A3 Genetic and immunological variability in patients with lymphoproliferation and autoimmunity


PRINCIPAL INVESTIGATOR
AND CO-INVESTIGATORS
OF THE SUBPROJECT

Bild von PD Dr. med. Carsten Speckmann

Carsten Speckmann

Carsten Speckmann, PD Dr. med.
CCI – Centre of Chronic Immunodeficiency
University Medical Center Freiburg
Breisacher Str. 117 – 2. OG
79106 Freiburg
Phone: +49 761 270-77550
Fax: +49 761 270-77600
E-Mail: carsten.speckmann@uniklinik-freiburg.de

Bild von Dr. med. Anne Rensing-Ehl

Anne Rensing-Ehl

Anne Rensing-Ehl, Dr. med.
CCI – Centre of Chronic Immunodeficiency
University Medical Center Freiburg
Breisacher Str. 117 – 2. OG
79106 Freiburg
Phone: +49 761 270-77550
Fax: +49 761 270-77600
E-Mail: anne.rensing-ehl@uniklinik-freiburg.de

Bild von Prof. Stephan Ehl

Stephan Ehl

Stephan Ehl, Prof. Dr. med.
CCI – Centre of Chronic Immunodeficiency
University Medical Center Freiburg
Breisacher Str. 117 – 2. OG
79106 Freiburg
Phone: +49 761 270-77550
Fax: +49 761 270-77600
E-Mail: stephan.ehl@uniklinik-freiburg.de


TITLE OF SUBPROJECT

Genetic and immunological variability in patients with lymphoproliferation and autoimmunity


CONDITION/TOPIC

Autoimmune Lymphoproliferative Syndrome (ALPS) (OMIM*601859).


OBJECTIVE(S) 

This study will use the PID-NET registry of patients with lymphoproliferation and autoimmunity to achieve three main objectives:

  1. To determine the value of biomarkers for the evaluation of response to therapy and prognosis in patients with ALPS-FAS.
  2. To identify novel pathways for the pathogenesis of early-onset lymphoproliferation and autoimmunity.
  3. To understand the role of Fas in human T cell differentiation and DNT ontogeny.

 

SUMMARY

Lymphoproliferation and autoimmunity are frequent manifestations of primary immunodeficiencies, but the genetic and pathophysiological basis remains poorly understood. In the PID-NET registry, we have enrolled 300 patients with lymphoproliferation and autoimmunity, 60 of which carry mutations in the FAS gene. In the last funding period, we have established diagnostic biomarkers allowing prediction of FAS mutations with high specificity. These prospective biomarker studies shall be extended to determine their value for monitoring disease activity and response to therapy. Exome sequencing of sorted double negative T cells will be performed to detect novel genetic defects associated with lymphoproliferation and autoimmunity. We will also better characterize the clinical and immunological phenotype in a subgroup of about 60 patients with normal biomarkers, but early (<6J) onset of lymphoproliferation and cytopenia. Since most cases are sporadic, grouping patients into phenotypic clusters will facilitate identification of novel genes. On a cell biological level, we have shown that Fas determines differentiation of CD4+ and CD8+ T cells early in their life cycle rather than just eliminating senescent T cells. We will perform transcriptional profiling and signalling studies of Fas positive versus Fas deficient T cells isolated from ALPS-FAS-sLOH patients or generated by FAS knock down to further understand non-apoptotic functions of FAS with the ultimate goal to identify novel principles for therapeutic interventions.