Ulm

University | International Graduate School in Molecular Medicine Ulm | Meyerhofstrae, N 27/2.011 | 89081 Ulm

Ulm University | International Graduate School in Molecular Medicine Ulm | Albert-Einstein-Allee 11 | 89081 Ulm

Supervisor: Prof. Dr. Klaus Schwarz, Institute of Transfusion Medicine

Project Title:
Analyzing a signaling defect in disturbed human NK-cell development
Project description:
Inborn errors of the immune system have contributed significantly to the understanding of the
development of the human immune system and its function including the elucidation of major
signaling pathways. Severe combined immunodeficiency (SCID) is the most severe
phenotype of all primary immunodeficiencies in humans. "Classical" SCID is associated with
the absence of T cells due to defects in lymphocyte development. Affected genes encode for
proteins involved in V(D)J recombination (such as RAG1, RAG2, ARTEMIS, DNA-PKcs or
Ligase IV), for cytokine receptors and their signaling intermediates (such as the common
gamma chain, IL-7 receptor alpha chain or JAK3), for proteins involved in TCR signalling
(various chains of the CD3 complex, CD45) or enzymes involved in nucleotide (ADA, PNP)
or energy metabolism (AK2). The SCID phenotype can also manifest in patients with partly
reduced or normal numbers of T cells, which are poorly functional. Affected genes mostly
encode proteins that are involved in T-cell receptor and co-receptor signaling (such as ZAP70, ORAI1 or STIM1, CARD11, IKK2). Combined immunodeficiency (CID) is a less severe
phenotype associated with T-cell deficiency. A relevant proportion of patients carry
hypomorphic (leaky) mutations in SCID-causing genes. Another group of patients carry null
or hypomorphic mutations in genes that are relevant, but not absolutely essential for T-cell
development or function. Examples include genes encoding proteins that are involved in
thymic maturation (FOXN1, 22q11, CORONIN 1A) or TCR signalling (TCR alpha, ZAP70,
LCK, ITK, STIM1, MAGT1, MALT1, RHOH).
Isolated human B-cell deficiencies have helped to define the (pre-) BCR signalling cascade
by exhibiting defects of the BCR itself or of IGLL, CD79A/B, BLNK and PIK3R1. Patients with
these defects have no or only very low B cell numbers and lack immunoglobulins.
Very recently, the generation of patient human induced pluripotent stem cells (hiPSC) from
primary dermal fibroblasts and the in vitro differentiation of hiPSC into various cell
compartments opened an avenue for disease specific cellular models and analyses with
otherwise sparse or unobtainable material.
It is to be expected that the genetic analysis of unexplored primary human
immunodeficiencies will help to establish hiPSC derived cell models and will elucidate
signaling pathways involved in lymphocyte development and function. This knowledge will
pave the way for the design of small molecular inhibitory compounds to be used in oncology
and/or haematology as exemplified by BTK- or JAK inhibitors.