On predictions from spontaneously broken flavor symmetries

We discuss the predictive power of supersymmetric models with flavor symmetries, focusing on the lepton sector of the standard model. In particular, we comment on schemes in which, after certain `flavons' acquire their vacuum expectation values (VEVs), the charged lepton Yukawa couplings and the neutrino mass matrix appear to have certain residual symmetries. In most analyses, only corrections to the holomorphic superpotential from higher-dimensional operators are considered (for instance, in order to generate a realistic $\theta_{13}$ mixing angle). In general, however, the flavon VEVs also modify the K\"ahler potential and, therefore, the model predictions. We show that these corrections to the naive results can be sizable. Furthermore, we present simple analytic formulae that allow us to understand the impact of these corrections on the predictions for the masses and mixing parameters.Comment: 12 pages, 4 figures; improved version matching PLB articl

Predictivity of models with spontaneously broken non-Abelian discrete flavor symmetries

In a class of supersymmetric flavor models predictions are based on residual symmetries of some subsectors of the theory such as those of the charged leptons and neutrinos. However, the vacuum expectation values of the so-called flavon fields generally modify the K\"ahler potential of the setting, thus changing the predictions. We derive simple analytic formulae that allow us to understand the impact of these corrections on the predictions for the masses and mixing parameters. Furthermore, we discuss the effects on the vacuum alignment and on flavor changing neutral currents. Our results can also be applied to non--supersymmetric flavor models.Comment: 34 pages, 4 figures, related Mathematica package can be found at http://einrichtungen.ph.tum.de/T30e/codes/KaehlerCorrections/, updated version with added reference, matching NPB articl

Chronic Inflammatory Demyelinating Polyneuropathy – immune markers for diagnosis, therapy strategies and prognosis

Die Chronisch Inflammatorische Demyelinisierende Polyneuropathie (CIDP) ist die häufigste autoimmune periphere Neuropathie und führt bei mehr als 50% der Patienten zu gravierender Behinderung. Mit einer Prävalenz von 0,8-8,9:100.000 bleibt sie eine seltene Erkrankung, die aber aufgrund variabler klinischer Manifestationsformen und fehlender Diagnosemarker wahrscheinlich unterdiagnostiziert ist. Ziel der Studie war es, Immunmarker zu identifizieren, die prädiktiv Aussagen über den individuellen Krankheitsverlauf erlauben sowie als Diagnoseparameter herangezogen werden können. Zu diesem Zweck erhoben wir prospektiv bei 28 klinisch-instabilen CIDP-Patienten zu 5 Untersuchungszeitpunkten über 12 Monate immunologische Parameter (mittels Enzyme Linked Immunosorbent Spot Assay-ELISPOT, Fluorescence Activated Cell Sorting-FACS). Wir formulierten anhand der aktuellen Literatur Arbeitshypothesen, unterteilten unsere Kohorte in Subgruppen und verglichen sie mit 28 gesunden Kontrollprobanden. Im Ergebnis konnten wir sowohl signifikant erhöhte T-Lymphozyten-Antworten auf periphere Myelinantigene als auch signifikant höhere Frequenzen einzelner Lymphozytenpopulationen (vor allem CD4+ Memory T-Lymphozyten) beobachten. Erstmals war es möglich, signifikant erhöhte P0 180-199- und MBP 82-100-spezifische T-Lymphozyten-Antworten zu messen, was für die immunpathogenetische Relevanz dieser peripheren Myelinantigene sprechen könnte. In der Subgruppenanalyse zeigten sich bei atypischen CIDP-Verläufen tendenziell höhere T-Lymphozyten-Antworten auf PMP-22, P0 180-199 und MBP 82-100 sowie signifikant erhöhte Frequenzen der T-Lymphozyten, insbesondere der CD4+ Effector Memory T-cells (TEM) und der CD4+ Central Memory T-cells (TCM). Dies nutzten wir post-hoc zur Definition von Schwellenwerten, die zukünftig in Studien überprüft werden müssen und dann gegebenenfalls (ggf.) zur Diagnosestellung bei atypischen Krankheitsverläufen herangezogen werden können. Da die CIDP meist chronisch-progredient verläuft und Patienten mit einer gravierenderen klinischen Beeinträchtigung daher häufig schon länger betroffen sind, verglichen wir die Subgruppen „Zeit seit Diagnosestellung“ und „Inflammatory Neuropathy Cause And Treatment (INCAT) Score“ miteinander. Interessanterweise zeigten Patienten mit kürzerer Krankheitsdauer (≤2 Jahre) und auch Patienten mit geringerem Schweregrad (INCAT≤2) tendenziell höhere Myelinantigen-spezifische T-Lymphozyten-Antworten sowie signifikant erhöhte Frequenzen der CD4+ und CD8+ naive T-Lymphozyten. Damit konnten wir erstmals nachweisen, dass Patienten im Frühstadium der CIDP ein starkes inflammatorisches Milieu aufweisen können. Diese Ergebnisse könnten nach Bestätigung in weiteren Studien für die Empfehlung von immunmodulatorischen oder –suppressiven Therapien bereits im frühen Krankheitsstadium sprechen. Dies würde die aktuellen Richtlinien ergänzen, die erst ab gravierender klinischer Beeinträchtigung oder Krankheitsprogression zu solchen Therapien raten. Zur Bestätigung unserer explorativen Ergebnisse bedarf es zukünftig groß angelegter, multizentrischer Studien. Wir empfehlen, dass diese einerseits die von uns untersuchten diagnostischen Schwellenwerte prüfen und ggf. etablieren. Andererseits wäre es nützlich, diese Schwellenwerte in Bezug zu CIDP-Subgruppen zu setzen, um prädiktiv eine individuelle Aussage über den Krankheitsverlauf geben zu können.Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the most common autoimmune peripheral neuropathy leading to severe disability in more than 50% of the patients. CIDP remains rare with a prevalence of 0,8-8,9:100.000 but is probably underdiagnosed due to different clinical phenotypes and missing diagnostic markers. The goal of our study was to identify immune markers which would possibly allow us to predict individual course of disease and which could serve as future diagnostic parameters. Therefore, we evaluated 28 patients with active-unstable CIDP over 12 months using 5 immunological examinations (via Enzyme Linked Immunosorbent Spot Assay-ELISPOT, Fluorescence Activated Cell Sorting-FACS). To gain insight into the pathomechanisms of CIDP, we divided our cohort in subgroups, developed hypotheses and compared the results to 28 healthy controls. We could not only find significantly elevated T lymphocyte-immune responses to peripheral myelin antigens but also significantly higher frequencies of lymphocyte subpopulations (especially Memory T cell subsets). For the first time, we showed significantly increased T lymphocyte-responses to P0 180-199 und MBP 82-100 in CIDP-patients which could indicate the immunopathogenic relevance of these two peripheral myelin antigens. Via subgroup-analysis, we described a stronger activated immune system in atypical CIDP based on high myelin antigen-specific T lymphocyte responses as well as significantly elevated frequencies of T lymphocytes, especially CD4+ effector memory T cells (TEM) and CD4+ central memory T cells (TCM). These findings led us to the definition of immunological cut-off parameters which after validation could prospectively be used to diagnose atypical CIDP. Since CIDP mostly progresses chronically, patients with severe disability usually suffered several years from this disease. Therefore we compared the subgroups “time since diagnosis” and “INCAT-score” in order to investigate the autoimmune potential in the early stage of CIDP. Interestingly, we could demonstrate higher auto-inflammatory T lymphocyte- responses to myelin antigens and significantly elevated levels of CD4+ and CD8+ naïve T cells early after diagnosis and in mildly affected patients suggesting an aggressive immune environment. These results should be evaluated in future studies and could after validation recommend early immunosuppressive or –modulating therapies to prevent irreversible axonal degeneration. This recommendation would be an addition to current guidelines which indicate these interventions only in stages of severe clinical disability or disease progression. To confirm our results, further long-term multi-center studies are needed which should confirm our suggested diagnostic cut-off values. Furthermore, a correlation between clinical stage and immunological results is needed to predict the individual’s course of disease

Neurofascin and Compact Myelin Antigen-Specific T Cell Response Pattern in Chronic Inflammatory Demyelinating Polyneuropathy Subtypes

ObjectiveThe objective of this study is to investigate whether chronic inflammatory demyelinating polyneuropathy (CIDP) and its subtypes differ in their type 1 T-helper (TH1) cell response against nodal/paranodal neurofascin (NF186, NF155) as well as myelin protein zero (P0 180–199) and myelin basic protein (MBP 82–100).MethodsInterferon-gamma (IFN-γ) enzyme-linked immunospot assay was used to detect antigen-specific T cell responses in 48 patients suffering typical CIDP (n = 18), distal acquired demyelinating polyneuropathy (n = 8), multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM; n = 9), and sensory CIDP (n = 13) compared to other non-immune polyneuropathy (ON; n = 19) and healthy controls (n = 9).ResultsCompared to controls, MADSAM and sensory CIDP patients showed broadest IFN-γ T cell responses to all four antigens. Positive IFN-γ responses against two or more antigens were highly predictive for CIDP (positive predictive value = 0.95) and were found in 77% of CIDP patients. Patients with limited antigen-specific response were females, more severely affected with neuropathic pain and proximal paresis. The area under the receiver operating characteristics curve (AUC) of NF186 in MADSAM was 0.94 [95% confidential interval (CI) 0.82–1.00] compared to ON. For sensory CIDP, AUC of P0 180–199 was 0.94 (95% CI 0.86–1.00) and for MBP 82–100 0.95 (95% CI 0.88–1.00) compared to ON.ConclusionCell-mediated immune responses to (para)nodal and myelin-derived antigens are common in CIDP. TH1 response against NF186 may be used as a biomarker for MADSAM and TH1 responses against P0 180–199 and MBP 82–100 as biomarkers for sensory CIDP. Larger multicenter studies study are warranted in order to establish these immunological markers as a diagnostic tools