy morbidity and anti‐phospholipid antibodies (aPL). In clinical practice, it is possible to find patients with APS who are persistently negative for the routine aPL tests (seronegative APS; SN‐APS). Recently, the identification of aPL immunoglobulin (Ig)A and/or anti‐β2‐glycoprotein‐I (β2‐GPI) IgA was shown to represent a further test in SN‐APS patients. In this study we analyzed the presence of anti‐vimentin/cardiolipin (aVim/CL) IgA in a large cohort of patients with SN‐APS, evaluating their possible association with clinical manifestations of the syndrome. This study includes 60 consecutive SN‐APS patients, 30 patients with APS and 40 healthy donors. aVim/CL IgA were detected by enzyme‐linked immunosorbent assay (ELISA). Results show that 12 of 30 APS patients (40%) and 16 of 60 SN‐APS patients (26.7%) resulted positive for aVim/CL IgA. Interestingly, SN‐APS patients who tested positive for aVim/CL IgA showed a higher prevalence of arterial thrombosis (p = 0.017, likelihood positive ratio = 5.7). This study demonstrates for the first time, to our knowledge, the presence of aVim/CL IgA in sera of patients with APS. In particular, they revealed a potential usefulness in identification of a significant proportion of SN‐APS patients. Moreover, as patients tested positive for aVim/CL IgA reported a high likelihood ratio to have the clinical features of APS, this test may be considered a suitable approach in the clinical evaluation of SN‐APS., This study demonstrates the presence of aVim/CL IgA in patients with APS. They revealed potential usefulness in the identification of a significant proportion of ‘seronegative’ APS patients (SN‐APS). Patients tested positive for aVim/CL IgA showed a higher prevalence of arterial thrombosis, suggesting that this test may be considered a suitable approach in the evaluation of SN‐APS patients.

This study used recently developed, more specific islet autoantibody tests, to characterise differences in humoral autoimmunity between two childhood general population cohorts, from Lithuania and England, in greater detail. The new data support our previous observation that certain aspects of the autoantibody profile associated with more rapid progression, including responses related to IA‐2A, are different in Lithuanian compared with English schoolchildren., Summary During a 15‐year period, the incidence of type 1 diabetes has doubled in Lithuania, while increasing by a third in England; however, England still has a higher incidence. Analysis of sera collected from non‐diabetic schoolchildren from Lithuania and England more than 20 years ago showed a similar number of multiple autoantibody‐positive schoolchildren between the populations, but a higher prevalence of islet antigen‐2 autoantibodies (IA‐2A) in English schoolchildren. We aimed to use recently developed, more specific islet autoantibody tests to characterize differences in humoral autoimmunity between these two general population cohorts in greater detail. Samples from 88 Lithuanian and 133 English schoolchildren previously found islet autoantibody‐positive were selected for measurement of additional islet autoantibodies by radioimmunoassay. Samples were tested for autoantibodies to zinc transporter 8 (ZnT8A), GAD (96–585), the protein tyrosine phosphatase region of islet antigen‐2 (PTPA) and the related IA‐2βA, while autoantibodies to IA‐2A were reassayed using the current harmonized method. IA‐2‐related autoantibodies PTPA (0·13 versus 0·45%, P = 0·027) and IA‐2βA (0 versus 0·35%, P

Our goal was to explore immunoserological relations between IgM and IgG isotypes of natural autoantibodies (nAAbs) and pathogen (or vaccine)‐induced or disease‐related antibodies in systemic autoimmune diseases (SAD); systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA). The found significant associations between IgG isotype nAbs and specific humoral antibodies may underscore the immune response‐inducible nature of the diseases investigated, and may corroborate the notion that nAbs can act as a mediator between the innate‐like and the adaptive arms of the immune system .The relationship between protective anti‐dsDNA IgM and the IgM isotype of anti‐F4 and anti‐CS may provide immuno‐serological evidence for the beneficial roles of nAAbs in SLE patients., Summary Infection or vaccine‐induced T cell‐dependent immune response and the subsequent high‐affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease‐specific antibodies has not been thoroughly investigated. Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine‐induced and disease‐related autoantibody levels in systemic autoimmune diseases (SAD). A previously described indirect enzyme‐linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti‐CS) and F4 fragment (anti‐F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups. Anti‐measles IgG and anti‐dsDNA IgG/IgM autoantibodies were measured using commercial and in‐house indirect ELISA tests. In all SAD groups the anti‐measles IgG‐seropositive cases showed significantly higher anti‐CS IgG titers (P = 0·011). In anti‐dsDNA IgG‐positive SLE patients, we detected significantly higher levels of anti‐CS and anti‐F4 IgG nAAbs (P = 0·001 and

AIMS: Multiple sclerosis (MS) is a chronic neurodegenerative disease characterised by demyelination, inflammation and neurodegeneration throughout the central nervous system. Although spinal cord pathology is an important factor contributing to disease progression, few studies have examined MS lesions in the spinal cord and how they differ from brain lesions. Here we have compared brain and spinal cord white and grey matter from MS and control tissues focussing on small heat shock proteins (HSPB) and HSP16.2.METHODS: Western blotting was used to examine protein levels of HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 in brain and spinal cord from MS and age-matched non-neurological controls. Immunohistochemistry was used to examine expression of the HSPs in MS spinal cord lesions and controls. Expression levels were quantified using ImageJ.RESULTS: Western blotting revealed significantly higher levels of HSPB1, HSPB6 and HSPB8 in MS and control spinal cord compared to brain tissues. No differences in HSPB5 and HSP16.2 protein levels were observed although HSPB5 protein levels were higher in brain WM versus GM. In MS spinal cord lesions, increased HSPB1 and HSPB5 expression was observed in astrocytes, and increased neuronal expression of HSP16.2 was observed in normal appearing grey matter and type 1 grey matter lesions.CONCLUSIONS: The high constitutive expression of several HSPBs in spinal cord and increased expression of HSPBs and HSP16.2 in MS illustrate differences between brain and spinal cord in health and upon demyelination. Regional differences in HSP expression may reflect differences in astrocyte cytoskeleton composition and influence inflammation, possibly affecting the effectiveness of pharmacological agents. This article is protected by copyright. All rights reserved.

Summary The aim of this study was to evaluate secretory antibodies to citrullinated proteins (ACPA) in plasma and immunoglobulin (Ig)A ACPA in saliva from patients with rheumatoid arthritis (RA) and their unaffected first‐degree relatives (FDRs). Patients with RA (n = 194) and first‐degree relatives unaffected by RA (n = 191) were recruited for analysis of secretory antibodies to second‐generation cyclic citrullinated peptides (anti‐CCP) in plasma. From a subpopulation (25 RA patients, 21 first‐degree relatives and 11 controls), saliva samples were obtained for IgA anti‐CCP analysis. The presence of secretory ACPA was compared between subject categories, and related to genetic and environmental risk factors. Secretory ACPA occurred in 37 (19%) plasma samples from patients with RA, but only in two (1%) of FDRs. IgA ACPA in saliva was found in three of 25 (12%) patients with RA, but not in any of the 21 FDRs (, We hypothesized that mucosa‐associated anti‐citrullinated protein antibodies (ACPA) would be increased in first‐degree relatives to rheumatoid arthritis (RA) patients, as mucosal involvement has been suggested in early steps of RA pathogenesis and FDRs are at increased risk of developing the disease. However, circulating secretory ACPA and salivary IgA ACPA were rare in FDRs despite substantial occurrence in RA patients. These results do not support mucosal ACPA production as early steps of RA development but highlight the need for longitudinal studies of at‐risk populations.

Summary There have been many studies on the mechanisms of internalization of DNA–anti‐DNA immune complexes by cells, including the one used for rheumatoid factor‐expressing mouse B cells. In parallel, studies on the role of intracellular DNA sensors in the pathogenesis of systemic lupus erythematosus (SLE) have been conducted, including the one using a mouse model lacking one of the sensors. These and other data have established a framework for understanding the pathogenic role of anti‐DNA antibodies, but studies on normal cells are limited. Here, we used the monoclonal anti‐dsDNA antibody 2C10, 2‐kbp dsDNA and healthy human peripheral blood mononuclear cells (PBMCs) to test whether and how 2C10 and/or DNA cause pathology in normal cells. We found that on culture with PBMCs, 2C10 preferentially entered monocytes and that DNA enhanced this internalization. In contrast, DNA alone was not significantly internalized by monocytes, but 2C10 facilitated its internalization. This was suppressed by cytochalasin D, but not by methyl‐β‐cyclodextrin, chloroquine or an Fc blocker, suggesting the involvement of macropinocytosis in this process. Internalization of 2C10 and DNA together resulted in production of interferon (IFN)‐α, IFN‐γ, tumor necrosis factor (TNF)‐α, monocyte chemoattractant protein‐1 (MCP‐1), interleukin (IL)‐1β, IL‐6, IL‐10 and IL‐33 by PBMCs. Cytokine production was suppressed by chloroquine and shikonin, but not by RU.521, suggesting dependence on activation of the Toll‐like receptor (TLR)‐9 and absent in melanoma 2 (AIM‐2) pathways. These results established a simple model to demonstrate that anti‐DNA antibodies can cause dysregulation of cytokine network mimicking systemic lupus erythematosus in culture of normal PBMCs, and emphasize again the importance of maintaining anti‐DNA antibodies at low levels by treatment., Fluorescence‐labeled DNA (D) entered normal monocytes with the help of anti‐DNA antibody 2C10 (2).

Summary Ubiquitin is highly conserved across eukaryotes and is essential for normal eukaryotic cell function. The bacterium Bacteroides fragilis is a member of the normal human gut microbiota, and the only bacterium known to encode a homologue of eukaryotic ubiquitin. The B. fragilis gene sequence indicates a past horizontal gene transfer event from a eukaryotic source. It encodes a protein (BfUbb) with 63% identity to human ubiquitin which is exported from the bacterial cell. The aim of this study was (i) to determine if there was antigenic cross-reactivity between B. fragilis ubiquitin and human ubiquitin and (ii) to determine if humans produced antibodies to BfUbb. Molecular model comparisons of BfUbb and human ubiquitin predicted a high level (99·8% confidence) of structural similarity. Linear epitope mapping identified epitopes in BfUbb and human ubiquitin that cross-react. BfUbb also has epitope(s) that do not cross-react with human ubiquitin. The reaction of human serum (n = 474) to BfUbb and human ubiquitin from the following four groups of subjects was compared by enzyme-linked immunosorbent assay (ELISA): (1) newly autoantibody-positive patients, (2) allergen-specific immunoglobulin (Ig)E-negative patients, (3) ulcerative colitis patients and (4) healthy volunteers. We show that the immune system of some individuals has been exposed to BfUbb which has resulted in the generation of IgG antibodies. Serum from patients referred for first-time testing to an immunology laboratory for autoimmune disease are more likely to have a high level of antibodies to BfUbb than healthy volunteers. Molecular mimicry of human ubiquitin by BfUbb could be a trigger for autoimmune disease.