A new MHC-linked susceptibility locus for primary Sjögren's syndrome: MICA.

The association of primary Sjögren's syndrome (pSS) with Major Histocompatibility Complex (MHC) alleles is quintessential of MHC-disease associations. Indeed, although disease associations with classical HLA class I and II alleles/haplotypes are amply documented, further dissection is often prevented by the strong linkage disequilibrium across the entire MHC complex. Here we study the association of pSS, not with HLA genes, but with the non-conventional MHC encoded class I gene, MICA (MHC class I chain-related gene A). MICA is selectively expressed within epithelia, and is the major ligand for the activatory receptor, NKG2D, both attributes relevant to pSS' etiology. MICA-pSS association was studied in two independent (French and UK) cohorts representing a total of 959 cases and 1,043 controls. MICA*008 allele was shown to be significantly associated with pSS (pcor=2.61 × 10-35). A multivariate logistic regression showed that this association was independent of all major known MHC-linked risk loci/alleles, as well as other relevant candidate loci that are in linkage disequilibrium with MICA*008 i.e. HLA-B*08:01, rs3131619 (T), MICB*008, TNF308A, HLA-DRB1*03:01 and HLA-DRB1*15:01 (P = 1.84 × 10-04). Furthermore, independently of the MICA*008 allele, higher levels of soluble MICA proteins were detected in sera of pSS patients compared to healthy controls. This study hence defines MICA as a new, MHC-linked, yet HLA-independent, pSS risk locus and opens a new front in our understanding of the still enigmatic pathophysiology of this disease. The fact that the soluble MICA protein is further amplified in MICA*008 carrying individuals, might also be relevant in other auto-immune diseases and cancer.

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD.

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

On the genetics of the Silk Route: association analysis of HLA, IL10, and IL23R-IL12RB2 regions with Behçet's disease in an Iranian population.

Despite that the association of Behçet's disease (BD) with the HLA-B5 was first established in the 1970s, a number of recent genome-wide association studies have both confirmed and furthered this association--in various populations--to individual SNPs both inside and outside the HLA. The former include HLA-B, MICA, and HLA-A, while the latter encompass IL10 and IL23R-IL12RB2 regions. The present study examined whether some of these SNPs could be replicated in an Iranian population, where the prevalence of disease is amply documented. Eight SNPs were selected and tested in 552 patients and 417 controls. These were rs7539328, rs12119179, rs1495965, rs1518111, and rs1800871 in IL10 and IL23R-IL12RB2 regions and rs114854070, rs12525170, and rs76546355 (formerly rs116799036) in the HLA locus. The well-known BD-associated genes HLA-B and MICA were independently genotyped. Although we were not able to formally replicate the association with IL10 and IL23R-IL12RB2, we do report that BD in Iran is strongly associated with HLA-B*51, MICA-A6, and the three HLA-linked SNPs (odds ratio (OR) = 3.38, P = 6.21 × 10(-14); OR = 2.08, P = 1.58 × 10(-13); and OR = 1.67-4.05, P = 1.45 × 10(-04) to 4.79 × 10(-34), respectively). Our data further indicate that the robust HLA-B/MICA association may be explained by a single variant (rs76546355) between the two genes. Overall, these data contribute to a better appraisal of the intriguing linkage between BD and the ancient Silk Route, spanning from the Mediterranean shores to Japan.

Support Person Presence and Child Victim Testimony: Believe it or Not.

This study examined the effects of support person presence on participants' perceptions of an alleged child sexual abuse victim and defendant. Two hundred jury-eligible community members (n = 100 males) viewed a DVD of an 11-year-old girl's simulated courtroom testimony either with or without a female support person seated next to her. Participants found the child victim to be less accurate and trustworthy, and the defendant to be less guilty and less likely to have sexually abused children, when the support person was present. Participants who viewed the female support person (n = 100) believed that she had probably coached and spent a great deal of time with the child victim before testifying. Female participants perceived the child to be more accurate, and the defendant to be more guilty and likely to have sexually abused children, than male participants. The degree to which the child victim's testimonial behavior violated participants' expectancies mediated the negative relation between support person presence and child victim accuracy and trustworthiness. Support person presence was positively associated with expectancy violation, which in turn was negatively associated with child victim accuracy and trustworthiness. These preliminary findings suggest that seating a support person next to an alleged child victim in court may have the unintended effect of decreasing the child's perceived credibility and, if replicated, suggest that alternative seating arrangements might be necessary.

Effects of add-on montelukast on airway hyperresponsiveness in patients with well-controlled asthma - a pilot study.

OBJECTIVE: Control of airway inflammation is the cornerstone of asthma management. The aim of the present pilot study was to assess the effects of a leukotriene receptor antagonist (LTRA) added to a basic treatment of inhaled corticosteroids (ICS) and long-acting beta-agonist (LABA) on airway hyperresponsiveness, inflammation, and quality of life in well-controlled patients with asthma. RESEARCH DESIGN AND METHODS: Seventeen patients (age 18-65, 11 women) with well-controlled asthma presenting airway hyperresponsiveness to mannitol and methacholine challenge were given add-on montelukast on a stable ICS + LABA for 4 weeks. Quality of life and selected parameters of airway inflammation were measured at baseline and at study end. (ClinicalTrials.gov (NCT01725360)). RESULTS: Adding montelukast to ICS + LABA resulted in an increase in mean FEV1 (+4.5%, p = 0.057), cumulated higher dose of mannitol (+32.5%, p = 0.023) and methacholine (+17.2%, 0.237) in the provocation test, lower airway reactivity with mannitol and methacholine (response dose ratio (RDR) -50.0%, p = 0.024 and -44.3%, p = 0.006, respectively), and improved airway sensitivity to mannitol and methacholine (+12.1%, p = 0.590 and +48.0%, p = 0.129 for PD15 and PD20 FEV1, respectively). Changes in inflammation parameters (blood eosinophil count, serum eosinophil cationic protein, and exhaled nitric oxide) were consistent with these findings. Asthma-related quality of life improved significantly in all domains and overall (from 5.3 at baseline to 6.1 at the final visit, p < 0.001). The main limitation was the absence of a control group. CONCLUSION: The consistency of the changes in airway hyperresponsiveness and inflammation as well as in quality of life observed with an add-on therapy with montelukast in well-controlled asthma patients during 4 weeks suggests that residual inflammation may represent an area for further improvement of asthma control to be explored in adequately powered randomized controlled trials.