Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). This study evaluated the clinical manifestations, laboratory findings, and molecular genetic results of 215 patients referred as possibly having ALPS. Double-negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by fluorescence-activated cell sorting; interleukin 10 (IL-10) and IL-18 and soluble FAS ligand (sFASL) were measured by enzyme-linked immunosorbent assay. Genetic analysis was performed by next-generation sequencing. Clinical background data were collected from patients' records. Patients were categorized into definite, suspected, or unlikely ALPS groups, and laboratory parameters were compared among these groups. Of 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient populations showed higher DNT percentages than unlikely ALPS and had higher rates of lymphoproliferation. Definite ALPS patients had a significantly more abnormal in vitro apoptosis function, with lower annexin, than patients with suspected ALPS (P = .002) and patients not meeting ALPS criteria (P < .001). The combination of elevated DNTs and an abnormal in vitro apoptosis functional test was the most useful in identifying all types of ALPS patients; the combination of an abnormal in vitro apoptosis functional test and elevated sFASLs was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test, and DNTs are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASLs and abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.

Absence of γ-Chain in Keratinocytes Alters Chemokine Secretion, Resulting in Reduced Immune Cell Recruitment.

Loss-of-function mutations in the common gamma (γc) chain cytokine receptor subunit give rise to severe combined immunodeficiency characterized by lack of T and natural killer cells and infant death from infection. Hematopoietic stem cell transplantation or gene therapy offer a cure, but despite successful replacement of lymphoid immune lineages, a long-term risk of severe cutaneous human papilloma virus infections persists, possibly related to persistent γc-deficiency in other cell types. Here we show that keratinocytes, the only cell type directly infected by human papilloma virus, express functional γc and its co-receptors. After stimulation with the γc-ligand IL-15, γc-deficient keratinocytes show significantly impaired secretion of specific chemokines including CXCL1, CXCL8, and CCL20, resulting in reduced chemotaxis of dendritic cells and CD4+ T cells. Furthermore, γc-deficient keratinocytes also exhibit defective induction of T-cell chemotaxis in a model of stable human papilloma virus-18 infection. These findings suggest that persistent γc-deficiency in keratinocytes alters immune cell recruitment to the skin, which may contribute to the development and persistence of warts in this condition and would require different treatment approaches.