CD161(high)CD8+T cells bear pathogenetic potential in multiple sclerosis.

To identify differentially expressed genes in multiple sclerosis, microarrays were used in a stringent experimental setting-leukapheresis from disease-discordant monozygotic twins and gene expression profiling in CD4(+) and CD8(+) T-cell subsets. Disease-related differences emerged only in the CD8(+) T-cell subset. The five differentially expressed genes identified included killer cell lectin-like receptor subfamily B, member 1, also known as natural killer receptor protein 1a/CD161, presented by the International Multiple Sclerosis Genetics Consortium as one of the non-MHC candidate loci. Flow cytometric analysis on peripheral blood of healthy donors and patients with multiple sclerosis and rheumatoid arthritis confirmed an upregulation of CD161 at the protein level, showing also a significant excess of CD161(high)CD8(+) T cells in multiple sclerosis. This subset prevalently included chemokine (C-C motif) receptor 6(+), cytokine-producing, effector-memory T cells with proinflammatory profiles. It also included all circulating interleukin-17(+)CD8(+) T cells. In the CD161(high)CD8(+) subset, interleukin-12 facilitated proliferation and interferon-γ production, with CD161 acting as a co-stimulatory receptor. CD161(+)CD8(+)CD3(+) T cells producing interferon-γ were part of intralesional immune infiltrates and ectopic B cell follicles in autopsy multiple sclerosis brains. Variations of CD161 expression on CD8(+) T cells identify a subset of lymphocytes with proinflammatory characteristics that have not been previously reported in multiple sclerosis and are likely to contribute to disease immunopathology.

Food protein-induced gastrointestinal syndromes in identical and fraternal twins.

BACKGROUND: It has been suggested that gene-environmental interactions play crucial roles in the development of allergy, especially in early life. Analysis of twin cases may provide novel insights into the pathogenesis and pathophysiology of allergy. Though several studies have indicated the importance of a genetic contribution to the expression of allergic diseases based on twin analyses, very few data are available regarding twins with Food Protein-Induced Gastrointestinal Syndrome (FPIGS). Two pairs of identical and fraternal twins with FPIGS are presented. CASE SUMMARY: The twins were born with no abnormalities and fed breast milk and supplemental formula. The identical twins developed vomiting and bloody stool simultaneously. The fraternal twins developed prolonged vomiting and loose stools at different times. Since their symptoms disappeared with when formula feeding was stopped, the symptoms were thought to indicate the presence of an allergy to cow's milk. The clinical symptoms and laboratory findings of the four patients were highly suggestive of FPIGS. The identical and fraternal twins showed very similar symptoms, including their onset and clinical courses. However, a substantial clinical disparity existed in the clinical features of the two pairs of twins. DISCUSSION: Comparisons of the twins' similarities and disparities suggest a profound genetic effect on the patients' clinical features, along with individual environmental factors. The prevalence of FPIGS is increasing, and it is now a major topic of public concern in Japan. Further accumulation of data on twins with FPIGS is needed to clarify the genetic contributions to this disease.

Monozygotic twin pairs discordant for Hashimoto's thyroiditis share a high proportion of thyroid peroxidase autoantibodies to the immunodominant region A. Further evidence for genetic transmission of epitopic "fingerprints".

Thyroid peroxidase antibodies (TPOAbs) in patients with Hashimoto's thyroiditis (HT) predominantly react with two immunodominant regions (IDR-A, IDR-B). Theoretically, as shown for the level of TPOAbs, the autoantibody epitopic recognition of the IDRs could be under genetic control. To examine this, we compared the distribution of TPOAb epitopic fingerprints between healthy monozygotic (MZ) co-twins and siblings to patients with clinically overt HT with a control group of euthyroid subjects, matched for sex and age, but without autoimmune thyroid disease (AITD) among their first-degree relatives. Two ELISAs based on competition with rabbit antisera were used to determine the IDR specificities in 23 patients with HT, 6 MZ co-twins, 8 siblings to patients with HT, and 11 healthy euthyroid subjects without predisposition to AITD. The fraction of TPOAbs recognizing IDR-A was 19, 18, and 9% in HT patients, MZ-co-twins, and siblings, respectively, which was higher than the 0% found in the group of healthy subjects without predisposition to AITD (p = 0.007 vs. HT; p = 0.1078 vs. MZ co-twin and p = 0.069 vs. siblings). Moreover, the IDR-A fraction differed between healthy MZ-co-twins and ordinary siblings (18% vs. 9%, p = 0.0127). In conclusion, our data indicate that the propensity to produce autoantibodies directed against the IDR-A epitope of TPO is genetically determined. This finding may have implications with respect to inheritance of autoantibody specificities in other autoimmune diseases.

A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes.

BACKGROUND & AIMS: The composition of the gastrointestinal microbiota is thought to have an important role in the etiology of inflammatory bowel diseases (IBDs) such as Crohn's disease (CD) and ulcerative colitis (UC). Interindividual variation and an inability to detect less abundant bacteria have made it difficult to correlate specific bacteria with disease. METHODS: We used 454 pyrotag sequencing to determine the compositions of microbial communities in feces samples collected from a cohort of 40 twin pairs who were concordant or discordant for CD or UC, and in mucosal samples from a subset of the cohort. The cohort primarily comprised patients who were in remission, but also some with active disease. RESULTS: The profiles of the microbial community differed with disease phenotypes; relative amounts of bacterial populations correlated with IBD phenotypes. The microbial compositions of individuals with CD differed from those of healthy individuals, but were similar between healthy individuals and individuals with UC. Profiles from individuals with CD that predominantly involved the ileum differed from those with CD that predominantly involved the colon; several bacterial populations increased or decreased with disease type. Changes specific to patients with ileal CD included the disappearance of core bacteria, such as Faecalibacterium and Roseburia, and increased amounts of Enterobacteriaceae and Ruminococcus gnavus. CONCLUSIONS: Bacterial populations differ in abundance among individuals with different phenotypes of CD. Specific species of bacteria are associated with ileal CD; further studies should investigate their role in pathogenesis.

Monozygotic twins are discordant for chronic periodontitis: white blood cell counts and cytokine production after ex vivo stimulation.

OBJECTIVES: The aim of this study was to investigate the extent of concordance in the number of leucocytes and their cytokine secretion after ex vivo stimulation in a twin population discordant for the amount of periodontal breakdown. MATERIAL AND METHODS: Venous blood was collected from 18 adult twin pairs (10 monozygotic and eight dizygotic twins). Each twin pair consisted of a diseased twin (proband) and his/her co-twin. In venous blood, leucocytes were counted. The cytokines interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-12p40 were assessed after stimulation of monocytic cells, while IL-13 and interferon (IFN)-gamma were determined after lymphocytic stimulation. RESULTS: In the study population as a whole, probands showed higher total numbers of leucocytes and lower IL-12p40 levels compared with their co-twins. In monozygotic twins, no difference was found in the leucocyte counts, but probands secreted more IL-6 than their co-twins; an opposite trend was found for IL-12p40. CONCLUSION: The results suggest that the observed discordance in periodontal breakdown in the studied monozygotic twin population may be related to the relatively high levels of IL-6 and the low levels of IL-12p40 secretion after ex vivo stimulation of whole-blood cell cultures. This cytokine secretion profile may be regarded as a risk indicator of periodontitis.

Epigenetics lessons from twins: prospects for autoimmune disease.

The existence of phenotypic differences between monozygotic (MZ) twins is a prime case where the relationship between genetic determinants and environmental factors is illustrated. Although virtually identical from a genetic point of view, MZ twins show a variable degree of discordance with respect to different features including susceptibility to disease. Discordance has frequently been interpreted in terms of the impact of the environment with genetics. In this sense, accumulated evidence supports the notion that environmental factors can have a long-term effect on epigenetic profiles and influence the susceptibility to disease. In relation with autoimmune diseases, the identification of DNA methylation changes in individuals who develop the disease, and the influence of inhibitors of DNA methyltransferases and histone modification enzymes in the development of autoimmunity are attracting the attention of researchers in the epigenetics field. In this context, the study of discordant MZ twins constitutes an attractive model to further investigate the epigenetic mechanisms involved in their development as well as to dissect the contribution of environmental traits. The implications of novel strategies to map epigenetic profiles and how the use of MZ twins can contribute to dissect the epigenetic component of autoimmune disease are discussed.

Does heredity determine the allergy manifestation or the sensitisation to a specific allergen?

BACKGROUND: The role of genetics in allergy development is well accepted. However, studies could not delineate the mode of inheritance or what is specifically being inherited. The purpose of this study was to determine the effect of genetics on the development of allergy manifestation, serum IgE level, and sensitization to specific allergens. METHODS: Fifty-eight twin sets (age 7 months to 11 years) were evaluated for allergy by medical history, family history, physical examination, serum total IgE level, and percutaneous testing to selected common allergens. RESULTS: In 25 monozygotic (MZ) sets, concordance of atopy was significantly higher than in 33 dizygotic (DZ) sets (84.6% vs 62.5%). The age at onset tended to be earlier when the mother was allergic than when the father was (23.5 months vs 30.5 months). When both twins were allergic, the intra-pair difference in age at onset was within <6 months in 50% of MZ sets versus 31.8% in DZ sets. Total IgE level in twins showed a very strong correlation in MZ sets (r 0.92), but only a moderate correlation among DZ sets (r 0.57). Skin test positivity to specific allergens did not show a significant concordance between twins in either group. CONCLUSION: Our study indicates that the genetic influence was strongest on the inheritance of IgE phenotype, the development of the atopic tendency, the age of onset, and to some extent on the specific allergy manifestation. The effect seemed less on determining the specific offending allergen(s), suggesting possible roles of epigenetic and environmental factors.

Calculated withdrawal of low-dose immunosuppression based on a detailed immunological monitoring after kidney transplantation between monocygotic twins.

BACKGROUND: Pretransplant screening in living donor kidney transplantation includes human leukocyte antigen matching, and panel reactive antibody analysis, whereas T cell mediated anti-donor reactivity is not assessed routinely. We investigated T cell reactivity after living related kidney transplantation between two monocygotic twins and in consequence correlated the withdrawal of individual immunosuppressive medication with immunological findings. METHODS: Immunosuppression consisted of mycophenolate mofetil, glucocorticoid single shot, and induction therapy with antithymocyte immunoglobulin. RESULTS: FACS analysis of recipient peripheral blood cells revealed a normal haemogram after transplantation, showing non-activated CD4 and CD8 cells. Mixed lymphocyte reaction did not reveal donor-specific T cell activity. IFN-gamma and IL-10 ELISA of supernatants of recipient cells cocultivated with donor cells support the lack of Th1 and Th2 cell differentiation. CONCLUSION: Based on immunological findings on days 5 and 20 MMF-therapy was reduced and stopped. Immunological monitoring on day 90 confirmed the absence of immune reactions directed against donor tissue.

Genetic and environmental contributions to allergen sensitization in a Chinese twin study.

BACKGROUND: Allergic disease is on the rise worldwide. Effective prevention of allergic disease requires comprehensive understanding of the factors that contribute to its intermediate phenotypes, such as sensitization to common allergens. OBJECTIVE: To estimate the degree of genetic and environmental contributions to sensitization to food and aeroallergens. METHODS: Sensitization was defined as a positive skin prick test to an allergen. We calculated the zygosity-specific concordance rates and odds ratios (ORs) for sensitization to food and aeroallergens in 826 Chinese twin pairs [472 monozygotic (MZ) and 354 dizygotic (DZ)] aged 12-28 years. We also applied structural equation modelling procedures to estimate genetic and environmental influences on sensitization. RESULTS: The concordance rates and risk of sensitization in one twin given the presence vs. the absence of sensitization in the other twin were higher in MZ twins than those in DZ twins. However, a large number of MZ twins were discordant in sensitization to common allergens. These observations suggest both genetic and environmental factors influence sensitization. Consistently, the estimated heritability and individual environmental components of the liability to sensitization ranged from 0.51 to 0.68 and 0.32 to 0.49, respectively, based on the best-fitted structural equation model. We also observed high phenotypic correlations between sensitization to two aeroallergens (cockroach and dust mite: 0.83) and two food allergens (peanut and shellfish: 0.58), but only moderate correlations for the pairs between sensitization to a food and an aeroallergen (0.31-0.46). The shared genetic and environmental factors between paired sensitizations contribute to the observed correlations. CONCLUSION: We demonstrated that sensitization to common food and aeroallergens were influenced by both genetic and environmental factors. Moreover, we found that paired allergen sensitizations might share some common sets of genes and environmental factors. This study underscores the need to further delineate unique and/or pleiotropic genetic and environmental factors for allergen sensitization.

Long-term survival after kidney transplantation from homozygotic twin--a case report.

Grafts from genetically related living donors have better survival rates than ones from deceased donors. Immunological match is one of the beneficial factors involved. The aim of this paper is to discuss a case of a 55-year old patient living for 33 years with transplanted kidney, weaned off immunosuppressive therapy for 20 years. Perfect match between donor and recipient, homozygotic siblings, was vital for such long-term graft survival.

T cell selection and differentiation in AIDS disease: the model of HIV-discordant monozygotic twins.

The model of monozygotic twins has been repeatedly studied to control the genetic and age-specific effects on HIV disease. Focusing on this natural model, the expression of CD27/CD45RA differentiation markers and the distribution of the Vbeta TCR repertoire was analyzed on CD4+ and CD8+ T cells. In our HIV-discordant monozygotic twins, a significant reduction of naive T cells and a parallel accumulation of effector/memory T cells was induced by HIV infection, as well as a skewing of T cell repertoire evidenced by VbetaTCR analysis. The block of HIV replication by highly active antiretroviral therapy (HAART) restored most of the T cell maturation and selection process, with some exception among CTL differentiation and repertoire. Altogether, the model of HIV-discordant monozygotic twins is a valuable tool showing that HAART is not able to completely restore the CTL profile.

The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins.

OBJECTIVE: In euthyroid individuals, autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) are regarded as early markers of thyroid autoimmunity. Family and twin studies suggest that development of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is under genetic influence. We aimed to estimate the relative importance of genetic and environmental effects for the presence of thyroid autoantibodies in euthyroid subjects. METHODS: A representative sample of healthy twin pairs was identified through the Danish Twin Registry; 1372 individuals, divided into 283 monozygotic (MZ), 285 dizygotic same sex (DZ), and 118 opposite sex twin pairs were investigated. Serum TPOab and serum Tgab were measured. Proband-wise concordance and intraclass correlations were calculated, and quantitative genetic modelling was performed. RESULTS: Probandwise concordance and intraclass correlations were consistently higher for MZ than for DZ twin pairs indicating genetic influence. Genetic components (with 95% confidence intervals) accounted for 73% (46-89%) of the liability of being thyroid antibody positive. Adjusting for covariates (age, TSH and others), the estimate for genetic influence on serum TPOab concentrations was 61% (49-70%) in males and 72% (64-79%) in females. For serum Tgab concentrations, the estimates were 39% (24-51%) and 75% (66-81%) respectively. CONCLUSIONS: Early markers of thyroid autoimmunity appear to be under strong genetic influence. The analyses suggest that it is the same set of genes that operate in males and females. However, complex mechanisms such as dominance and/or epistasis may be involved.

Heritability estimates of innate immunity: an extended twin study.

Cytokines are key players in numerous inflammatory processes. Demonstration of a heritable component in the variation of cytokine production would indicate that simultaneous occurrence of conditions might be caused by a heritable inflammatory characteristic. We applied an extended twin study approach to assess heritability estimates of interleukin (IL)-1beta, IL-1ra, IL-10, IL-6, and TNF-alpha production capacity after ex vivo stimulation with lipopolysaccharide. Cytokine production capacity was assessed in 42 monozygotic pairs, 52 dizygotic pairs, one trizygotic triplet, 33 single twins, and 83 additional siblings. Heritability estimates were derived from variance decomposition models using maximum likelihood estimation. For all cytokines, over 50% of the variance was genetically determined. IL-1ra and TNF-alpha had the lowest heritability estimate of 53%. Estimates for IL-6 and IL-10 were 57 and 62%, respectively. IL-1beta had the highest estimate of 86%. We conclude that the production of cytokines is under tight genetic control.

Genetic factors in nickel allergy evaluated in a population-based female twin sample.

Environmental exposures are important for development of allergic contact dermatitis, but genetic factors have been proposed to be of additional importance for contact sensitization. Recently genetic factors were shown to be of significance for hand eczema. In this study, a sample of twins recruited on the basis of hand eczema has been evaluated with respect to influence of genetic factors on development of nickel sensitization. A total of 1076 individual twins were patch tested and underwent clinical examination, and in the final genetic statistical analysis 630 females were available, of which 146 had a positive patch test to nickel. The aggregation of nickel allergy among twin pairs was measured by the casewise concordance and the twin odds ratio. The twin odds ratio were adjusted for effects of risk factors known to be associated with nickel allergy, namely, wet work, atopic dermatitis, and self-reported hand eczema. There was a small tendency for larger odds ratio among monozygotic twins than among dizygotic twins, which was not statistically significant. As a result of the statistical analysis, it is concluded that allergic nickel contact dermatitis is mainly caused by environmental and only to a lesser degree genetic factors. The selection of twins on the basis of hand eczema may theoretically influence the prevalence of nickel allergy and concordance estimates, which should be considered before extrapolating the data to a random population-based twin sample.