Elevated Levels Of Autoantibodies Research Articles

The Actin Cytoskeleton Controls FcgRIIB-Mediated Inhibition of B-Cell Signaling

Abstract FcgRIIB is a major inhibitory coreceptor of B cell receptor (BCR), and its deficiency leads to B cell autoimmunity. Upon colligated with the BCR by immune complexes (ICs), this coreceptor activates SH2-containing inositol-5 phosphatase (SHIP) and inhibits BCR clustering in lipid rafts. However, the molecular mechanisms underlying FcgRIIB-mediated inhibition of BCR activation remain elusive. This study reveals a critical role of the actin cytoskeleton in FcgRIIB-mediated inhibition. Upon interacting with ICs tethered to lipid bilayers, an actomyosin ring is quickly formed surrounding the B cell membrane region interacting with the lipid bilayer (contact zone). Perturbing the actomyosin ring, by myosin inhibitors or B cell-specific gene knockout of non-muscle myosin IIA (NMIIA) or neuronal Wiskott-Aldrich syndrome protein (N-WASP), releases B cell spreading, BCR clustering and signaling from the inhibition by FcgRIIB. Using conditional gene knockout mice, we further show that NMIIA is recruited to the B cell contact zone in an SHIP-dependent manner, while N-WASP-mediated actin remodeling organizes NMIIA and actin into a ring. Surprisingly, WASP-mediated actin dynamics is required for the FcgRIIB-induced activation of SHIP but not the formation of the actomyosin ring. Our results suggest that FcgRIIB-triggered signaling induces unique actin remodeling involving NMII, WASP, and N-WASP, which limits B cell morphological changes and BCR lateral mobility and enhances the activation of inhibitory signaling. These data potentially provide a mechanistic explanation for the elevated autoantibody levels caused by WASP or N-WASP deficiency.

BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis.

Tissue-specific immune responses play an important role in the pathology of autoimmune diseases. In systemic lupus erythematosus, deposits of IgG-immune complexes and the activation of complement in the kidney have long been thought to promote inflammation and lupus nephritis. However, the events that localize cells in non-lymphoid tertiary organs and sustain tissue-specific immune responses remain undefined. In this manuscript, we show that BAFF promotes events leading to lupus nephritis. Using an inducible model of systemic lupus erythematosus, we found that passive transfer of antinucleosome IgG into AID-/-MRL/lpr mice elevated autoantibody levels and promoted lupus nephritis by inducing BAFF production in the kidneys, and the formation of renal tertiary lymphoid structures (TLSs). Reducing BAFF in vivo prevented the formation of TLSs and lupus nephritis; however, it did not reduce immune cell infiltrates, or the deposits of IgG and complement in the kidney. Mechanistically, lowering BAFF levels also diminished the number of T cells positioned inside the glomeruli and reduced inflammation. Thus, BAFF plays a previously unappreciated role in lupus nephritis by inducing renal TLSs and regulating the position of T cells within the glomeruli.

Increased Interleukin-17F is Associated with Elevated Autoantibody Levels and More Clinically Relevant Than Interleukin-17A in Primary Sjögren's Syndrome.

Th17 related immune response is pathogenic in primary Sjögren's syndrome (pSS). However, the role of IL-17F, one potent inflammatory member of IL-17 family cytokines in pSS, has not been specifically defined. We recruited one hundred and nine pSS patients and forty-two healthy controls and their serum levels of IL-17A and IL-17F were determined by multiplex cytokine assays. White blood cell, red blood cell, neutrophil, lymphocyte, IgM, IgG, C3, C4, RF, ANA, anti-SSA antibody, and anti-SSB antibody were measured by standard laboratory techniques. EULAR Sjögren's syndrome disease activity index (ESSDAI) score was also evaluated accordingly. We found that IL-17F was significantly increased in pSS patients. Elevated levels of IL-17F were associated with increased IgG and IgM, higher titers of ANA and anti-SSA antibodies, and reduction of C3 and C4. Patients with higher disease activity also showed higher serum IL-17F levels. However, serum IL-17A was only increased in patients with longer disease duration and showed few correlation with clinical and laboratory features in pSS patients. In conclusion, IL-17F was correlated with increased autoantibody levels and disease activity in pSS and is more clinically relevant than IL-17A.

Autoantibody profile, disease activity and organ involvement in Iranian systemic lupus erythematosus patients

Autoantibodies have been implicated with increased risk of organ involvement in systemic lupus erythematosus (SLE). In the present study, we looked for autoantibody profiles and their association with clinical symptoms in a group of Iranian patients with SLE. In this study, 98 lupus patients (78 females and 20 males) were evaluated for the presence of autoantibodies against nRNP/Sm, Sm, SSA, Ro52, SSB, Scl-70, Jo-1, CENP B, nucleosomes, histones and Rib-P protein using immunoblotting technique. Anti-dsDNA was the most prevalent autoantibody (69.1%). The increased amount of autoantibodies, of the affected organs, and presence of anti-histone and anti-dsDNA correlated with disease activity. In the SLE patients with renal involvement, presence of anti-nucleosome (54.8% vs. 39.4%, P= 0.04) and decreased levels of anti-SSB (14.3% vs. 26.3%, P= 0.007) were significantly different campared with patients without renal involvement. Our results showed that elevated levels of autoantibodies including anti-dsDNA and anti-histone, and increasing number of involved organs, could be used as predictors for assessment of disease activity in patients with lupus. In addition, the increased levels of anti-nucleosome and the lower occurrence of anti-SSB could be used in the verification of renal damage.

Salvianolic acid A alleviates renal injury in systemic lupus erythematosus induced by pristane in BALB/c mice

The purpose of this study was to investigate the effects of salvianolic acid A (SAA) in systemic lupus erythematosus (SLE) induced by pristane in BALB/c mice. Lupus mice were established by confirming elevated levels of autoantibodies and IL-6 after intraperitoneal injection of pristane. Mice were then treated with daily oral doses of SAA for 5 months in parallel with mice treated with prednisone and aspirin as positive controls. The levels of autoantibodies were monitored at monthly intervals and nephritic symptoms observed by hematoxylin and eosin (H&E) and periodic acid–Schiff (PAS) staining. Western blot analysis of renal tissue was also employed. SAA treatment caused a significant reduction in the levels of anti-Sm autoantibodies and reduced renal histopathological changes and pathological effects. SAA treatment also significantly inhibited the phosphorylation of IKK, IκB and NFκB in renal tissues of lupus mice. In conclusion, the results suggest that SAA alleviates renal injury in pristane-induced SLE in BALB/c mice through inhibition of phosphorylation of IKK, IκB and NFκB.

Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity

Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3-/- mice. Although Neil3-/- mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3-/- mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity.

Elevated IgA Plasmablast Levels in Subjects at Risk of Developing Rheumatoid Arthritis.

The disease process in rheumatoid arthritis (RA) starts years before the clinical diagnosis is made, and elevated levels of disease-specific autoantibodies can be detected during this period. Early responses to known or novel autoantigens likely drive the eventual production of pathogenic autoimmunity. Importantly, the presence of disease-specific autoantibodies can identify individuals who are at high risk of developing RA but who do not currently have arthritis. The goal of the current study was to characterize plasmablasts from individuals at risk of developing RA. We investigated antibody-secreting plasmablasts derived from a well-characterized cohort of individuals who were at risk of developing RA, based on RA-related serum autoantibody positivity, as compared to patients with early (<1 year) seropositive RA as well as healthy control subjects. The plasmablast antibody repertoires of at-risk subjects were analyzed using DNA barcode-based methods with paired heavy- and light-chain gene sequencing. Cells were single-cell sorted, the cell- and plate-specific DNA barcodes were sequentially added, and next-generation sequencing was performed. Total plasmablast levels were similar in the antibody-positive (1%) and control (0.4-1.6%) groups. However, increased frequencies of IgA+ versus IgG+ plasmablasts were observed in the antibody-positive group (39% IgA+ and 37% IgG+) as compared to other groups (1-9% IgA+ and 71-87% IgG+). Paired antibody sequences from antibody-positive subjects revealed cross-isotype clonal families and similar sequence characteristics in the IgA and IgG plasmablast repertoires. Antibody-positive individuals also demonstrated elevated serum levels of IgA isotype anti-cyclic citrullinated peptide 3 antibodies. The IgA plasmablast dominance in these antibody-positive individuals suggests that a subset of RA-related autoantibodies may arise from mucosal immune responses and may be involved in early disease pathogenesis in individuals who are at risk of developing RA.

Autoantibodies against tumor-associated antigens in the early detection of lung cancer

ObjectivesAutoantibodies against tumor-associated antigens (TAAs) identified in patients with advanced lung cancer may be detected in subjects with early lung cancer or even predate the diagnosis. The purpose of this study is to address the temporal relationship between lung cancer development and serum autoantibody response. Materials and methodsTwo cohorts of patients with newly diagnosed lung cancer were included. The first cohort included 90 sera from patients with lung cancer (Stages I–III) and 89 normal control sera. In the second cohort, 93 serial serum samples from 25 patients with CT-scan screen-detected stage I lung cancer were collected before the diagnosis of lung cancer (average 32 months) and 56 controls were matched on age, gender, and smoking. Autoantibody levels were measured by immunoassay. ResultsMeasurement of autoantibodies against seven TAAs (14-3-3ζ, c-Myc, MDM2, NPM1, p16, p53 and cyclin B1) individually could discriminate lung cancer patients from normal individuals in the first cohort and the area under curve (AUC) was 0.863 based on a panel of seven autoantibodies, with sensitivity of 68.9% and specificity of 79.5%. Autoantibodies in serial pre-diagnostic serum samples against the same panel of seven TAAs were detected prior to lung cancer diagnosis with sensitivity of 76.0% and specificity of 73.2% (AUC) (95%CI): 0.885 (0.797–0.973)). Elevated autoantibody levels could be detected greater than four years prior to lung cancer diagnosis. ConclusionA panel of seven TAAs may enhance the early detection of lung cancer, consistent with a humoral immune response to TAAs that can be detected months to years prior to the diagnosis.

Slamf6 negatively regulates autoimmunity

The nine SLAM family (Slamf) receptors are positive or negative regulators of adaptive and innate immune responses, and of several autoimmune diseases. Here we report that the transfer of Slamf6−/− B6 CD4+ T cells into co-isogenic bm12 mice causes SLE-like autoimmunity with elevated levels of autoantibodies. In addition, significantly higher percentages of Tfh cells and IFN-γ-producing CD4+ cells, as well as GC B cells were observed. Interestingly, the expression of the Slamf6-H1 isoform in Slamf6−/− CD4+ T cells did not induce this lupus-like phenotype. By contrast, Slamf1−/− or Slamf5−/− CD4+ T cells caused the same pathology as WT CD4+ T cells. As the transfer of Slamf [1+6]−/− or Slamf [1+5+6]−/− CD4+ T cells induced WT levels of autoantibodies, the presence of Slamf1 was requisite for the induction of increased levels of autoantibodies by Slamf6−/− CD4+ T cells. We conclude that Slamf6 functions as an inhibitory receptor that controls autoimmune responses.

Abnormal increase of neuronal precursor cells and exacerbated neuroinflammation in the corpus callosum in murine model of systemic lupus erythematosus.

Purpose: Systemic Lupus Erythematosus (SLE) is an autoimmune disease which is characterised by elevated levels of autoantibodies and cytokines in the body. Via alteration of the regulation of inflammation, damage to different organ systems, including the central nervous system (CNS), was found in SLE patients. Patients diagnosed with SLE were reported to suffer from different kinds of psychiatric signs and symptoms. As neurogenesis has been suggested to be a potential key player of psychiatric symptoms and emotional behavior disturbances, this study aims to investigate whether neurogenesis is altered in an animal model of SLE. Also, neuroinflammation was studied.Methods: Female NZB/W F1 mice were used as an animal model of SLE. Animals were divided into two groups: 1. pre-diseased mice (lupus-prone NZB/W F1 female mice, age 10–15 weeks, negative for proteinuria and with basal levels of serum anti-dsDNA autoantibodies) and 2. diseased mice (NZB/W F1 female mice, > 25 weeks of age, with elevated serum levels of anti-dsDNA autoantibodies and with persistent proteinuria of > 3 mg/ml for more than 2 weeks). Comparisons of the levels of neurogenesis and neuroinflammtion between two groups of mice were studied by the immunohistochemistry.Results: After the onset of SLE symptoms, a reduction of neurogenesis in the hippocampus was found, while there was a dramatic increase of doublecortin (DCX+) neuronal precursor cells in the corpus callosum (CC) and in the subventricular zone (SVZ). Meanwhile, exacerbated inflammation was present in the corpus callosum of the diseased mice, which was suggested by the increased number of GFAP+ cells and IBA-1+ cells.Conclusions: To the best of our knowledge, this is the first study showing an increase of neuronal precursor cells in the corpus callosum of the female NZB/W F1 mice. The present study suggests a coincidence but not a causal relationship between neurogenesis and neuroinflammation. The present results have also provided new insight showing that the altered neurogenesis and neuroinflammation may be a potential neurological mechanism for the cognitive and mood disturbance found in the SLE patients.

Seropositivity for West Nile Virus Antibodies in Patients Affected by Myasthenia Gravis.

BackgroundMyasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal muscles. Specific auto-antibodies against acetylcholine receptor (AChR) are present in the majority of MG patients, although the main cause behind its development still remains unclear. Recently MG development following West Nile virus (WNV) infection has been described in patients without any earlier evidence of MG. It is known that infectious agents trigger immune response and occasionally initiate autoimmune disease. WNV, the causative agent of both benign illness and neuroinvasive disease, has become endemic in many countries in all continents.MethodsIn the present study, 29 patients (15 males and 14 females, 19 - 78 years old) with confirmed diagnosis of MG and elevated levels of AChR autoantibodies were screened for the presence of serum anti-WNV antibodies and compared to a similar population affected by different autoimmune diseases. Indirect immunofluorescent antibody technique was used to evaluate the reaction of patients’ sera on cells infected by WNV.ResultsPositive fluorescent signals for anti-WNV IgG were obtained in 17% of MG patients, although no clinical manifestations related to WNV infection were reported. These results are in agreement with previous data and appear of great interest in the understanding of the pathogenic autoimmune mechanisms at the bases of MG development.ConclusionAs already observed in other human autoimmune diseases, pathogen-triggered autoimmunity could be involved in MG by breaking immunological self-tolerance through possible mechanisms of molecular mimicry between virus proteins and AChR subunits. In predisposed individuals, WNV infection could also represent an additional risk factor to initiate MG.

Elevated Levels of Plasma IgA Autoantibodies against Oxidized LDL Found in Proliferative Diabetic Retinopathy but Not in Nonproliferative Retinopathy.

Aims. This study investigated the association of autoantibodies binding to oxidized low-density lipoproteins (oxLDL) in diabetic retinopathy (DR). Methods. Plasma from 229 types 1 and 2 patients with DR including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) was analysed with ELISA-based assay to determine IgA, IgG, and IgM autoantibody levels binding to oxLDL. The controls were 106 diabetic patients without retinopathy (NoDR) and 139 nondiabetic controls (C). Results. PDR group had significantly higher IgA autoantibody levels than DME or NoDR: mean 94.9 (SD 54.7) for PDR, 75.5 (41.8) for DME (p = 0.001), and 76.1 (48.2) for NoDR (p = 0.008). There were no differences in IgG, IgM, or IgA that would be specific for DR or for DME. Type 2 diabetic patients had higher levels of IgA autoantibodies than type 1 diabetic patients (86.0 and 65.5, resp., p = 0.004) and the highest levels in IgA were found in type 2 diabetic patients with PDR (119.1, p > 0.001). Conclusions. IgA autoantibodies were increased in PDR, especially in type 2 diabetes. The high levels of IgA in PDR, and especially in type 2 PDR patients, reflect the inflammatory process and enlighten the role of oxLDL and its autoantibodies in PDR.

Изучение уровней нейротропных аутоантител у больных шизофренией

Plasma levels of IgG autoantibodies to the NMDA-receptors, human S-100 protein, and dopamine Type 2 receptors were detected in 26 males suffering from schizophrenia. Half of the patients had their levels of autoantibodies to the NMDA-receptors above average values, while in the rest of the group the antibody level was within norm. Following that, the patients were divided into two groups: Group 1 with a higher level of antibodies to the NMDA-receptors, Group 2 – with their normal levels of antibodies to the NMDA-receptor. The patients in the Group 1 also revealed significantly elevated levels of autoantibodies to the dopamine Type 2 receptors as well as to the S-100 protein in their blood plasma. Psychometric testing involving the PANSS scale showed that the positive symptoms’ values in the Group 1 were below those in the Group 2 while the negative symptoms’ values in the Group 1 were higher. Respectively, the composite index, which is determined as the difference between the positive and the negative scores, was lower in the Group 1 and higher in the Group 2.

Tyrosyl-tRNA Synthetase and its Separated Domains are Suppositional Components of Prostate Cancer Pathogenesis

Elevated levels of autoantibodies against tyrosyl-tRNA synthease and its separated fragments enriched with proinflammatory and angiogenic properties in sera of patients with prostate cancer were shown. In serum samples of patients the highest levels of autoantibodies against C-terminal domain were observed. Minimal autoreactivity among persons with oncopathology was shown against N-terminal domain of tyrosyl-tRNA synthetase.

Impact of the combined loss of BOK, BAX and BAK on the hematopoietic system is slightly more severe than compound loss of BAX and BAK.

It is well established that BAX and BAK play crucial, overlapping roles in the intrinsic pathway of apoptosis. Gene targeted mice lacking both BAX and BAK have previously been generated, but the majority of these animals died perinatally. BOK is a poorly studied relative of BAX and BAK that shares extensive amino acid sequence homology to both proteins, but its function remains largely unclear to date. To determine whether BOK plays an overlapping role with BAX and BAK, we utilized a hematopoietic reconstitution model where lethally irradiated wild type mice were transplanted with Bok−/−Bax−/−Bak−/− triple knockout (TKO) fetal liver cells, and compared alongside mice reconstituted with a Bax−/−Bak−/− double knockout (DKO) hematopoietic compartment. We report here that mice with a TKO and DKO hematopoietic system died at a similar rate and much earlier than control animals, mostly due to severe autoimmune pathology. Both TKO and DKO reconstituted mice also had altered frequencies of various leukocyte subsets in the thymus, bone marrow and spleen, displayed leukocyte infiltrates and autoimmune pathology in multiple tissues, as well as elevated levels of anti-nuclear autoantibodies. Interestingly, the additional deletion of BOK (on top of BAX and BAK loss) led to a further increase in peripheral blood lymphocytes, as well as enhanced lymphoid infiltration in some organs. These findings suggest that BOK may have some functions that are redundant with BAX and BAK in the hematopoietic system.

Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice

Siglec-G, a member of the sialic acid-binding Ig-like lectin (Siglec) family, is expressed on B cell and dendritic cell surfaces. It acts as an inhibitory coreceptor and modulates B cell activation, especially on B1 cells, as Siglec-G-deficient mice show mainly a B1 cell-restricted phenotype resulting in increased B1 cell numbers. Although higher B1 cell numbers are discussed to be associated with autoimmunity, loss of Siglec-G does not result in autoimmune disease in BALB/c mice. However, there is evidence from Siglec-G × CD22 double-deficient mice and Siglec-G(-/-) mice on an autoimmune-prone MRL/lpr background that Siglec-G is important to maintain tolerance in B cells. In this study, we analyzed the role of Siglec-G in induction and maintenance of B cell tolerance on C57BL/6 background and in the FcγRIIb-deficient background. We find that aging Siglec-G-deficient and Siglec-G × FcγRIIb double-deficient mice develop an autoimmune phenotype with elevated autoantibody levels and mild glomerulonephritis. Aging Siglec-G-deficient mice have elevated numbers of plasma cells and germinal center B cells, as well as a higher number of activated CD4 T cells, which likely all contribute to autoantibody production. Additional loss of the inhibitory receptor FcγRIIb in Siglec-G(-/-) mice does not result in exacerbation of disease. These results indicate that Siglec-G is important to maintain tolerance in B cells and prevent autoimmunity.

Sialic acid-binding immunoglobulin-type lectin H-positive plasmacytoid dendritic cells drive spontaneous lupus-like disease development in B6.Nba2 mice.

Patients with systemic lupus erythematosus (SLE) often present with elevated levels of interferon-α (IFNα) in serum. Plasmacytoid dendritic cells (pDCs) have been suggested to be the primary source of IFNα in SLE due to their capacity to produce high levels of IFNα. During viral infection, a subset of pDCs expressing sialic acid-binding immunoglobulin-type lectin H (Siglec H) produces the majority of pDC-derived IFNα. The aim of this study was to provide evidence that Siglec H-positive pDCs are pathogenic in the IFNα-dependent B6.Nba2 mouse model of lupus. B6.Nba2 blood dendritic cell antigen 2 (BDCA-2)-diphtheria toxin receptor (DTR)-transgenic (Tg) mice were treated intraperitoneally with DT 3 times weekly starting at 4 weeks or 12 weeks of age and analyzed at 12 weeks and 18 weeks of age, respectively. Lupus-like disease development was measured by the presence of elevated levels of autoantibodies in serum (as determined by enzyme-linked immunosorbent assay), increased expression of IFN-inducible genes (as determined by real-time reverse transcription-polymerase chain reaction), increased IgG immune complex deposition in kidney glomeruli (as determined by immunofluorescence staining), spontaneous lymphocyte activation, and differentiation of B cells into antibody-producing plasma cells (as determined by flow cytometry). B6.Nba2 mice in which Siglec H-positive pDCs were depleted for 6-8 weeks displayed reduced levels of IFNα-induced gene transcripts and decreased anti-chromatin autoantibody levels in serum, and significantly fewer activated splenic T cells and B cells, germinal center B cells, follicular helper T cells, and splenic plasma cells. In 18-week-old mice, IgG immune complex deposition in kidney glomeruli was similarly reduced. The development of lupus-like disease in congenic B6.Nba2 mice depends on Siglec H-positive pDCs. We suggest that depletion of Siglec H-positive pDCs represents a novel cellular target in SLE.

A possible association between elevated serum levels of brain-specific auto-antibodies and reduced plasma levels of docosahexaenoic acid in autistic children.

Polyunsaturated fatty acids (PUFAs) are not only essential for energy production, but they also exhibit a range of immunomodulatory properties that progress through T cell mediated events. Autoimmunity may have a pathogenic role in a subgroup of autistic children. This study is the first to investigate the relationship between serum levels of anti-myelin basic protein (anti-MBP) brain-specific auto-antibodies and reduced plasma levels of PUFAs in autistic children. Plasma levels of PUFAs (including linoleic, alphalinolenic, arachidonic "AA" and docosahexaenoic "DHA" acids) and serum anti-MBP were measured in 80 autistic children, aged between 4 and 12 years, and 80 healthy-matched children. Autistic patients had significantly lower plasma levels of PUFAs than healthy children. On the other hand, ω6/ω3 ratio (AA/DHA) was significantly higher in autistic patients than healthy children. Low plasma DHA, AA, linolenic and linoleic acids were found in 67.5%, 50%, 40% and 35%, respectively of autistic children. On the other hand, 70% of autistic patients had elevated ω6/ω3 ratio. Autistic patients with increased serum levels of anti-MBP auto-antibodies (75%) had significantly lower plasma DHA (P<0.5) and significantly higher ω6/ω3 ratio (P<0.5) than patients who were seronegative for these antibodies. In conclusions, some autistic children have a significant positive association between reduced levels of plasma DHA and increased serum levels of anti-MBP brain-specific auto-antibodies. However, replication studies of larger samples are recommended to validate whether reduced levels of plasma PUFAs are a mere association or have a role in the induction of the production of anti-MBP in some autistic children.

Elevated Levels of Autoantibodies against ATP2B4 and BMP-1 in Sera of Patients with Atherosclerosis-related Diseases

Background: Atherosclerosis-related life-style diseases such as cerebral infarction (CI), cardiovascular disease (CVD), diabetes mellitus (DM), and chronic kidney disease (CKD) are a serious problem in the recently aging society. The development of novel and sensitive diagnostic markers is necessary and expected for the early treatment. Methods and Results: Through the first screening by phage expression cloning, we identified ATPase, Ca++ transporting, plasma membrane 4 (ATP2B4) and bone morphogenetic protein 1 (BMP-1) as antigens recognized by IgG antibodies in the sera of patients with atherosclerosis. The presence of autoantibodies against these antigens in serum specimens was confirmed by Western blotting. We then compared serum antibody levels against recombinant ATP2B4 and BMP-1 proteins between healthy donors (HD) and patients with atherosclerotic diseases, such as CI, transient ischemic attack (TIA), CVD, DM, or CKD, by the Alpha (amplified luminescent proximity homogeneous assay)-LISA method. The results revealed that both antibody levels were significantly higher in patients with these diseases than in HD and exhibited most prominent differences in CKD vs. HD. Correlation analysis showed that both antibody levels were well correlated with the degree of artery stenosis, such as maximum intima-media thickness with some different patterns, i.e., anti-ATP2B4 antibody levels were related to hypertension, whereas anti-BMP-1 antibodies were related to smoking habits. Conclusions: The serum antibody levels against ATP2B4 and BMP-1 can be useful diagnostic markers for atherosclerosis and its related diseases caused by hypertension and smoking habits, respectively.

PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis.

Loss-of-function variants within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with increased risk for Crohn's disease (CD). A disturbed regulation of T helper (Th) cell responses causing loss of tolerance against self- or commensal-derived antigens and an altered intestinal microbiota plays a pivotal role in CD pathogenesis. Loss of PTPN2 in the T-cell compartment causes enhanced induction of Th1 and Th17 cells, but impaired induction of regulatory T cells (Tregs) in several mouse colitis models, namely acute and chronic dextran sodium sulfate colitis, and T-cell transfer colitis models. This results in increased susceptibility to intestinal inflammation and intestinal dysbiosis which is comparable with that observed in CD patients. We detected inflammatory infiltrates in liver, kidney, and skin and elevated autoantibody levels indicating systemic loss of tolerance in PTPN2-deficient animals. CD patients featuring a loss-of-function PTPN2 variant exhibit enhanced Th1 and Th17 cell, but reduced Treg markers when compared with PTPN2 wild-type patients in serum and intestinal tissue samples. Our data demonstrate that dysfunction of PTPN2 results in aberrant T-cell differentiation and intestinal dysbiosis similar to those observed in human CD. Our findings indicate a novel and crucial role for PTPN2 in chronic intestinal inflammation.