Immunoglobulin G4-related multiple cardiovascular lesions successfully treated with a combination of open surgery and corticosteroid therapy.

Immunoglobulin G4-related disease, a newly emerging systemic autoimmune disorder, can potentially involve the cardiovascular system. The standard treatment for immunoglobulin G4-related cardiovascular disease has not been established. We encountered a very rare case of an immunoglobulin G4-related inflammatory abdominal aortic aneurysm coexisting with a coronary artery aneurysm and periarteritis. The patient underwent surgical resection for the abdominal aortic aneurysm, followed by successful corticosteroid therapy for the coronary artery lesions. This is the first report of steroid-sensitive immunoglobulin G4-related coronary artery disease. A carefully planned treatment strategy for the multiple cardiovascular lesions was invaluable in the present case.

Association between IFNA genotype and the risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by multisystem inflammation and production of autoantibodies, which can generate immune complexes and may cause tissue damage through the recognition of an autoantigen. Although many factors have been proposed, such as genetic factors, environmental factors, hormonal action, viruses, and dysregulation of cytokine production, the cause of this disease is not well understood. It has been reported that the levels of interferon (IFN)-alpha in the sera of some SLE patients are elevated and that IFN-alpha induces maturation of monocytes into highly active antigen-presenting dendritic cells (DCs). We analyzed the association between IFN-alpha genotype and the risk of SLE to clarify whether IFN-alpha plays a central role in susceptibility to SLE. The results showed that no IFN-alpha genotype was significantly associated with the risk of SLE.

Deficiency in EBV-induced gene 3 (EBI3) in MRL/lpr mice results in pathological alteration of autoimmune glomerulonephritis and sialadenitis.

MRL/lpr mice develop a systemic autoimmune disease that is reminiscent of systemic lupus erythematosus (SLE) and Sjögren's syndrome in humans. To investigate the role of IL-27 in the development of autoimmune disorders in MRL/lpr mice, we disrupted the EBV-induced gene 3 (EBI3), which is a subunit of IL-27. Consequently, the pathophysiology of glomerulonephritis and sialadenitis, which develops in MRL/lpr mice, was drastically changed. EBI3-/- MRL/lpr mice developed disease that resembles human membranous glomerulonephritis (MGN), not diffuse proliferative glomerulonephritis (DPGN), with a predominance of IgG1 in glomerular deposits, and different type sialadenitis from Sjögren's syndrome, with IgG1 producing plasma cell infiltration in salivary glands, accompanied by increased IgG1 and IgE in the sera. T cells in these mice displayed significantly reduced IFN-gamma production along with elevated IL-4 expression. Loss of EBI3 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of phenotypes of human autoimmune diseases.

Peripheral CD4+ T cells showing a Th2 phenotype in a patient with Mikulicz's disease associated with lymphadenopathy and pleural effusion.

Mikulicz's disease (MD) is a unique IgG4-related systemic disease indicated by enlargement of the lachrymal and salivary glands and which differs substantially from Sjögren's syndrome. A male patient with pleural effusion, swelling of the submandibular glands, and swelling of the paraaortic, mediastinal, and pararenal lymph nodes was diagnosed with MD. Analysis of peripheral CD4+ T cells from the patient revealed deviation of the Th1/Th2 balance to Th2. Prednisolone therapy ameliorated the disease and corrected the Th1/Th2 imbalance.

Acquired hemophilia in a patient with systemic lupus erythematosus: a case report and literature review.

We report the case of a 38-year-old female patient with systemic lupus erythematosus (SLE) who developed acquired hemophilia caused by factor VIII (FVIII) inhibitors. She manifested spontaneous bleeding symptoms such as ecchymoses and hematuria. Laboratory findings showed an isolated prolongation of the activated partial thromboplastin time, reduced FVIII activity, and a high titer of FVIII inhibitors. She was successfully treated with oral predonisolone and cyclosporine in combination with steroid and cyclophosphamide pulse therapy.

Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice.

OBJECTIVE: To determine whether innate receptor signals play an important role in the development of autoimmune nephritis in MRL/lpr mice, an experimental model of lupus nephritis. METHODS: MyD88 is a critical adaptor that is involved in signaling pathways through all of the Toll-like receptors (TLRs) except TLR-3. We therefore generated MyD88-knockout (MyD88-KO) MRL/lpr mice and examined them for histopathologic changes in the kidneys, cumulative survival rates, extent of lymphadenopathy and splenomegaly, serum chemistry, and immunologic parameters. In addition, to define the role of the MyD88-independent pathway in autoimmune nephritis, we injected MyD88-KO MRL/lpr mice intraperitoneally with either poly(I-C) (50 or 100 microg per mouse) or phosphate buffered saline and examined them for survival as well as for histopathologic, serologic, and immunologic parameters. RESULTS: In comparison with wild-type mice, MyD88-KO MRL/lpr mice exhibited a prolonged lifespan, with no apparent development of autoimmune nephritis. Their kidneys showed no glomerular cell proliferation or crescent formation, along with a drastic decrease in the mesangial matrix. Lymphadenopathy and splenomegaly were less pronounced. Serum titers of anti-double-stranded DNA (anti-dsDNA) and production of cytokines, including interferon-alpha (IFNalpha), interleukin-12 (IL-12), IL-6, and IFNgamma, in splenocytes were significantly reduced in MyD88-KO MRL/lpr mice. Interestingly, MyD88-KO MRL/lpr mice that had been treated with the MyD88-independent TLR-3 ligand poly(I-C) showed an almost complete reversion to the features of wild-type mice, demonstrating crescentic glomerulonephritis, with significant elevation of serum anti-dsDNA titers and increased cytokine production in splenocytes. CONCLUSION: The findings indicate that both MyD88-dependent and MyD88-independent innate signals play a crucial role in the development of autoimmune nephritis in MRL/lpr mice.

Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1).

MRL/lpr mice develop spontaneous glomerulonephritis that is essentially identical with diffuse proliferative glomerulonephritis (World Health Organization class IV) in human lupus nephritis. Lupus nephritis is one of the most serious complications of systemic lupus erythematosus. Diffuse proliferative glomerulonephritis is associated with autoimmune responses dominated by Th1 cells producing high levels of IFN-gamma. The initial mounting of Th1 responses depends on the function of the WSX-1 gene, which encodes a subunit of the IL-27R with homology to IL-12R. In mice deficient for the WSX-1 gene, proper Th1 differentiation was impaired and abnormal Th2 skewing was observed during infection with some intracellular pathogens. Disruption of the WSX-1 gene dramatically changed the pathophysiology of glomerulonephritis developing in MRL/lpr mice. WSX-1-/- MRL/lpr mice developed disease resembling human membranous glomerulonephritis (World Health Organization class V) with a predominance of IgG1 in glomerular deposits, accompanied by increased IgG1 and IgE in the sera. T cells in WSX-1-/- MRL/lpr mice displayed significantly reduced IFN-gamma production along with elevated IL-4 expression. Loss of WSX-1 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of human lupus nephritis development.

Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice.

OBJECTIVE: To examine whether the platelet-derived growth factor (PDGF) receptor antagonist imatinib ameliorates glomerulonephritis in MRL/lpr mice, a condition that is similar to severe lupus nephritis in humans. METHODS: Sixteen-week-old MRL/lpr female mice having an advanced stage of glomerulonephritis were divided into 3 groups according to treatment: 1) 50 mg/kg or 2) 10 mg/kg of imatinib (administered orally 4 times a week up to 24 weeks of age) or 3) vehicle solution (untreated group). The histopathologic condition of the kidneys and salivary glands of each mouse as well as the cumulative survival rates, extent of lymphadenopathy and splenomegaly, and serum chemistry and immunologic values were assessed. RESULTS: In mice treated with 50 mg/kg imatinib, neither proliferation of glomerular cells nor crescent formation occurred. A drastic decrease in mesangial matrix was noted. Mice treated with 50 mg/kg imatinib had a prolonged life span compared with mice treated with 10 mg/kg imatinib and untreated mice. Expression of PDGF receptor and transforming growth factor beta messenger RNA in the kidneys was significantly reduced in the 50 mg/kg imatinib-treated mice compared with that in the 10 mg/kg imatinib-treated mice (P < 0.05) and the untreated mice (P < 0.01). Intriguingly, lymphadenopathy and salivary gland inflammation were also attenuated in imatinib-treated mice, in a dose-dependent manner. Serum levels of IgG and anti-double-stranded DNA antibodies were also reduced in the imatinib-treated mice. CONCLUSION: These findings indicate that imatinib has a pleiotropic therapeutic effect, namely, the inhibition of PDGF signaling and immunosuppression, on the glomerulonephritis of MRL/lpr mice, which suggests a potential application of this drug in the treatment of human lupus nephritis.