An Autoimmune Basis for Raynaud's Phenomenon: Murine Model and Human Disease.

OBJECTIVE: Raynaud's phenomenon (RP) is common in anti-RNP-positive patients with rheumatic diseases but is not itself known to be caused by autoimmunity. The aim of this study was to assess autoantibodies that could mediate this process. METHODS: Antibodies derived from patient sera and from murine models of anti-RNP autoimmunity were screened for the ability to induce RP-like tissue ischemia and endothelial cell apoptosis in murine models and in vitro systems. RESULTS: RNP-positive sera from RP patients and murine sera from RNP-positive B cell adoptive transfer recipients induced RP-like tissue ischemia and endothelial cell apoptosis. Proteomic analysis identified cytokeratin 10 (K10) as a candidate autoantigen in RP. Monoclonal anti-K10 antibodies reproduced patterns of ischemic tissue loss and endothelial cell apoptosis; K10 knockout or depletion of anti-K10 activity in serum was protective. Cold exposure enhanced K10 expression and in vivo tissue loss. CONCLUSION: Anti-K10 antibodies are sufficient to mediate RP-like ischemia in murine models and are implicated in the pathogenesis of RP in patients with anti-RNP autoimmunity.

Serum anti-lipocalin 2 IgG is a novel biomarker in the diagnosis of systemic lupus erythematosus.

BACKGROUND: Previous work suggests that lipocalin 2 is involved in the pathogenesis of systemic lupus erythematosus (SLE) and that this novel antigen could serve as a high-quality renal biomarker of acute kidney injury in SLE. However, serum lipocalin 2 antibody levels remain unclear. We have therefore undertaken this study to assess the level of serum IgG antibody against lipocalin 2 in different disease states and to evaluate the diagnostic value of this potential biomarker in SLE. METHODS: Serum levels of anti-lipocalin IgG antibodies were measured by ELISA in 103 SLE patients, 93 rheumatoid arthritis (RA) patients, 29 primary Sjögren's syndrome (pSS) patients, 13 systemic sclerosis (SSc) patients, and 91 healthy controls. Diagnostic properties of anti-lipocalin IgG were determined by receiver-operating characteristic (ROC) curve analysis. RESULTS: The level of serum anti-lipocalin IgG in patients with SLE was significantly higher than in patients with RA, pSS, SSc, or healthy controls (p < 0.05), effectively distinguishing SLE from other conditions with high sensitivity and specificity (49.5% and 90.7%, respectively). In ROC curve analysis, the area under the curve (AUC) is 0.783, with a 95% confidence interval (CI) extending from 0.729 to 0.839. Anti-lipocalin antibodies were present in 48.1% of anti-Sm-negative SLE patients, and also occurred in SLE patients lacking anti-dsDNA (52%) or anti-nucleosome antibodies (46.3%) antibodies. Finally, SLE patients with positive anti-lipocalin IgG possessed higher levels of IgA and CRP than the negative group (p < 0.05), clearly demonstrating a positive correlation between anti-lipocalin IgG and these laboratory parameters. CONCLUSIONS: Anti-lipocalin 2 IgG is a promising biomarker for the diagnosis of SLE, particularly when obtained in conjunction with anti-Sm, anti-dsDNA, and anti-nucleosome antibody levels.

Lupus vasculopathy: Diagnostic, pathogenetic and therapeutic considerations.

A rare form of vascular disease in systemic lupus erythematosus (SLE), lupus vasculopathy is characterized by necrosis and accumulation of immunoglobulins (IGs) and complements in the wall of arterioles and small arteries resulting in luminal narrowing. Lupus vasculopathy often accompanies lupus nephritis and portends a poor prognosis. Although there is general agreement on the treatment of lupus nephritis, effective treatment strategies for lupus vasculopathy remain to be defined. We report a 20-year-old woman with SLE who presented with generalized tonic-clonic seizure. Her immunosuppressive regimen consisted of mycophenolate mofetil, prednisone and hydroxychloroquine. On physical examination, she was Cushingoid in appearance and hypertensive. Laboratory tests indicated renal disease. Coagulation studies disclosed de novo lupus anticoagulant. Magnetic resonance imaging of the brain demonstrated acute focal cerebral hemorrhage. Echocardiography revealed reduced ejection fraction and severe mitral regurgitation. Despite high-dose glucocorticoids and mycophenolate mofetil, renal function remained poor. Kidney biopsy demonstrated lupus vasculopathy and glomerulonephritis. Plasma exchange therapy and intravenous cyclophosphamide were administered. Over the ensuing four weeks, renal function improved, complement levels increased, autoantibody titers decreased and lupus anticoagulant disappeared. In conclusion, lupus vasculopathy can occur in SLE despite a heavy immunosuppressive regimen. Antiphospholipid antibodies might be involved in the pathogenesis of lupus vasculopathy. Plasma exchange therapy in conjunction with intravenous cyclophosphamide may represent an effective treatment strategy for lupus vasculopathy.

CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling.

CIS is a cytokine-induced SH2-containing protein that was originally cloned as an interleukin (IL)-3-inducible gene. CIS is known to associate with the IL-3 receptor beta chain and erythropoietin receptor and to inhibit signaling mediated by IL-3 and erythropoietin. We now demonstrate that CIS also interacts with the IL-2 receptor beta chain (IL-2Rbeta). This interaction requires the A region of IL-2Rbeta (residues 313-382), which also mediates the association of IL-2Rbeta with Lck and Jak3. Correspondingly, CIS inhibits functions associated with both of these kinases: Lck-mediated phosphorylation of IL-2Rbeta and IL-2-mediated activation of Stat5. Thus, we demonstrate that CIS can negatively control at least two independent IL-2 signaling pathways. Although a functional SH2 binding domain of CIS was not required for its interaction with IL-2Rbeta in vitro, its phosphotyrosine binding capability was essential for the inhibitory action of CIS. On this basis, we have generated a mutant form of CIS protein with an altered SH2 domain that acts as a dominant negative and should prove useful in further understanding CIS action.

Interleukin-2 (IL-2)-mediated induction of the IL-2 receptor alpha chain gene. Critical role of two functionally redundant tyrosine residues in the IL-2 receptor beta chain cytoplasmic domain and suggestion that these residues mediate more than Stat5 activation.

The interleukin-2 receptor alpha chain (IL-2Ralpha) is potently induced by antigens, mitogens, and certain cytokines that include IL-2 itself. This induction leads to the formation of high affinity IL-2 receptors when IL-2Ralpha is co-expressed with the beta (IL-2Rbeta) and gamma (gammac) chains of this receptor. We investigated the signaling pathways mediating IL-2-induced IL-2Ralpha mRNA expression using 32D myeloid progenitor cells stably transfected with either wild type IL-2Rbeta or mutants of IL-2Rbeta containing tyrosine to phenylalanine substitutions. Of the six cytoplasmic tyrosines in IL-2Rbeta, we have found that only the two tyrosines that mediate Stat5 activation (Tyr-392 and Tyr-510) contribute to IL-2-induced IL-2Ralpha gene expression and that either tyrosine alone is sufficient for this process. Interestingly, the IL-7 receptor contains a tyrosine (Tyr-429)-based sequence resembling the motifs encompassing Tyr-392 and Tyr-510 of IL-2Rbeta. Further paralleling the IL-2 system, IL-7 could activate Stat5 and drive expression of IL-2Ralpha mRNA in 32D cells transfected with the human IL-7R. However, IL-3 could not induce IL-2Ralpha mRNA in 32D cells, despite its ability to activate Stat5 via the endogenous IL-3 receptor. Moreover, the combination of IL-3 and IL-2 could not "rescue" IL-2Ralpha mRNA expression in cells containing an IL-2Rbeta mutant with phenylalanine substitutions at Tyr-392 and Tyr-510. These data suggest that Tyr-392 and Tyr-510 couple to an additional signaling pathway beyond STAT protein activation in IL-2-mediated induction of the IL-2Ralpha gene.

Isolated Candida albicans Arthritis In a Non-Intravenous Drug-Abusing Patient With Acquired Immune Deficiency Syndrome.

We describe a case of isolated Candida albicans arthritis in a non-intravenous drug-abusing, human immunodeficiency virus positive patient. This presentation is extremely unusual without other systemic features or risk factors for candidemia, as Candida septic arthritis normally reflects disseminated infection. In terms of diagnosis, this case also highlights the potential utility of magnetic resonance imaging for early detection of osteomyelitis.

Systemic lupus erythematosus, pemphigus erythematosus, and thymoma in the same patient.

We describe a case of thymoma and pemphigus erythematosus developing in a 68-year-old woman 8 years after an initial diagnosis of systemic lupus erythematosus. Although numerous reports describe associations between any two of these entities, this case represents the first clearcut report of all three diseases in the same patient. The case description outlines the diagnostic approach to these diseases and reveals the importance of adhering to specific diagnostic criteria. Furthermore, by highlighting the potential role of thymic pathology in autoimmune disease, the case raises questions concerning pathogenesis of these disorders.