The aim of this prospective, cross-sectional, multicentre study performed by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) was to investigate different therapeutic strategies and their efficacies in cutaneous lupus erythematosus (CLE) throughout Europe. Using the EUSCLE Core Set Questionnaire, topical and systemic treatment options were analysed in a total of 1002 patients (768 female and 234 male) with different CLE subtypes. The data were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the criteria of the American College of Rheumatology for the classification of systemic lupus erythematosus. Sunscreens were applied by 84.0% of the study cohort and showed a high efficacy in preventing skin lesions in all disease subtypes, correlating with a lower CLASI activity score. Topical steroids were used in 81.5% of the patients, with an efficacy of 88.4%, whereas calcineurin inhibitors were only applied in 16.4% of the study population and showed an efficacy of 61.7%. Systemic agents including antimalarials and several immunomodulating drugs, such as systemic steroids and methotrexate, were used in 84.4% of the 1002 patients, particularly in cases of acute CLE. The CLASI activity and damage score was higher in treated CLE patients as compared to untreated patients, regardless of therapy with topical or systemic agents. In summary, preventive and therapeutic strategies of 1002 patients with different subtypes of CLE were analysed in this prospective, multicentre, Europe-wide study. Sunscreens were confirmed to be successful as preventive agents, and topical steroids showed a high efficacy, whereas antimalarials were used as first-line systemic treatment.
In 1909, the term "lupus erythematodes tumidus" was first introduced by the German Dermatologist E. Hoffmann. The next case reports of lupus erythematosus tumidus (LET) were not described until 1930, and in the following years, only a few further cases were reported. This might have been due to the fact that authors have not considered LET as a separate entity different from other variants of cutaneous lupus erythematosus (CLE), and it is likely that skin lesions described under different designations represent the same disease entity. Therefore, LET has been underestimated and neglected in the literature and has been characterized by clinical, histopathological, and immunohistochemical features only in recent years. In particular, phototesting has been crucial in defining LET as a very photosensitive entity of CLE. Up to now, more than 40 reports of LET have been published demonstrating that the course and prognosis of LET are generally more favorable than in other subtypes of CLE. A new classification system, including LET as the intermittent subtype of CLE (ICLE) has been suggested. On the occasion of the 100th anniversary of the first description of LET, we have reviewed the literature and provide here an overview on the different aspects of the disease.
The term "rhupus" is traditionally used to describe patients with coexistence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim of the present work was to investigate prevalence, clinical and radiological picture as well as the serological profile of a series of rhupus patients; SLE patients and RA patients from our Unit were used as disease control groups. A total of 103 consecutive SLE patients were screened; among the entire cohort, 10 patients (9.7%) were classified as "rhupus". In our rhupus patients SLE features preceded the onset of arthritis in 5 patients (50%) while in the remaining patients arthritis appeared before or simultaneously (3 and 2 patients respectively). As compared with SLE patients, rhupus patients have significantly less kidney involvement (p=0.01) while no differences were observed between neuropsychiatric, cutaneous, hematological involvement or serositis. At our physical examination, 9 (90%) rhupus patients were presenting active joint involvement; CRP positivity and ESR levels resulted significantly higher than in SLE (p=0.006) patients while no differences were observed with respect to RA patients. In all rhupus patients, at least one pathological finding was revealed by ultrasound (US) examination at wrist and/or hand joints; overall, rhupus patients presented higher scores in all the US parameters with respect to SLE patients, especially at hands; no statistically significant differences have been observed with respect to RA patients. Magnetic resonance (MR) revealed erosions in all rhupus patients with a concomitant bone edema in five patients. The cumulative erosive burden in rhupus patients was significantly higher than in SLE patients and similar to RA patients (SLE vs rhupus p=0.005); bone pathology distribution was also similar between rhupus patients and RA patients. These data suggest the importance of assessing joint involvement in SLE with advanced imaging techniques and of evaluating the presence of prognostic factors for joint disease severity in order to establish adequate disease monitoring and to institute early appropriate therapies to avoid late consequences of unrecognized concomitant rheumatoid arthritis (Bojalil, 2006 ; Zhao et al., 2009 ).
The 10th International Congress on Antiphospholipid Antibodies (Sicily, Italy, September 29-October 3, 2002) (Fig. 1) provided enlightening aspects on the recent developments in antiphospholipid syndrome (APS) and antiphospholipid antibodies in more than 150 lectures and posters. Researchers from all aspects of medicine attended the meeting, implicating the systemic characteristics of APS. The important breakthroughs are summarized.
During the 10th International Symposium on Sjögren's Syndrome held in Brest, France, from October 1-3, 2009 (http://www.sjogrensymposium-brest2009.org), the creation of an international epigenetic autoimmune group has been proposed to establish gold standards and to launch collaborative studies. During this "epigenetics session", leading experts in the field presented and discussed the most recent developments of this topic in Sjögren's Syndrome research. The "Brest epigenetic task force" was born and has scheduled a meeting in Ljubljana, Slovenia during the 7th Autoimmunity congress in May 2010.The following is a report of that session.
Rheumatoid arthritis (RA) is an immune-mediated disease involving chronic low-grade inflammation that may progressively lead to joint destruction, deformity, disability and even death. Despite its predominant osteoarticular and periarticular manifestations, RA is a systemic disease often associated with cutaneous and organ-specific extra-articular manifestations (EAM). Despite the fact that EAM have been studied in numerous RA cohorts, there is no uniformity in their definition or classification. This paper reviews current knowledge about EAM in terms of frequency, clinical aspects and current therapeutic approaches. In an initial attempt at a classification, we separated EAM from RA co-morbidities and from general, constitutional manifestations of systemic inflammation. Moreover, we distinguished EAM into cutaneous and visceral forms, both severe and not severe. In aggregated data from 12 large RA cohorts, patients with EAM, especially the severe forms, were found to have greater co-morbidity and mortality than patients without EAM. Understanding the complexity of EAM and their management remains a challenge for clinicians, especially since the effectiveness of drug therapy on EAM has not been systematically evaluated in randomized clinical trials.
This review focuses on the use of immunglobulin (Ig) variable region genes by B cells from patients with primary Sjögren's syndrome (pSS) and the biologic insights that this provides. Comparison of the Ig repertoire from the blood and parotid gland of pSS patients with that of normal donors suggests that there are typical disturbances of B cell homeostasis with depletion of memory B cells from the peripheral blood and accumulation/retention of these antigen-experienced B cells in the inflamed tissue. Although there are clonally expanded B cells in the parotid gland, generalized abnormalities in the B cell repertoire are also found in pSS patients. The vast majority of the current data indicate that there is no major molecular abnormality in generating the IgV chain repertoire in patients with pSS. In contrast, disordered selection leads to considerable differences in the V(L) gene usage and V(H) CDR3 length of the B cell Ig repertoire in pSS patients. The nature of the influences that lead to disordered selection in pSS remains to be determined, but should provide important clues to the etiology of this autoimmune inflammatory disorder.
Predicting granulomatosis with polyangiitis (Wegener's) (GPA) relapses based on ANCA titers remains a source of debate. Our objective was to evaluate the relevance of monitoring PR3-ANCA titers for GPA management.
This retrospective study included 126 patients fulfilling the 1990 ACR criteria for GPA and PR3-ANCA-positive at the time of diagnosis. Disease activity was assessed with BVAS/WG and Disease Extent Index. For each patient, a median of 12 serum samples was analyzed, i.e. one every 5.5months.
Induction therapy obtained remission in 88% of the patients. ANCA became negative by IF for 70/115 (60.9%) patients and by ELISA for 90/115 (78.3%). After median follow-up of 70months, 85/126 (67.5%) patients had 154 clinical relapses associated with cANCA and PR3-ANCA-positivity for 122 (79.2%) and 102 (66.2%) of them, respectively. Relapse-free survival was significantly longer for patients who remained PR3-ANCA-negative (HR 0.60 [95% CI 0.39-0.92], P=0.02). Individual ANCA-profile analysis revealed that, for 60% of GPA patients, clinical outcomes and ANCA-titer changes were closely associated, i.e., ANCA were always positive during relapses and negative during remission. The 35 patients with fluctuating ANCA-positivity during remission were in partial remission or had developed grumbling GPA.
Although ANCA were positive during most systemic relapses or residual disease, no strict clinical-immunological correspondence was observed for 25% of the patients. Thus, GPA management cannot be based on ANCA levels alone.
Vitiligo is an acquired hypomelanotic disorder characterised by circumscribed depigmented macules in the skin resulting from the loss of functional melanocytes. Population surveys have shown a prevalence ranging from 0.38 to 1.13%. The frequent association of vitiligo with autoimmune diseases, together with studies demonstrating that vitiligo patients can have autoantibodies and autoreactive T lymphocytes against pigment cells supports the theory that there is an autoimmune involvement in the aetiology of the disease. Although the pathogenic mechanisms of T cells have recently been well studied in vitiligo, the role of autoantibodies in the disease remains obscure. However, even if antibodies to melanocytes are not an agent of the disease, identifying their target antigens could provide for the development of diagnostic tests that are not yet available for vitiligo and could serve as markers for important T cell responses in patients with the disease.
The 'Task Force on Catastrophic Antiphospholipid Syndrome (CAPS)' was developed on the occasion of the 14th International Congress on Antiphospholipid Antibodies. The objectives of this Task Force were to assess the current knowledge on pathogenesis, clinical and laboratory features, diagnosis and classification, precipitating factors and treatment of this condition in order to address recommendations for future research. This article summarizes the studies analyzed by the Task Force, its recommendations and the future research agenda.
Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for venous thrombosis controlled clinical trials with the new oral direct thrombin or anti-Factor Xa inhibitors pending the results of ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients.
Apoptosis has been clearly characterised by the ability to limit the activation of inflammatory responses through the disposal of the apoptotic cell by rapid uptake by phagocytes. The exposure of phosphatidylserine deriving from the loss of plasma lipid asymmetry is the early membrane signal which alerts the phagocyte about the imminent apoptotic death of the cell. Also modifications of membrane carbohydrate groups on apoptotic cells contribute to phagocyte recognition. Soluble proteins such as C1q, mannose-binding lectin, surfactant proteins A and D, C-reactive protein, C3bi, beta2-glycoprotein I and growth arrest specific gene-6 bind to apoptotic cells and act as "opsonins" thus favouring their clearance. A redundant and promiscuous system of receptors including integrins, scavenger receptors, CR3 and CR4, calreticulin, CD14 and Mer receptor ensures an efficient and rapid uptake of apoptotic cells. In animal models and in human pathology, single genetic defects of molecules involved in apoptotic cell clearance seem to be the main determinant in the development of autoimmunity. The uptake of apoptotic cells by phagocytes provides an immunomodulatory effect in that it triggers the release of anti-inflammatory cytokines, inhibits the production of inflammatory cytokines and leads to T cell tolerance. Impaired clearance of apoptotic cells or the presence of 'danger' signals may modify the balance between tolerance induction and activation of T cells leading to an effective autoimmune response.
To present a pooled analysis of the efficacy of rituximab from European cohorts diagnosed with biopsy-proven lupus nephropathy (LN) who were treated with rituximab.
Consecutive patients with biopsy-proven LN treated with rituximab in European reference centers were included. Complete response (CR) was defined as normal serum creatinine with inactive urinary sediment and 24-hour urinary albumin <0.5 g, and partial response (PR) as a >50% improvement in all renal parameters that were abnormal at baseline, with no deterioration in any parameter.
164 patients were included (145 women and 19 men, with a mean age of 32.3 years). Rituximab was administered in combination with corticosteroids (162 patients, 99%) and immunosuppressive agents in 124 (76%) patients (cyclophosphamide in 58 and mycophenolate in 55). At 6- and 12-months, respectively, response rates were 27% and 30% for CR, 40% and 37% for PR and 33% for no response. Significant improvement in 24-h proteinuria (4.41 g. baseline vs 1.31 g. post-therapy, p=0.006), serum albumin (28.55 g. baseline to 36.46 g. post-therapy, p<0.001) and protein/creatinine ratio (from 421.94 g/mmol baseline to 234.98 post-therapy, p<0.001) at 12 months was observed. A better response (CR+PR) was found in patients with type III LN in comparison with those with type IV and type V (p=0.007 and 0.03, respectively). Nephrotic syndrome and renal failure at the time of rituximab administration predicted a worse response (no achievement of CR at 12 months) (p<0.001 and p=0.024, respectively).
Rituximab is currently being used to treat refractory systemic autoimmune diseases. Rituximab may be an effective option for patients with lupus nephritis, especially those refractory to standard treatment or who experience a new flare after intensive immunosuppressive treatment.
Recent studies demonstrated an IL-17-producer CD4+ T cell subpopulation, termed Th17, distinct from Th1 and Th2. It represents a different pro-inflammatory Th-cell lineage. This notion is supported by gene-targeted mice studies. Mice lacking IL-23 (p19-/-) do not develop experimental autoimmune encephalomyelitis (EAE) or collagen-induced arthritis (CIA), while knockout mice for the Th1 cytokine IL-12 (p35-/-) strongly develop both autoimmune diseases. Disease resistance by IL-23 knockout mice correlates well with the absence of IL-17-producing CD4(+) T lymphocytes in target organs despite normal presence of antigen-specific-IFN-gamma-producing Th1 cells. This finding may thus explain previous contradictory reports showing that anti-IFN-gamma-treated mice, IFN-gamma- or IFNR-deficient mice develop CIA or EAE. TGF-beta, IL-6 and IL-1 are the differentiation factors of Th17 cells. IL-23 is dispensable for this function, but necessary for Th17 expansion and survival. The master regulator that directs the differentiation program of Th17 cells is the orphan nuclear receptor RORgammat. IL-27, a member of the IL-12/IL-23 family, potently inhibits Th17 development. Evidence suggesting rheumatoid arthritis and multiple sclerosis as primarily IL-17 autoimmune inflammatory-mediated diseases is rapidly accumulating. The IL-17/23 axis of inflammation and related molecules may rise as therapeutic targets for treating these and perhaps other autoimmune diseases.
With all the incredible progress in scientific research over the past two decades, the trigger of the majority of autoimmune disorders remains largely elusive. Research on the biology of T helper type 17 (T(H)17) cells over the last decade not only clarified previous observations of immune regulations and disease manifestations, but also provided considerable information on the signaling pathways mediating the effects of this lineage and its seemingly dual role in fighting the invading pathogens on one hand, and in frightening the host by inducing chronic inflammation and autoimmunity on the other hand. In this context, recent reports have implicated T(H)17 cells in mediating host defense as well as a growing list of autoimmune diseases in genetically-susceptible individuals. Herein, we summarize the current knowledge on T(H)17 in autoimmunity with emphasis on its differentiation factors and some mechanisms involved in initiating pathological events of autoimmunity.
Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR≥50 criteria, while the IL-6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile.
Takayasu's arteritis (TA) is a rare disease affecting the large arteries, particularly the aorta. Standard test to demonstrate abnormal vascular anatomy is angiography. This invasive procedure is limited in differentiating inflammatory and fibrotic lesions. Acute phase reactants have shown to have poor sensitivity and specificity in confirming disease activity in TA patients. Fluorine-18 flourodeoxyglucose Positron Emission Tomography (FDG-PET) scan has been utilized to detect areas of active inflammation in neoplastic, infectious and recently, vasculitic conditions.
To describe the FDG-PET scan findings of patients with Takayasu's arteritis.
This is a case series of four patients fulfilling the American College of Rheumatology classification criteria for TA. They were evaluated with FDG-PET scan to establish disease activity in correlation with other clinical and laboratory features.
Three out of four patients showed evidence of increased radiotracer uptake in the aorta. Of these three patients, one had increased radiotracer uptake in the lungs secondary to active pulmonary tuberculosis.
PET scan is a promising but non-specific tool that provides clinicians with a non-invasive measure of disease activity in TA patients. Further studies confirming its utility in monitoring disease activity and response to treatment is recommended.
Interleukin-18 is a cytokine member of the IL-1 super family that seems to exert powerful Th1-promoting activities in synergy with IL-12. Here we describe the participation of IL-18 in inflammatory joint diseases, in particular rheumatoid arthritis, adult onset Still's disease and juvenile idiopathic arthritis. The emphasis of this study was to summarize in vivo and in vitro studies that focused the action of this pro-inflammatory cytokine on the arthritic process as well as its role in the complex network of chemical mediators involved.
Excessive T helper cell function is a hallmark of systemic lupus erythematosus and abnormalities of T helper cytokine profiles have been implicated in loss of immune tolerance, increased antigenic load, defective B cell suppression and a variety of clinical manifestations. Here, we emphasize the importance of T helper 1-type (i.e., IFN-gamma) with respect to T helper 2-type (i.e., IL-4) cytokines in promoting the pathogenesis of lupus nephritis focusing on the critical role of IL-18, a major T helper 1 differentiation factor. IL-18 is overexpressed in patients with lupus nephritis along with higher INF-gammaand lower IL-4 production as compared to non-nephritic lupus patients. We hypothesize a pathogenic model where both the onset and aggravation of nephritis are promoted by an imbalance of immune response towards a T helper 1 cytokine predominance due to IL-18 up-regulation. In contrast, a T helper 2-skewed cytokine profile may possibly prevent the development of renal disease. In this context, IL-18 represents a novel marker of lupus nephritis and its measurement may be helpful in the assessment of patients.
IL-18 belongs to the IL-1 family of cytokines and has recently regained interest in the context of inflammasome activation. The inflammasome dependent caspase 1 cleaves pro-IL-18 into the active form - similar to what is known for IL-1ss. Still, the action and importance of IL-18 are not completely understood. There are several indications that it plays a pathogenetically important role in chronic inflammatory conditions of epithelial organs (such as skin, gut, kidney) and importantly also in responses against self. Here, we summarise current knowledge on the role of IL-18 in human skin inflammation with a focus on its role in Cutaneous Lupus Erythematosus (CLE). There is evidence that IL-18 plays a role in CLE upstream of TNFalpha. In CLE but not normal keratinocytes IL-18 strongly induces TNFalpha release, which then results in apoptosis. Blocking TNFalpha in vitro prevents apoptosis of keratinocytes but anti-TNFalpha therapy is not applicable in LE conditions. We will discuss potential approaches to control IL-18 in skin inflammation.
To determine the value of FDG-PET/CT to assess disease activity in patients with Sjögren's syndrome (SS).
Thirty-two patients with SS who underwent PET/CT were retrospectively analyzed. PET/CT activity score was measured using a 6-point scale including the 6 following items (0/1:absence or presence of an item): lymphadenopathy on CT, high-resolution CT (HRCT) evidence of interstitial lung disease (ILD), parotid glands SUVmax >3, submandibular glands SUVmax >3, lymph node uptake, ILD uptake. Combined PET/CT score was correlated to ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index) score and other parameters of SS activity.
Pathological FDG uptake was observed in 75% of patients (24/32): lymph-nodes (n=19, 60%), salivary glands (n=17, 53%), lungs (n=9, 28%), and thyroid (n=2). Median ESSDAI and PET/CT activity scores were 10 [5-12.5] and 2 [0-3], respectively. PET/CT activity score correlated with ESSDAI (r=0.49, p=0.005), unlike maximum SUV. Patients with an high ESSDAI score had a higher PET/CT activity score than patients with a low ESSDAI score (3 vs 1, p=0.004). PET was also correlated with gammaglobulin levels (r=0.43, p=0.02), but not with the presence of cryoglobulinemia, activated complement or beta-2 microglobulin levels. The FDG uptake in patients with lymphoma (n=4) was higher than in patients without lymphoma (SUVmax=5.4 vs. 3.2, p=0.05).
We described a new PET/CT activity score, which correlates to ESSDAI and could help to assess disease activity in SS patients. PET can also help in the diagnosis of lymphoma, even if inflammatory lymph nodes can be frequently observed in SS patients.
Systemic autoimmune diseases, which comprise a family of conditions which share common pathogenetic mechanisms, are frequently associated to cardiac involvement and to a high prevalence of ischemic coronary events often occurring at a younger age than in normal population. A large increase in mortality is related to premature atherosclerosis with coronary artery disease and stroke in patients with connective tissue diseases. Coronary heart disease is responsible for 40-50% of the death of patients with rheumatoid arthritis. Moreover, a growing body of evidence supports the view that autoimmune mechanisms are involved in the pathogenesis of cardiovascular disease. Inflammatory heart disease is a rising concern worldwide. Similar mechanisms link autoimmune diseases, including the association of increased disease with proinflammatory cytokines and the importance of regulatory mechanisms in the control of chronic inflammation. The role of the immune system in modulating atherosclerosis has recently been well documented. Studies have revealed that cellular and humoral immunity plays crucial roles in atherogenic plaque formation. This includes macrophages, CD4+ T cells and dendritic cells as well as autoantigens such as oxidized low-density lipoprotein (oxLDL), heat shock proteins and beta2-glycoprotein I. The inflammatory component is not localized to the "culprit" plaque, but it is diffused to the entire coronary vascular bed, and involves also the myocardium. The aim of the conference (2nd conference on heart, rheumatism and autoimmunity) was to focus the attention of the participants on some pathogenetic, clinical and therapeutic aspects at the boundary between cardiology and rheumatology and to encourage the debate among clinicians and basic researchers with different backgrounds and experiences.
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for refractory autoimmune diseases. The safety and long-term outcome have been also acceptable. Infectious diseases under immune suppressive state after autologous HSCT are common transplantation related complications whereas autoimmune diseases are uncommon. Organ specific autoimmune diseases, such as immune mediated thrombocytopenia and thyroid dysfunction, are the most common after autologous HSCT. Systemic autoimmune diseases can also develop after autologous HSCT in patients with hematological disorders with genetic predisposition to autoimmune diseases. Although the mechanism of autoimmunity after HSCT is not well-known, long-term follow-up is essential in patients with autoimmune diseases treated with autologous HSCT.
Type 1 diabetes of both the NOD mouse and man is associated with autoimmunity directed against insulin which is the only beta cell specific autoantigen identified to date. One can use autoantibodies to insulin to predict diabetes, use insulin peptides to create insulin autoantibodies, insulitis and diabetes, and use insulin or its peptides in animal models to prevent diabetes. An expanding set of resources are now available for the development and testing in man of therapies to prevent type 1 diabetes, and a number of trials utilizing insulin peptides are now underway.
B-1a cells are distinguished from conventional B cells (B2) by their developmental origin, their surface marker expression and their functions. They were originally identified as a B cell subset of fetal origin that expresses the pan-T cell surface glycoprotein, CD5. B-1a cells also differ from B2 by the expression levels of several surface markers, including IgM, IgD, CD43 and B220 [R. Berland, H.H. Wortis, Origins and functions of B-1 cells with notes on the role of CD5. Ann Rev Immunol, 20 (2002) 253-300.]. The majority of B-1a cells are located in peritoneal and pleural cavities. Compared to B2 cells, B-1a are long-lived, non-circulating, with reduced BCR diversity and affinity [A.B. Kantor, C.E. Merrill, L.A. Herzenberg, J.L. Hillson, An unbiased analysis of V-H-D-J(H) sequences from B-1a, B-1b, and conventional B cells. J Immunol, 158 (1997) 1175-1186.]. B-1a cells are largely responsible for the production of circulating IgM referred to as natural antibodies. These low affinity antibodies are polyreactive and constitute as such a first line of defense against bacterial pathogens [M.C. Carroll, A.P. Prodeus, Linkages of innate and adaptive immunity. Curr Opin Immunol, 10 (1998) 36-40.]. This polyreactivity also results into the recognition of autoantigens, which serves in the clearance of apoptosis products. The weak autoreactivity of the B-1a cells has been postulated to play a role in autoimmune pathogenesis. In addition, other characteristics, such as the production of high level of IL-10 [A. O'Garra, R. Chang, N. Go, R. Hastings, G. Haughton, M. Howard, et al. Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur J Immunol, 22 (1992) 711-717.] and enhanced antigen presentation capacities [C. Mohan, L. Morel, P. Yang, E.K. Wakeland, Accumulation of splenic B1a cells with potent antigen-presenting capability in NZM2410 lupus-prone mice. Arthritis and Rheumatism, 41 (1998) 1652-1662.], have implicated B-1a cells in autoimmunity. This review will discuss the current understandings of their role in autoimmune diseases with focus on lupus.
CAPS is the prototype of an IL-1β driven auto inflammatory disorder. Features of recurrent systemic inflammation compromises patient's quality of life, and may reduce life expectancy by inducing definite organ damage. Recent treatment targeting IL-1 have shown dramatic effect on patient's clinical symptoms and quality of life. Anakinra was first used successfully in treating small series of patients with all CAPS phenotypes. Two pivotal randomized placebo-controlled studies allowed licensing of rilonacept and canakinumab as orphan drugs for CAPS patients. The use of anti-IL-1 drugs in CAPS is still relatively new, and their effect on a long term is not well known. As we can suppress the clinical symptoms of patients with CAPS, important questions remain regarding the full effect of anti-IL-1 treatment on organ involvement and their potential ability to prevent them. As important variations of treatment doses and schedules appear in reaching effectiveness, pharmacologic studies are still warranted to determine a potential diffusion of anti-IL-1 drugs in the fluids and tissues. More studies evaluating the efficacy and safety of anti-IL-1 drugs given in patients before 2years of age are warranted, since it is believed that the earliest treatment could avoid secondary CAPS complications to develop.
An unusual variant of the antiphospholipid syndrome (APS) termed the Catastrophic Antiphospholipid Syndrome (CAPS) in 1992 by Asherson is described. The condition may arise "de-novo" in a patient previously not suspected of having an APS or during the course of a "Primary" APS or Secondary APS (most commonly SLE). The patient may already be on therapy. "Trigger" factors (infections most commonly) have been identified in 45% of patients but in the majority, they remain unidentified. Clinically, the patients present with small vessel occlusions involving organs (e.g. bowel, brain, heart, kidney) but large vessels occlusions do occur. Unusual organs are involved and the clinical features depend on which organs are affected. Because of tissue necrosis, the Systemic Inflammatory Response ensues ("SIRS") and many patients develop ARDS. Despite seemingly adequate therapy (parenteral heparin, steroids, antibiotics), the mortality remains high (approximately 50%).
The Clinical Immunology Society established didactic forums, called Schools in 2006 to impart training in various subfields of Clinical Immunology, including hypersensitivity, systematic autoimmunity, and primary immunodeficiency. The teaching format includes presenting challenges and solutions through live demonstrations involving patients and presenting the latest clinical or basic science projects and results. A small group of doctors and scientists, appointed as teachers discuss each presentation and offer advice for future development. Four selected professionals from the United States and nine other countries met at the third School on Systematic Autoimmune Diseases, held in Santa Fe, New Mexico to discuss on issues related with such diseases. Some of the diseases discussed at the event included juvenile rheumatoid arthritis, systemic lupus erythematosus, and juvenile myositis.
The concept of "probable" antiphospholipid syndrome (APS) is almost identical with several conditions which may presage the development of the APS with its major complications of large vessel thromboses resulting in deep vein occlusions in the lower limbs (DVT) particularly and strokes. These conditions comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions. These conditions, comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions may be followed, often years later by diagnosable APS. The issue whether these patients should be more aggressively treated on presentation in order to prevent the thrombotic complications. A new subset of the APS is proposed viz. microangiopathic antiphospholipid syndrome ("MAPS") comprising those patients presenting with thrombotic microangiopathy and demonstrable antiphospholipid antibodies who may share common although not identical provoking factors (e.g. infections, drugs), clinical manifestations and haematological manifestations (severe thrombocytopenia, hemolytic anaemia) and treatments viz. plasma exchange. Patients without large vessel occlusions may be included in the MAPS subset. These conditions include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and the HELLP syndrome. Patients with catastrophic antiphospholipid syndrome (CAPS) who do not demonstrate large vessel occlusions also fall into this group. Disseminated intravascular coagulation (DIC) has also been reported with demonstrable antiphospholipid antibodies and also manifests severe thrombocytopenia and small vessel occlusions. It may cause problems in differential diagnosis.
The Autoantibody Standardization Committee was established in the early 1980s based on the recognized needs for reference human autoimmune sera that were critical for academic, clinical, and industrial laboratories. To date, 14 reference reagents are available without charge from the Biological Reference Reagents distribution center at the Centers for Disease Control and Prevention. A web site has been developed under "AutoAbSC.Org" to communicate to the wider stakeholder community and to facilitate ongoing activities in continuing the mission in autoantibody standardization.
On March 3-5, 2006, The HK Society of Rheumatology, University of Hong Kong and Singapore National Arthritis Foundation organized the second Asia Autoimmunity Forum (AAF) in Hong Kong which was attended by over 200 delegates from around Asia. More than 20 invited international and regional experts in the field of autoimmune rheumatic diseases spoke on topics including the pathogenetic mechanisms, clinical aspects and novel therapeutic approaches of autoimmune rheumatic diseases. There were 8 plenary lectures and 4 symposia and the AAF provided an excellent avenue to promote the co-ordination and knowledge exchange in the area of autoimmune rheumatic diseases in Asia.
The number of 2009 publications in indexed journals dealing with 'autoimmunity' has maintained its increasing trend compared to the previous five years. Numerous developments have been proposed in our understanding of systemic and organ-specific autoimmune diseases (particularly multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis) and of basic autoimmunity mechanisms (particularly Th17, T regulatory cells, and autoantibodies). Both these lines of evidence share a significant potential to be translated into new therapeutic options to impact clinical practice. This article will discuss selected publications from prominent scientific journals dedicated to immunology and autoimmunity and ultimately include some expectations in branches of autoimmunity that appear promising for future developments.
There is now growing evidence that autoimmunity is the common trait connecting multiple clinical phenotypes albeit differences in tissue specificity, pathogenetic mechanisms, and therapeutic approaches cannot be overlooked. Over the past years we witnessed a constant growth of the number of publications related to autoimmune diseases in peer-reviewed journals of the immunology area. Original data referred to factors from common injury pathways (i.e. T helper 17 cells, serum autoantibodies, or vitamin D) and specific diseases such as multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. As an example, the issue of a latitudinal gradient in the prevalence and incidence rates has been proposed for all autoimmune diseases and was recently coined as geoepidemiology to suggest new environmental triggers for tolerance breakdown. The present article is aimed at reviewing the articles that were published over the past year in the major autoimmunity and immunology journals.
While our knowledge of the pathogenesis of Takayasu's arteritis (TA) has considerably improved during the last decade, the exact pathogenic sequence remains to be elucidated. It is now hypothesised that an unknown stimulus triggers the expression of the 65kDa Heat-shock protein in the aortic tissue which, in turn, induces the Major Histocompatibility Class I Chain-Related A (MICA) on vascular cells. The γδ T cells and NK cells expressing NKG2D receptors recognize MICA on vascular smooth muscle cells and release perforin, resulting in acute vascular inflammation. Pro-inflammatory cytokines are released and increase the recruitment of mononuclear cells within the vascular wall. T cells infiltrate and recognize one or a few antigens presented by a shared epitope, which is associated with specific major Histocompatibility Complex alleles on the dendritic cells, these latter being activated through Toll-like receptors. Th1 lymphocytes drive the formation of giant cells through the production of interferon-γ, and activate macrophages with release of VEGF resulting in increased neovascularisation and PDGF, resulting in smooth muscle migration and intimal proliferation. Th17 cells induced by the IL-23 microenvironnement also contribute to vascular lesions through activation of infiltrating neutrophils. Although still controversial, dendritic cells may cooperate with B lymphocytes and trigger the production of anti-endothelial cell auto-antibodies resulting in complement-dependent cytotoxicity against endothelial cells. In a near future, novel drugs specifically designed to target some of the pathogenic mechanisms described above could be expanding the physician's therapeutic arsenal in Takayasu's arteritis.