Enhanced lymphocyte interferon (IFN)-γ responses in a PTEN mutation-negative Cowden disease kindred.

Abstract

Identification of immune modifiers of inherited cancer syndromes may provide a rationale for preventive therapy. Cowden disease (CD) is a genetically heterogeneous inherited cancer syndrome that arises predominantly from germline phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation and increased phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) signalling. However, many patients with classic CD diagnostic features are mutation-negative for PTEN (PTEN M-Neg). Interferon (IFN)-γ can modulate the PI3K/mTOR pathway, but its association with PTEN M-Neg CD remains unclear. This study assessed IFN-γ secretion by multi-colour flow cytometry in a CD kindred that was mutation-negative for PTEN and other known susceptibility genes. Because IFN-γ responses may be regulated by killer cell immunoglobulin-like receptors (KIR) and respective human leucocyte antigen (HLA) ligands, KIR/HLA genotypes were also assessed. Activating treatments induced greater IFN-γ secretion in PTEN M-Neg CD peripheral blood lymphocytes versus healthy controls. Increased frequency of activating KIR genes, potentially activating KIR/HLA compound genotypes and reduced frequency of inhibitory genotypes, were found in the PTEN M-Neg CD kindred. Differences of IFN-γ secretion were observed among PTEN M-Neg CD patients with distinct KIR/HLA compound genotypes. Taken together, these findings show enhanced lymphocyte secretion of IFN-γ that may influence the PI3K/mTOR CD causal molecular pathway in a PTEN mutation-negative CD kindred.

• Authors: R Stevenson, A Fatehullah, I Jagan, R K Deevi, V Bingham, A E Irvine, M Armstrong, P J Morrison, I Dimmick, R Stewart, F C Campbell
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 164 Issue 2 Pg. 202-10 (May 2011) ISSN: 1365-2249 [Electronic] England
• PMID: 21361912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

Chemical References

• HLA Antigens
• Receptors, KIR
• Ionomycin
• Interferon-gamma
• MTOR protein, human
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Female
• Flow Cytometry
• Genotype
• HLA Antigens (biosynthesis)
• Hamartoma Syndrome, Multiple (genetics, metabolism)
• Haplotypes (genetics)
• Humans
• Interferon-gamma (metabolism)
• Ionomycin (pharmacology)
• Killer Cells, Natural (drug effects, immunology)
• Male
• PTEN Phosphohydrolase (analysis)
• Pedigree
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Polymerase Chain Reaction
• Receptors, KIR (physiology)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)