Severe Immunodeficiency Disorder Research Articles

Periodontal Management of Leukocyte Adhesion Deficiency Type-I with Photodynamic Therapy-A Case Report

Leukocyte Adhesion Deficiency type I (LAD-I) is a rare autosomal recessive disorder affecting the immune system which is characterised by defects in white blood cell integrin receptors leading to impaired adhesion and chemotaxis with increased susceptibility to recurrent infections, delayed wound healing, and periodontitis. A case of aggressive form of generalised periodontitis in a 19- year-old girl with LAD-I is presented in this case report. The medical diagnosis was made on the basis of characteristic clinical and laboratory findings suggestive of LAD, particularly the total absence of Cluster of Differentiation (CD)18, CD11a, CD11b, and CD11c which were determined by flow cytometry. After non surgical periodontal therapy, photodynamic therapy with Low Level Laser Therapy (LLT) was performed. After 3 months, reduced inflammatory signs and improved periodontal health was observed. This report highlights the importance of the differential diagnosis of severe immunodeficiency disorders. It also emphasises the joint role of medical and dental specialists to control oral infections and thereby preventing tooth loss.

Cytoskeletal function in the immune system

Cytoskeletal function in the immune system

Challenges in Vector and Trial Design Using Retroviral Vectors for Long-Term Gene Correction in Hematopoietic Stem Cell Gene Therapy

Over the past two decades, incredible progress has been made using gene therapy for inherited severe immunodeficiency disorders, such as X-linked severe combined immunodeficiency disorder (SCID-X1) and adenosine deaminase deficiency–severe combined immunodeficiency disorder (ADA-SCID).1,2,3 However, for reasons that remain unclear, gene transfer for SCID-X1 has also been associated with some cases of vector-induced leukemia whereas no cases have been seen in the ADA-SCID trials despite the common use of g-retroviral vectors. The first case was reported in a French gene transfer trial for SCID-X1.4 Over the next six years, an additional three cases were reported in that trial and one in a second SCID-X1 trial that enrolled a combined total of 20 subjects.2 Unfortunately, genotoxicity would not remain confined to SCID-X1. Recent reports of insertional mutagenesis leading to myelodysplastic syndrome in a trial for chronic granulomatous disease and a case of leukemia in a trial for Wiskott-Aldrich syndrome (WAS), both of which used g-retroviral vectors, underscored that this type of toxicity can also apply to other disease settings.5,6,7 In all these cases, insertion of the g-retroviral vector near known proto-oncogenes led to enhancer-mediated expression of these proto-oncogenes.

Solution Structure of the Heterotrimeric Complex between the Interaction Domains of RFX5 and RFXAP from the RFX Gene Regulatory Complex

The mammalian immune response is mediated by a heterotetrameric transcriptional control complex, called regulatory factor X (RFX), that regulates the expression of major histocompatibility complex class II genes. RFX comprises three proteins: RFX5 (two copies), RFXAP, and RFXB, and mutations and deletions that prevent the assembly of the RFX complex have been linked to a severe immunodeficiency disorder. Two RFX5 molecules and one RFXAP molecule assemble in the cytoplasm prior to nuclear localization, a process mediated by an N-terminal “dimerization domain” of RFX5 (RFX5N) and a C-terminal domain of RFXAP (RFXAPC). We previously presented evidence that RFXAPC is unstructured in the absence of RFX5N but adopts a regular structure in the RFX5N2–RFXAPC complex and that the RFX5N2–RFXAPC complex binds RFXB with high affinity. We now report the structure of the RFX5N2–RFXAPC complex, determined in solution by 15N- and 13C-edited NMR spectroscopy. RFX5N consists of a long central helix flanked by two shorter helices. The central helices of the two RFX5N molecules form an antiparallel coiled coil, and the flanking helices pack at the ends of the long helices in a perpendicular arrangement such that the RFX5N dimer is shaped like a staple. RFXAPC consists of two α-helices that form a V-shaped structure that packs within the RFX5N2 staple. Leucine residues in the leucine-rich region of RFX5N (62-LYLYLQL-68) that are critical for major histocompatibility complex class II gene expression in vivo contribute to both the dimer (Leu64 and Leu68) and the RFX5N–RFXAPC interfaces (Leu62 and Leu66). The clustering of hydrophobic residues from different regions of RFXAPC suggests a potential binding site for RFXB.

Investigation of the Interaction between RFX5 and CREB: Implications for the Regulation of MHC II Gene Expression

Major Histocompatibilty Class II (MHC II) molecules play a major role in the proper functioning of our immune system. MHC II molecules are responsible for the presentation of antigenic peptides from foreign bodies to the receptors of CD4+ T lymphocytes which in turn initiate an immune system response. MHC II gene expression is dependent upon the assembly of a multi‐protein complex. Mutations or deletions in specific proteins of this multi‐protein complex lead to a severe immunodeficiency disorder. The RFX complex is a key DNA binding component of this multi‐ protein complex. In the RFX complex there are three proteins: RFX5, RFXAP, and RFXB. The ability of the RFX complex to bind DNA is proposed to be stabilized by an interaction between RFX5 and CREB another protein that binds to the MHC II promoter adjacent to the RFX complex. The interaction between CREB and RFX5 is proposed to be mediated by the bZIP domain of CREB. Little is currently known about the regions of RFX5 that are required to interact with the bZIP domain of CREB. Full length CREB was inserted into a bacterial expression vector, and the protein was successfully expressed in E. coli bacterial cells. This therefore places us in a position to analyze the interaction between CREB and RFX5 using chemical cross linking, size exclusion chromatography, and static light scattering techniques, in order to determine the minimal regions of RFX5 required interacting with CREB.

Periodontal Manifestation of Leukocyte Adhesion Deficiency Type I

Leukocyte adhesion deficiency type I (LAD-I) is an autosomal recessive immunodeficiency disorder characterized by defects in the integrin receptors of white blood cells that lead to impaired adhesion and chemotaxis. Affected patients are susceptible to recurrent bacterial and fungal infections, impaired pus formation, delayed wound healing, and periodontitis. A case of generalized advanced periodontal destruction of the permanent and deciduous dentition in a young Jordanian girl with a severe phenotype of LAD-I is presented in this report. The medical diagnosis was made based on the characteristic clinical and laboratory findings, in particular the total absence of CD18, CD11b, and CD11c as determined by flow cytometry sorting. Periodontal findings in this patient include the early onset of the disease, which affected the primary teeth and permanent dentitions, the intense redness and inflammation of the gingiva, and the rapid periodontal destruction that seems refractory to conventional non-surgical periodontal therapy. This report emphasizes the importance of the differential diagnosis of severe immunodeficiency disorders in children and adolescents and mandates the importance of combined care by medical and dental practitioners to prevent tooth loss and control oral infection.

Abnormal interleukin-7 function in common variable immunodeficiency

AbstractCommon variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins, leading to frequent infections, particularly of the respiratory tract. Frequently, T-cell abnormalities are observed. Interleukin-7 (IL-7) is involved in the homeostasis of lymphocytes, and may be elevated in lymphopenia. Mutations of genes related to IL-7 may lead to severe immunodeficiency disorders. We report elevated plasma levels of circulating IL-7 in a subgroup of CVID. These patients have increased numbers of circulating CD8+ T cells with decreased apoptosis and a predominance of CC chemokine receptor 7- (CCR7-) effector-memory T cells. Moreover, in some of these patients there is impaired response to IL-7 as assessed by in vitro proliferation and secretion of interferon γ and transforming growth factor β. These findings suggest novel pathogenic mechanisms and specific targets for further research in CVID.

In utero stem cell transplantation in humans.

The prospect of in utero fetal transplantation represents a potential major step forward in the management of patients with congenital hematological, metabolic and immunological disorders. Successful allogeneic in utero transplantations (IUTs) of hematopoietic stem cells HSC) have been reported in several animal models. The first successful transplantation in man was reported by Touraine et al. in 1989 in a case of bare lymphocyte syndrome. Since then more than 35 IUTs have been published or reported at national or international meetings. The transplantations have been reported for a variety of indications, at various gestational ages, and with different sources of the transplant. All cases of IUT performed in fetuses with normal immunological function have failed, and unequivocal engraftment could so far only be demonstrated in fetuses suffering from severe immunodeficiency disorders. Most publications reviewing in utero stem cell transplantation have stated that the fetus is the ideal candidate for therapy due to its immature immune system, which should permit the transplantation of non-human leukocyte antigen (HLA) matched cells and allow the developing fetus to recognize the donor cells as “self” (Flake 1986; Crombleholme et al. 1990, 1991; Flake et al. 1991; Touraine et al. 1991; Zanjani et al. 1991; Zanjani 1992; Westgren and Ringden 1994; Jones et al. 1996; Flake and Zanjani 1997, 1999; Surbek et al. 1999). In addition, there should be abundant and readily available hematopoietic niches from donor cells to engraft secondary to fetal growth. However, when one considers that all attempted allogeneic transplantations in immunocompetent human fetuses have failed, then doubts have to be cast on these theories and the whole concept needs to be reappraised. The purpose of this chapter is to provide a critical review of the clinical progress in this field.