TNF2, a polymorphism of the tumour necrosis-α gene promoter,is a component of the celiac disease major histocompatibility complex haplotype

Celiac disease (CD) is an immune disease triggered by the cereal antigen gliadin, resulting in villous atrophy in the small intestine. Susceptibility to the development of CD is strongly influenced by genes in the major histocompatibility complex, in particular alleles of the DQ genes in the class II region. However recent evidence has suggested that the major histocompatibility complex (MHC) class III region may be linked to celiac disease independently of the class II region. Among the genes located in this area is TNF-α, which encodes the cytokine tumor necrosis factor-α which has a broad range of pro-inflammatory, immunomodulatory and catabolic activities. Therefore, aberrant expression of TNF-α could be important in the pathogenesis of MHC-associated immune disorders. A TNF-α variant with a polymorphism in its promoter region has been described and designated TNF2. TNF2 has been associated with a variety of MHC-linked diseases, including systemic lupus erythematosus, dermatitis herpetiformis and insulin-dependent diabetes mellitus (IDDM), as well as parasitic infections. TNF2 has previously been shown to be associated with the MHC haplotype HLAA1-B8-DR3-DQ2, which confers susceptibility to CD. We have analyzed the distribution of TNF2 alleles in a group of celiac patients (n = 52) compared to controls (n = 52) in an effort to evaluate its role, if any, in susceptibility to the condition. TNF2 has a frequency of 0.5000 (SE ± 0.0490) in CD, compared to 0.1635 (± 0.0362) in a control sample (p < 10⁻⁶). Of 52 patients, 44 carried one or more TNF2 alleles. Analysis indicates that the distribution of TNF2 is best explained by assuming 100% allelic association between it and HLA-DQB1*0201 (frequency = 0.7791 ± 0.0447). However, the number of TNF2 heterozygotes significantly exceeds expectations and measurements of linkage disequilibrium confirm that allelic associations spanning the DQ and TNF regions are strongly maintained in CD. Taken together, these results indicate that TNF2 may have a role in the pathogenesis of CD; however, since it is not an independent association, the possibility that TNF2 constitutes a passive component of the CD haplotype cannot be excluded.     

Epidemiology,Pathophysiology, and the Future of Ocular Toxoplasmosis

Abstract

Despite large advances in the field of ocular toxoplasmosis, large gaps still exist in our knowledge concerning the epidemiology and pathophysiology of this potentially blinding infectious disease. Although ocular toxoplasmosis is considered to have a high health burden, still little is known about its exact prevalence and how it affects the quality of life. The epidemiology of toxoplasmosis depends on local habits throughout the globe, and changes are likely in view of increased meat consumption in developing countries and demands for higher animal welfare in the Western world. Water is increasingly seen as an important risk factor and more studies are needed to quantitate and control the role of water exposure (drinking, swimming). Tools are now becoming available to study both the human host as well as parasite genetic factors in the development of ocular toxoplasmosis. Further research on the role of Toxoplasma strains as well as basic studies on parasite virulence is needed to explain why Toxoplasma associated eye disease is so severe in some countries, such as Brazil. Although genetic analysis of the parasite represents the gold standard, further developments in serotyping using peptide arrays may offer practical solutions to study the role of parasite strains in the pathogenesis of Toxoplasma retinochoroiditis. More research is needed concerning the pathways whereby the parasite can infect the retina. Once in the retina further tissue damage may be due to parasite virulence factors or could be caused by an aberrant host immune response. Local intraocular immune responses are nowadays used for diagnostic procedures. Future developments may include the use of Raman technology or the direct visualization of a Toxoplasma cyst by optical coherence tomography (OCT). With the availability of ocular fluid specimens obtained for diagnostic purposes and the development of advanced proteomic techniques, a biomarker fingerprint that is unique for an eye with toxoplasmosis may become available. It is hoped that such a biomarker analysis may also be able to distinguish between acquired versus congenital disease. Recently developed mouse models of congenital ocular toxoplasmosis are extremely promising with regard to disease pathogenesis, diagnosis, and treatment.     

Familial occurrence of primary glomerulonephritis: evidence for a role of genetic factors.

Chronic glomerulonephritis was diagnosed in 23 patients born in a small valley in Northern Italy and in five additional patients with one parent or a more remote ancestor born in the same area, all belonging to three potentially related families. Eighteen patients had biopsy-proven glomerulonephritis: 11 IgA nephropathy, 3 IgM nephropathy, 2 membranoproliferative type I, and 2 mesangial proliferative glomerulonephritis with isolated C3 deposits. Ten had clinical glomerulonephritis. A community screening programme discovered six additional related patients. Two underwent renal biopsy (1 IgA nephropathy; 1 focal glomerulosclerosis); four were diagnosed as having clinical glomerulonephritis. Genealogical investigation identified five deceased family members with diagnoses of chronic nephritis recorded on their death certificates. No environmental nephrotoxic factors were identified. Restriction fragment length polymorphism (RFLP) analysis of HLA-DR beta, HLA-DQ alpha and beta genes, and complement typing for C4A, C4B, and Bf polymorphisms were carried out for 29 patients, 168 healthy relatives, and 24 local controls. The frequency of HLA-Dw8.1 specificity, related to DR beta 8, DQ beta 3b, and DQ alpha 1a RFLPs, was significantly increased more in the affected and unaffected pedigree members than in Italian controls.     

Genetic aspect of pulmonary arterial hypertension

This paper concentrates on the genetic aspects of pulmonary arterial hypertension (PAH), a diagnostically based subclass of pulmonary hypertension that includes primary pulmonary hypertension (PPH). During the past year, patients with familial and sporadic PPH were found to have germline heterozygous missense, nonsense and frameshift mutations in bone morphogenetic protein receptor II (BMPRZ). Mutations in BMPR2, a member of the transforming growth factor-β (TGF-β) receptor superfamily, are predicted to interrupt the bone morphogenetic protein (BMP) signalling pathway, resulting in proliferation, rather than apoptosis of cells within small arterioles. Mechanistically, haploinsufficiency was found by using in vitro gene expression experiments, but a dominant-negative mechanism has not been excluded. The failure to find BMPR2 mutations in all families with familial PPH and in all patients with sporadic PPH suggests that other genes remain to be identified. Mutations in ALK1, a TGF-β type 1 receptor, previously known to cause type 2 hereditary haemorrhagic telangiectasia (HHT), have also been reported in a few HHT families with clinical and histological features of PPH. The clinical development of PPH, as in neoplasia, appears to require ‘two hits’. The two hits can be provided either by genetic or environmental factors.     

Personalized vaccines: the emerging field of vaccinomics

The next ‘golden age’ in vaccinology will be ushered in by the new science of vaccinomics. In turn, this will inform and allow the development of personalized vaccines, based on our increasing understanding of immune response phenotype: genotype information. Rapid advances in developing such data are already occurring for hepatitis B, influenza, measles, mumps, rubella, anthrax and smallpox vaccines. In addition, newly available data suggest that some vaccine-related adverse events may also be genetically determined and, therefore, predictable. This paper reviews the basis and logic of personalized vaccines, and describes recent advances in the field.