Intercellular adhesion molecule 1 K469E gene polymorphism is associated with presence of skin lesions in Tunisian Behçet's disease patients

Abstract
Intercellular adhesion molecule 1 ( ICAM1 ) gene polymorphisms have been implicated in the susceptibility to inflammatory diseases. The expression of both soluble and tissue ICAM1 were increased in Behçet's disease (BD) but the contribution of ICAM1 gene polymorphisms to this disease remains unknown. We sought to establish the association of ICAM1 gene K469E polymorphism in exon 6 with susceptibility for BD. One hundred and thirty-five Tunisian patients who satisfied the International Study Group criteria for BD and 157 healthy blood donor controls from the same geographic area were genotyped by polymerase chain reaction method for the K469E ICAM1 gene polymorphisms in exon 6. There were no significant differences in the distribution of the K469E allele or genotype frequencies between the BD patients and healthy controls in the ICA1 gene. Among patients, significant association was found between the presence of skin lesions and the studied polymorphism in the distribution of the K469E allele ( P = 0.004; odds ratio = 1.26; 95% confidence interval = 2.13–3.62) and genotype frequencies ( P = 0.0028;χ² = 11.75). Our findings suggest that K469E ICAM1 gene polymorphism was associated with Tunisian BD patients with skin lesions.     

Mifepristone as an Anti-Implantation Contraceptive Drug: Roles in Regulation of Uterine Natural Killer Cells during Implantation Phase

Problem  To investigate the immunological mechanism of low-dose mifepristone acting as a contraceptive at the level of the endometrium.
Method of study  Endometrial explants were cultured in vitro with or without mifepristone treatment for 24 hr. Some tissues were fixed and immunostained for CD56, while other tissues were dissociated and cells analysed by three colour flow cytometry for CD3, CD56 and CD16.
Results and conclusion  Results showed a significant increase in the number of CD56⁺ natural killer (NK) cells and the percentages of CD3⁻ CD56⁺ CD16⁻ NK cell subset in the tissue treated with mifepristone, while the percentage of CD3⁻ CD56⁺ CD16⁺ NK cell subset remained unaffected. It shows that low-dose mifepristone increases the number of CD56⁺ NK cells and the percentage of CD3⁻ CD56⁺ CD16⁻ NK subset in receptive endometrium and provides new insights into the immunological mechanism of low-dose mifepristone as an anti-implantation contraceptive drug.     

Variation in Gut-Homing CD27-Negative Lymphocytes in Inflammatory Colon Disease

Prolonged antigenic stimulation results in lymphocyte shedding of CD27, a member of the tumour necrosis factor receptor (TNFR) family, and transformation to a stable phenotype capable of synthesizing interleukin-4 (IL-4). Co-expression of α4β7 identifies those cells with gut-homing potential. We have investigated these cell populations in patients with inflammatory colonic disease. Circulating and lamina propria mononuclear cells were isolated from patients with Crohn's disease (CD), ulcerative colitis (UC), non-inflammatory bowel disease (non-IBD) colonic inflammation and healthy controls. Double and triple colour flow cytometry for CD3, CD4, CD27, α4β7 and intracellular cytokines was performed. Circulating CD4+CD27– populations were increased in patients with CD (8.8 ± 0.8%, P  < 0.001), UC (12.2 ± 1.9%, P  < 0.001) and non-IBD colitis (10.5 ± 1.3%, P  < 0.01) as compared with controls (6.1 ± 0.5%). CD4⁺CD27⁻α4β7⁺ cells were increased in CD ( P  < 0.01). Lamina propria CD4⁺CD27⁻ populations were depressed significantly in CD ( P  < 0.05), UC ( P  < 0.02) and non-IBD colitis ( P  < 0.03). Mucosal CD4⁺CD27⁻ cells synthesized IL-4 in preference to interferon-γ. Thus, colonic inflammation is associated with alterations in gut-tropic circulating and mucosal populations of differentiated memory T cells with the phenotype of predominantly IL-4-synthesizing cells.     

Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's disease

In this study we aimed to investigate IVS3 +17T/C single nucleotide polymorphism (SNP) of CD28 gene, +49A/G and ?318C/T SNPs of CTLA‐4 gene in patients with Behçet's disease (BD) and their potential association to the main clinical features of the disease. These polymorphisms were investigated in a Turkish population of 123 patients with BD and 179 healthy controls, by using PCR‐RFLP technique. HLA‐B*51 genotype was also studied in both groups by using PCR‐SSP. The frequency of IVS3 +17TC genotype of the CD28 gene was significantly increased in BD patients compared to controls (43.6% vs. 31.2%, OR = 1.663, 95% CI = 1.033–2.679, P = 0.039). CTLA‐4 +49GG genotype frequency was found to be significantly lower in patients with BD than those of healthy controls (4% vs. 10.6%, OR = 0.357, 95% CI = 0.130–0.983, P = 0.05). Genotype and allele frequencies of the CTLA‐4–318C/T polymorphism between the BD and healthy control groups were not significantly different (12.2% vs. 10.6%, OR = 1.170, 95% CI = 0.570–2.402, P = 0.713). There were no associations between the studied polymorphisms and the main clinical features of BD. The frequencies of HLA‐B*51 were 60.3% and 30.7% in BD and control groups, respectively (OR = 3.429, 95% CI = 2.115–5.559, P = 0.0001). Association between HLA‐B*51 and each studied polymorphism did not reach to significant levels (OR = 0.479, 95% CI = 0.228–1.004, P = 0.064 for CD28 IVS3 +17TT genotype; OR = 2.180, 95% CI = 1.025–4.639, P = 0.061 for TC genotype; OR = 1.570, 95% CI = 0.870–2.836, P = 0.146 for C allele). These results may suggest that CD28 IVS3 +17TC genotype may be a risk factor for the development of BD, on the contrary CTLA‐4 +49GG genotype may be protective in the studied Turkish population.     

Association of the leukocyte immunoglobulin G (Fcγ) receptor IIIa-158V/F polymorphism with inflammatory myopathies in Dutch patients

Leukocytes are involved in the pathogenesis of idiopathic inflammatory myopathies (IIMs). Immunoglobulin G (IgG) receptors (FcγR) link the specificity of IgG to the effector functions of leukocytes. Several FcγR subclasses display functional polymorphisms that determine in part the vigour of the inflammatory response. FcγRIIIa genotypes were differentially distributed among 100 IIM patients compared with 514 healthy controls with a significant increase of the homozygous FcγRIIIa-V-158 genotype (3 × 2 contingency table, χ² = 6.3, P  = 0.04). Odds ratios (ORs) increased at the addition of each FcγRIIIa-V-158 allele, in particular among patients with non-specific myositis and dermatomyositis {OR 2.1 [95% confidence interval (CI) 1.1–4.3] and 2.7 (95% CI 1.1–6.4) for FcγRIIIa-V/F158 and FcγRIIIa-V/V158 genotypes, respectively, using FcγRIIIa-F/F158 as a reference group}. These data suggest that the FcγRIIIa-V-158 allele may constitute a genetic risk marker for IIM.     

Comparative Analysis of Peripheral Natural Killer Cells in the Two Phases of the Ovarian Cycle

Changes in endometrial Natural Killer (NK) cells during the luteal phase of the ovarian cycle are important in initiating/maintaining a subsequent pregnancy. In the present study it was investigated whether during the menstrual cycle changes occur also in peripheral blood (PB) NKs.

Method of study

Blood samples during the follicular and the luteal phase were collected from 30 women without fertility problems. Samples were analyzed by flow-cytometry for: (1) NK cells (CD3⁻CD16⁺CD56⁺) and (2) intracellular production of interferon-γ (IFN-γ) by NK cells. For the comparison and correlation of the two populations between the two phases, Wilcoxon signed-rank test and Spearman's Coefficient were used.

Results

The differences in percentages of CD3⁻CD16⁺CD56⁺ cells and that of CD3⁻CD16⁺CD56⁺/IFN-γ⁺ cells between the follicular and the luteal phase were not statistically significant (10.61 ± 5.11 versus 9.76 ± 4.57 and 6.48 ± 7.90 versus 7.30 ± 6.77, respectively, P  > 0.05). The correlation between the two variables (NK% and NK/IFN-γ%) was weakly positive ( P  = 0.07) only in the follicular phase.

Conclusion

The study did not reveal menstrual cycle-depended changes in PB NK cells. Thus, a suggestion to measure these cells in a specific phase of the cycle in order to predict the outcome of a subsequent pregnancy in women with fertility problems is objected.     

Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension

The renin-angiotensin system is involved in control of blood pressure and salt and fluid homeostasis. Genes for components of this system have been of major focus in research on the causation of the common, complex, polygenic trait, essential hypertension (HT). Association of an A→C variant at nucleotide 1166 of the angiotensin II type 1 receptor (AT₁R) gene with HT, but an absence of linkage of this locus with this disease, has been reported recently. Since confirmation in a different setting is imperative, we performed a cross-sectional case-control study of the A1166C variant in a well-characterized group of 108 Caucasian HT subjects with a strong family history (two affected parents) and early onset disease. Genotyping was by mismatch polymerase chain reaction/ Bfr I restriction fragment length polymorphism analysis. Frequency of the C¹¹⁶⁶allele was 0.40 in HTs and 0.29 in normotensives. The difference in genotype (χ²= 13, P = 0.0015) and allele (χ²= 5.3, P = 0.02) frequencies between the two groups was significant (odds ratio for CC vs AA+AC = 7.3 [95% CI, 1.9–31.9). The present results implicate the AT₁R gene, or a locus in linkage disequilibrium with the variant tested, in the causation of essential HT.     

Strict Adherence to a Common Rank Order of T-Cell Receptor Vβ Usage in Human Leucocyte Antigen Disparate Individuals

In order to investigate the T-cell receptor (TCR) Vβ usage in different T-cell subsets, the authors performed flow cytometric analyses using a large panel of TCR Vβ-specific monoclonal antibodies on CD4⁺, CD8⁺ CD28⁺ and CD8⁺ CD28⁻ T cells from 15 random blood donors, six umbilical cords and seven human leucocyte antigen (HLA) identical non-twin sibling pairs. The authors found that the proportion of T cells expressing each Vβ gene product was similar within CD4⁺ and CD8⁺ CD28⁺ T cells from all samples studied. For these T-cell subsets a rank order of Vβ usage could be identified which was adhered to by all donors. In contrast, within CD8⁺ CD28⁻ T cells a wide variation of Vβ usage was found between individuals, and no rank order correlation could be detected. Members of HLA identical sibling pairs were found to be no more similar in their usage of Vβ gene products than pairs of HLA disparate random blood donors. Groups of individuals sharing HLA antigens were no different from the groups not sharing such antigens in their usage of Vβ segments. The results suggest that HLA polymorphisms play no more than a minor part in determining TCR Vβ usage.     

CTLA4 gene polymorphisms and soluble CTLA4 protein in Behcet's disease

Cytotoxic T lymphocyte antigen 4 (CTLA4; CD152) is a costimulatory molecule expressed on activated T cells that plays a key inhibitory role during T lymphocyte activation. The gene encoding for CTLA4 has been suggested as a candidate for conferring susceptibility to autoinflammatory diseases. We investigated the polymorphisms of the CTLA4 gene [promoter region (−1722 T/C, −1661 A/G and −318 C/T) and exon 1 (+49 G/A)] and the differences of serum soluble sCTLA4 levels in 285 patients with Behcet's disease (BD) and 287 controls. The frequency of the CTLA4 −1661 GG genotype was significantly higher in BD patients than in controls [ P  = 0.019, odds ratio (OR) = 5.2, 95% confidence interval (CI) = 1.13–23.86]. Also, the genotype frequency for CTLA4 −1722 TC was significantly higher ( P  = 0.014, OR = 1.8, 95% CI = 1.13–2.99), while CTLA4 −1722 CC was significantly lower ( P  = 0.018, OR = 0.4, 95% CI = 0.20–0.87) in BD patients with ocular lesions compared with patients without this symptom. Serum sCTLA4 levels in BD patients were significantly lower, especially in BD patients with the CTLA4 +49 G allele, than those in healthy controls ( P  < 0.05). Although our understanding of the role of the CTLA4 gene and its protein product in BD is incomplete, these results suggest that single nucleotide polymorphisms of the promoter and exon regions in the CTLA4 gene are candidates that predispose to BD and that sCTLA4 may be related to the immunological abnormalities and disease expressions associated with BD.     

Expression of glucose-regulated stress protein GRP78 is related to progression of melanoma

Aims:  Glucose-regulated protein 78 (GRP78) is a protein translated in response to endoplasmic reticulum (ER) stress that has been implicated in the pathogenesis and resistance to therapy of a variety of cancers. The aim of this study was to investigate its expression and role in the development and progression of human melanoma.
Methods and results:  The immunohistochemical expression of GRP78 in naevi, primary melanoma and melanoma metastases from 171 patients was correlated with clinicopathological factors and patient survival. The GRP78 immunoreactivity score (IRS) was 0.2 in compound naevi, 0.65 in dysplastic naevi, 4.65 in naevi adjacent to primary melanoma, 2.4 in melanoma in situ , 11.2 in thin (≤1.0 mm) and 18.1 in thick (>1.0 mm) primary melanoma. It was 18 and 17.3 in subcutaneous and lymph node metastases, respectively ( P  < 0.0001). GRP78 expression was positively correlated with increasing tumour thickness ( P  = 0.001) and with increasing dermal tumour mitotic index ( P  = 0.0004). Disease-free survival (χ² = 8.0703, P  = 0.0045) and overall survival (χ² = 6.2633, P  = 0.0123) in melanoma patients with IRS >25 were significantly lower than in melanoma patients with IRS <25.
Conclusions:  GRP78 expression appears to correlate with known correlates of melanoma progression and survival and requires further evaluation as a prognostic biomarker in melanoma.     

The Effects of Mitogens, IL-2 and Anti-CD3 Antibody on the T-Cell Receptor Vβ Repertoire

Phytohaemagglutinin (PHA), Concanavalin A (Con A), interleukin-2 (IL-2), and monoclonal antibodies to CD3 (CD3MoAbs) are used for the assessment of the T-cell receptor (TCR) BV gene family expression in autoimmune disorders and multiple sclerosis, and to produce clones for assessment of cytokine profiles in progressive human immunodeficiency virus infection. The authors examined the effects of these stimulants on the TCR Vβ repertoire of resting and blastic CD4⁺ and CD8⁺ normal human peripheral blood lymphocytes, using three-colour cytofluorometry and a panel of anti-TCR Vβ monoclonal antibodies. IL-2 was associated with an increased percentage of blastic CD4⁺ cells expressing V_β5.1 (from median of 3.7% to 8.0%, P  = 0.0002) and blastic CD8⁺ cells expressing V_β5.3 (1.0 to 1.5%, P  = 0.0039). CD3MoAb caused a slight increase in V_β6.7 + blastic CD4⁺ cells (4.5 to 6.9%, P  = 0.0078). PHA did not alter the Vβ repertoire of blastic cells. Con A caused skewing in CD8⁺ blastic cells, toward expression of V_β5.2/5.3 (3.1 to 8.1%) and V_β5.3 (0.8 to 4.8%) ( P  = 0.0020). Thus, IL-2 stimulation causes slight alterations in the Vβ repertoire that should be taken into account in certain research settings. Con A produced skewing in CD8⁺ blastic cells suggesting that, in the presence of CD8, either Con A binds selectively to certain Vβ or the three-dimensional complex created by Con A's binding to other T-cell surface molecules induces preferential V_β5 stimulation.     

Effect of polymorphism in insulin locus and HLA on type 1 diabetes in four ethnic groups in Israel

This study examined a possible association of the insulin ( INS ) gene with type 1 diabetes (T1D) in patients and controls from four ethnic groups in Israel. We analyzed the distribution of −23 Hph I single nucleotide polymorphism (SNP) T/A alleles that correspond to INS variable number of tandem repeat short class I alleles (26–63 repeats) and class III alleles (141–209 repeats), respectively. The −23 Hph I T/T genotype was found to be positively associated with T1D in three Jewish groups (Yemenites: 93.9% patients vs 68.8% controls, P  = 0.0002; Ashkenazi: 80.6% vs 50.8%, P  < 10⁻⁴; Ethiopians: 75% vs 40.5%, P  = 0.002). The Yemenite healthy controls have the highest frequency of T allele from all Jewish groups studied (83.5% vs 68.8% in Ashkenazi and 64.3% in Ethiopians). The high frequency of a susceptibility allele in the Yemenites is in line with the high incidence of T1D in this population. No association was observed between T1D and the INS gene in Israeli Arabs studied (70.6% vs 66.7%). Variable incidence of T1D among different ethnicities in Israel is largely attributed to heterogeneous genetics. Human leukocyte antigen (HLA) results of our previous studies describing the susceptibility and protective haplotypes were used for combined analysis to determine possible interaction between the HLA and INS loci. Only in the Ashkenazi group such interaction was presented with statistical significance.     

Association of KIR2DL2 polymorphism rs2756923 with type 1 diabetes and preliminary evidence for lack of inhibition through HLA-C1 ligand binding

Killer cell immunoglobulin-like receptors (KIRs) on chromosome 19q13.4 regulate the function of not only human natural killer (NK) cells but also T cells. An increase in activating KIR– human leucocyte antigen ligand pairs has been associated with an additional risk to develop type 1 diabetes (T1D). T1D families [ n  = 184 (552 individuals); n  = 176 (528 subjects)], unrelated T1D patients ( n  = 380; n  = 394) and healthy controls ( n  = 315; n  = 401) from Germany and Belgium, respectively, were genotyped for the rs2756923 polymorphism within the KIR gene cluster haplotype B in exon 8 of the KIR2DL2 gene. We observed in both Germans and Belgians an overtransmission of the allele 'G' of the KIR2DL2-rs2756923 polymorphism (64.2% vs 35.8%, P  = 3 × 10⁻⁴ and 60.0% vs 40.0%, P  = 0.02, respectively). In addition, this allele was more frequent in German patients than in healthy controls (78.4% vs 21.6%, P  = 1 × 10⁻³). Preliminary results from a cytotoxicity assay suggest that inhibition of NK-cell cytotoxicity may be impaired in individuals carrying the rs2756923 G allele. These data suggest a potential role of the KIR2DL2-rs2756923 polymorphism in T1D in Germans and Belgians.     

Confirmation of the novel association at the BTNL2 locus with ulcerative colitis

Linkage in families and association in population case–control investigations have clearly shown that genes within the major histocompatibility complex region on chromosome 6p are relevant to the susceptibility and pathogenesis of ulcerative colitis (UC) and Crohn's disease. However, identifying the causative variants by fine mapping has not been conclusive. In this study using 58 single nucleotide polymorphisms (SNPs) with 616 UC cases, there was significant association with SNP rs2294881 of the (butyrophilin-like 2) BTNL2 gene with odds ratio (OR) = 2.80, confidence interval (CI) = 1.62–4.84 and P  = 5.69 × 10⁻⁴ ( P _Bonferroni = 3.3 × 10⁻²) and replication of SNP rs9268480. The missense SNP rs2076523 (K196E) showed novel association with a subset of UC cases with colectomy ( n  = 126), OR = 0.25, CI = 0.11–0.58 and P  = 4.42 × 10⁻⁴ ( P _Bonferroni = 2.56 × 10⁻²). These three associated variants within the BTNL2 gene were neither in linkage disequilibrium with each other nor correlated with the SNPs tagging the human leukocyte antigen (HLA)-DRB1*1502 and HLA-DRB1*0301 alleles.     

Interaction of maternal atopy, CTLA-4 gene polymorphism and gender on antenatal immunoglobulin E production

BACKGROUND: Genetic heritability and maternal atopy have been correlated to antenatal IgE production, but very few studies have studied gene-maternal atopy interaction on antenatal IgE production. This study investigated the interaction of CTLA-4 polymorphism with prenatal factors on the elevation of cord blood IgE (CBIgE). METHODS: Pregnant women were antenatally recruited for collection of prenatal environmental factors by a questionnaire. Umbilical cord blood samples were collected for CBIgE detection by fluorescence-linked enzyme assay and CTLA-4 polymorphism measurement by restriction fragment length polymorphism. RESULTS: A total of 1104 pregnant women initially participated in this cohort study, and 898 of them completed cord blood collection. 21.4% of the newborns had elevation of CBIgE (>or=0.5 kU/L). The CTLA-4+49A allele (P=0.021), maternal atopy (P<0.001) and gender (P=0.034), but not the CTLA-4+49G allele, -318C allele, -318T allele, parental smoking or paternal atopy, were significantly correlated with the CBIgE elevation in multivariate analysis. A dichotomous analysis of gene-maternal atopy interactions identified maternal atopy and CTLA-4+49A allele had an additive effect on the CBIgE elevation, especially prominent in male newborns; and in the absence of maternal atopy, CTLA-4+49GG genotype had a protective effect on CBIgE elevation in female newborns. CONCLUSIONS: Maternal but not paternal atopy has significant impacts on CBIgE elevation depending on gender and CTLA-4+49A/G polymorphism of newborns. Control of maternal atopy and modulation of CTLA-4 expression in the prenatal stage may be a target for the early prevention of perinatal allergy sensitization.     

Cytokine and chemokine expression in the skin from patients with maculopapular exanthema to drugs

Background:  Maculopapular exanthema (MPE) is the most frequent clinical manifestation of nonimmediate allergic reactions to drugs and T helper 1 (Th1) cytokines and CD4⁺ T cells have been shown to play an important role in its pathogenesis. We assessed the role of cytokines and chemokines and their receptors in the pathogenesis of MPE.
Methods:  We evaluated skin biopsies and peripheral CD4⁺ and CD8⁺ T cells from 27 patients during the acute phase of the reaction and 26 exposed controls. Semiquantitative real-time PCR was performed to determine the expression of cytokines and chemokines and their receptors and immunohistochemistry was used to determine the same chemokines and their receptor proteins in skin.
Results:  There was a high expression of the Th1 cytokines interferon-γ ( P  = 0.006) and tumor necrosis factor-α ( P  = 0.022) in skin and CD4⁺ T cells ( P  = 0.007 and P  = 0.005, respectively); and of the Th1 chemokines CXCL9 ( P  = 0.005) and CXCL10 ( P  = 0.028) in the skin, while their receptor CXCR3 was increased in skin ( P  = 0.006) and CD4⁺ T cells ( P  = 0.03). Homing chemokine receptors were also increased: CCR6 in skin ( P  = 0.026) and CD4⁺ T cells ( P  = 0.016), and CCR10 only in CD4⁺ T cells ( P  = 0.016), as well as their ligands, CCL20 and CCL27, in skin alone. Immunohistochemistry confirmed these results.
Conclusions:  These data show significant differences in the expression of chemokines and chemokine receptors, related with a Th1 profile, in both skin biopsies and peripheral CD4⁺ T cells in patients with drug-induced MPE.     

CD 127- and FoxP3+ expression on CD25+CD4+ T regulatory cells upon specific diabetogeneic stimulation in high-risk relatives of type 1 diabetes mellitus patients

Abnormalities in CD4⁺CD25⁺ regulatory T cells (Treg) may contribute to type 1 diabetes (T1D) development. First-degree relatives of T1D patients are at increased risk especially when they carry certain HLA II haplotypes. Using two novel markers of CD4⁺CD25⁺ Treg (CD127⁻ and FoxP3⁺ respectively), we evaluated number and function of Treg after specific stimulation with diabetogeneic autoantigens in 11 high-risk (according to HLA-linked risk) relatives of T1D patients and 14 age-matched healthy controls using a cytokine secretion assay based on interferon- γ (IFN- γ ) production. High-risk relatives of T1D patients had significantly lower pre- and post-stimulatory number of CD127⁻ Treg than that of healthy controls ( P  < 0.05). Labelling Treg with FoxP3⁺ demonstrated similar trend but did not reach statistical significance. Although the stimulation with diabetogenic autoantigens did not lead to a significant change in number of Treg in both groups, the defective function of Treg was performed by significantly higher activation of diabetogeneic T cells in high-risk relatives of T1D patients compared to healthy controls ( P  ≤ 0.02). Individuals at increased HLA-associated genetic risk for T1D showed defects in Treg.     

Biofilm and the role of the ica operon and aap in Staphylococcus epidermidis isolates causing neurosurgical meningitis

Fifty-five Staphylococcus epidermidis isolates, classified as contaminants or causing device-related meningitis, from external ventricular drain (EVD) and non-EVD cerebrospinal fluid specimens were characterized. Thirty-three of 42 (78.6%) meningitis isolates were PCR-positive for ica and aap , known determinants of polysaccharide- and protein-mediated biofilm production, whereas five of 13 (38.5%) contaminants were ica - and aap -negative; 71.4% of meningitis isolates and 84.6% of contaminants produced biofilm. ica ⁺ aap ⁺ meningitis isolates produced more biofilm than ica ⁺ aap ⁻ isolates (p 0.0020). ica ⁺ aap ⁻ isolates did not produce more biofilm than ica ⁻ aap ⁺ isolates (p 0.4368). Apparently, ica and aap are associated with biofilm production in S. epidermidis device-related meningitis isolates.     

Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma

Background:  A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3 ) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans.
Objective:  We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like ( GSDML ) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population.
Methods:  We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4–17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens.
Results:  Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19–2.53, P  = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12–2.38, P  = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high ( r ² = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35–1.54, P  < 0.00001).
Conclusions:  Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.     

Altered Allogeneic Response in Neonatally Anti-MHC Class I-Treated Mice

Neonatal treatment of C3H mice (H-2^k) with anti-K^k monoclonal antibodies results in altered cytotoxic responses against allogeneic targets. After 2–3 weeks of antibody treatment, no difference in the number of CD4⁺8⁻ or CD4⁻ 8⁺ T cells was observed between the antibody- and saline-treated mice. However, antibody-treated mice had a significantly reduced cytotoxic response against various allogeneic major histocompatibility complex (MHC) class I-expressing targets. The strongest reduction was observed in very young mice (up to 2 weeks of age). As the mice got older, the allo MHC-specific responses reached control levels. No significant changes in T-cell receptor (TCR)-V-region usage was observed even in young antibody-treated mice. The results suggest that the reduction in the number of positively selecting elements reduces alloreactivity and most likely also the diversity of TCR-repertoire. However, the reduced alloresponsiveness was not restricted to either allogeneic K- or D-encoded molecules, suggesting that self MHC-D-region encoded molecules can mediate positive selection of T cells able to react against both K and D region-encoded allogeneic MHC class I molecules.