Systemic Autoimmune Manifestations Research Articles

Local and systemic autoimmune manifestations linked to hepatitis A infection.

Hepatitis A virus (HAV) represents a global burdening infectious agent causing in the majority of cases a self-limiting acute icteric syndrome, the outcome is related to the hepatic substrate and the potential pre-existing damage, whereas a plethora of extra-hepatic manifestations has also been reported. Despite the absence of post- HAV chronicity it has been associated with an additional burden on existing chronic liver diseases. Moreover, the induced immune response and the antigenic molecular mimicry are considered as triggering factors of autoimmunity with regional and distal impact. Diseases such as autoimmune hepatitis, Guillain-Barré syndrome, rheumatoid arthritis, Still's syndrome, Henoch-Schönlein purpura, autoimmune hemolytic anemia, antiphospholipid syndrome, systematic lupus erythematosus or cryoglobulinemic vasculitis have been described in patients with HAV infection. Although the exact mechanisms remain unclear, this review aims to accumulate and clarify the pathways related to this linkage.

Clinical Phenotype and Mechanisms of Leukopenia/Neutropenia in Patients with Primary Sjögren's Syndrome.

Sjögren’s syndrome (SS) is a chronic, systemic autoimmune disease which afflicts mainly the exocrine salivary and lachrymal glands, leading to mouth and eye dryness. However, any organ can be affected during the disease course, resulting in a variety of clinical manifestations. Sjögren’s syndrome clinical manifestations can be classified into glandular (sicca manifestations or parotid swelling), extra-glandular, either nonspecific (arthralgias, arthritis, Raynaud’s phenomenon, fatigue) or peri-epithelial (primary biliary cirrhosis, interstitial nephritis, bronchiolitis), and extra-epithelial (palpable glomerulonephritis, peripheral neuropathy, purpura). In addition, SS patients display high risk for B cell lymphomas due to chronic antigenic stimulation. Although disease pathogenesis remains unclear, genetic, environmental, and immunologic factors are implicated. In the context of systemic autoimmune manifestations, SS patients may also present with hematologic abnormalities including anaemia, leukopenia (mainly neutropenia or lymphopenia), and thrombocytopenia. Although leukopenia has been reported as a laboratory finding in many case series or cohorts of SS patients and in very few studies it has been proposed as an independent risk factor for lymphoma, the clinical phenotype of SS patients with leukopenia/neutropenia and the implicated pathogenetic mechanisms have not been elucidated. In the current study, we intend to analyse the clinical phenotype of leukopenic/neutropenic SS patients and explore the possible pathogenetic mechanisms by detecting anti-neutrophil antibodies and investigate the role of apoptotic pathways, especially the contribution of TRAIL pathway and the cFLIP molecule.

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer\u2019s disease-associated markers in 3xTg-AD mice

BackgroundCirculating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer’s disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model.MethodsYoung 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration.ResultsChronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors.ConclusionThe results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.

Autoantibodies in interstitial lung diseases

The role of autoantibody testing for patients with interstitial lung disease is an evolving area. Recent guidelines recommend routine anti-nuclear antibodies, rheumatoid factor, and anti-citrullinated cyclic peptide antibody testing for patients undergoing diagnostic evaluation for interstitial lung disease, with further autoantibody testing reserved for selected cases guided by rheumatological features. Even this approach may miss patients with clinically significant autoantibodies when interstitial lung disease is the dominant or first manifestation of autoimmune disease. We retrospectively performed autoimmune serology in a clinically well characterised cohort of interstitial lung disease patients. Using stored serum, additional testing was performed to ensure all patients had complete autoantibody profiles including anti-nuclear antibodies, extractable nuclear antigen antibodies, double-stranded DNA antibodies, rheumatoid factor, anti-citrullinated cyclic peptide antibodies, anti-neutrophil cytoplasmic antibodies, and myositis antibodies. Eighty patients with interstitial lung disease, and available stored serum, were assessed. Mean age at interstitial lung disease diagnosis was 65.2 years and 42 patients were male. Positive autoimmune serology was found in 56 of 80 (70.0%) patients; the most common positive result was anti-nuclear antibodies (n=34; 42.5%). Myositis antibodies were detected in 13 of 80 (16.2%) patients. Four (5%) patients had elevated anti-citrullinated cyclic peptide antibodies, and two (2.5%) patients had detectable myeloperoxidase antibodies. Eleven (13.7%) patients with negative anti-nuclear antibodies had other significant disease associated autoantibodies. An extended panel of autoantibody testing may detect cases of connective tissue disease associated interstitial lung disease, regardless of clinical or radiological subtype, and prior to extra-pulmonary manifestations of systemic autoimmunity.

PO130 A case of neuromyelitis optica spectrum disease, necrotizing myositis and breast cancer

We present the case of a 46-year-old Caucasian woman, who developed seronegative necrotizing myositis (with elevated creatine kinase [CK, 54 000]) whilst on tamoxifen treatment following remission of breast carcinoma (Grade II mucinous, solid papillary and ductal breast carcinoma), which was treated six months previously with surgery and adjuvant radiotherapy. The necrotizing myositis was initially treated successfully with prednisolone. However, on prednisolone cessation, she represented with myositis, which required steroid therapy again. Within two weeks, patient developed acute loss of vision in the left eye, which deteriorated to counting fingers over days, leading to the diagnosis of severe left optic neuritis. Serum positivity for Aquaporin-4 antibodies confirmed a diagnosis of neuromyelitis optica spectrum disease (NMOSD). The patient had no other relevant past medical history or co-morbidities, namely other organ-specific or systemic autoimmune manifestations. She was treated with intravenous steroids and plasma exchange, but she did not recover her vision. She continues on immune therapy and her three pathologies remain stable. Previous case reports have noted possible associations of NMOSD with myositis and others with malignancies, including breast cancer. Our case illustrates that NMOSD may be, very rarely, associated with, or preceded by, necrotizing myositis and may also be a paraneoplastic presentation.

Endosomal RNA-sensing toll-like receptor stimulated T cells play a unique role in autoimmune manifestations in murine model of DNA accrual.

Abstract DNaseII is a lysosomal DNase that plays a critical role in immune homeostasis. DNaseII deficiency in mice causes embryonic lethality, due to severe anemia associated with excessive production of type I interferon (IFN), and can be rescued by IFN receptor knockout (IFNaR). The DNaseII/IFNaR double knockout (DKO) mice develop a late-onset inflammatory arthritis, dependent on the cytosolic DNA sensor STING (Stimulator of Interferon Genes). They also develop early-onset clinical manifestations of systemic autoimmunity including disrupted hematopoiesis and B cell lymphopoiesis, splenomegaly (due to increased accumulation of Ter119+ cells), and the production of anti-nuclear antibodies (ANA), through a mechanism that is STING-independent, Unc93B1-dependent and likely to result from endosomal RNA-sensing TLRs. Bone marrow (BM) chimera studies have shown that the DNaseII deficiency is essential in both radioresistant host cells and hematopoietic donor cells for all disease manifestations. Development of arthritis requires the presence of STING in both host and donor. The TLR-dependent defects require TLR expression in only the hematopoietic compartment but still need DNaseII−/− recipients. Remarkably transplantation of DKO spleen fragments or injection of DKO spleen cells alone into DNaseII-sufficient Rag−/− mice leads to splenomegaly and disrupted hematopoiesis and lymphopoiesis. Moreover DKO T cells are sufficient to transfer these TLR-associated defects to the Rag−/− mice. As activated T cells are known to be radioresistant, T cells activated in a DKO environment may account for the radioresistant host component required to precipitate the TLR-dependent disease manifestations.

The immune system and kidney disease: basic concepts and clinical implications

The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.

T-regs in autoimmune hepatitis-systemic lupus erythematosus/mixed connective tissue disease overlap syndrome are functionally defective and display a Th1 cytokine profile

Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects. Compared to health, CD4posCD25pos cells were decreased in number and expressed high levels of the CD127 activation marker in all three disease groups; in AIH-SLE/MCTD and in SLE they displayed low levels of FOXP3. In AIH-SLE/MCTD, they also contained a high proportion of IFNγ positive cells, indicating a Th1 profile. Similarly, in AIH-SLE/MCTD, CD4posCD25posCD25high T-regs were reduced in number and contained an increased proportion of activated CD127pos and IFNγpos cells. Such skewing towards a Th1 profile was also present at effector level, as a high frequency of IFNγ-producing cells was observed within AIH-SLE/MCTD CD4posCD25neg responder cells. Impairment in suppressor function both of CD4posCD25pos cells and CD4posCD25posCD127neg T-regs was observed in all three autoimmune conditions, but while addition of CD4posCD25posCD127neg T-regs decreased CD4posCD25neg responder cell proliferation in healthy subjects and partially in AIH patients, it had no effect in AIH-SLE/MCTD and SLE patients.In conclusion, in AIH-SLE/MCTD T-regs display a distinctive phenotypic and functional signature, characterized by marked activation, elevated IFNγ production and by a profound impairment of suppressive function, suggesting that multiple autoimmune manifestations may derive from a complex defect of immune-regulation.

β2-microglobulin is required for the full expression of xenobiotic-induced systemic autoimmunity

Mercury exposure in both humans and mice is associated with features of systemic autoimmunity. Murine HgCl2-induced autoimmunity (mHgIA) requires MHC Class II, CD4+ T-cells, co-stimulatory molecules, and interferon-γ (IFN-γ), similar to spontaneous models of systemic lupus erythematosus (SLE). β2-microglobulin (B2m) is required for functional MHC Class I molecules and the neonatal Fc receptor (FcRn). Deficiency of B2m in lupus-prone strains is consistently associated with reduced IgG levels, but with variable effects on other manifestations. Herein, we examined the role of B2m in mHgIA and show that in the absence of B2m, mercury-exposed mice failed to exhibit hypergammaglobulinemia, had reduced anti-nucleolar autoantibodies (ANoA), and had a lower incidence of immune complex deposits in splenic blood vessels, whereas IgG anti-chromatin autoantibodies and renal immune deposits were largely unaffected. Subclass analysis of the IgG anti-chromatin, however, revealed a significant reduction in the IgG1 subtype. Examination of IFNγ, IL-4, and IL-2 in exposed skin, draining lymph nodes, and spleen following mercury exposure showed reduced IL-4 in the spleen and skin in B2m-deficient mice, consistent with the lower IgG1 anti-chromatin levels, and reduced IFNγ expression in the skin. These findings demonstrate how a single genetic alteration can partially but significantly modify the clinical manifestations of systemic autoimmunity induced by exposure to xenobiotics.

A loss‐of‐function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients

Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease.

Chronic Periaortitis (Retroperitoneal Fibrosis) Concurrent with Recurrent Cutaneous Eosinophilic Vasculitis

Chronic periaortitis (CP) is usually accompanied by at least mild manifestations of systemic autoimmunity; however, skin manifestations are rare. Here, we report an 82-year-old woman presenting with a pruritic annular eosinophilic dermatosis that led to the diagnosis of recurrent cutaneous eosinophilic vasculitis (RCEV) coexisting with a latent CP. The present paper is reminder that a CP should be included as a potential differential diagnosis in the elaboration of patients with cutaneous vasculitis that is suspicious of underlying autoimmunity.

Manifestations of systemic autoimmunity in vaccinated salmon

The development of systemic autoimmunity may result as an undesired side-effect following vaccination, and this condition was recently shown to occur in farmed salmon ( Salmo salar). Several of previously reported side-effects following vaccination of fish should therefore be reviewed in the light of this condition. Here, organs and pathological changes in three separate groups of fish severely affected by vaccination were investigated by different morphological methods ( n = 84). Granulomas or microgranulomas were observed at the injection site and in several organs. Mott cells were observed in all tissues examined. Pannus-like changes with lymphocyte infiltrates were observed in spines. In conclusion, the reactions following vaccination were of a systemic nature that may be explained by a pathogenetic mechanism caused by systemic autoimmunity.

Scleritis and multiple systemic autoimmune manifestations in chronic natural killer cell lymphocytosis associated with elevated TCRα/β+CD3+CD4−CD8− double-negative T cells

Background/aimsChronic natural killer lymphocytosis (CNKL) has been associated with systemic autoimmunity; however, its association with scleritis or ocular autoimmunity has not been characterised. The natural killer (NK) cell function and...

Deficiency in activation-induced cytidine deaminase promotes systemic autoimmunity inlprmice on a C57BL/6 background

Activation-induced deaminase (AID) is a prerequisite for immunoglobulin (Ig) class-switch recombination and somatic hypermutation, which is critical for antibody affinity maturation. IgM and IgG autoantibodies are characteristic of the systemic autoimmune disorders such as lupus. However, the relative contributions of hypermutated high-affinity IgG antibodies and germline-encoded IgM antibodies to systemic autoimmunity are not defined fully. The role of AID in autoimmunity is unclear. The current study used AID-deficient mice to investigate the role of AID in the development and pathogenesis of murine lupus. C57BL/6 mice deficient in both Fas and AID were generated. Compared to their AID-competent littermates, AID(-/-) lymphoproliferative (lpr) mice produced significantly elevated levels of IgM autoreactive antibodies with enhanced germinal centre (GC) response, developed more advanced splenomegaly and exhibited more severe glomerulonephritis. Thus, AID may play an important role in the negative regulation of systemic autoimmune manifestations in murine lupus. The results also indicate that hypermutated high-affinity IgG antibodies are not necessary for the development of autoimmune syndrome in lpr mice on a C57BL/6 background.

Systemic Autoimmune Manifestations: When Should Underlying Thyroid Autoimmunity be Considered?

Autoimmune thyroid disease is among the most common autoimmune disorders affecting 10% of the population. It is characterized by diffuse lymphocytic infiltration of the thyroid gland, the presence of antithyroid antibodies and diffuse hypoechogenicity on thyroid ultrasound. Despite the fact that autoimmune thyroid disease is classically considered a localized disease of the thyroid gland, systemic features, such as musculoskeletal complaints, sicca symptomatology, pregnancy loss and even neurological manifestations are not uncommon. Although thyroid dysfunction could account for some of these features, concomitant autoimmune disorders or even thyroid autoimmunity itself could be involved. In the current report new clinical and laboratory data from our department are presented and the existing literature regarding the systemic/rheumatic features of autoimmune thyroid disease is reviewed. Keywords: Organ specific autoimmunity, systemic autoimmunity, antithyroid antibodies, chronic autoimmune thyroiditis, rheumatic manifestations

Dendritic Cell Apoptosis in the Maintenance of Immune Tolerance

Apoptosis in the immune system is critical for maintaining self-tolerance and preventing autoimmunity. Nevertheless, inhibiting apoptosis in lymphocytes is not alone sufficient to break self-tolerance, suggesting the involvement of other cell types. We investigated whether apoptosis in dendritic cells (DCs) helps regulate self-tolerance by generating transgenic mice expressing the baculoviral caspase inhibitor, p35, in DCs (DC-p35). DC-p35 mice displayed defective DC apoptosis, resulting in their accumulation and, in turn, chronic lymphocyte activation and systemic autoimmune manifestations. The observation that a defect in DC apoptosis can independently lead to autoimmunity is consistent with a central role for these cells in maintaining immune self-tolerance.

Autoimmunity Caused by Cell Type-Specific Deficiency in Apoptosis.

Apoptosis in the immune system is essential for maintaining self-tolerance. Defective apoptosis causes systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone does not induce significant autoimmune responses, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. To study whether apoptosis in dendritic cells (DCs) regulates self-tolerance, we generated transgenic mice expressing a potent caspase inhibitor from baculovirus, p35, in dendritic cells (DC-p35). DC-p35 transgenic mice displayed defective apoptosis in DCs, leading to DC accumulation, chronic lymphocyte activation and systemic autoimmune manifestations resembling the phenotypes in Fas-deficient lpr mice. Our results suggest that apoptosis in DCs is critical for limiting lymphocyte activation and preventing autoimmunity.

BCG and Autoimmunity: Another Two-Edged Sword

BCG immunotherapy for bladder carcinoma has been a long-standing treatment modality that has proved itself efficient and safe. Most of the side-effects of this treatment are minor and of short duration. There have been, nevertheless, several reports regarding more severe and long-term complications of BCG therapy—namely inflammatory arthritis, and occasionally systemic autoimmune manifestations. Here, we present four cases of patients who received intravesical instillation with BCG for bladder carcinoma and developed long-standing inflammatory arthritis. One of these patients developed Reiter's syndrome. We also refer to the possible immune mechanisms by which BCG can trigger arthritis, as well as to the link between mycobacterial infection, BCG immunotherapy and autoimmunity.

Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL/6-Faslpr mice.

Background genes determine the incidence and severity of lymphoaccumulation and histopathologic manifestations of systemic autoimmunity in mice homozygous for the apoptosis-defective Faslpr mutation. By interval mapping of 274 F2 mice intercrossed between MRL-Faslpr (severe disease) and C57BL/6-Faslpr (minimal disease), four loci were identified with significant linkage to lymphadenopathy and/ or splenomegaly on chromosomes 4, 5, 7, and 10, which were named lupus in (MRL-Faslpr x B6-Faslpr)F2 cross1-4 (Lmb1-4), respectively. Lmb1, -2, and -3 were also linked to the production of anti-dsDNA antibodies, but not glomerulonephritis, whereas Lmb4 was associated with glomerulonephritis. Lmb2, -3, and -4 were inherited from the MRL background, but interestingly, Lmb1 was derived from the C57BL16-Faslpr. Nevertheless, each locus, regardless of the strain of origin, appeared to act in an additive manner, although certain combinations were more effective. Only a single suggestive locus on chromosome 1 could be correlated with arthritis. The identification of loci with highly significant linkage to disease manifestations in Faslpr strains will make it possible to map and clone new genetic defects contributing to autoimmunity.

The oral mucosa of the MRL/I mouse: a synoptic picture of systemic autoimmune disorders

The oral manifestations of systemic autoimmunity were investigated in a kinetic study of the MRL/1 mouse. Lesions in the epithelium, connective tissue and minor salivary glands were characterized in serial sections of the soft palate and the cheeks with respect to 1) the type of inflammatory cells present, 2) the presence and type of vasculitis, 3) the presence of necrosis, 4) the occurrence of deposits. By the age of 16 wk, 100% of our animals had developed mild to severe lesions in at least one compartment of the mucosa. Between 16 and 32 wk of age, pathologic manifestations affected the epithelial and subepithelial tissues, the striated muscle tissue, the vascular system and, much less frequently, the minor salivary gland network.