Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later.

BACKGROUND: The CD3 co-receptor complex is essential for signal transduction after specific binding of the T-cell receptor (TCR). CD3E encodes the CD3ε chain, one of the protein components (γ-, δ-, ε- and ζ-chain) of the CD3 co-receptor. As previously reported in one family CD3ε deficiency causes SCID. PATIENT: We report on a patient with SCID due to CD3ε deficiency treated by HLA-haploidentical stem cell transplantation (SCT) (donor: mother) 15 years ago which resulted in development of normal T- and B-cell immunity. Despite conditioning donor cell engraftment was confined to T cells, while all other blood cell lineages remained of patient origin (split chimerism). In spite of normal functions, T-cell numbers never reached normal levels and naïve CD45+RA+ T-cells remained low. At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG. RESULTS: In a retrospective genetic work up 11 years after SCT, a homozygous splice site mutation in CD3E was identified resulting in the loss of CD3ε protein. The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed. DISCUSSION: The clinical presentation of a secondary loss of specific humoral immunity in this constellation of split chimerism after allogeneic haploidentical SCT is unusual and unexpected in a patient with a primary T-cell defect. A most likely explanation is the gradual loss of T-helper-cell function.

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity.

Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m-CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4(+) and CD8(+) HLA-A1-specific T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m-CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases.

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

[Does social support have an impact on the prognosis in cancer?]. / Har sosial støtte betydning for prognosen ved kreftsykdommer?

Social support is a compound concept. It is being used about different aspects of social integration and about the support provided by people in a social network. Increasing research has been done on the effect of social support on malignant diseases. However, weaknesses in the methodology make it difficult to evaluate the results. For example, the concept of social support may not be adequately defined and the aspects of social support that are studied may be somewhat arbitrary. Both epidemiological research and studies on certain groups of patients support the idea that social support influences our health and our life expectancy. We have reviewed the existing literature on the impact of social support on malignant disease to find out if social support has proven to be of any prognostic value in the case of cancer.