Y. Shoenfeld, B. Gilburd, M. Abu-Shakra, H. Amital, O. Barzilai, Y. Berkun, M. Blank, G. Zandman-Goddard, U. Katz, I. Krause, P. Langevitz, Y. Levy, H. Orbach, V. Pordeus, M. Ram, Y. Sherer, E. Toubi and Y. Tomer
Y. Shoenfeld, G. Zandman-Goddard, L. Stojanovich, M. Cutolo, H. Amital, Y. Levy, M. Abu-Shakra, O. Barzilai, Y. Berkun, M. Blank, J.F. de Carvalho, A. Doria, B. Gilburd, U. Katz, I. Krause, P. Langevitz, H. Orbach, V. Pordeus, M. Ram, E. Toubi and Y. Sherer
Y. Shoenfeld, M. Blank, M. Abu-Shakra, H. Amital, O. Barzilai, Y. Berkun, N. Bizzaro, B. Gilburd, G. Zandman-Goddard, U. Katz, I. Krause, P. Langevitz, I.R. Mackay, H. Orbach, M. Ram, Y. Sherer, E. Toubi and M.E. Gershwin
R.E. Voll, V. Urbonaviciute, M. Herrmann and J.R. Kalden
High mobility group box 1 is a nuclear protein participating in chromatin architecture and transcriptional regulation. When released from cells, HMGB1 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, 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.
E. Zifman and H. Amitai
Medical screening is not a tangible existent tool in autoimmune disorders as it is in other illnesses. Numerous attempts are made to identify individuals destined to develop an autoimmune disease, including analysis of the genetic background, which along with the immunological profile, may assist in identifying those individuals. If these efforts turn out to be successful they may lead to the possibility of proactive measures that might prevent the emergence of such disorders. This review will summarize the attempts made to pursue autoantibodies specific for the central nervous system as potential predictors of autoimmune neurological disorders.
M. Szyper-Kravitz, A. Altman, J.F. de Carvalho, F. Bellisai, M. Galeazzi, Y. Eshet and Y. Shoenfeld
The antiphospholipid syndrome is characterized by recurrent fetal loss, venous and/or arterial thrombosis, and thrombocytopenia associated with elevated titers of lupus anticoagulant and anticardiolipin antibodies. Although thrombosis is the characteristic vascular involvement in APS, the development of vascular aneurysms in patients with APS has been reported. We describe four patients with established APS, who developed abdominal aortic aneurysm, and review the literature on previous published cases of arterial aneurysms developing in patients with APS. In addition, we discuss the possible pathophysiological association between APS and the development of this vascular abnormality.
Y. Sherer, S. Kuechler, J. Jose Scali, J. Rovensky, Y. Levy, G. Zandman-Goddard and Y. Shoenfeld
Background: Systemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations that cannot always be regulated by steroids and immunosuppressive therapy. Intravenous immunoglobulin is an optional immunomodulatory agent for the treatment of SLE, but the appropriate indications for its use, duration of therapy and recommended dosage are yet to be established. In SLE patients, most publications report the utilization of a high dose (2 g/kg body weight) protocol.
Objectives: To investigate whether lower doses of IVIg are beneficial for SLE patients.
Methods: We retrospectively analyzed the medical records of 62 patients who received low dose IVIg (approximately 0.5 g/kg body weight).
Results: The treatment was associated with clinical improvement in many specific disease manifestations, along with a continuous decrease in SLEDAI scores (SLE Disease Activity Index). However, thrombocytopenia, alopecia and vasculitis did not improve following IVIg therapy.
Conclusions: Low dose IVIg is a possible therapeutic option in SLE and is associated with lower cost than the high dose regimen and possibly fewer adverse effects.
S. Fuchs, T. Feferman, R. Meidler, T. Brenner, O. Laub and M.C. Souroujon
Backgraound: Intravenous immunoglobulin administration has been beneficially used for the treatment of a variety of autoimmune diseases including myasthenia gravis, although its mode of action and active components have not yet been fully identified.
Objectives: To isolate from IVIg a disease-specific fraction involved in the therapeutic activity in myasthenia and to identify its properties and function.
Results: IVIg administration in experimental autoimmune MG results in suppression of disease that is accompanied by decreased Th1 cell and B cell proliferation. Chromatography of IVIg on columns of IgG from rats with EAMG or from MG patients resulted in depletion of the suppressive activity that IVIg has on rat EAMG. Moreover, the minute amounts of IgG fractions eluted from the EAMG or MG-specific columns retained the immunosuppressive activity of IVIg.
Conclusions: Our study supports the notion that the therapeutic effect of IVIg is mediated by a minor disease-specific immunoglobulin fraction that is present in IVIg and is essential for its therapeutic activity.
V. Pordeus, O. Barzilai, Y. Sherer, R.R. Luiz, M. Blank, N. Bizzaro, D. Villalta, J-M. Anaya and Y. Shoenfeld
Background: Infectious agents are important in the pathogenesis of autoimmune disease since they are a major part of the environmental trigger of autoimmunity. A negative relationship between latitude and infectious disease species richness has been suggested.
Objectives: To examine whether their prevalence differs in two latitudinally different populations.
Methods: The prevalence of infections with Toxoplasma gondii, rubella virus, cytomegalovirus, Epstein-Barr virus and Treponema pallidum was compared between subjects from Italy and Colombia.
Results: We found high titers of antibodies against four of five microorganisms tested, Toxoplasma gondii (50.8%), rubella virus (German measles) (75%), cytomegalovirus (86.3%), Epstein-Barr virus (83.3%) and Treponema pallidum (6.3%) in completely healthy individuals from a tropical country (Colombia) and a European country (Italy). Differences between two groups of volunteers were noted regarding two infectious agents. The prevalence of immunoglobulin G anti-rubella antibodies was significantly higher among Italian subjects (85% vs. 67.9%, P = 0.002), whereas antibodies against CMV were less prevalent among Italian as compared to Colombian subjects (77% vs. 92.9%, P < 0.001).
Conclusions: These differences might also result in a different tendency towards development of autoimmune diseases associated with these infectious agents in different populations.
G. Zandman-Goddard and Y. Shoenfeld
Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA structures, signaling pathways and protein catalysts. Ferritin synthesis is regulated by cytokines (tumor necrosis factor-alpha and interleukin-1α) at various levels (transcriptional, post-transcriptional, translational) during development, cellular differentiation, proliferation and inflammation. The cellular response by cytokines to infection stimulates the expression of ferritin genes. The immunological actions of ferritin include binding to T lymphocytes, suppression of the delayed-type hypersensitivity, suppression of antibody production by B lymphocytes, and decreased phagocytosis of granulocytes. Thyroid hormone, insulin and insulin growth factor-1 are involved in the regulation of ferritin at the mRNA level. Ferritin and iron homeostasis are implicated in the pathogenesis of many disorders, including diseases involved in iron acquisition, transport and storage (primary hemochromatosis) as well as in atherosclerosis, Parkinson's disease, Alzheimer disease, and restless leg syndrome. Mutations in the ferritin gene cause the hereditary hyperferritinemia-cataract syndrome and neuroferritinopathy. Hyperferritinemia is associated with inflammation, infections and malignancies, and in systemic lupus erythematosus correlates with disease activity. Some evidence points to the importance of hyperferritinemia in dermatomyositis and multiple sclerosis, but further mechanistic investigations are warranted.
Y. Katz, M.R. Goldberg, G. Zadik-Mnuhin, M. Leshno and E. Heyman
Background: Immunoglobulin E-mediated allergy to cow’s milk protein represents a major problem for infants who are not breast fed. A search for substitute milks revealed a cross-allergenicity to milk derived from goat and sheep but not to milk from a mare. We noted that the cow, goat and sheep species are both artiodactyls and ruminants, defining them as kosher animals, in contrast to the mare.
Objectives: To determine whether patients with IgE-mediated cow’s milk allergy are cross-sensitized to milk from other species such as the deer, ibex, buffalo, pig and camel.
Methods: Patients with a clinical history consistent with IgE-mediated cow's milk protein allergy were tested by skin prick test to validate the diagnosis. They were then evaluated by skin-prick test for cross-sensitization to milk-derived proteins from other species.
Results: All patients allergic to cow's milk tested positive by skin-prick test for cross-reactivity to deer, Ibex and buffalo (n=24, P = 0). In contrast, only 5 of the 24 patients (20.83%) tested positive to pig milk and only 2 of 8 (25%) to camel’s milk. Cross-sensitization to soy milk was noted in 4 of 23 patients (17.39%), although they all tolerated oral ingestion of soy-containing foods.
Conclusions: A significant cross-sensitization to milk proteins derived from kosher animals exists in patients allergic to cow's milk protein, but far less so compared to the milk proteins from non-kosher animals tested. Patients with proven IgE-mediated allergy to cow’s milk can utilize the above findings to predict suitable alternative sources of milk.