Israel Medical Association Journal

Primary biliary cirrhosis is considered a model autoimmune disease because of the similarities between patients, their relative homogeneous presentation and natural history, and the presence of the signature autoantibody, the anti-mitochondrial antibodies. PBC[1] also illustrates the potential role of genetic and environmental influence and is unique in having several well-defined animal models that recapitulate distinct features of the disease. The pathogenesis of the disease includes genetic predisposition, the production of both innate and adaptive immune responses, and cholangiocyte-specific biology that addresses the specificity of disease. In this review we highlight these features of PBC in comparison to other autoimmune diseases.

Background: Epidemiological data show significant associations of vitamin D deficiency and autoimmune diseases. Vitamin D may prevent autoimmunity by stimulating naturally occurring regulatory T cells.

Objectives: To elucidate whether vitamin D supplementation increases Tregs[1] frequency (%Tregs) of circulating CD4+ T cells.

Methods: We performed an uncontrolled vitamin D supplementation trial among 50 apparently healthy subjects including supplementation of 140,000 IU at baseline and after 4 weeks (visit 1). The final follow-up visit was performed 8 weeks after the baseline examination (visit 2). Blood was drawn at each study visit to determine 25-hydroxyvitamin D levels and %Tregs. Tregs were characterized as CD4+CD25++ T cells with expression of the transcription factor forkhead box P3 and low or absent expression of CD127.

Results: Forty-six study participants (65% females, mean age ± SD 31 ± 8 years) completed the trial. 25(OH)D[2] levels increased from 23.9 ± 12.9 ng/ml at baseline to 45.9 ± 14.0 ng/ml at visit 1 and 58.0 ± 15.1 ng/ml at visit 2. %Tregs at baseline were 4.8 ± 1.4. Compared to baseline levels we noticed a significant increase of %Tregs at study visit 1 (5.9 ± 1.7, P < 0.001) and 2 (5.6 ± 1.6, P < 0.001).

Conclusions: Vitamin D supplementation was associated with significantly increased %Tregs in apparently healthy individuals. This immunomodulatory effect of vitamin D might underlie the associations of vitamin D deficiency and autoimmune diseases. Hence, our finding provides a rationale for further studies to investigate vitamin D effects on autoimmunological processes.

Background: Autoimmune neutropenia of infancy is caused by neutrophil-specific autoantibodies. Primary AIN[1] is characterized by neutrophil count < 500 ml and a benign self-limiting course. Detecting specific antibodies against the polymorphic human neutrophil antigen usually confirms the diagnosis. Current available tests, however, are expensive and inapplicable in many laboratories as they require the use of isolated and fixed granulocytes obtained from donors pretyped for their distinct HNA[2] alloform.

Objectives: To assess the performance of a modified test to identify by FACS-analysis granulocyte-specific antibodies in the sera of neutropenic children.

Methods: We evaluated 120 children with a clinical suspicion of AIN, whose sera were analyzed by flow cytometry for the presence of autoantibodies using the indirect granulocyte immunofluorescence test. In contrast to the traditional tests, the sera were tested against randomly selected untyped neutrophils derived from a batch of 10 anonymous healthy subjects, presumably including the common HNA alloforms. Control sera samples were from patients with chemotherapy-induced, familial or congenital neutropenias. To further assure the quality of the new test, we retested six samples previously tested by the gold standard method. All medical files were screened and clinical outcomes were recorded.

Results: Our method showed specificity of 85%, sensitivity of 62.5%, and a positive predictive value of 91.8%, values quite similar to those obtained by more traditional methods.

Conclusions: The new method showed high specificity for detection of anti-neutrophil antibodies in the appropriate clinical setting and could be an effective aiding tool for clinical decision making.

Approximately 1 in 31 people suffers from an autoimmune disease. The clinical care of patients with autoimmunity crosses multiple disciplines within pediatrics and internal medicine, including, for example, allergy-clinical immunology, rheumatology, nephrology, hematology, pulmonology and neurology. There are two major areas that are considered in the analysis of autoimmunity in human patients. The first of course is etiology and the second, and of even greater importance, is therapy. Towards that end, considerable attention has focused on the role of hematopoietic stem cell transplantation to either reverse or modulate autoimmune disease. Indeed, it is a field that has far more promise than premise based on a variety of issues, including economics, health care delivery, and obviously efficacy and safety. To put this in perspective, we have attempted to review some of the issues that pertain to this novel approach to the management of autoimmunity. Finally, we emphasize the need to incorporate basic research into therapeutic trials, a vacuum all too often present in clinical intervention.

Background Drug-specific CD8+ TH1 lymphocytes have been found in the peripheral blood and involved skin of patients with drug-induced bullous exanthems.

Objectives To determine whether the interferon-gamma release test can identify culprit drugs in pemphigus patients.

Methods Clinical and laboratory workup for pemphigus was performed in 14 pemphigus vulgaris patients who had been exposed to drugs, and the IFNl[1] release test was conducted on their lymphocytes from heparinized venous blood cultured with medium, phytohemagglutinin and one of 32 drugs, or medium and phytohemagglutinin alone.

Results Ten of the patients and 13 of the 32 drugs exhibited a positive response to the test. Eight of the 10 patients with positive IFNl test results had a less severe course of the disease, with fast reduction in steroid dosage.

Conclusions The findings demonstrate both the ability of the IFNl release test to identify drugs that can induce pemphigus, and its usefulness in the diagnostic workup of pemphigus patients.

Neonatal lupus erythematosus is an uncommon transplacentally Acquired Autoimmune Disorder. The most common clinical manifestations are skin rash, congenital atrioventricular block, thrombocytopenia, leucopenia, anemia, and hepatosplenomegaly. Usually, the skin rash resembles subacute cutaneous lupus, but different forms of rash have been reported in Neonatal lupus erythematosus and some are rare forms. NLE should be suspected in babies with atypical skin lesions, even if present at birth.  

High mobility group box 1 is a nuclear protein participating in chromatin architecture and transcriptional regulation. When released from cells, HMGB1[1] can also act as a pro-inflammatory mediator or alarmin. Upon stimulation with lipopolysaccharides or tumor necrosis factor-alpha, HMGB1 is secreted from certain cells such as monocytes/macrophages and fosters inflammatory responses. In addition, HMGB1 is passively released from necrotic cells and mediates inflammation and immune activation. In contrast, during apoptotic cell death, nuclear HMGB1 gets tightly attached to hypo-acetylated chromatin and is not released into the extracellular milieu, thereby preventing an inflammatory response. There is accumulating evidence that extracellular HMGB1 contributes to the pathogenesis of many inflammatory diseases, including autoimmune diseases. Increased concentrations of HMGB1 have been detected in the synovial fluid of patients with rheumatoid arthritis. In animal models of RA[2], HMGB1 appears to be crucially involved in the pathogenesis of arthritis, since neutralization of HMGB1 significantly ameliorates the disease. Also, in the serum and plasma of patients with systemic lupus erythematosus we detected substantial amounts of HMGB1, which may contribute to the disease process. However, investigations of blood concentrations of HMGB1 and its relevance in human diseases are hindered by the lack of reliable routine test systems.