Long-term orthognathic surgical outcomes in Treacher Collins patients.

INTRODUCTION: Treacher Collins syndrome is a rare disorder characterized by several orofacial findings including malar deficiency and hypoplastic mandibles. These patients often require a combined orthodontic-orthognathic approach to correct their malocclusion. This is most often characterized by a short posterior vertical height and an anterior open bite. Orthognathic correction often requires Le Fort I and bilateral sagittal split osteotomies. No long-term stability results have been reported after bimaxillary surgery in Treacher Collins patients. METHODS: A retrospective review of all Treacher Collins patients evaluated for orthognathic surgery by a single surgeon from 1993 to 2007 was performed. Patients were divided into groups who required surgery and those who did not. Part I analyzed the cephalometric differences between the surgical (S) and nonsurgical (NS) groups. Part II of the study assessed the preorthodontic treatment (T1), preoperative (T2), immediate postoperative (T3), and 1-year postoperative (T4) cephalometric measurement variables to determine the net surgical movement (T3 - T2) and relapse (T4 - T3). RESULTS: Twenty-two patients met the inclusion criteria, of which 11 had occlusal relationships requiring orthognathic surgery. Nine out of 11 chose to have surgery. At baseline, surgical patients exhibited a statistically significant retruded maxilla as measured by SNA and midface length compared to the NS group. In addition, the S group also had an increased gonial angle. There were significant movements in all maxillary and mandibular measurements. There was a significant relapse in the palatal plane angle when the maxilla was anteriorly impacted, with a 2.8-mm average relapse of the advancement. Relapse of the counterrotation movement of the mandible was identified, but this was not significant. Relapse did not affect the final occlusal result, which may have been compensated with postsurgical orthodontic treatment. CONCLUSION: Bimaxillary orthognathic surgery in the Treacher Collins patients may be performed safely with long-term dental and skeletal stability.

Interleukin-23 is sufficient to induce rapid de novo gut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells.

Chronic inflammation has been associated with increased risk for developing gastrointestinal cancer. Interleukin-23 (IL-23) receptor signaling has been correlated with inflammatory bowel disease pathogenesis, as well as promotion of tumor growth. However, little is known about the relative potential for IL-23-directed causality in gut tumorigenesis. We report that IL-23 transgene expression was sufficient to induce rapid (3-4 weeks) de novo development of intestinal adenomas with 100% incidence. Initiation of tumorigenesis was independent of exogenous carcinogens, Helicobacter colonization, or pre-existing tumor-suppressor gene mutations. Tumorigenesis was mediated by Thy1(+)IL-23R(+) innate lymphoid cells (ILC3), in part, through IL-17 responses as tumor development was inhibited in RAG(-/-) × IL-17(-/-) double knockout mice. Remarkably, IL-23 initiation of tumorigenesis by resident ILCs consistently occurred before recruitment of conspicuous inflammatory infiltrates. Our results reveal an explicit role for IL-23-mediated initiation of gut tumorigenesis and implicate a key role for IL-23R(+) ILC3 in the absence of overt cellular infiltrate recruitment.

Paediatric craniofacial fibrous dysplasia: the Hospital for Sick Children experience and treatment philosophy.

Craniofacial fibrous dysplasia is a benign developmental anomaly in which normal bone is replaced by fibro-osseous tissue. The aim of this study was to audit the patient population at a tertiary paediatric centre and report our treatment protocols. A retrospective chart review of all patients with craniofacial fibrous dysplasia treated at the Hospital for Sick Children between 1999 and 2010 was performed. The treatment algorithm used by our centre is presented. A total of 55 patient records were reviewed; 37 patients had sufficient documentation for study; 27 (16 male, 11 female) patients underwent surgery at our institution, of these patients, 26 had post-operative follow up of greater than one year (mean 41 months; median 24 months). Mean age at presentation was 9.9 years (median 10 years) and mean age of surgery was 13 years. Ten patients underwent surgery on the fronto-orbital region, 7 of the calvarium, 2 the skull base and 8 upon tooth-bearing bones. Fourteen cases underwent debulking surgery as their primary therapy whereas 13 patients had complete resection. Nine patients experienced recurrence and all but one case of these occurred in patients that underwent debulking therapy. When age of surgery is considered, total resection and reconstruction or debulking surgery after skeletal maturity has a lower recurrence rate (1/7 cases) than earlier surgery (8/16). Complete resection at any age and debulking surgery once skeletal maturity has been reached may be associated with lower recurrence rates than incomplete resections at an earlier age. Patients with McCune-Albright syndrome may benefit from repeated debulking procedures rather than complex resections and reconstructions.

Synthesis of cyclic sulfates by halocyclization.

[reaction: see text]. We report the synthesis of cyclic sulfates by halocyclization. The resulting cyclic sulfate products can be opened selectively with sodium azide to transform them into highly functionalized compounds that contain azide, alcohol, and halide groups.

Postoperative infections in craniofacial reconstructive procedures.

The rate of, and possible risk factors for, postoperative craniofacial infection is unclear. To investigate this problem, we reviewed 349 cases of craniofacial skeletal procedures performed from 1996 to 1999 at our institution. Infection rate was determined and correlated with the use of implants, operative site, and cause of deformity. The inclusion criteria consisted of all procedures requiring autologous or prosthetic implantation in craniofacial skeletal sites, as well as all procedures involving bone or cartilage resection, osteotomies, debridement, reduction and/or fixation. Procedures that did not involve bone or cartilage surgery were excluded. The criteria for diagnosis of infection included clinical confirmation and one or more of 1) intravenous or oral antibiotic treatment outside of the prophylactic surgical regimen; 2) surgical intervention for drainage, irrigation, and or debridement; and 3) microbiological confirmation. Among the 280 surgical cases that fit the inclusion criteria and had complete records, there were 23 cases of postoperative infection (8.2%). The most common site for postoperative infection was the mandible (infection rate = 16.7%). Multiple logistic regression analysis revealed gunshot wound to be the most significant predictor of postoperative infection. Additionally, porous polyethylene implantation through a transoral route was correlated with a significant risk of postoperative infection.

Cutting edge: the mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (alpha 2 integrin, very late antigen-2).

DX5 mAb is a useful reagent because it stains NK cells from all mouse strains examined. We have identified the molecule recognized by DX5 mAb by using a retrovirus-mediated expression cloning system. A 5-kb cDNA encoding a protein that is reactive with the DX5 mAb was isolated from a NK cell cDNA library, and this molecule was identical with CD49b (very late Ag-2, alpha(2) integrin). The DX5 mAb reacted with transfectants expressing CD49b, and binding of DX5 to the NK cells and CD49b transfectants was blocked in the presence of other anti-CD49b mAbs. When NK1.1(+) NK cells were cultured with IL-2, they progressively lost reactivity with DX5 mAb as a consequence of cellular proliferation. Cytotoxicity mediated by the DX5(+) NK cells was dramatically higher as compared with DX5(-) NK cells. Therefore, DX5 mAb recognizes CD49b and can be used to define functionally distinct subsets of NK cells.

The epithelial cellular adhesion molecule (Ep-CAM) is a ligand for the leukocyte-associated immunoglobulin-like receptor (LAIR).

Human leukocyte-associated immunoglobulin-like receptor (LAIR)-1 is expressed on many cells of the immune system and is predicted to mediate inhibitory functions based on the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain. Although the role of LAIR-1 in the regulation of immune responses in vivo is unknown, LAIR-1 cross-linking by monoclonal antibody inhibits various immune cell functions in vitro. Here, we identify the colon carcinoma-associated epithelial cellular adhesion molecule (Ep-CAM) as a ligand for LAIR-1 and LAIR-2, a related soluble LAIR-1 family member. Ep-CAM interacts with the LAIR molecules through its first epidermal growth factor domain; Ep-CAM--specific antibodies can abrogate the binding. Intraepithelial T lymphocytes express LAIR-1 and thus may interact with Ep-CAM present on human intestinal epithelium. We propose that LAIR-1--Ep-CAM interaction may contribute to mucosal tolerance and that LAIR-2 possibly modulates this function.

The repertoire of killer cell Ig-like receptor and CD94:NKG2A receptors in T cells: clones sharing identical alpha beta TCR rearrangement express highly diverse killer cell Ig-like receptor patterns.

Killer cell Ig-like receptor (KIR) and CD94:NKG2A molecules were first defined as human NK cell receptors (NKR), but now are known to be expressed and to function on subpopulations of T cells. Here the repertoires of KIR and CD94:NKG2A expression by T cells from two donors were examined and compared with their previously defined NK cell repertoires. T cell clones generated from peripheral blood of both donors expressed multiple NKR in different combinations and used the range of receptors expressed by NK cells. In both donors alpha beta T cells less frequently expressed the inhibitory receptors CD94:NKG2A and KIR2DL1 than either gamma delta T cells or NK cells. In contrast to NK cells, not all NKR(+) T cells expressed an inhibitory receptor for autologous HLA class I. This lack of specific inhibitory NKR was especially apparent on alpha beta T cells of one donor. Overall, alpha beta T cells exhibited a distinct pattern of NKR expression different from that of gamma delta T and NK cells, which expressed highly similar NKR repertoires. In one donor, analysis of TCR rearrangement revealed a dominant subset of NKR(+) T cells sharing identical TCR alpha- and beta-chains. Remarkably, among 55 T cell clones sharing the same TCR alpha beta rearrangement 18 different KIR phenotypes were seen, suggesting that KIR expression was initiated subsequently to TCR rearrangement.

Differential expression of leukocyte receptor complex-encoded Ig-like receptors correlates with the transition from effector to memory CTL.

The human leukocyte receptor complex (LRC) on chromosome 19q13.4 encodes Ig superfamily receptors expressed on hemopoietic cells. Killer Ig-like receptors (KIR) are expressed in cytotoxic lymphocytes but other LRC molecules (Ig-like transcript(ILT)/leukocyte Ig-like receptor (LIR)) are more ubiquitous. We investigated expression of the ILT2/LIR1 inhibitory receptor compared with the related KIR. Both ILT2/LIR1 and KIR were expressed by peripheral CD8(+) T cells with a memory/effector phenotype. ILT2/LIR1(+) T cells demonstrated diverse TCRBV repertoires in contrast to KIR(+) T cells, while numbers of peripheral ILT2/LIR1(+) T cells were greater than KIR(+) T cells and the majority of ILT2/LIR1(+) T cells did not coexpress KIR. Analysis of CD8(+) T cells with specific HLA class I tetramers confirmed this pattern of expression, indicating differential regulation of LRC gene expression in T lymphocytes. Only a minor proportion of ILT2/LIR1(+) KIR(-) clones survived in vitro cloning, were more susceptible to anti-CD3 or cognate peptide induced cell death than KIR(+) T cells and exhibited lower levels of the Bcl-2 survival molecule. Our results indicate a sequential program of LRC-encoded receptor expression with initial ILT2/LIR1 expression in effector T cells and KIR gene transcription in the minor proportion of expanded clones which survives activation-induced cell death to become long term memory T cells.

DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells.

Many of the activating receptors on natural killer (NK) cells are multisubunit complexes composed of ligand-binding receptors that are noncovalently associated with membrane-bound signaling adaptor proteins, including CD3zeta, FcstraightepsilonRIgamma, DAP12, and DAP10. Because the DAP10 and DAP12 genes are closely linked, expressed in NK cells, and have remarkably similar transmembrane segments, it was of interest to determine the specificity of their interactions with ligand-binding receptors and to examine their signaling properties. Despite their similarities, DAP10, DAP12, FcstraightepsilonRIgamma, and CD3zeta form specific receptor complexes with their ligand-binding partners in NK cells and transfectants. The transmembrane regions of DAP10 and DAP12 are sufficient to confer specific association with their partners. Although cross-linking of either DAP10- or DAP12-associated receptors has been shown to be sufficient to trigger NK cell-mediated cytotoxicity against Fc receptor-bearing cells, substantial synergy was observed in the induction of cytokine production when both receptors were engaged. Activation of the Syk/ZAP70 tyrosine kinases by the immunoreceptor tyrosine-based activation motif-containing DAP12 adaptor and of the phosphatidylinositol 3-kinase pathway by the YxNM-containing DAP10 adaptor may play an important role in the stimulation of NK cells and T cells.

Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome.

X-linked lymphoproliferative syndrome (XLP) is an immunodeficiency characterized by life-threatening infectious mononucleosis and EBV-induced B cell lymphoma. The gene mutated in XLP encodes SLAM (signaling lymphocytic activation molecule-associated protein)-associated protein (SAP), a small SH2 domain-containing protein. SAP associates with 2B4 and SLAM, activating receptors expressed by NK and T cells, and prevents recruitment of SH2 domain-containing protein tyrosine phosphatase-2 SHP-2) to the cytoplasmic domains of these receptors. The phenotype of XLP may therefore result from perturbed signaling through SAP-associating receptors. We have addressed the functional consequence of SAP deficiency on 2B4-mediated NK cell activation. Ligating 2B4 on normal human NK cells with anti-2B4 mAb or interaction with transfectants bearing the 2B4 ligand CD48 induced NK cell cytotoxicity. In contrast, ligation of 2B4 on NK cells from a SAP-deficient XLP patient failed to initiate cytotoxicity. Despite this, CD2 or CD16-induced cytotoxicity of SAP-deficient NK cells was similar to that of normal NK cells. Thus, selective impairment of 2B4-mediated NK cell activation may contribute to the immunopathology of XLP.

Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice.

Here we describe a family of GPI-anchored cell surface proteins that function as ligands for the mouse activating NKG2D receptor. These molecules are encoded by the retinoic acid early inducible (RAE-1) and H60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with MHC class I. Expression of the NKG2D ligands is low or absent on normal, adult tissues; however, they are constitutively expressed on some tumors and upregulated by retinoic acid. Ectopic expression of RAE-1 and H60 confers target susceptibility to NK cell attack. These studies identify a family of ligands for the activating NKG2D receptor on NK and T cells, which may play an important role in innate and adaptive immunity.

Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells.

The CD2-subset of the immunoglobulin superfamily of cell surface receptors is an emerging family of proteins involved in cellular activation. Members of this family are CD2, CD48, CD58, CD84, signaling lymphocytic activation molecule (SLAM), 2B4 and Ly-9. These proteins are expressed on different leukocyte populations and the receptors of this family, specifically CD2, 2B4 and SLAM, contribute to the activation of T cells and natural killer cells. 2B4 and SLAM associate with a protein termed SLAM-associated protein that is the genetic defect in the immunodeficiency X-linked lymphoproliferative syndrome. Impaired signaling via these receptors may contribute to this often-fatal immunodeficiency.

NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals.

A delicate balance between positive and negative signals regulates NK cell effector function. Activation of NK cells may be initiated by the triggering of multiple adhesion or costimulatory molecules, and can be counterbalanced by inhibitory signals induced by receptors for MHC class I. A common pathway of inhibitory signaling is provided by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domains of these receptors which mediate the recruitment of SH2 domain-bearing tyrosine phosphate-1 (SHP-1). In contrast to the extensive progress that has been made regarding the negative regulation of NK cell function, our knowledge of the signals that activate NK cells is still poor. Recent studies of the activating receptor complexes have shed new light on the induction of NK cell effector function. Several NK receptors using novel adaptors with immunoreceptor tyrosine-based activation motifs (ITAMs) and with PI 3-kinase recruiting motifs have been implicated in NK cell stimulation.

2B4-mediated activation of human natural killer cells.

2B4 is a member of the CD2 subset of the immunoglobulin superfamily of cell surface receptors. Other members of this family include CD2, CD48, CD58, CD84, signaling lymphocytic activation molecule and Ly-9. Some of these molecules are activating structures expressed by natural killer cells and T cells. We have recently cloned and characterised the human homologue of 2B4 and found that the cytoplasmic domain of 2B4 can interact with SAP, a signaling adaptor protein that is mutated in the immunodeficiency X-linked lymphoproliferative disease (XLP). Additionally, the natural ligand of 2B4 has been identified as CD48. These findings have facilitated the investigation of the functional role of this receptor-ligand pair, and associated signal transduction pathways, on immune cells. In this study, it was found that the interaction between 2B4 on effector cells and CD48 on target cells induced NK-cell activation, as evidenced by increased cytotoxicity and secretion of IFN-gamma. The responses induced by ligation of 2B4 could be reduced by the co-ligation of inhibitory receptors expressed by NK cells, demonstrating that activation signals delivered via 2B4 can be regulated by the action of certain inhibitory receptors. Because the signalling pathway of 2B4 involves SAP, it is possible that 2B4-mediated NK-cell activation may be compromised in patients with XLP due to mutations in SAP. This may contribute to the phenotype and progression of this disease.

Comparison of the morphology of the "cleft face" and the normal face: defining the anthropometric differences.

Morphological characteristics of the "cleft face" were analyzed by calculating proportion indices in young adults who had undergone surgery in childhood for cleft lip and/or palate: 592 in 37 subjects with unilateral clefts and 432 in 27 with bilateral clefts. Three areas of the face with 16 indices based on 12 projective linear measurements were analyzed in each subject: 5 indices in the general face, 6 in the upper face, and 5 in the lower. Although a balanced relationship was found in two thirds of the indices assessed, severe disproportions, which greatly influence appearance, were noted in about one quarter. In the general face, the most frequent abnormal anthropometric findings contributing to severe disproportions were small upper-face height and a severely high or moderately narrow mandible. In the soft tissues, disproportions included wide nose, small nasal tip protrusion, and short or long columella. Deviations from normality were rarely noted in the nose and upper-lip height, mouth width, total facial height, and width of the upper face. In the upper face, severe disproportions occurred much more frequently in bilateral cleft subjects (67.6%) than in unilateral clefts (30.3%). In the lower face, however, severe disproportions were twice as frequent among unilateral clefts (39.4%) than bilateral (14.7%). The results, although interesting, require complementary preoperative data for reliable analysis of the adult "cleft face."

Fc alpha/mu receptor mediates endocytosis of IgM-coated microbes.

IgM is the first antibody to be produced in a humoral immune response and plays an important role in the primary stages of immunity. Here we describe a mouse Fc receptor, designated Fc alpha/microR, and its human homolog, that bind both IgM and IgA with intermediate or high affinity. Fc alpha/microR is constitutively expressed on the majority of B lymphocytes and macrophages. Cross-linking Fc alpha/microR expressed on a pro-B cell line Ba/F3 transfectant with soluble IgM or IgM-coated microparticles induced internalization of the receptor. Fc alpha/microR also mediated primary B lymphocyte endocytosis of IgM-coated Staphylococcus aureus. Thus, Fc alpha/microR is involved in the primary stages of the immune response to microbes.

Physical and functional association of LFA-1 with DNAM-1 adhesion molecule.

Whereas ligation of the DNAM-1 adhesion molecule triggers cytotoxicity mediated by normal NK and T cells, this function was defective in NK cell clones from leukocyte adhesion deficiency syndrome. However, genetic reconstitution of cell surface expression of LFA-1 restored the ability of DNAM-1 to initiate anti-DNAM-1 mAb-induced cytotoxicity, indicating a functional relationship between DNAM-1 and LFA-1. Further studies demonstrated that LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role. In addition, cross-linking of LFA-1 induces tyrosine phosphorylation of DNAM-1, for which the Fyn protein tyrosine kinase is responsible. These results indicate that DNAM-1 is involved in the LFA-1-mediated intracellular signals.