LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma.

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.

The activating receptor NKp46 is essential for the development of type 1 diabetes.

The mechanism of action of natural killer (NK) cells in type 1 diabetes is still unknown. Here we show that the activating receptor NKp46 recognizes mouse and human ligands on pancreatic beta cells. NK cells appeared in the pancreas when insulitis progressed to type 1 diabetes, and NKp46 engagement by beta cells led to degranulation of NK cells. NKp46-deficient mice had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. Injection of soluble NKp46 proteins into nonobese diabetic mice during the early phase of insulitis and the prediabetic stage prevented the development of type 1 diabetes. Our findings demonstrate that NKp46 is essential for the development of type 1 diabetes and highlight potential new therapeutic modalities for this disease.

A Humanized Monoclonal Antibody against Heat Shock Protein 60 Suppresses Murine Arthritis and Colitis and Skews the Cytokine Balance toward an Anti-Inflammatory Response.

We have previously shown that naturally occurring as well as acquired Abs against the Mycobacterium tuberculosis heat shock protein (HSP)65 protect against the induction of murine autoimmune inflammatory arthritis. In the present work, we have studied the anti-inflammatory effect of prozumab, a humanized anti-HSP mAb in murine inflammatory arthritis and colitis, and its effects on cytokine secretion. Prozumab was shown to bind to HSP60, the highly conserved mammalian homolog of the bacterial protein, and it was found to be effective in protecting and suppressing autoimmune arthritis in the models of adjuvant arthritis and collagen-induced arthritis in rats and mice, respectively, as well as in acute hapten-mediated colitis and chronic, spontaneous colitis models. Mechanistically, prozumab induces IL-10 secretion from naive human PBMCs and suppresses the secretion of IFN-γ and IL-6 from anti-CD3-activated human PBMCs. These findings make prozumab a promising potential drug for treating human rheumatoid arthritis and inflammatory bowel disease, as well as a wide range of autoimmune inflammatory diseases.

Is B Cell-Targeted Therapy Effective in Systemic Lupus Erythematosus?

In the past decade we have witnessed a dramatic change in the management of autoimmune diseases, such as rheumatoid arthritis, due to the development of new biologic drugs designed to target key mediators in the autoimmune process. However, the development of similar target-specific drugs for the management of SLE has not been as successful. The B cell has long been considered central to the pathogenesis of SLE and has been regarded as an important target for biologic drugs. Several B cell-targeted drugs have been developed and although the mechanisms seem promising, most of the studies published to date have failed to achieve their primary endpoints, leading to an ongoing debate regarding the role of B cell therapy in SLE. The present report discusses the pros and cons of B cell-targeted therapy in SLE, reviews the clinical studies, and offers possible explanations forthe discrepancies between randomized control studies and real-life experience.

In-/off-label use of biologic therapy in systemic lupus erythematosus.

Current therapies for systemic lupus erythematosus (SLE) include corticosteroids as a persistent mainstay and traditional immunosuppressants which are given according to disease severity, organ involvement and patient status. No treatment entails certain efficacy devoid of mild-to-moderate adverse effects. Nowadays, novel therapies are being developed aiming to target specific molecules involved in SLE development and progression which show variable effectiveness and safety. Biologic agents considered for SLE comprise monoclonal antibodies (chimeric, humanized or fully human) as well as fusion molecules or antibody fragments mostly consisting of B cell-targeted therapies beside anti-cytokines as well as T cell-targeted therapies. Encouraging evidence on biologics is mostly provided by case series or uncontrolled studies; conversely, larger randomized controlled clinical trials have frequently missed their primary endpoints with the exception of BLISS-52 and BLISS-76 trials. Actually, apart from belimumab, biologics are employed in clinical practice as off-label treatments for lupus and results are often promising, depending on specific SLE features, dose regimens and individual responsiveness.

The effect of medical students' gender, ethnicity and attitude towards poetry-reading on the evaluation of a required, clinically-integrated poetry-based educational intervention.

BACKGROUND: Art-based interventions are widely used in medical education. However, data on the potential effects of art-based interventions on medical students have been limited to small qualitative studies on students' evaluation of elective programs, and thus their findings may be difficult to generalize. The goal of this study is to examine, in an unselected students' population, the effect of students' gender, ethnicity and attitude towards poetry on their evaluation of a clinically-integrated poetry-based educational intervention. METHODS: A required Clinically- Oriented Poetry-reading Experience (COPE) is integrated into the 4th year internal medicine clerkship. We constructed a questionnaire regarding the program's effects on students. Students completed the questionnaire at the end of the clerkship. We performed a Confirmatory Factor Analysis, and examined the relationship between students' evaluation of the program and students' ethnicity, gender, attitude towards poetry-reading, and the timing of the program (early/late) during the fourth year. RESULTS: 144 students participated in the program, of which 112 completed the questionnaires. We identified two effect factors: "student-patient" and "self and colleagues". The average score for "student-patient" factor was significantly higher as compared to the "self and colleagues" factor.Evaluation the "student- patient" effect factor was higher among Arab and Druze as compared to Jewish students. Students' attitude towards poetry-reading did not correlate with the "student-patient" effect, but correlated with the "self and colleagues" effect. The evaluation of the "self and colleagues" effect was higher among students who participated in the program during their second as compared with the first clerkship. Students' gender was not associated with any of the effects identified. Students favored obligatory participation in COPE as compared with elective course format. CONCLUSIONS: According to students' evaluation, a format of integrated, obligatory poetry-based intervention may be suitable for enhancing "student-patient" aims in heterogeneous student populations. The higher evaluation of the "patient-student" effect among Arab and Druze as compared to Jewish students may be related to cultural differences in the perception of this component of medical professionalism. Further research can provide insight into the effect of cultural and ethnic differences on actual empathy of medical students in patient encounters.

Recognition and killing of human and murine pancreatic beta cells by the NK receptor NKp46.

Type 1 diabetes is an incurable disease that is currently treated by insulin injections or in rare cases by islet transplantation. We have recently shown that NKp46, a major killer receptor expressed by NK cells, recognizes an unknown ligand expressed by ß cells and that in the absence of NKp46, or when its activity is blocked, diabetes development is inhibited. In this study, we investigate whether NKp46 is involved in the killing of human ß cells that are intended to be used for transplantation, and we also thoroughly characterize the interaction between NKp46 and its human and mouse ß cell ligands. We show that human ß cells express an unknown ligand for NKp46 and are killed in an NKp46-dependent manner. We further demonstrate that the expression of the NKp46 ligand is detected on human ß cells already at the embryonic stage and that it appears on murine ß cells only following birth. Because the NKp46 ligand is detected on healthy ß cells, we wondered why type 1 diabetes does not develop in all individuals and show that NK cells are absent from the vicinity of islets of healthy mice and are detected in situ in proximity with ß cells in NOD mice. We also investigate the molecular mechanisms controlling NKp46 interactions with its ß cell ligand and demonstrate that the recognition is confined to the membrane proximal domain and stalk region of NKp46 and that two glycosylated residues of NKp46, Thr(125) and Asn(216), are critical for this recognition.

An antibody profile of systemic lupus erythematosus detected by antigen microarray.

SUMMARY: Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states--SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Epstein-Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.

The "Sick immigrant" and "Healthy immigrant" phenomenon among Jews migrating from the USSR to Israel.

The "healthy immigrant" phenomenon finds that immigrants are in better health than natives, while the "sick immigrant" phenomenon finds the opposite. We examined this phenomenon using the relationship between immigration and mortality, stratified by income level, among Soviet immigrants to Israel in the 1990s, compared to veteran immigrants with similar ethnic origin. A retrospective cohort study of mortality during 1990-2016 was conducted among 63,847 immigrants born during 1940-1950 in the USSR or Eastern Europe, and who immigrated to Israel during 1990-1995. They were compared to a control group of 75,347 Israeli Jews born during the same period in the same countries or second-generation immigrants with parents from these countries and who immigrated by 1960. After adjusting for sex, age, income, and marital status, we found higher mortality rates among immigrants than non-immigrants for the total study population (adjusted hazard ratio (AHR) = 1.399, 99% confidence intervals (CI) = 1.341, 1.459) and among 19,033 men (AHR = 2.852, 99%CI = 2.619, 3.107) and 24,355 women (AHR = 1.705, 99%CI = 1.566, 1.857) with low incomes. The opposite relationship was found for 25,436 men (AHR = 0.710,99%CI = 0.617, 0.0.816) and for 12,922 women (AHR = 0.693,99%CI = 0.534, 0.900) with high incomes. When examining the total study population, we found evidence to support the "sick immigrant" phenomenon. However, both men and women in the high-income subgroup, and women in the middle-income subgroup, demonstrated the "healthy immigrant" phenomenon. Decision-makers in Israel should pay particular attention to immigrants from a low socioeconomic level. Our results emphasize the need for social stratification when examining the relationships between immigration and health outcomes.

Can we use NOACS in APS?

Secondary thromboprophylaxis with low molecular heparin or vitamin K antagonists (VKAs) is recommended in patients with definite antiphospholipid syndrome (APS). Direct oral anticoagulant (DOACs) have been approved in different prothrombotic conditions and have numerous advantages compared to VKAs. Whether DOACs can be used for secondary prophylaxis in APS is an open question. Data from the TRAPS randomized controlled Trial, meta-analysis and case reports indicate that we should not treat patients with triple positive APS and/or arterial thrombi with routine doses of DOACS. On the other hand, data from the literature including, case series, meta- analysis and the RAPS trial indicate that there are low risk patients, such as patients who suffered from a venous but not an arterial thromboembolism and are LAC negative who may benefit from the treatment with DOACs. Prospective trials addressing these low risk patients are needed in order to consider DOAC treatment in such patients.

[Reorganization of the Department of Medicine--how we should respond to the changes in internal medicine].

The dramatic increase in data burden has created a need for sub-specialization in medicine. This process has brought about the disappearance of the all-knowledgeable general internist and a situation in which sub-specialties have become the integral building blocks of internal medicine. The consolidation of internal medicine departments into a single division that includes all the requisite subspecialties, has provided an answer to many of the current changes in medicine in Israel and elsewhere. Under the division format, each department of medicine has at least one senior physician from each subspecialty, enabling both patients and residents to be exposed to the expertise of all these fields of medicine. The division format also facilitates the creation of centers of excellence, such as intensive care units and an ambulatory care center.

Is ACPA positivity the main driver for rheumatoid arthritis treatment? Pros and cons.

Rheumatoid Arthritis (RA) is an autoimmune chronic disease that is characterized by the positivity of various antibodies, the most specific being autoantibodies against citrullinated antigens (ACPA). Despite ACPA are not arthritogenic by themselves, ACPA positive individuals have high risk of RA development and ACPA positivity is associated with severe erosive phenotype and higher mortality rate compared to seronegative RA. Moreover, ACPA status is associated with favorable response to biologics targeting pathways involving autoantibody producing cells as B lymphocytes. In the current review we have discussed the pros and cons on the available scientific evidences, regarding the diagnostic, prognostic and management implications of ACPAs in RA.

Autoimmunity in the era of genomics and proteomics.

Autoimmune diseases arise from an aberrant recognition of self-epitopes by the immune system, resulting in inflammation and tissue damage. The wide range of affected organ systems and the overlap between different diseases pose several clinical challenges. Apart from establishing an accurate diagnosis, some of the problems frequently encountered are assessment of risk factors, prediction of prognosis and administration of an optimal treatment regimen. In recent years, the introduction of novel laboratory techniques have raised hopes that new answers will be provided to these challenges. In this work, we have summarized some of the prominent contributions of genetic works, microarray analyses and autoantigen microarrays to the understanding of autoimmunity and management of patients.

Immune modulation for prevention of type 1 diabetes mellitus.

Prevention of type 1 diabetes mellitus requires early intervention in the autoimmune process directed against beta cells of the pancreatic islets of Langerhans. This autoimmune inflammatory process is thought to be caused by the effect of Th1 cells and their secreted cytokines (e.g. interferon) and to be suppressed by Th2-secreted anti-inflammatory cytokines (e.g. IL-4, IL-10). Various methods aimed specifically at halting or modulating this response have been attempted. An alternative method is the re-induction of tolerance towards the putative self antigen that causes the disease. Proposed antigens such as insulin, glutamic acid decarboxilase (GAD) and the heat shock protein 60 (Hsp60)-derived peptide 277 have been used successfully in murine diabetes models and in initial clinical trials in early diabetes patients. Here, we review the results of these trials.

Removal of pathogenic autoantibodies by immunoadsorption.

Autoimmune diseases result from disrupted tolerance to self-antigens and subsequent damage to tissues and organs. In several diseases, specific autoantibodies have been either proved or suspected to play a role in this process. Consequently, several strategies have been devised in an attempt to discard the destructive immunoglobulins. Currently, both nonselective and epitope-specific methods are applied in several diseases. In this review, we provide a summary of the available data on elimination of pathogenic autoantibodies and discuss the advantages and pitfalls of the different approaches.

Global implementation of genomic medicine: We are not alone.

Around the world, innovative genomic-medicine programs capitalize on singular capabilities arising from local health care systems, cultural or political milieus, and unusual selected risk alleles or disease burdens. Such individual efforts might benefit from the sharing of approaches and lessons learned in other locales. The U.S. National Human Genome Research Institute and the National Academy of Medicine recently brought together 25 of these groups to compare projects, to examine the current state of implementation and desired near-term capabilities, and to identify opportunities for collaboration that promote the responsible practice of genomic medicine. Efforts to coalesce these groups around concrete but compelling signature projects should accelerate the responsible implementation of genomic medicine in efforts to improve clinical care worldwide.

Susceptibility and resistance to experimental adjuvant arthritis.

Autoimmunity is the result of an abnormal immune response against constituents of body tissues. For many years, the study of animal models of human diseases was aimed at defining the factors participating in the autoimmune process. During the past two decades, much of the attention was diverted to another intriguing aspect of animal models: the mechanisms rendering some animal strains autoimmune-susceptible and others resistant. In this report, we focus on one experimental model, adjuvant arthritis (AA) which is inducible in the Lewis rat following stimulation of the immune system by heat-killed mycobacterium and its 65kDa heat shock protein. We describe genetic loci regulating the severity of this disease as well as the contribution of microbial flora and endocrine activity to susceptibility and resistance. In our opinion, a better understanding of the processes underlying susceptibility and resistance to AA is an important step towards the development of new therapeutic approaches to autoimmunity.

Increased morbidity and mortality in patients with antiphospholipid syndrome undergoing valve replacement surgery.

OBJECTIVE: Heart valve abnormalities are commonly found in patients with antiphospholipid syndrome but experience with valve replacement in such patients is limited. We analyzed the results of valve replacement in patients with this condition at our institution. METHODS: Between 1989 and 2002, 10 patients with antiphospholipid syndrome (8 women, 2 men; aged 38-73 years, mean 49 years) with severe mitral valve disease (n = 7), aortic valve disease (n = 2), or combined mitral-aortic disease (n = 1) underwent valve replacement. We reviewed retrospectively their clinical data, operative and postoperative courses, and the long-term results. Pathological reassessment was performed in all cases. RESULTS: Procedures performed included mitral valve replacement in 7 patients, aortic valve replacement in 2 patients, and combined aortic valve replacement plus mitral valve replacement in 1 patient. In addition, 2 patients underwent tricuspid annuloplasty. The immediate mortality was 20% (2 patients). Major complications occurred in 2 other cases. During a follow-up period of up to 8 years, 2 patients required repeat operation for valve-related complications (1 death). An additional patient died of cardiac causes 13 months after surgery. One patient had major thromboembolic events 3 and 10 months after the operation. The late outcome was uneventful in only 4 patients. CONCLUSION: Valve replacement in patients with antiphospholipid syndrome may carry significant early and late mortality and morbidity, particularly when such patients are referred with advanced valvular heart disease.