Insights into NK cell biology from human genetics and disease associations

Rare human primary immunodeficiency disorders with extreme susceptibility to infections in infancy have provided important insights into immune function. Increasingly, however, primary immunodeficiencies are also recognized as a cause of other more common, often discrete, infectious susceptibilities. In a wider context, loss-of-function mutations in immune genes may also cause disorders of immune regulation and predispose to cancer. Here, we review the associations between human diseases and mutations in genetic elements affecting natural killer (NK) cell development and function. Although many such genetic aberrations significantly reduce NK cell numbers or severely impair NK cell responses, inferences regarding the role of NK cells in disease are confounded by the fact that most mutations also affect the development or function of other cell types. Still, data suggest an important role for NK cells in diseases ranging from classical immunodeficiency syndromes with susceptibility to viruses and other intracellular pathogens to cancer, autoimmunity, and hypersensitivity reactions.     

Mononuclear phagocyte-mediated antifungal immunity: the role of chemotactic receptors and ligands

Over the past two decades, fungal infections have emerged as significant causes of morbidity and mortality in patients with hematological malignancies, hematopoietic stem cell or solid organ transplantation and acquired immunodeficiency syndrome. Besides neutrophils and CD4⁺ T lymphocytes, which have long been known to play an indispensable role in promoting protective antifungal immunity, mononuclear phagocytes are now being increasingly recognized as critical mediators of host defense against fungi. Thus, a recent surge of research studies has focused on understanding the mechanisms by which resident and recruited monocytes, macrophages and dendritic cells accumulate and become activated at the sites of fungal infection. Herein, we critically review how a variety of G-protein coupled chemoattractant receptors and their ligands mediate mononuclear phagocyte recruitment and effector function during infection by the most common human fungal pathogens.     

Atomic model of human cystic fibrosis transmembrane conductance regulator: Membrane-spanning domains and coupling interfaces

We describe herein an atomic model of the outward-facing three-dimensional structure of the membrane-spanning domains (MSDs) and nucleotide-binding domains (NBDs) of human cystic fibrosis transmembrane conductance regulator (CFTR), based on the experimental structure of the bacterial transporter Sav1866. This model, which is in agreement with previous experimental data, highlights the role of some residues located in the transmembrane passages and directly involved in substrate translocation and of some residues within the intracellular loops (ICL1-ICL4) making MSD/NBD contacts. In particular, our model reveals that D173 ICL1 and N965 ICL3 likely interact with the bound nucleotide and that an intricate H-bond network (involving especially the ICL4 R1070 and the main chain of NBD1 F508) may stabilize the interface between MSD2 and the NBD1F508 region. These observations allow new insights into the ATP-binding sites asymmetry and into the molecular consequences of the F508 deletion, which is the most common cystic fibrosis mutation.     

Common antigenicity between a human thymic epithelial cell product and a thymus-dependent serum factor

Summary Specific immunofluorescence of human thymic epithelial cytoplasm was obtained with antibodies to supernatant of thymic epithelial cultures, and with anti-prealbumin antibodies. These antibodies also reacted with normal serum but not with serum from Di George patients. The data indicates that thymic epithelium and a component of the prealbumin fraction of normal serum share a common antigen believed to be thymic hormone.Acknowledgment. The authors wish to thank Mrs Francine Rivard and Claire Prévost for technical assistance and Dr A.R.C. Dobell for human thymic material. This work was supported by the National Cancer Institute of Canada and the Medical Research Council of Canada.     

The role of genetics in the establishment and maintenance of the epigenome

Epigenetic mechanisms play an important role in gene regulation during development. DNA methylation, which is probably the most important and best-studied epigenetic mechanism, can be abnormally regulated in common pathologies, but the origin of altered DNA methylation remains unknown. Recent research suggests that these epigenetic alterations could depend, at least in part, on genetic mutations or polymorphisms in DNA methyltransferases and certain genes encoding enzymes of the one-carbon metabolism pathway. Indeed, the de novo methyltransferase 3B (DNMT3B) has been recently found to be mutated in several types of cancer and in the immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF), in which these mutations could be related to the loss of global DNA methylation. In addition, mutations in glycine-N-methyltransferase (GNMT) could be associated with a higher risk of hepatocellular carcinoma and liver disease due to an unbalanced S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio, which leads to aberrant methylation reactions. Also, genetic variants of chromatin remodeling proteins and histone tail modifiers are involved in genetic disorders like α thalassemia X-linked mental retardation syndrome, CHARGE syndrome, Cockayne syndrome, Rett syndrome, systemic lupus erythematous, Rubinstein–Taybi syndrome, Coffin–Lowry syndrome, Sotos syndrome, and facioescapulohumeral syndrome, among others. Here, we review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease.     

Immigration of lymphoid precursor cells into the thymic rudiment inXenopus

Summary The origin of thymic lymphocytes was investigated, using a new reliable method to mark cells inXenopus. It was easily observed that extraneous cells immigrated into the thymic rudiment 4 days after fertilization and differentiated into a cell population identified as thymic lymphocytes in a fully developed thymus. Clearly, lymphoid precursor cells are of extrinsic origin.This work was supported in part by a grant from the Ministry of Education, Science and culture of Japan (No. 59770026).     

Inflammatory bowel disease: is it a primary immunodeficiency?

Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea, bleeding and malabsorption. IBD has been considered a hyperinflammatory state due to disturbed interactions between the immune system and the commensal bacterial flora of the gut. However, there is evidence that Crohn’s disease might be the consequence of a reduced release of pro-inflammatory cytokines and an impaired acute inflammatory response, thereby suggesting that IBD might be an immunodeficiency rather than an excessive inflammatory reaction. This theory has been supported by observations in patients with primary immunodeficiencies such as the Wiskott–Aldrich syndrome and IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In contrary, defects in the anti-inflammatory down-regulation of the immune response as they are seen in patients with Mendelian defects in the IL10 signaling pathway support the hyper-inflammatory theory. In this review, we describe and discuss primary immunodeficiencies associated with IBD and show that the bowel is a highly sensitive indicator of dysregulations, making IBD a model disease to study and identify key regulators required to balance the human mucosal immune system.     

The genomic basis of the Williams – Beuren syndrome

The Williams-Beuren syndrome is a genomic disorder (prevalence: 1/7,500 to 1/20,000), caused by a hemizygous contiguous gene deletion on chromosome 7q11.23. Typical symptoms comprise supravalvular aortic stenosis, mental retardation, overfriendliness and visuospatial impairment. The common deletion sizes range of 1.5–1.8 mega base pairs (Mb), encompassing app. 28 genes. For a few genes, a genotype-phenotype correlation has been established. The best-explored gene within this region is the elastin gene; its haploinsufficiency causes arterial stenosis. The region of the Williams-Beuren syndrome consists of a single copy gene region (~1.2 Mb) flanked by repetitive sequences – Low Copy Repeats (LCR). The deletions arise as a consequence of misalignment of these repetitive sequences during meiosis and a following unequal crossing over due to high similarity of LCRs. This review presents an overview of the Williams-Beuren syndrome region considering the genomic assembly, chromosomal rearrangements and their mechanisms (i.e. deletions, duplications, inversions) and evolutionary and historical aspects. Received 11 July 2008; received after revision 15 October 2008; accepted 16 October 2008     

Human progeroid syndromes,aging and cancer: new genetic and epigenetic insights into old questions

Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes. Received 28 July 2006; received after revision 5 September 2006; accepted 13 October 2006     

The surface glycopeptidolipids of mycobacteria: structures and biological properties

One of the most important opportunistic pathogens associated with acquired immunodeficiency syndrome (AIDS) is the M. avium complex. M. avium infections are found in up to 70% of individuals in advanced stages of AIDS. It is apparent that M. avium can replicate in host macrophages and persist for long periods. This group of mycobacteria are distinguished by the presence of unique, highly antigenic, surface-located lipids known as the glycopeptidolipids (GPLs). The GPLs are the chemical basis of the 31 distinct serovars of the M. avium complex, and have also been identified in some other species. The M. avium lipids are immunosuppressive and can induce a variety of cytokines that affect general host responses. Despite extensive chemical characterization of the structures of these GPLs, much work is needed to elucidate the molecular mechanism involved in this complex glycosylation pathway and its genetic basis. The challenges for the future lie in explaining the roles of these copious products in the intracellular life and infectivity of mycobacteria. The intention of our review is to offer a concise account of the structures of the M. avium lipids, their putative roles in the host responses, bacterial physiology and pathogenesis, particularly in immunocompromised patients such as those infected with human immunodeficiency virus (HIV). Advances in chemical synthesis of the various haptenic oligosaccharides are also given to demonstrate how these have helped to define the immunogenic determinants. We believe that future research should involve the creation of conditional mutants defective in these lipids for both functional and biosynthesis studies which will complement biological assays using chemically defined or modified neoglycoconjugates. Received 7 May 2001; received after revision 28 June 2001; accepted 28 June 2001     

Origin of a mitogrenic factor for cultivated macrophages (IMF: Inflammatory Mitogenic Factor) found in exudates of non-specific acute inflammation]

The mitogenic activity of inflammatory exudate obtained from irradiated Rats is reduced. After transfer of bone marrow syngeneic cells into irradiated Rats this mitogenic activity is further decreased, while after transfer of thymic cells it is increased. It is postulated that the mitogenic activity of inflammatory exudate could be related to thymic cells and that T lymphocytes may be involved in non specific-inflammatory reactions.     

Induced recovery of defective membrane expression of a CC chemokine receptor 5 mutant by phytohemagglutinin

CC chemokine receptor 5 (CCR5) is a member of the G-protein-coupled receptor superfamily. It plays an important role in macrophage tropic human immunodeficiency virus-1 entry and in some inflammatory reactions. CCR5-893(–) is a single-nucleotide deletion that results in complete truncation of the C tail of the gene product. We detected CCR5-893(–) in a sample of patients infected with non-tuberculosis mycobacteria and found that it was maintained heterozygously with a frequency of 2%. There is no association between this mutation and any immunodeficiency. Membrane expression of CCR5-893(–) was substantially reduced compared to the wild type, but this defective surface presentation recovered greatly recovered in the presence of 2 mg l-1 phytohemagglutinin (PHA). However, PHA inducement did not affect the total intracellular expression of CCR5-893(–) or wild-type CCR5. Thus we suggest there exist some PHA-induced factor(s) that could mediate the presentation of truncated CCR5.Received 23 July 2003; accepted 18 August 2003     

Fatigue in neuromuscular disorders: focus on Guillain–Barré syndrome and Pompe disease

Fatigue accounts for an important part of the burden experienced by patients with neuromuscular disorders. Substantial high prevalence rates of fatigue are reported in a wide range of neuromuscular disorders, such as Guillain–Barré syndrome and Pompe disease. Fatigue can be subdivided into experienced fatigue and physiological fatigue. Physiological fatigue in turn can be of central or peripheral origin. Peripheral fatigue is an important contributor to fatigue in neuromuscular disorders, but in reaction to neuromuscular disease fatigue of central origin can be an important protective mechanism to restrict further damage. In most cases, severity of fatigue seems to be related with disease severity, possibly with the exception of fatigue occurring in a monophasic disorder like Guillain–Barré syndrome. Treatment of fatigue in neuromuscular disease starts with symptomatic treatment of the underlying disease. When symptoms of fatigue persist, non-pharmacological interventions, such as exercise and cognitive behavioral therapy, can be initiated.     

Glial versus melanocyte cell fate choice: Schwann cell precursors as a cellular origin of melanocytes

Melanocytes and Schwann cells are derived from the multipotent population of neural crest cells. Although both cell types were thought to be generated through completely distinct pathways and molecular processes, a recent study has revealed that these different cell types are intimately interconnected far beyond previously postulated limits in that they share a common post-neural crest progenitor, i.e. the Schwann cell precursor. This finding raises interesting questions about the lineage relationships of hitherto unrelated cell types such as melanocytes and Schwann cells, and may provide clinical insights into mechanisms of pigmentation disorders and for cancer involving Schwann cells and melanocytes.     

Wasting syndrome in neonatal mice after administration of salivary gland homogenate

Summary A wasting syndrome, similar to that occurring after cortisol treatment, was induced in neonatal mice by means of the daily i.p. administration of salivary gland homogenate: 24 h after a single injection of the, homogenate, profuse cell necrosis was observed in the thymic cortex, 48 h later the cortex was devoid of lymphocytes. It is hypothesized that the submandibular glands of mice contain substance which are capable of inducing a cortisol-like effect.We should like to thank Miss Angela Würfler for her careful technical assistance.     

Genetic susceptibility to hypertensive renal disease

Hypertensive renal disease occurs at increased frequency among the relatives of patients with this disease compared to individuals who lack a family history of disease. This suggests a heritable risk in which genetic variation may play a role. These observations have motivated a search for genetic variation contributing to this risk in both experimental animal models and in human populations. Studies of animal models indicate the capacity of natural genetic variants to contribute to disease risk and have produced a few insights into the disease mechanism. In its current phase, human population genetic studies have sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome-wide association studies (GWAS) have been productive and are a clear technical success; they have also identified narrowly defined loci and genes containing variation contributing to disease risk. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few additional variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining unaccounted heritable risk may be located. At present, much consideration is being given to this question and to the challenge of testing hypotheses that lead from the various alternative mechanisms under consideration. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews the current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise.     

Mylip makes an Idol turn into regulation of LDL receptor

High blood low-density-lipoprotein (LDL) cholesterol is a serious health problem among an increased number of patients in the Western world. Statins and other cholesterol lowering drugs have proven to be beneficial as therapy but are not optimal and show adverse effects in some patients. The LDL receptor is a crucial determinant of cholesterol metabolism in the body and amenable for drug interventions. Novel insights into the physiology of this receptor come from studies on the ubiquitination and degradation of LDL receptor by the ubiquitin ligase Mylip/Idol that is induced in cells by the nuclear receptor, LXR. This may open up new possibilities in the future to influence LDL receptor levels and cholesterol metabolism pharmacologically in various diseases.