Lupus Erythematosus-like Syndrome Research Articles

Investigating Concomitant RAG-2 and LRBA Mutations in SCID and Autoimmunity.

Inborn errors of immunity (IEI) are a large heterogenous group of diseases characterized by immunodeficiency, immune dysregulation, allergy, auto-inflammation and predisposition for malignancies. Most are inherited in an autosomal recessive trait. We studied a patient with severe combined immunodeficiency (SCID) and immune dysregulation who harbored two distinct bi-allelic IEI-associated genetic mutations. Clinical, immunological and genetic data were collected. Genetic investigation included whole exome sequencing on DNA extracted from skin fibroblasts. Family segregation was performed by Sanger sequencing. Immunological evaluation included absolute and functional evaluation of lymphocytes and chimerism analysis post hematopoietic stem cell transplantation (HSCT). Treg subsets, LRBA and CTLA4 expression levels were measured by flow-cytometric analysis. A nineteen-year-old female patient from a consanguine background underwent unconditioned matched sibling related HSCT during infancy due to clinical presentation of SCID with an Omenn phenotype. At that time her underlying genetic defect was not defined. Years after HSCT, severe auto-immune phenomena were noted, including a systemic lupus erythematosus-like syndrome and ophthalmic manifestations. Genetic evaluation revealed bi-allelic homozygous mutations in RAG-2 (c.685C>T, p.Arg229Trp) and a previously undescribed mutation in LRBA (c.3325G>T, p.Asp1109Tyr). LRBA and CTLA4 expression levels were normal, suggesting that the LRBA variant identified in these kindred is unlikely to be pathogenic. Multiple genetic defects causing complex IEIs may be identified in the same individual in highly consanguineous populations. Functional immunological testing is essential for evaluation of novel genetic variants.

Hematological and Extra-Hematological Manifestations of Parvovirus B19 Disease

Abstract Objective Parvovirus B19 (PVB19) is a virus that can present with many hematological and extra-hematological findings. Its prognosis is relatively good in immunocompetent patients, but severe disease may develop in immunocompromised patients. We retrospectively reviewed a series of children who presented with PVB19 during a 6-year period at our institution. Methods Nine children with positive polymerase chain reaction and serological test results for PVB19 were studied. Their demographic data, atypical clinical and laboratory findings, treatment regiments, clinical course, and prognosis were noted. Results The hematological abnormalities associated with PVB19 were anemia, neutropenia, and thrombocytopenia, and the extra-hematological abnormalities were systemic lupus erythematosus-like syndrome, hemophagocytic lymphohistiocytosis, and acute kidney injury. All patients had good outcomes with no significant sequelae. Conclusion This case review suggests that clinicians should not consider PVB19 only as a cause of hematological events; they should also be alert to the possibility that it may cause extra-hematological diseases.

Efficacy and Safety of Two Salts of Trientine in the Treatment of Wilson's Disease.

Background: Wilson’s disease (WD) is one of the few genetic disorders that can be successfully treated with pharmacological agents. Copper-chelating agents (D-penicillamine and Trientine salts) and zinc salts have been demonstrated to be effective. There are two salts of trientine. Trientine dihydrochloride salt (TETA 2HCL) is unstable at room temperature and requires storage at 2–8 °C. Trientine tetrahydrochloride (TETA 4HCL) is a more stable salt of trientine that can be stored at room temperature. No comparative study between both of the salts of trientine has been performed to date. As the two chemical forms were available in France between 1970 and 2009, we conducted a study to evaluate their efficacy and safety profiles. Methods: This retrospective cohort study was conducted by reviewing data from the national WD registry in France. Forty-three WD patients who received TETA 2HCL or TETA 4HCL monotherapy for at least one year until 2010 were included. The primary endpoints were hepatic and neurological outcomes. Secondary endpoints were the events leading to a discontinuation of medication. Results: Changes in medication were common, leading to the analysis of 57 treatment sequences of TETA 4HCL or TETA 2HCL. The mean duration of treatment sequence was significantly longer in the TETA 4 HCL group (12.6 years) than in the TETA 2HCL group (7.6 years) (p = 0.011). Ten patients experienced both trientine salts: eight stopped TETA 4 HCL (six had a hepatologic phenotype and two had a neurological phenotype) because this treatment was not available anymore (mean duration 7.4 years). Three of these patients already experienced TETA 2 HCL before the sequence. Two patients with a hepatologic phenotype (one had a previous sequence of TETA 4 HCL before) stopped TETA 2 HCL because of cold storage issues (mean duration 42.8 years). The total number of sequences was 57. All of the patients were clinically stable. No difference in efficacy was detected. Both treatments were well tolerated, except for a case of recurrence of lupus erythematosus-like syndrome in the TETA 2HCL group. The major reason for interruption of TETA 4HCL was due to a discontinuation in production of this salt. The reasons for stopping TETA 2HCL were mainly due to adherence issues largely attributed to the cold storage requirement. Conclusions: The two salts of trientine were effective in treating patients with WD. However, interruption of TETA 2HCL was frequent, linked to the cold storage requirement. As adherence to treatment is a key factor in the successful management of WD, physicians need to be even more vigilant in detecting adherence difficulties in patients receiving treatment with TETA 2HCL.

Induction of Systemic Lupus Erythematosus-like Syndrome in BALB/c Mice Leads to Disturbance in Splenic T Cell Subpopulations.

Mechanisms underlying the systemic lupus erythematosus (SLE) have not yet been elucidated. In this study, we evaluated the balance of T cell subsets in BALB/c mice model of SLE induced; using Con A and polyamines as DNA immunogenicity modifiers. BALB/c mice were immunized subcutaneously with 50 µg extracted DNA from cells cultured in different conditions: splenocytes+ polyamines (group P), splenocytes+ Con A (group A), splenocytes+ polyamines+ Con A (group PA) and splenocytes only (control). Anti-double-stranded DNA -(ds-DNA) antibodies, proteinuria, and antinuclear autoantibodies were assessed by enzyme-linked immunosorbent assay, Bradford method, and immunofluorescence respectively. Transcription factors of different T helper subsets were examined by real-time polymerase chain reaction. The serum level of the anti-dsDNA antibody in group PA was higher than that in the other groups (p>0.05). Antinuclear antibody (ANA) titer increased in groups A and PA. Proteinuria level in group PA was significantly higher than that in the control group (p<0.001). Expression of Foxp3 was decreased in group A (p=0.001). Additionally, the ratios of T-bet/GATA3 andT-bet/Foxp3 were also increased in group A. (p>0.05). Our results revealed an increased ratio of Th1 to Th2 and decreased expression of Foxp3 in group A, but group PA manifested more obvious signs of the disease. These results suggest that other mechanisms rather than disturbance in T cells' balance may involve the development of disease symptoms.

Broad spectrum of interferon-related nephropathies—glomerulonephritis, systemic lupus erythematosus-like syndrome and thrombotic microangiopathy: A case report and review of literature

Broad spectrum of interferon-related nephropathies—glomerulonephritis, systemic lupus erythematosus-like syndrome and thrombotic microangiopathy: A case report and review of literature

Etanercept Induced Myopericarditis and Subacute Cutaneous Lupus Erythematosus

Etanercept is a tumor necrosis factor inhibitor currently used for the treatment of autoimmune diseases such as rheumatoid arthritis and most spondyloarthropathies. The increased use of this medication has continued to reveal more of its adverse effects. These adverse effects include reactivation of infections such as mycobacterium tuberculosis, cutaneous disorders, systemic lupus erythematosus-like syndromes and cardiovascular-related conditions.

Management of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD? All High-Risk Patients Should Receive an Implantable Cardiac Defibrillator.

Management of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD? All High-Risk Patients Should Receive an Implantable Cardiac Defibrillator.

Penicillamine Revisited: Historic Overview and Review of the Clinical Uses and Cutaneous Adverse Effects

Penicillamine is a well-known heavy metal chelator, classically used in the treatment of Wilson disease, rheumatoid arthritis, and cystinuria. From a dermatologic standpoint, penicillamine was found to be useful in the treatment of systemic sclerosis. The successful therapeutic uses of penicillamine have been hindered by its numerous adverse effects, both cutaneous and extra-cutaneous. It is a unique drug since it provokes a diversity of dermatologic manifestations that include (1) acute hypersensitivity reactions, (2) dermopathies characterized by elastic fiber abnormalities including elastosis perforans serpiginosa and pseudo-pseudoxanthoma elasticum, (3) autoimmune disorders such as pemphigus and penicillamine-induced lupus erythematosus-like syndrome, and (4) miscellaneous dermatoses that result from undefined mechanisms. These cutaneous adverse effects may correlate with the dosage and duration of penicillamine therapy as well as the disease being treated.

Neprhrotic syndrome in a patient with rheumatoid arthritis treated with adalimumab: a case report

The pathogenetic role of TNFalpha in inflammatory diseases has been known for a long time and has modified the therapeutic approach towards this pathology. All over the word, about 400.000 patients have been treated with biological anti-TNF alpha drugs. Particular attention has been taken for the safety of their use. We describe a case of 60 year old man affected by rheumatoid arthritis who has developed nephrotic syndrome with histological pattern typical of systemic lupus erythematosus-like syndrome, without autoantibodies.

Beneficial Effect of Eucommia Polysaccharides on Systemic Lupus Erythematosus-like Syndrome Induced by Campylobacter jejuni in BALB/c Mice

The stem bark of Eucommia ulmoides Oliv. is commonly used for the treatment of hypertension, rheumatoid arthritis, lumbago, and ischialgia in traditional Chinese medicine. This study was to determine whether the crude polysaccharides (EUPs) isolated from the stem bark of E. ulmoides had beneficial effects on lupus-like syndrome in mice. BALB/c mice were immunized with CJ-S(131) in Freund's complete adjuvant on day 0, and then boosted on day 14. EUPs 15 or 30 mg kg(-1)·day(-1), or prednisone 5 mg kg(-1)·day(-1) was given to BALB/c mice intragastrically from day 0 to 34. Treatment with EUPs 15 or 30 mg kg(-1)·day(-1) for 35 days protected kidney from glomerular injury with reduced immunoglobulin deposition and lowered proteinuria. The increased production of serum autoantibodies and total immunoglobulin G (IgG) was also inhibited. These findings suggested that Eucommia polysaccharides had a beneficial effect on systemic lupus erythematosus-like syndrome induced by CJ-S(131) in BALB/c mice.

Spontaneous lupus-like syndrome in HLA-DQ2 transgenic mice with a mixed genetic background

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE(0)DQ2). These AE(0)DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE(0)DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE(0)DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE(0)DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE(0)DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a 'fingerprint' substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE(0)DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE(0)DQ2 mice compared with AE(0)DQ6 mice (p < 0.001). In conclusion, AE(0)DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815-829.

Reversible proteinuria after adalimumab discontinuation in a patient with Crohn's disease.

Sir, Renal complications are not infrequent in patients with inflammatory bowel diseases and seem to be more prevalent in patients with Crohn's disease. The spectrum of renal complications in Crohn's disease patients involves nephrolithiasis, amyloidosis, renal hypertension, glomerulonephritis (from minimal change nephropathy to rapidly progressive crescentic), tubulointerstitial abnormalities and iatrogenic complications related to medications such as aminosalicylates and cyclosporine. Anti-tumour necrosis factor (anti-TNFa) agents, including adalimumab, constitute a new generation of biological agents used in the treatment of a variety of autoimmune diseases such as rheumatoid and psoriatic arthritis, ankylosing spondylitis and Crohn's disease. We report herein a Crohn's disease patient diagnosed with proteinuria that was totally reversed after discontinuation of adalimumab. A 38-year-old male with terminal ileum Crohn's disease diagnosed 6 months previously was admitted to our hospital due to a relapse. Before admission, the patient was administered methylprednisolone 32 mg/day with sub-optimal response. On admission, the patient underwent routine screening to exclude underlying infection prior to prescription of anti-TNF-α agents. Subsequently, the patient was started on adalimumab induction scheme (160 mg subcutaneously). Two weeks afterwards, the patient complained of lower limb oedema, and laboratory screening revealed proteinuria of 1600 mg/day without any evidence of other extraintestinal comorbidity. Adalimumab was discontinued and patient was followed up. Proteinuria resolved completely 4 weeks after adalimumab discontinuation, but we decided no adalimumab rechallenge and no renal biopsy. The patient was started on therapy with azathioprine 150 mg/day and is currently in excellent clinical status. To the best of our knowledge, this is the first report of a patient with Crohn's disease and adalimumab-associated proteinuria. Treatment with adalimumab may lead to antibody formation, but renal complications are rare and have so far been reported only in 11 patients with rheumatoid arthritis [1–5] but not in patients with inflammatory bowel disease. Of interest, in rheumatoid arthritis patients, proteinuria has also been reported during therapy with other than adalimumab biological agents such as infliximab and etanercept [3]. Renal histology, when performed in rheumatoid arthritis patients with adalimumab-related renal dysfunction, showed patterns of systemic lupus erythematosus-like syndrome [1], necrotizing and crescenting glomerulonephritis [3,5], minimal lesion glomerulopathy [2], extracapillary glomerulonephritis with IgA deposits or active follicular necrosis against a background of glomerular sclerosis [4]. It is noteworthy that, as with this Crohn's disease case, favourable outcomes have been reported in all other rheumatoid arthritis cases. After adalimumab discontinuation and glucocorticoid [4] and/or immunosuppressive therapy [3,5], renal function recovered within a few weeks. Of interest, in one case proteinuria relapsed after adalimumab rechallenge [2]. In this case, the relative contributions of adalimumab and of the underlying Crohn's disease to the development of proteinuria cannot be exactly determined. However, it is questionable whether in this particular patient adalimumab induction scheme was the only factor able to induce proteinuria. We believe that the complete reversibility of proteinuria after adalimumab discontinuation points towards adalimumab as a triggering factor to a strongly predisposed for a renal dysfunction individual. As there have been some concerns regarding safety issues during administration of anti-TNF-α agents, it is of importance to understand the mechanism(s) of their interference in the normal kidney function. By this way, we may able to properly screen and possibly identify high-risk groups before initiation of anti-TNF-α therapies. For the moment, careful patient selection for biological agents as well as regular follow-up can promptly diagnose and completely reverse rare or unexpected episodes. Conflict of interest statement. None declared.

Recurrent Kikuchi–Fujimoto disease during pregnancy: Report of case evolving into systemic lupus erythematosus and review of published work

Kikuchi-Fujimoto disease (KFD) is a distinctive, benign type of necrotizing lymphadenitis. KFD is a rare entity, especially during pregnancy. Although first described in Japan, subsequently it has been reported in the West. We communicate herein a case of KFD in African women with bouts during pregnancy. Diagnosis was difficult because peripheral enlarged lymph nodes were absent and an extended differential diagnosis and adequate work-up was necessary. The patient suffered a miscarriage coinciding with a KFD bout. Further pregnancies were uneventful. Follow up showed that KFD evolved into a systemic lupus erythematosus-like syndrome.

The severe combined immunodeficient (SCID) mouse as a model for the study of autoimmune diseases.

There are no readily available in vivo models to study immune cells from humans with autoimmune diseases. SCID mice, which virtually lack both T and B lymphocytes and accept xenogeneic cells, have been used during the last 5 years to provide a milieu for lymphocytes isolated from individuals with various autoimmune diseases, or for lymphocytes from mice that have a systemic lupus erythematosus-like syndrome. Whilst human autoantibodies to organ antigens have been demonstrated in most SCID mice engrafted with human lymphocytes from the peripheral blood or the target organ, inflammation of the mouse target organ has not generally been observed. This review critically analyses experiments in this area reported so far. Some pitfalls of the SCID mouse model of human autoimmune diseases are mentioned, and future experiments to study mouse and human autoimmunity with this model are proposed.

DNase X Is a Glycosylphosphatidylinositol-anchored Membrane Enzyme That Provides a Barrier to Endocytosis-mediated Transfer of a Foreign Gene

DNase X is the first mammalian DNase to be isolated that is homologous to DNase I. In this study, we have examined its function using a novel monoclonal antibody and showed it to be expressed on the cell surface as a glycosylphosphatidylinositolanchored membrane protein. High level expression was observed in human muscular tissues and in myotubes obtained in vitro from RD rhabdomyosarcoma cells. We observed that RD myotubes incorporated a foreign gene, lacZ, by endocytosis but that expression of the encoded coding product, beta-galactosidase, was strongly inhibited. Overexpression of DNase X inhibited endocytosis-mediated gene transfer, whereas knockdown of DNase X with small interfering RNA had the opposite effect. These results reveal that DNase X provides a cell surface barrier to endocytosis-mediated gene transfer.

Human DcR3 overexpression in mice results in a systemic lupus erythematosus-like syndrome (129.15)

Abstract OBJECTIVE: DcR3, a TNFR family member, is a secreted protein, and can enhance cell survival by interfering with multiply apoptosis pathways. The objective of this study was to understand the role of DcR3 in pathogenesis of autoimmune diseases. METHODS: We generated transgenic (Tg) mice with actin promoter-driven expression of human DcR3, and investigated the development of autoimmune diseases in these mice. RESULTS: Beyond 5–6 months of age, DcR3 Tg mice developed a systemic lupus erythematosus (SLE)-like syndrome. They produced autoantibodies against various organs, and against dsDNA and Smith Ag. The kidneys of these Tg mice showed pathological changes indicative of glomerular nephritis and IgG and C3 deposition; kidney dysfunctions, such as proteuria, leukocyturia, and hemuresis, were obvious. Aged Tg mice also developed skin lesions and lymphocyte infiltration in the liver, and suffered from leukopenia, anemia and thrombocytopenia. The SLE-like symdrome penetrance in DcR3 Tg mice was gender-dependent, with about 60% in females versus 20% in males. Mechanistically, exogenous recombinant DcR3 or endogenous DcR3 produced by Tg T cells effectively protected CD4 cells from activation-induced apoptosis in vitro. Probably as a consequence, in the peripheral blood of Tg mice beyond 6 months of age, CD4 cells with a phenotype of previous activation were increased. CONCLUSION: DcR3 overexpression could lead to a SLE-like syndrome in mice.

Induction of systemic lupus erythematosus-like syndrome in syngeneic mice by immunization with activated lymphocyte-derived DNA

Systemic lupus erythematosus (SLE) is the prototype of autoimmune disease and the mechanisms underlying the disease have not yet been elucidated. Thus, animal models of SLE would facilitate investigation of pathogenetic mechanisms involved in the development of the disease. This study characterizes a murine model of SLE-like syndrome induced by syngeneic activated lymphocyte-derived DNA (referred to as ALD DNA). Normal BALB/c mice were immunized subcutaneously with highly purified ALD DNA. Anti-double-stranded DNA (anti-dsDNA) antibodies were determined by enzyme-linked immunosorbent assay. Other SLE-associated autoantibodies were examined by indirect immunofluorescence and anti-ENA (extractable nuclear antigen) profile assay. Pathological changes were analysed by light microscopy and electron microscopy. Kidney cryostat sections were viewed by immunofluorescence for the presence of glomerular IgG and C3 deposits. Proteinuria was measured by Coomassie brilliant blue assay. High levels of anti-dsDNA antibodies and other autoantibodies frequently appearing in SLE were detectable in the sera of ALD DNA-immunized mice. Glomerulonephritis and glomerular deposition of IgG plus C3 were observed in the kidney sections. Moreover, proteinuria was seen in the immunized mice. SLE-like syndrome can be induced by ALD DNA in normal mice. This induced model may be useful for elucidating the mechanisms involved in autoimmunity to DNA and the development of SLE.

Long-term risks associated with biologic response modifiers used in rheumatic diseases.

The introduction of tumor necrosis factor-alpha antagonists in 1998 has had a significant impact on the treatment of rheumatoid arthritis. However, as use of these agents has increased worldwide, infrequent adverse events that were not apparent in pivotal controlled clinical trials required for registration have emerged. These adverse events include serious infections, particularly tuberculosis, which may be atypical in presentation. Concern regarding increased risk of lymphoma has also emerged, although it remains unclear whether the risk exceeds that observed in other rheumatoid arthritis patients with comparable disease activity. Development of a systemic lupus erythematosus-like syndrome, which typically abates after discontinuation of the drug, is another rare complication that was further reported during the past year. Finally, additional cases of congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy) have been reported that appear to be related to the tumor necrosis factor-alpha antagonists. Additional postmarketing surveillance of these and other serious adverse events is necessary to determine the true risk of their occurrence, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required.

Maintenance infliximab therapy in patients with crohn’s disease: how long, how much, how frequent?

Maintenance infliximab therapy in patients with crohn’s disease: how long, how much, how frequent?

T cell studies in a peptide-induced model of systemic lupus erythematosus.

We have previously reported that immunization with a peptide mimetope of dsDNA on a branched polylysine backbone (DWEYSVWLSN-MAP) induces a systemic lupus erythematosus-like syndrome in the nonautoimmune BALB/c mouse strain. To understand the mechanism underlying this breakdown in self tolerance, we examined the role of T cells in the response. Our results show that the anti-foreign and anti-self response induced by immunization is T cell dependent and is mediated by I-E(d)-restricted CD4(+) T cells of the Th1 subset. In addition, generation of the critical T cell epitope requires processing by APCs and depends on the presence of both DWEYSVWLSN and the MAP backbone. The breakdown in self tolerance does not occur through cross-reactivity between the T cell epitope of DWEYSVWLSN-MAP and epitopes derived from nuclear Ags. In this induced-model of SLE, therefore, autoreactivity results from the activation of T cells specific for foreign Ag and of cross-reactive anti-foreign, anti-self B cells. Despite the fact that tissue injury is mediated by Ab, the critical initiating T cell response is Th1.