Autoimmune Regulator (AIRE) in the Maintenance of Immunological Tolerance

Autoimmune regulator (AIRE) is the gene mutated in the human polyglandular autoimmune disease called Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) that belongs to the Finnish disease heritage. Murine Aire has been shown to be important in the generation of the T cell central tolerance in the thymus by promoting the expression of ectopic tissue-specific antigens in the thymic medulla. Aire is also involved in the thymus tissue organization during organogenesis. In addition to the thymus, AIRE/Aire is expressed in the secondary lymphoid organs. Accordingly, a role for AIRE/Aire in the maintenance of peripheral tolerance has been suggested. Peripheral tolerance involves mechanisms that suppress immune responses in secondary lymphoid organs. Regulatory T cells (Tregs) are an important suppressive T cell population mediating the peripheral tolerance. Tregs are generated in the thymus but also in the peripheral immune system T cells can acquire the Treg-phenotype. The aim of this study was to characterize Tregs in APECED patients and in the APECED mouse model (Aire-deficient mice). In the mouse model, it was possible to separate Aire expression in the thymus and in the secondary lymphoid organs. The relative importance of thymic and peripheral Aire expression in the maintenance of immunological tolerance was studied in an experimental model that was strongly biased towards autoimmunity, i.e. lymphopenia-induced proliferation (LIP) of lymphocytes. This experimental model was also utilised to study the behaviour of T cells with dual-specific T cell receptors (TCR) during the proliferation. The Treg phenotype was studied by flow cytometry and relative gene expression with real-time polymerase chain reaction. TCR repertoires of the Tregs isolated from APECED patients and healthy controls were also compared. The dual-specific TCRs were studied with the TCR repertoire analysis that was followed with sequencing of the chosen TCR genes in order to estimate changes in the dual-specific TCR diversity. The Treg function was tested with an in vitro suppression assay. The APECED patients had normal numbers of Tregs but the phenotype and suppressive functions of the Tregs were impaired. In order to separate Aire functions in the thymus from its yet unknown role in the secondary lymphoid organs, the phenomenon of LIP was utilised. In this setting, the lymphocytes that are adoptively transferred to a lymphopenic recipient proliferate to stimuli from self-originating antigens. This proliferation can result in autoimmunity if peripheral tolerance is not fully functional. When lymphocytes that had matured without Aire in the thymus were transferred to lymphopenic Aire-sufficient recipients, no clinical autoimmunity followed. The Aire-deficient donor-originating lymphocytes hyperproliferated, and other signs of immune dysregulation were also found in the recipients. Overt autoimmunity, however, was prevented by the Aire-deficient donor-originating Tregs that hyperproliferated in the recipients. Aire-deficient lymphopenic mice were used to study whether peripheral loss of Aire had an impact on the maintenance of peripheral tolerance. When normal lymphocytes were transferred to these Aire-deficient lymphopenic recipients, the majority of recipients developed a clinically symptomatic colitis. The colitis was confirmed also by histological analysis of the colon tissue sections. In the Aire-deficient lymphopenic recipients Tregs were proliferating significantly less than in the control group s recipients that had normal Aire expression in their secondary lymphoid organs. This study shows that Aire is not only important in the central tolerance but is also has a significant role in the maintenance of the peripheral tolerance both in mice and men. Aire expressed in the secondary lymphoid organs is involved in the functions of Tregs during an immune response. This peripheral expression appears to be relatively more important in some situations since only those lymphopenic recipients that had lost peripheral expression of Aire developed a symptomatic autoimmune disease. This AIRE-related Treg defect could be clinically important in understanding the pathogenesis of APECED.

Oral health and kidney disease with emphasis on diabetic nephropathy

Chronic kidney disease (CKD) is a worldwide health problem, with adverse outcomes of cardiovascular disease and premature death. The ageing of populations along with the growing prevalence of chronic diseases such as diabetes and hypertension is leading to worldwide increase in the number of CKD patients. It has become evident that inflammation plays an important role in the pathogenesis of atherosclerosis complications. CKD patients also have an increased risk of atherosclerosis complications (including myocardial infarction, sudden death to cardiac arrhythmia, cerebrovascular accidents, and peripheral vascular disease). In line with this, oral and dental problems can be an important source of systemic inflammation. A decline in oral health may potentially act as an early marker of systemic disease progression. This series of studies examined oral health of CKD patients from predialysis, to dialysis and kidney transplantation in a 10-year follow-up study and in a cross-sectional study of predialysis CKD patients. Patients had clinical and radiographic oral and dental examination, resting and stimulated saliva flow rates were measured, whilst the biochemical and microbiological composition of saliva was analyzed. Lifestyle and oral symptoms were recorded using a questionnaire, and blood parameters were collected from the hospital records. The hypothesis was that the oral health status, symptoms, sensations, salivary flow rates and salivary composition vary in different renal failure stages and depend on the etiology of the kidney disease. No statistically significant difference were seen in the longitudinal study in the clinical parameters. However, some saliva parameters after renal transplantation were significantly improved compared to levels at the predialysis stage. The urea concentration of saliva was high in all stages. The salivary and plasma urea concentrations followed a similar trend, showing the lowest values in kidney transplant patients. Levels of immunoglobulin (Ig) A, G and M all decreased significantly after kidney transplantation. Increased concentrations of IgA, IgG and IgM may reflect disintegration of the oral epithelium and are usually markers of poor general oral condition. In the cross-sectional investigation of predialysis CKD patients we compared oral health findings of diabetic nephropathy patients to those with other kidney disease than diabetes. The results showed eg. more dental caries and lower stimulated salivary flow rates in the diabetic patients. HbA1C values of the diabetic patients were significantly higher than those in the other kidney disease group. A statistically significant difference was observed in the number of drugs used daily in the diabetic nephropathy group than in the other kidney disease group. In the logistic regression analyses, age was the principal explanatory factor for high salivary total protein concentration, and for low unstimulated salivary flow. Poor dental health, severity of periodontal disease seemed to be an explanatory factor for high salivary albumin concentrations. Salivary urea levels were significantly linked with diabetic nephropathy and with serum urea concentrations. Contrary to our expectation, however, diabetic nephropathy did not seem to affect periodontal health more severely than the other kidney diseases. Although diabetes is known to associate with xerostomia and other oral symptoms, it did not seem to increase the prevalence of oral discomfort. In summary, this series of studies has provided new information regarding the oral health of CKD patients. As expected, the commencement of renal disease reflects in oral symptoms and signs. Diabetic nephropathy, in particular, appears to impart a requirement for special attention in the oral health care of patients suffering from this disease.

Coral Disease and Health Workshop: Coral Histopathology II

The health and continued existence of coral reef ecosystems are threatened by an increasing array of environmental and anthropogenic impacts. Coral disease is one of the prominent causes of increased mortality among reefs globally, particularly in the Caribbean. Although over 40 different coral diseases and syndromes have been reported worldwide, only a few etiological agents have been confirmed; most pathogens remain unknown and the dynamics of disease transmission, pathogenicity and mortality are not understood. Causal relationships have been documented for only a few of the coral diseases, while new syndromes continue to emerge. Extensive field observations by coral biologists have provided substantial documentation of a plethora of new pathologies, but our understanding, however, has been limited to descriptions of gross lesions with names reflecting these observations (e.g., black band, white band, dark spot). To determine etiology, we must equip coral diseases scientists with basic biomedical knowledge and specialized training in areas such as histology, cell biology and pathology. Only through combining descriptive science with mechanistic science and employing the synthesis epizootiology provides will we be able to gain insight into causation and become equipped to handle the pending crisis. One of the critical challenges faced by coral disease researchers is to establish a framework to systematically study coral pathologies drawing from the field of diagnostic medicine and pathology and using generally accepted nomenclature. This process began in April 2004, with a workshop titled Coral Disease and Health Workshop: Developing Diagnostic Criteria co-convened by the Coral Disease and Health Consortium (CDHC), a working group organized under the auspices of the U.S. Coral Reef Task Force, and the International Registry for Coral Pathology (IRCP). The workshop was hosted by the U.S. Geological Survey, National Wildlife Health Center (NWHC) in Madison, Wisconsin and was focused on gross morphology and disease signs observed in the field. A resounding recommendation from the histopathologists participating in the workshop was the urgent need to develop diagnostic criteria that are suitable to move from gross observations to morphological diagnoses based on evaluation of microscopic anatomy. (PDF contains 92 pages)

Expanding the repertoire of DNA-mediated signaling in DNA repair

DNA damage is extremely detrimental to the cell and must be repaired to protect the genome. DNA is capable of conducting charge through the overlapping π-orbitals of stacked bases; this phenomenon is extremely sensitive to the integrity of the π-stack, as perturbations attenuate DNA charge transport (CT). Based on the E. coli base excision repair (BER) proteins EndoIII and MutY, it has recently been proposed that redox-active proteins containing metal clusters can utilize DNA CT to signal one another to locate sites of DNA damage.

To expand our repertoire of proteins that utilize DNA-mediated signaling, we measured the DNA-bound redox potential of the nucleotide excision repair (NER) helicase XPD from Sulfolobus acidocaldarius. A midpoint potential of 82 mV versus NHE was observed, resembling that of the previously reported BER proteins. The redox signal increases in intensity with ATP hydrolysis in only the WT protein and mutants that maintain ATPase activity and not for ATPase-deficient mutants. The signal increase correlates directly with ATP activity, suggesting that DNA-mediated signaling may play a general role in protein signaling. Several mutations in human XPD that lead to XP-related diseases have been identified; using SaXPD, we explored how these mutations, which are conserved in the thermophile, affect protein electrochemistry.

To further understand the electrochemical signaling of XPD, we studied the yeast S. cerevisiae Rad3 protein. ScRad3 mutants were incubated on a DNA-modified electrode and exhibited a similar redox potential to SaXPD. We developed a haploid strain of S. cerevisiae that allowed for easy manipulation of Rad3. In a survival assay, the ATPase- and helicase-deficient mutants show little survival, while the two disease-related mutants exhibit survival similar to WT. When both a WT and G47R (ATPase/helicase deficient) strain were challenged with different DNA damaging agents, both exhibited comparable survival in the presence of hydroxyurea, while with methyl methanesulfonate and camptothecin, the G47R strain exhibits a significant change in growth, suggesting that Rad3 is involved in repairing damage beyond traditional NER substrates. Together, these data expand our understanding of redox-active proteins at the interface of DNA repair.

The health significance of heterotrophic bacteria in drinking water

Tap water is not sterile; it contains organisms which grow in water distribution systems or inside taps and their fittings. The absence of known pathogenic bacteria is assured by the absence of the indicator organisms but concerns have been raised in the past few years that drinking water fulfilling the standards laid down in the EC Directive ECC 80/778 may still cause disease. These concerns have arisen from several sources: the fact that a cause has been identified in only half of all suspected waterborne outbreaks of disease; reports have suggested that heterotrophic bacteria possessing single pathogenic mechanisms such as haemolysin may cause disease; reports of heterotrophic organisms causing water contact diseases in hospitals. These concerns led to a reappraisal of the pathogenic potential of heteretrophic bacteria, by carrying out an extensive literature search and review commissioned by the UK Water Research Company. This research identified many papers showing an association between drinking water and heterotrophic bacteria but only very few reports of suspected waterborne disease associated with the heterotrophs. The organisms demonstrating potential to cause disease were species of Aeromonas and Yersinia, but typing of organisms identified in patients and isolated from the water revealed very few similarities. The potential of Aeromonas and Yersinia to cause waterborne disease is thought to be very low and the Communicable Disease Surveillance Centre database of laboratory infections due to these two genera of organisms was analysed to produce population-related incidences for each health region in England and Wales. Additionally a laboratory questionnaire revealed different levels of ascertainment of these two organisms in different laboratories of the Public Health Laboratory Service.

The Status of Eelgrass, Zostera marina, as Bay Scallop Habitat: Consequences for the Fishery in the Western Atlantic

Zostera marina is a member of a widely distributed genus of seagrasses, all commonly called eelgrass. The reported distribution of eelgrass along the east coast of the United States is from Maine to North Carolina. Eelgrass inhabits a variety of coastal habitats, due in part to its ability to tolerate a wide range of environmental parameters. Eelgrass meadows provide habitat, nurseries, and feeding grounds for a number of commercially and ecologically important species, including the bay scallop, Argopecten irradians. In the early 1930’s, a marine event, termed the “wasting disease,” was responsible for catastrophic declines in eelgrass beds of the coastal waters of North America and Europe, with the virtual elimination of Z. marina meadows in the Atlantic basin. Following eelgrass declines, disastrous losses were documented for bay scallop populations, evidence of the importance of eelgrass in supporting healthy scallop stocks. Today, increased turbidity arising from point and non-point source nutrient loading and sediment runoff are the primary threats to eelgrass along the Atlantic coast and, along with recruitment limitation, are likely reasons for the lack of recovery by eelgrass to pre-1930’s levels. Eelgrass is at a historical low for most of the western Atlantic with uncertain prospects for systematic improvement. However, of all the North American seagrasses, eelgrass has a growth rate and strategy that makes it especially conducive to restoration and several states maintain ongoing mapping, monitoring, and restoration programs to enhance and improve this critical resource. The lack of eelgrass recovery in some areas, coupled with increasing anthropogenic impacts to seagrasses over the last century and heavy fishing pressure on scallops which naturally have erratic annual quantities, all point to a fishery with profound challenges for survival.

The Great Albatross Philippine Expedition and Its Fishes

The Philippine Expedition of 1907-10 was the longest and most extensive assignment of the Albatross's 39-year career. It came about because the United States had acquired the Philippines following the Spanish-American War of 1898 and the bloody Philippine Insurection of 1899-1902. The purpose of the expedition was to surbey and assess the aquatic resources of the Philippine Islands. Dr. Hugh M. Smith, the Deputy Commissioner of the U.S. Bureau of Fisheries, was the Director of the Expedition. Other scientific participants were Frederick M. Chamberlain, Lewis Radcliffe, Paul Bartsch, Harry C. Fasset, Clarence Wells, Albert Burrows, Alvin Seale, and Roy Chapman Andrews. The expedition consisted of a series of cruises, each beginning and ending in Manila and exploring a different part of the island group. In addition to the Philippines proper, the ship also explored parts of the Dutch East Indies and areas around Hong Kong and Taiwan. The expedition returned great quantities of fish and invertebrate speciments as well as hydrographic and fisheries data; most of the material was eventually deposited in the Smithsonian Institution's National Museum of Natural History. The fisehs were formally accessioned into the museum in 1922 and fell under the car of Barton A. Bean, Assistant Curator of Fishes, who then recruited Henry W. Fowler to work up the material. Fowler completed his studies of the entire collection, but only part of it was ever published, due in part to the economic constraints caused by the Depression. The material from the Philippine Expedition constituted the largest single accession of fishes ever received by the museum. These speciments are in good condition today and are still being used in scientific research.

Salt and water balance in the Mundel Lake: a strongly choked coastal lagoon

The Mundel Lake is an extremely shallow lagoon on the west coast of Sri Lanka. It is connected to the Puttalam Lagoon through 15 km long Dutch Canal. Salinity measurements and daily sea level data were obtained fortnightly from January 1993 to March 1994 and they were used to quantify the salt and water budget along with precipitation, evaporation and freshwater runoff. Extreme fluctuations of salinity and sea level are striking features of the system. Salinity of the Mundel Lake and Dutch Canal varied from 5-46.5 and 6 61 ppt respectively while the sea level ranged from -0.25 to +1.2 m. Tidal variations were not seen in the lagoon due to its long narrow canal system. Salt budget showed that the deposition of salt on the lagoon bottom during periods of decreasing water level. During increasing water level, salt is dissolved again. Flow of water through the Dutch Canal between the Puttalam Lagoon and Mundel Lake is driven by the changes in sea level. These changes are mainly due to seasonal changes of net freshwater supply and, to a lesser degree, to seasonal changes in sea surface height. As the flow rates are small due to the long and narrow canal, the residence time ranges between two months and several months in the Mundel Lake, except during season of high freshwater supply. As the water exchange is weak, the Mundel Lake becomes hyper saline with strong fluctuations in salinity. This implies a stress to all lagoon dwelling aquatic organisms and also to aquaculture practices in the area.

Disease problems in shrimp sector in Khulna district of Bangladesh: a question of sustainability

Disease is the main restraining factor for the development of shrimp sector in Bangladesh. Both brackish water shrimp bagda (Penaeus monodon) and freshwater prawn golda, (Macrobrachium rosenbergii) farming in Bangladesh have been facing disease problem. A study on disease outbreak in both brackish water and freshwater small-scale shrimp farms (gher) in Khulna district was carried out through interviewing randomly selected 3-5% of shrimp farmers with a structured questionnaire during March to December, 2002. The study showed that 97% bagda farming ghers and 80% golda farming ghers were affected by disease. White spot disease was the severe disease for bagda, whereas, antenna rot was the main disease for freshwater prawn. Change of water and liming were carried out as control measures of disease for bagda shrimp farming, while it was only liming for golda farming. A small number of shrimp farmers (15%) used chemicals for treatment of shrimp diseases. Development of suitable farming technology to prevent disease contamination and innovation of proper treatments for diseases are required to overcome the disease problems for sustainable shrimp farming in Bangladesh.

Three different viruses observed from the tissues of diseased mandarin fish Siniperca chuatsi

Three different kinds of viruses, the spherical virus SCSV with a diameter of about 280 nm, the rhabdovirus SCRV with a size about 250 x 120 nm, and the baculovirus SCBV with a size about 200 x 100 nm, were observed from the tissues of diseased mandarin fish Siniperca chuatsi with outbreak of infection and acute lethality. This phenomenon implicated that the reason why the epizootic disease of mandarin fish could not be quenched by only one kind of virus vaccine can be explained by the fact that the fish may be infected by different kinds of viruses. Therefore, more attention should be paid to the complexity of virus pathogens in the prevention strategy for mandarin fish diseases.

Assessment of LD matrix measures for the analysis of biological pathway association.

Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression (Wang et al., 2008). To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis). In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r=0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.

HBHA-specific IFN-{gamma} Synthesis at the Site of Infection during Active Tuberculosis in Humans.

RATIONALE: Tuberculosis (TB) remains a major cause of mortality. A better understanding of the immune responses to mycobacterial antigens may be helpful to develop improved vaccines and diagnostics. OBJECTIVE: The mycobacterial antigen heparin-binding-hemagglutinin (HBHA) induces strong interferon-gamma (IFN-gamma) responses by circulating lymphocytes from Mycobacterium tuberculosis latently infected subjects, and low responses associated with CD4(+) regulatory T (Treg) cells in TB patients. Here, we investigated HBHA-specific IFN-gamma responses at the site of the TB disease. METHODS: Bronchoalveolar lavages, pleural fluids and blood were prospectively collected from 61 patients with a possible diagnosis of pulmonary and/or pleural TB. HBHA-specific IFN-gamma production was analyzed by flow cytometry and ELISA. The suppressive effect of pleural Treg cells was investigated by depletion experiments. MEASUREMENTS AND MAIN RESULTS: The percentages of HBHA-induced IFN-gamma(+) alveolar and pleural lymphocytes were higher for pulmonary (P<0.0001) and for pleural (P<0.01) TB than for non-TB controls. Local CD4(+) and CD8(+) T cells produced the HBHA-specific IFN-gamma. This local secretion was not suppressed by Treg lymphocytes, contrasting with previously reported data on circulating lymphocytes. CONCLUSION: TB patients display differential effector and regulatory T cell responses to HBHA in local and circulating lymphocytes with a predominant effector CD4(+) and CD8(+) response locally, compared to a predominant Treg response among circulating lymphocytes. These findings may be helpful for the design of new vaccines against TB, and the detection of HBHA-specific T cells at the site of the infection may be a promising tool for the rapid diagnosis of active TB.

Implementing a resuscitation policy for patients at the end of life in an acute hospital setting: qualitative study

Objective : To explore attitudes and experiences of doctors and nurses regarding cardiopulmonary resuscitation for patients with end stage illness in an acute hospital. Design : Qualitative study; thematic analysis of two audio-taped focus groups and four semi-structured interviews. Setting : Acute district hospital, Northern Ireland. Participants : Seven nurses and nine doctors; varying nationality, gender and years of professional experience; involved in cardiopulmonary resuscitation decision-making. Results : Participants reported different interpretations of resuscitation policy and of what do not attempt to resuscitate (DNAR) decisions meant in relation to practical care for patients. This confusion in translating policy into practice contributed to communication difficulties in initiating, documenting and implementing cardiopulmonary resuscitation decisions. Participants were aware of how clinical conditions could change and reported uncertainty in determining end stage illness; they expressed fears of potential consequences of DNAR decisions for patients' care. The more disease-centred approach of doctors to patients' management, compared to nurses' more patient-centred approach, contributed to inter-professional conflict within teams. Doctors identified training needs in applying resuscitation policy and ethical principles in `real life' and nurses identified a need for ongoing professional support, which was perceived as being less available to junior doctors. Personal relationships between staff and patients, cultural reluctance to address sensitive issues and local community expectations of relatives being involved in decisions added to policy implementation difficulties. Conclusions : The findings indicate a need for ongoing staff support and training in applying resuscitation policy to decisions for patients with end stage illness in an acute hospital. They support suggestions that reviews of local resuscitation policy and of national guidelines should be undertaken with openness and honesty regarding the goals, opportunities and difficulties involved in trying to deliver good end of life care in local settings. Palliative Medicine 2007; 21 : 305—312 Key Words: do not attempt resuscitation (DNAR) • end stage illness • inter-professional • policy • resuscitation decisions

Alpha-1 antitrypsin deficiency: A conformational disease associated with lung and liver manifestations

Alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 μmol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called 'Z' mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols. © Springer Science+Business Media B.V. 2008.

Proteomic analysis of circulating immune complexes in juvenile idiopathic arthritis reveals disease-associated proteins

Juvenile idiopathic arthritis reflects a group of clinically heterogeneous arthritides hallmarked by elevated concentrations of circulating immune complexes. In this study, the circulating immune complex proteome was examined to elucidate disease-associated proteins that are overexpressed in patients with an aggressive, and at times destructive, disease phenotype. To solve this proteome, circulating immune complexes were isolated from the sera of patients with chronic, erosive or early-onset, aggressive disease and from patients in medical remission or healthy controls subsequent to protein separation by 2-DE. Thirty-seven protein spots were overexpressed in the circulating immune complexes of the aggressive disease groups as compared to controls, 28 of which have been confidently identified to date. Proteolytic fragments of glyceraldehyde-3-phosphate dehydrogenase, serotransferrin, and a-1-antitrypsin have been identified among others. In total, these 28 putative disease-associated proteins most definitely contribute to immune complex formation and likely have a significant role in disease etiology and pathogenesis. Moreover, these proteins represent markers of aggressive disease, which could aid in diagnosis and management strategies, and potential therapeutic targets to prevent or control disease outcome. This is the first in-depth analysis of the circulating immune complex proteome in juvenile idiopathic arthritis.