ImmunArray Key Publications Portfolio
Systemic Lupus Erythematosus (SLE)
1. Massenburg D, Oldenberg J, Sell A, Krause T and Wells A.F, Rheumatology and Immunotherapy Center, Franklin, WI, “Using the SLE-key® Rule-Out Test in Clinical Practice”, Lupus: Open Access, Received date: April 10, 2017; Accepted date: May 10, 2017; Published date: May 26, 2017
Conclusions: The SLE-key® Rule-Out test increased efficiency in saving undue concern, time and resources both to the patient and to the healthcare system.
2. Massenburg D, Oldenberg J, Sell A, Krause T, Wells A.F. “An Antigen Microarray to Rule-out Systemic Lupus Erythematosus, the SLE-Key® Rule-out Test, Performs Well as an Aid in Clinical Practice.” ACR 2016 meeting. Arthritis Rheumatol. 68 (suppl 10) 2016.
Conclusion: While the incidence of SLE is relatively low, ANA testing and the subsequent referrals of patients with positive ANA and/or ENA to tertiary care specialists creates an unnecessary burden on the health care system resulting in increased waiting time for rheumatology consultations. The SLE-key® rule out test provides a laboratory aid to improve diagnosis and to increase the efficiency of disposition; thus saving undue concern, time and resources to both patients and the healthcare system. In a multisite cohort, SLE was ruled out in 65% of 159 ANA positive patients. In our 55 patient cohort, the SLE-key® test provided actionable clinical information, leading to termination of evaluation for SLE or initiation of therapy. Multi-center experience is warranted to further validate the clinical advantages of this serologic multi-analyte test.
3. Putterman C, Safer P, Tamir I, Jakobi K, Sorek R, Gilkaite I, Ferber K, Wallace S, Harris Altice A, Batty S, and Cohen I.R. “Autoantibody Reactivities Correlated with SLE Disease Activity Identified By the SLE-key® iCHIP®” ACR 2016 meeting. Arthritis Rheumatol. 68 (suppl 10) 2016.
Conclusion: The iCHIP® platform can be used to successfully separate between SLE patients with high and low SLEDAI scores. Our analysis suggests that in addition to being useful for the development of a single MAAA test (Multianalyte Assays with Algorithmic Analyses) the iCHIP® can also provide information regarding the mechanisms related to disease activity and a window to support development of therapeutic options for these patients.
4. Cohen IR, “Antigen-Microarray Profiling of Antibodies in SLE: A Personal View of Translation from Basic Science to the Clinic.” Lupus Open Access 2016, 1:3.
Conclusion: A review of the development of the first iChip® product – the SLE-key® Rule Out test – describes how basic observations and a philosophical notion of how the immune system functions led to the development by a company to a clinically useful product for dealing with complex diseases, the first of which is SLE, and why SLE, like other complex medical problems, can be better managed using immune profiling.
5. Putterman C, Safer P, Jakobi K, Sorek R, Gilkaite I, Wallace S, Harris Altice A, Batty DS, Cohen I. “SLE-key® iCHIP® Platform Identifies a ‘Lupus Autoantibodies Signature’ Early in Disease Which Persists Independent of Disease Duration and Activity.” Lupus 2016 meeting. Venice; October 5-8, 2016
Conclusion: The SLE-key® microarray test that we previously reported for reliably ruling out SLE detects a lupus signature close to diagnosis which persists independent of disease activity or duration. This signature is stable, and even patients with inactive disease are clearly differentiated from healthy individuals.
6. Putterman C, Wu A, Reiner-Benaim A, Batty DS, Sanz I, Oates J, Jakobi K, Petri M, Safer P, Gerwien R, Sorek R, Blumenstein Y, Cohen IR. (2015). SLE-key® Rule-Out Serologic Test for Excluding the Diagnosis of Systemic Lupus Erythematosus: Developing the ImmunArray iCHIP®, The Journal of Immunological Methods, 2016, 429, 1-6.
Conclusion: The iCHIP® autoantibody detection platform combined with a multi-analyte-based assay with an algorithm is able to overcome the complexity and variability inherent in SLE to enable clear discrimination between affected and unaffected individuals. The SLE-key® rule-out test device achieves a sensitivity of 94% and a specificity of 75% and NPV of 93%.
7. Fattal I, Shental N, Molad Y, Gabrielli A, Pokroy-Shapira E, Oren S, Livneh A, Langevitz P, Pauzner R, Sarig O, Gafter U, Domany E, Cohen IR, Epstein–Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA, Immunology, 141(2), 276-285. 2014 Feb.
Conclusion: the ability of the antigen microarray to measure quantitative reactivity to a relatively large set of antigens present in a relatively small volume of blood provides a novel view of complex diseases. Characterization of antibody repertoires in SLE, SSc and other autoimmune diseases may pave the way to serological diagnosis of disease and a better understanding of the complex pathological processes unique for SLE or shared with other conditions.
8. Fattal I, Shental N, Mevorach D, Anaya JM, Livneh A, Langevitz P, Zandman-Goddard G, Pauzner R, Lerner M, Blank M, Hincapie ME, Gafter U, Naparstek Y, Shoenfeld Y, Domany E, Cohen IR. An antibody profile of systemic lupus erythematosus detected by antigen microarray, Immunology 2010 Jul;130(3):337-43. Epub 2010 Feb 26.
Conclusion: Our antigen microarray and informatic views of SLE differ considerably from the standard ways of characterizing antibodies in lupus and from the ways in which others have deployed antigen microarrays to study SLE. The data appear to be meaningful: the signal generated by the microarray was prominent and highly significant statistically. Moreover, the subjects were recruited from three different centres on two continents, and the core reactivity profile was robust in being able to detect subjects in remission for as long as 30 years, as well as one subject who was diagnosed with clinical SLE more than 1 year after her serum sample was collected and tested. Microarray technology and informatic analysis thus provide a promising entry into immunomics – a global view of a subject’s immune state.
9. Fattal I, Rimer J, Shental N, Molad Y, Gabrielli A, Livneh A, Sarig O, Goldberg I, Gafter U, Domany E, Cohen IR. Pemphigus Vulgaris is characterized by low IgG reactivities to specific self-antigens along with high IgG reactivity to Desmoglein 3. Immunology. 2014 May 12.
Conclusion: Here we studied the antibody signatures of Pemphigus vulgaris (PV) patients compared with healthy subjects and with patients with two other autoimmune diseases with skin manifestations (systemic lupus erythematosus (SLE) and scleroderma), using an antigen microarray and informatics analysis. Patients with PV, compared with the healthy subjects and the two other diseases, show a significant decrease in IgG autoantibodies to a specific set of self-antigens. This novel finding demonstrates that an autoimmune disease may be associated with a loss of specific, healthy IgG autoantibodies and not only with a gain of specific, pathogenic IgG autoantibodies.
10. Fattal I, Shental N, Molad Y, Gabrielli A, Shapira E, Oren S, Livneh A, Langevitz P, Pauzner R, Sarig O, Gafter U, Domany E, Cohen IR. “EBV Antibodies Mark SLE and Scleroderma Patients Negative for Anti-DNA.” Immunology, 2014 Feb;141(2):276-85. doi: 10.1111/imm.12200.
Conclusion: Many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein–Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The Scleroderma patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.
11. Quintana JF, Merbl Y, Sahar E, Domany E, Cohen IR. “Antigen-chip technology for accessing global information about the state of the body.” Lupus, 2006; 15: 428-430.
Conclusion: The state of the body appears to be encoded by the immune system in collectives of reactivities and not by single reactivities. Here we describe our use of microarray technology and informatics to develop an antigen chip capable of detecting global patterns of antibodies binding to hundreds of antigens simultaneously. The patterns fashion diagnostic signatures.
12. Herkel J, Erez-Alon N, Mimran A, Wolkowicz R, Harmelin A, Ruiz P, Rotter V. Cohen IR. “Systemic lupus erythematosus in mice, spontaneous and induced, is associated with autoimmunity to the C-terminal domain of p53 that recognizes damaged DNA.” Eur J Immunol 2000; 30(4):977-84.
Conclusion: The tumor suppressor molecule p53 features a regulatory domain at the C terminus that recognizes damaged DNA. Since damaged DNA might be involved in activating anti-DNA autoantibodies, we tested whether autoimmunity to the C terminus of p53 might mark murine systemic lupus erythematosus (SLE). It was reported in this paper that MRL/MpJ-Faslpr mice, which spontaneously develop SLE, produce antibodies both to the C terminus of p53 and to a monoclonal antibody (PAb-421) that binds the p53 C terminus. This, immunization of BALB/c mice to PAb-421 induced anti-DNA antibodies and antibodies to the C terminus of p53, and most of the mice developed an SLE-like disease. Network autoimmunity to the domain of p53 that recognizes damaged DNA can be a pathogenic feature in SLE in genetically susceptible strains of mice.
13. Herkel J, Mimran A, Erez N, Kam N, Lohse AW, Marker-Hermann E, Rotter V, Cohen IR. “Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies.” J Autoimmun 2001; 17(1):63-9.
Conclusion: On this study, it was reported that SLE patients, in addition to anti-DNA, produce antibodies to the carboxy-terminal domain of the tumour suppressor molecule p53. Binding of affinity-purified anti-DNA both to DNA and to the anti-p53 antibody could be blocked by a p53 peptide derived from the DNA-binding domain. This mimicry of the p53 DNA-binding domain by the SLE anti-DNA antibodies is functional: activation of the p53 molecule could be inhibited by such anti-DNA antibodies. Thus, anti-DNA antibodies may arise in SLE patients by a chain of idiotypic autoimmunity centered around p53 autoimmunity. Thus, it is possible that anti-DNA might aggravate cell damage by inhibiting p53-dependent apoptosis.
1. Bransburg-Zabary S, Kenett DY, Dar G, Madi A, Merbl Y, Quintana FJ, Tauber AI, Cohen IR, Ben-Jacob E., Individual and meta-immune networks, Physical biology, 10(2), 025003. 2013 Mar 15.
Conclusion: The use of network science conceptual and methodological approaches is prevalent in a variety of scientific disciplines. In our works we presented a new approach to investigate antigen microarray data of autoantibody reactivity of IgM and IgG isotypes present in the sera of 10 mothers and their newborns. We were able to show that using advanced network analysis tools, mainly developed in physics, new findings regarding immune development can be uncovered. We were able to show the immune repertoire, which represents both antibody reactivity to antigens, and can be treated as a network.
2. Madi A, Kenett DY, Bransburg-Zabary S, Merbl Y, Quintana FJ, Boccaletti S, Tauber AI, Cohen IR, Ben-Jacob E. “Analyses of antigen dependency networks unveil immune system reorganization between birth and adulthood.” Chaos 2011 Mar;21(1):016109.
Conclusion: We investigated antigen dependency networks computed from antigen microarray data of autoantibody reactivity of IgM and IgG isotypes present in the sera of ten mothers and their newborns. Networks comparison in terms of modularity and of topology revealed that, at birth, the IgG networks exhibit a more profound global reorganization while the IgM networks exhibit a more profound local reorganization. During immune system development, the modularity of the IgG network increases and becomes comparable to that of the IgM networks at adulthood.
3. Madi A, Kenett DY, Bransburg-Zabary S, Merbl Y, Quintana FJ, Tauber AI, Cohen IR, Ben-Jacob E. “Network theory analysis of antibody-antigen reactivity data: the immune trees at birth and adulthood.” PLoS One2011 Mar 8;6(3):e17445. PMID: 21408156.
Conclusion: Comparison of the immune network topology at birth and adulthood revealed partial conservation of the IgG immune network topology, and significant reorganization of the IgM immune networks. Inspection of the antigen importance revealed some dominant (in terms of high centrality) antigens in the IgG and IgM networks at birth, which retain their importance at adulthood.
4. Cohen SJ, Cohen IR, Nussbaum G. “IL-10 mediates resistance to adoptive transfer experimental autoimmune encephalomyelitis in MyD88(-/-) mice.” J Immunol. 2010 Jan 1;184(1):212-221. Epub 2009 Nov 30.
Conclusion: IL-10–producing anti-MOG T cells isolated from immunized MyD882/2 mice suppressed the induction of active EAE in WT recipients. Moreover, the absence of IL-10 production in MyD88/IL-10 double-knockout mice rendered the mice susceptible to adoptive transfer of EAE. Thus, MyD88 signaling appears to be a key factor in determining the cytokine phenotype of T cells involved in autoimmune inflammation and regulation.
5. Volovitz I, Mor F, Machlenkin A, Goldberger O, Marmor Y, Eisenbach L, Cohen IR. “T-cell seeding: Neonatal transfer of anti-myelin basic protein T-cell lines renders Fischer rats susceptible later in life to the active induction of EAE.” Immunology 2009; 128: 92-102.
Conclusion: T-cell seeding describes the phenomenon reported here in which the injection of resting, antigen-specific T cells endows the recipient with a potential for an enhanced effector T-cell response to a subsequent encounter with the specific antigen without inducing any apparent clinical effects immediately following transfer. A practical question is whether T-cell seeding can be exploited to endow recipients with desirable T-cell effector responses to infectious agents or to tumor cells.
6. Cohen-Sfady M, Pevsner-Fischer M, Margalit R, Cohen IR. “Heat shock protein 60, via MyD88 innate signaling, protects B cells from apoptosis, spontaneous and induced.” J Immunol. 2009 Jul 15;183(2):890-6.
Conclusion: Heat shock protein 60 (HSP60) via TLR4 signaling activates B cells and induces them to proliferate and secrete IL-10. In this paper it was found that HSP60 inhibits mouse B cell apoptosis. B cells incubated with HSP60 manifested prolonged survival following transfer into recipient mice. These results extend the varied role of HSP60 in the innate regulation of the adaptive immune response.
7. Swerdlin N, Cohen IR, Harel D. “The lymph node B cell immune response: Dynamic analysis in silico.” Proceedings of the IEEE. 2008; 96 (8): 1421-43.
Conclusion: Here, we present a fully executable, bottom-up computerized model of the lymph node (LN). We studied the effects of amount of antigen and LN size on the emergent properties of lymphocyte dynamics, differentiation and anatomic localization. The dynamic organization of the LN sheds new light on how the immune system transforms antigen stimulation into a highly sensitive, yet buffered response.
8. Zanin-Zhorov A, Tal G, Shivtiel S, Cohen M, Lapidot T, Nussbaum G, Margalit R, Cohen IR, Lider O. “Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation.” J Immunol. 2005;Jul 1;175(1):276-285.
Conclusion: it was demonstrated that treatment of T cells with the 60-kDa heat shock protein (HSP60) inhibits chemotaxis. It was also demonstrated that the inhibitory effects of HSP60 on SDF-1a-induced T cell responses, in vitro and in vivo, are mediated through up-regulation of cytokine signalling 3 (SOCS3), and implicate a SOCS3-mediated molecular signaling mechanism for the innate effects of HSP60 on T cells. Thus, HSP60 can regulate T cell-mediated inflammation via specific signal transduction and SOCS3 activation.
9. Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A, Kuchroo V, Cohen IR, Weiner H, Schwartz M. “Protective autoimmunity is a physiological response to CNS trauma.” J Neurosci 2001; 21(11):3740-8.
Conclusion: Primary damage caused by injury to the CNS is often followed by delayed degeneration of initially spared neurons. Studies have shown that active or passive immunization with CNS myelin-associated self-antigens can reduce this secondary loss. CNS trauma spontaneously evokes a beneficial T cell-dependent neuroprotective immune response, which reduces neuronal loss.
1. Cohen IR. “Autoantibody repertoires, natural biomarkers and system controllers.” Trends in Immunology. 2013 December; 34 (12): 620-5.
Conclusion: This review describes the use of an antigen microarray device and informatics to profile the repertoires of autoantibodies in health and disease. Autoantibody profiling provides an insight into the biomarkers used by the immune system in its dialog with the body. HSP molecules and peptides can be viewed as natural regulators because the immune system itself deploys them to modulate inflammatory reactions. The discovery of such natural biomarkers paves the way towards control.
2. Madi A, Bransburg-Zabary S, Kenett DY, Ben-Jacob E, Cohen IR. The natural autoantibody repertoire in newborns and adults: a current overview. In Naturally Occurring Antibodies (NAbs), pp. 198-212. Springer New York, 2012.
Conclusion: The recent development of antigen microarray chip technology for detecting global patterns of antibody reactivities makes it possible to study the immune system quantitatively using network analysis tools. Here, we review the analyses of IgM and IgG autoantibody reactivities of sera of mothers and their offspring (umbilical cords) to 300 defined self-antigens; the autoantibody reactivities present in cord blood represent the natural autoimmune repertories with which healthy humans begin life and the mothers’ reactivities reflect the development of the repertoires in healthy young adults.
3. Swiatczak B, Rescigno M, Cohen IR. “Systemic features of immune recognition in the gut.” Microbes Infect. 2011 Nov;13(12-13):983-91.
Conclusion: The immune system, to protect the body, must discriminate between the pathogenic and non-pathogenic microbes and respond to them in different ways. How the mucosal immune system manages to make this distinction is poorly understood. We suggest here that the distinction between pathogenic and non-pathogenic microbes is made by an integrated system rather than by single types of cells or single types of receptors; a systems biology approach is needed to understand immune recognition.
4. Cohen, Irun R; Atlan, Henri; and Efroni, Sol (December 2009) “Genetics as Explanation: Limits to the Human Genome Project.” In Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0005881.pub2.
Conclusion: The genome project has spawned powerful technologies and has opened biology to the age of informatics. The very success of the genome project; biology is now aware of its true complexity. The genome project, wittingly or not, has built the foundation for deeper probes into the complexity of life. The limitations of the project are only the limitations of the genome itself.
5. Cohen IR. Activation of Benign Autoimmunity as Both Tumor and Autoimmune Disease Immunotherapy: A Comprehensive Review. J Autoimmunity. 2014 Jun 9. pii: S0896-8411(14).
Conclusion: Different autoimmune diseases manifest clinically distinct phenotypes and they all result from the transition of benign, healthy recognition of key body molecules into a damaging effector reaction. Tumors, in contrast to autoimmune diseases, grow by subverting the immune system into supporting and protecting the growing tumor from immune surveillance. Inducing the immune system to regulate itself is safer than global immune suppression and may be more effective in the long run.
6. Rimer J, Cohen IR, Friedman N. Do all creatures possess an acquired immune system of some sort? Bioessays. 2014; 36: 273-281.
Conclusion: Recent findings have provided evidence for the existence of non-vertebrate acquired immunity. In this review, these findings were surveyed and propose that all living organisms must express both innate and acquired immunity. Despite incomplete information, we reason that common principles have shaped the evolution of immune systems in all creatures. Indeed, better understanding of other immune systems will provide new insights into our own immunity.
7. Cohen IR. “Infections, Biomarkers, and Vaccines.” in The Art & Science of Tuberculosis Vaccine Development, Eds. N.M. Nor, A. Acosta, and Sarmiento, M.E. Oxford University Press, 2010. pp. 36-45.
Conclusion: the theory of the immunological Homunculus is proposed in this chapter: T cells and B cells with receptors capable of recognizing self-molecules, easily detectable despite being forbidden by the CST, play a physiological role in orchestrating the regulation of inflammation, a process vital both to maintaining the body and to defending it. Thus, immunity cannot be reduced to a simple binary attack-or-not decision. Beyond antigen recognition, the immune system has to decide what type of inflammatory response suits the situation. Moreover, the inflammation that heals the body and the inflammation that destroys pathogens are dynamic processes; they evolve with the changing state of the healing or the infection.
8. Quintana FJ, Cohen IR. The HSP60 immune system network, Trends in Immunology February 2011, Vol. 32, No. 2.
Conclusion: The natural roles of HSP60 in immune regulation recommend that we continue to explore its potential both in the context of cancer and autoimmune disorders. Its dual role as a biomarker and an immune modulator offer a physiologic avenue to monitor the inflammatory response in health and disease, and to amend the architecture of immune networks for therapeutic purposes.
9. Cohen IR. “Biomarker vaccines.” Human Vaccines 2009;5(9):637-639.
Conclusion: Effective vaccine should be fashioned to provide the immune system with the information it needs to prepare an immune response that annuls or circumvents the pathogen’s game plan. An effective vaccine can engineer the host immune response by using effective biomarkers. the immune system is an accomplished healthcare specialist; vaccines should be designed to allow us to talk to it in its own biomarker language.
10. Cohen IR, Klareskog L. “Antiinflammatory therapy for rheumatoid arthritis?” Arthritis & Rheumatism, 2008 Jan; 58:2-4.
Conclusion: It was suggested in this review that if primary inflammation is a necessary feature in the pathogenesis of much rheumatoid arthritis, then anti-inflammatory agents that restore well regulated inflammation might be sufficient to abort or reverse the emerging disease process. It is important to investigate the potential of the glucocorticoid-charged liposome preparation both in patients in whom arthritis has already developed and in individuals with high-risk genetic and autoimmune markers for future disease development.
11. Cohen IR. (2007) “Real and artificial immune systems: computing the state of the body.” Nat Rev Immunol.,2007 Jul;7(7):569-74.
Conclusion: The immune system uses a computational strategy to carry out its many functions in protecting and maintaining the body. The concept of immune computation of body state should influence the technologies used by immunologists and other informatic scientists to model the immune system. State-based modelling languages that simulate dynamic changes in the organizational states of discrete molecules, cells, organisms and species across the scales of life could well fit a computational view of the immune system.
12. Quintana FJ, Cohen IR. “The natural autoantibody repertoire and autoimmune disease.” Biomedicine & Pharmacotherapy, 2004; 58: 276-281.
Conclusion: It was concluded that the repertoire of natural autoantibodies (NA) reflects the susceptibility to develop autoimmune disease by investigating strains of mice known to differ in their susceptibility to autoimmune disease. NA are organized in clusters that can differentiate healthy subjects from patients with several autoimmune diseases. The study of the human repertoire of NA required the development of bio-informatic tools to overcome the variation introduced by individual differences in the genetic background and immune history.
1. Madi A, Hecht I, Bransburg-Zabary S, Merbl Y, Pick A, Zucker-Toledano M, Quintana FJ, Tauber AI, Cohen IR, Ben-Jacob E. “Organization of the autoantibody repertoire in healthy newborns and adults revealed by system level informatics of antigen microarray data.” Proc Natl Acad Sci USA. 2009; Aug 25;106(34):14484-9. Epub 2009 Aug 10.
Conclusion: The natural autoantibody repertoire of humans shows relatively little organization at birth, but, by young adulthood, it becomes sorted out into a modular organization of subgroups (cliques) of correlated antigens. These features revealed by antigen microarrays can be used to define personal states of autoantibody organizational motifs.
2. Merbl Y, Itzchak R, Vider-Shalit T, Louzoun Y, Quintana FJ, Vadai E, Eisenbach L, Cohen IR. “A systems immunology approach to the host-tumor interaction: large-scale patterns of natural autoantibodies distinguish healthy and tumor-bearing mice.” PLoS One, 2009 Jun 25;4(6):e6053.
Conclusion: A systems biology approach to immunology suggests that large-scale patterns in the antibody repertoire might also reflect the functional state of the immune system. Here it was asked whether antibody-repertoire patterns might reflect the state of an implanted tumor. It was found that antibody patterns, but not single antibodies, were informative. These informative patterns included autoantibodies binding to self-molecules not known to be tumor-associated antigens (including insulin, DNA, myosin, fibrinogen) as well as to known tumor-associated antigens (including p53, cytokeratin, carbonic anhydrases, tyrosinase). System-wide profiling of autoantibody repertoires can be informative.
3. Bransburg-Zabary S, Kenett DY, Dar G, Madi A, Merbl Y, Quintana FJ, Tauber AI, Cohen IR, Ben-Jacob E. “Individual and meta-immune networks.” Phys Biol. 2013 Mar 15;10(2):025003.
Conclusion: In this paper it was presented how antigen networks can be used as a model to study network interaction and architecture. Utilizing antigen microarray data of the reactivity of hundreds of antibodies of sera of ten mothers and their newborns, we reconstruct networks, either isotype specific (IgM or IgG) or person specific mothers or newborns and investigate the network properties.
4. Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. (2007) “Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics.” J Clin Invest., 2007 Mar;117(3):712-8.
Conclusion: Humans develop IgM and IgA autoantibodies to relatively uniform sets of self-molecules. The global patterns of maternal IgM autoantibodies significantly diverged from those at birth, although certain reactivities remained common to both maternal and cord samples. Maternal and cord IgG autoantibodies showed essentially identical reactivities. It was found that some self antigens that bind cord autoantibodies were among the target self antigens associated with autoimmune diseases later in life. It is reasonable to conclude that these autoantibodies must provide advantages that offset the occasional autoimmune disease associated with their target autoreactivities.
5. Cohen IR, Quintana FJ, Merbl Y. “Antigen–chip technology for assessing global information concerning the state of the body.” Falk Symposium 142 Autoimmune Liver Disease eds. Dienes H-P, Leuschner U, Lohse AW, Manns MP. Springer 2005; pp. 14-18.
Conclusion: the patterns of reactivity detected using microarray chips will make it possible to profile subjects and identify those who are more likely or less likely to respond to a particular treatment. The new informatics can be expected to provide a new outlook on important medical problems. The antigen chip provides a voice for the immunological homunculus to tell us about the individual’s body state.
6. Quintana FJ, Hagedorn PH, Elizur G, Merbl Y, Domany E, Cohen IR. “Functional immunomics: microarray analysis of IgG autoantibody repertoires predicts the future response of mice to induced diabetes.” Proc Natl Acad Sci U S A., 2004 Oct 5;101: Suppl 2:14615-21. Epub 2004 Aug 12.
Conclusion: an antigen microarray chip was developed to study a model of type 1 diabetes developing in nonobese diabetic male mice in which the disease was accelerated by cyclophosphamide-accelerated diabetes (CAD). A selected panel of 27 different antigens (subset) revealed a pattern of IgG antibody reactivity in the pre-CAD sera that discriminated between the mice resistant or susceptible to CAD. New antigen set became critical for post-CAD repertoire discrimination. Thus, present antibody repertoires can predict future disease, predictive and diagnostic repertoires can differ, and decisive information about immune system behavior can be mined by bioinformatics technology.
Multiple Sclerosis, SLE
1. Volovitz I, Marmor Y, Mor F, Flügel A, Odoardi F, Eisenbach L, Cohen IR. “T cell vaccination induces the elimination of EAE effector T cells: Analysis using GFP-transduced, encephalitogenic T cells.” J Autoimmun. 2010 Sep;35(2):135-144. Epub 2010 Jun 26.
Conclusion: T cell vaccination (TCV) is being used for the treatment of a variety of autoimmune diseases including multiple sclerosis. Several hundreds of people suffering from multiple sclerosis have been treated with TCV using vaccines composed of attenuated (irradiated) autologous, autoimmune T cells responsive to myelin antigens. The direct in vivo effects on the encephalitogenic T cells shown here, demonstrates that Tcell vaccination has significant in vivo effects on the population of encephalitogenic T cells targeted by the process of T-cell vaccination.
2. Achiron A, Lavie G, Kishner I, Stern Y, Sarova-Pinhas I, Ben-Aharon T, Barak Y, Raz H, Lavie M, Barliya T, Faibel M, Cohen IR, Mandel M. “T cell vaccination in multiple sclerosis relapsing–remitting nonresponders patients.” Clin. Immunol 2004:113,155– 160.
Conclusion: Vaccination with autologous autoreactive T cells to MS patients having aggressive MS, to whom immunomodulatory treatments could not induce prolonged remission, was examined. Significant reduction in the number and volume of active lesions, as well as reduction in T2 lesion burden, was demonstrated by quantitative MRI analysis. TCV could serve as a potential alternative therapy for this subgroup of nonresponders patients.
3. Karussis D, Shor H, Yachnin J, Lanxner N, Amiel M, Baruch K, Keren-Zur Y, Haviv O, Filippi M, Petrou P, Hajag S, Vourka-Karussis U, Vaknin-Dembinsky A, Khoury S, Abramsky O, Atlan H, Cohen IR, Abulafia-Lapid R. “T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial.” PLoS One. 2012;7(12):e50478. doi: 10.1371/journal.pone.0050478. Epub 2012 Dec 14.
Conclusion: T-cell vaccination (TCV) for multiple sclerosis (MS) refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. This paper is aiming at evaluating the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial. The results demonstrate the feasibility and safety of the procedure, and provide significant indications of clinical efficacy. Further studies with larger groups of subjects are warranted.
4. Quintana FJ, Farez MF, Viglietta V, Iglesias AH, Merbl Y, Izquierdo G, Lucas M, Basso AS, Khoury SJ, Lucchinetti CF, Cohen IR, Weiner HL. “Antigen microarrays identify unique serum autoantibody signatures associated with different clinical forms and pathologic subtypes of multiple sclerosis.” Proc Natl Acad Sci U S A. 2008;Dec 2;105(48):18889-94.
Conclusion: We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer’s disease, adrenoleukodystropy, and lupus erythematosus. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.
5. Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL. “Antigen microarrays identify CNS-produced autoantibodies in RRMS.” Neurology. 2012 Feb 21;78(8):532-9.
Conclusion: Antigen arrays allow the study of antibody reactivity against a large number of antigens using small volumes of fluid with greater sensitivity than ELISA. These studies provide a new avenue to investigate the local antibody response in the CNS, which may serve as a biomarker to monitor both disease progression and response to therapy in MS.
6. Snir O, Lavie G, Achiron A, Bank I, Benn-Aharon T, Sredni B, Cohen IR, Mandel M. “G-CSF enhances the adhesion of encephalitogenic T cells to extracellular matrix components: a possible mechanism for exacerbation of multiple sclerosis.” J Neuroimmunol. 2006 Mar;172(1-2):145-55.
Conclusion: This study proposes that MS clinical symptoms worsening, noted to occur following treatment with G-CSF, involves enhanced activation of integrin mediated adhesion and cell migration-promoting mechanisms. We demonstrate that G-CSF enhances myelin reactive T cell line adhesion to ECM components in a manner that is at least as strong as TNFa and IFNg. This is likely to trigger inflammatory responses which may flare the disease.
7. Mandel M, Gurevich M, Lavie G, Cohen IR, Achiron A. “Unique gene expression patterns in human T-cell lines generated from multiple sclerosis patients by stimulation with a synthetic MOG peptide. ” Clinical & Developmental Immunology September 2005; 12(3):203-209.
Conclusion: Gene expression patterns of myelin oligodendrocytic glycoprotein (MOG) responsive T-cell lines generated from multiple sclerosis (MS) patients and healthy subjects was explored. It was found that activation in MS that promotes T-cell survival and expansion, has its own state and that the unique gene expression pattern that characterize autoreactive T-cells in MS represent a constellation of factors in which the chronicity, timing and accumulation of damage make the difference between health and disease.
8. Cohen IR. “Autoimmune Inflammation and Multiple Sclerosis.” In Early Indicators Early Treatments Neuroprotection in Multiple Sclerosis, Ed. OR Hommes, G. Commi Springer Publishers.
Conclusion: Inflammation is seen as the cause of MS. Autoimmunity to myelin triggers aberrant inflammation, and this inflammation injures the white matter of the central nervous system (CNS) producing MS. Inflammation has a spectrum of manifestations; gene activation, cells to die or move or proliferate, differentiate etc. Therefore inflammation is a manifold agent for body maintenance. Autoimmune inflammation has the capacity to heal as well as harm, it might be useful to enlist the immune system itself to regulate the type, timing, site and strength of inflammation that takes place in the patient. Modulation of autoimmune inflammation is likely to be more successful if it is instituted as early as possible in the course of the disease.
1. Margel D, Pesvner-Fischer M, Baniel J, Yossepowitch O, Cohen IR. “Stress Proteins and Cytokines are Urinary Biomarkers for Diagnosis and Staging of Bladder Cancer.” European Urology 2011; 59:113-119.
Conclusion: Cancer often involves inflammatory processes. We hypothesized that immune mediators in urine may serve as biomarkers for bladder cancer (BCa). The results showed that Urinary concentrations of IL-8, IL-10, and IL-13 were significantly elevated in BCa. A urinary biomarker might be developed for BCa and raise the possibility that expression of anti-inflammatory cytokines and HSPs might allow BCa to evade immune surveillance.
1. Amir-Kroll H, Riveron L, Sarmiento ME, Sierra G, Acosta A, Cohen IR. “A conjugate vaccine composed of a heat shock protein 60 T-cell epitope peptide (p458) and Neisseria meningitidis type B capsular polysaccharide.” Vaccine. 2006 Oct 30;24(42-43):6555-63.
Conclusion: Meningococcus type B capsular polysaccharide (MnB) is very poorly immunogenic and no vaccine to the antigen exists. MnB was conjugated to the T-cell carrier peptide (p458) derived from the self-60 kDa heat shock protein molecule. The conjugate vaccine was effective in inducing long-lasting IgG antibodies to the MnB antigen in mice. The p458 carrier peptide can induce T-cell help for the switch to IgG Ab to the MnB antigen.
2. Quintana FJ, Carmi P, Mor F, Cohen IR. “Network cross-reactivity: DNA vaccination with HSP70 or HSP90 modulates immunity to HSP60 and inhibits adjuvant arthritis.” Immunology 2004, Medimond Srl, Italy. 2004 pp.207-213.
Conclusion: DNA vaccines coding for human pHSP70 and pHSP90 were used in order to study the control of adjuvant arithritis (AA) by self-HSP molecules other than HSP60. Both pHSP70 and pHSP90 induced T-cell responses to HSP60 and vaccination with pHSP70 triggered the release of endogenous HSP60 to the circulation. The study of the anti-inflammatory mechanisms mediated by HSP could lead to the design of novel therapies for auto-immunity.
3. Quintana FJ, Cohen IR. “DNA vaccines coding for heat-shock proteins (HSPs): tools for the activation of HSP-specific regulatory T cells.” Expert Opinion 2005;5(4):545-554.
Conclusion: HSP specific T-cells can have a regulatory phenotype, controlling arthritogenic T cells and inhibiting adjuvant arithritis (AA) progression. DNA vaccines coding for HSPs were investigated to study the role of these proteins in the regulation of arthritis. It was found that DNA vaccines coding for HSPs may serve not only as tools for the dissection of immunoregulatory mechanisms, but also as agents for the treatment of autoimmune disorders.
4. Quintana FJ, Rotem A, Carmi P, Cohen IR. “Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity.” J Immunol 2000; 165(11):6148-55.
Conclusion: On this study it was reported that Nonobese diabetic (NOD) diabetes can be inhibited by vaccination with a DNA construct encoding human HSP60, with the pcDNA3 empty vector, or with an oligonucleotide containing the CpG motif. Prevention of diabetes was associated with a decrease in the degree of insulitis and with down-regulation of spontaneous proliferative T cell responses to HSP60 and its peptide p277. Immunostimulation by bacterial DNA motifs can modulate spontaneous HSP60 autoimmunity and inhibit NOD diabetes.
1. Hagedorn PH, Burton CM, Carlsen J, Steinbruechel D, Andersen CB, Sahar E, Domany E, Cohen IR, Flyvberg H, Iversen M. “Chronic rejection of a lung transplant is marked by a profile of specific autoantibodies.” Immunology, 2010 Jul;130(3):427-435. Epub 2010 Feb 26.
Conclusion: This study demonstrates that lung transplant recipients show widespread IgG and IgM autoantibody reactivities and that specific patterns of reactivity to self-antigens discriminate between patients with greater and lesser degrees of bronchiolitis obliterans syndrome. Thus, a profile of autoantibodies may reflect pathological processes in the lung allograft, suggesting a role for autoimmunity in chronic rejection leading to Obliterative bronchiolitis.
2. Hagedorn PH, Burton CM, Sahar E, Domany E, Cohen IR, Flyvbjerg H, Iversen M. “Integrative analysis correlates donor transcripts to recipient autoantibodies in primary graft dysfunction after lung transplantation.” Immunology. 2010 Nov 11.
Conclusion: This study demonstrates that lung transplant recipients manifest widespread IgG and IgM autoantibody reactivity, and that specific patterns of reactivity to self-antigens discriminate between patients with and without primary graft dysfunction (PGD). We observed significant positive correlation between differences in IgM reactivity and differences in gene expression levels. This connection between donor lung gene expression and long-lasting recipient IgM autoantibodies towards a specific set of proteins suggests a mechanism for the development of autoimmunity in PGD.