Localized Darier disease: three cases of Type 1 segmental mosaicism.

Darier disease (DD) is an autosomal dominant acantholytic dermatosis with an estimated prevalence of 1 in 30 000-100 000. A localized form of DD was first described by Kreibich in 1906 and is thought to account for 10% of all cases. A number of clinical variants have been reported including: unilateral, linear, segmental or zosteriform DD. We present a case series of three patients with localized DD.

Thrombalexins: Cell-Localized Inhibition of Thrombin and Its Effects in a Model of High-Risk Renal Transplantation.

Allograft transplantation into sensitized recipients with antidonor antibodies results in accelerated antibody-mediated rejection (AMR), complement activation, and graft thrombosis. We have developed a membrane-localizing technology of wide applicability that enables therapeutic agents, including anticoagulants, to bind to cell surfaces and protect the donor endothelium. We describe here how this technology has been applied to thrombin inhibitors to generate a novel class of drugs termed thrombalexins (TLNs). Using a rat model of hyperacute rejection, we investigated the potential of one such inhibitor (thrombalexin-1 [TLN-1]) to prevent acute antibody-mediated thrombosis in the donor organ. TLN-1 alone was able to reduce intragraft thrombosis and significantly delay rejection. The results confirm a pivotal role for thrombin in AMR in vivo. This approach targets donor organs rather than the recipient and is intended to be directly translatable to clinical use.

Evidence of genetic association between TNFRSF1A encoding the p55 tumour necrosis factor receptor, and ankylosing spondylitis in UK Caucasians.

OBJECTIVES: To replicate the possible genetic association between ankylosing spondylitis (AS) and TNFRSF1A. METHODS: TNFRSF1A was re-sequenced in 48 individuals with AS to identify novel polymorphisms. Nine single nucleotide polymorphisms (SNPs) in TNFRSF1A and 5 SNPs in the neighbouring gene SCNN1A were genotyped in 1604 UK Caucasian individuals with AS and 1019 matched controls. An extended study was implemented using additional genotype data on 8 of these SNPs from 1400 historical controls from the 1958 British Birth Cohort. A meta-analysis of previously published results was also undertaken. RESULTS: One novel variant in intron 6 was identified but no new coding variants. No definite associations were seen in the initial study but in the extended study there were weak associations with rs4149576 (p=0.04) and rs4149577 (p=0.007). In the meta-analysis consistent, somewhat stronger associations were seen with rs4149577 (p=0.002) and rs4149578 (p=0.006). CONCLUSIONS: These studies confirm the weak genetic associations between AS and TNFRSF1A. In view of the previously reported associations of TNFRSF1A with AS, in Caucasians and Chinese, and the biological plausibility of this candidate gene, replication of this finding in well powered studies is clearly indicated.

The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis.

Associations with disease identified by genome-wide association studies (GWAS) must be replicated and refined to validate causative variants. In the Wellcome Trust Case Control Consortium (WTCCC) GWAS using 14 500 non-synonymous single nucleotide polymorphisms (nsSNP), rs11062385 (a nsSNP in JARID1A) showed nominal association with ankylosing spondylitis (AS) (P=0.0006, odds ratio (OR)=1.26, 95% confidence interval (95% CI)=1.1-1.4). To replicate and refine the association of JARID1A, rs11062385 was genotyped in 730 further cases and compared with allele frequencies in non-AS disease cohorts typed by WTCCC. We replicated the initial association (P=0.04, OR=1.16, 95% CI=1.01-1.34) and identified a strengthened association with AS in a meta-analysis of this new study combined with the original WTCCC study (P=0.0001, OR=1.21, 95% CI=1.10-1.33). We also genotyped nine further intronic tagging SNPs in JARID1A in 1604 AS cases and 1020 new control samples, but none was associated with AS. JARID1A or a locus in strong linkage disequilibrium with it is a positional candidate for susceptibility to AS.

Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene.

Ankylosing spondylitis (AS) is polygenic with contributions from the immunologically relevant genes HLA-B*27, ERAP1 and IL23R. A recent genome-wide association screen (GWAS) identified associations (P approximately 0.005) with the non-synonymous single-nucleotide polymorphisms (nsSNPs), rs4077515 and rs3812571, in caspase recruitment domain-containing protein 9 (CARD9) and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) on chromosome 9q that had previously been linked to AS. We replicated these associations in a study of 730 AS patients compared with 2879 historic disease controls (rs4077515 P=0.0004, odds ratio (OR)=1.2, 95% confidence interval (CI)=1.1-1.4; rs3812571 P=0.0003, OR=1.2, 95% CI=1.1-1.4). Meta-analysis revealed strong associations of both SNPs with AS, rs4077515 P=0.000005, OR=1.2, 95% CI=1.1-1.3 and rs3812571 P=0.000006, OR=1.2, 95% CI=1.1-1.3. We then typed 1604 AS cases and 1020 controls for 13 tagging SNPs; 6 showed at least nominal association, 5 of which were in CARD9. We imputed genotypes for 13 additional SNPs but none was more strongly associated with AS than the tagging SNPs. Finally, interrogation of an mRNA expression database revealed that the SNPs most strongly associated with AS (or in strong linkage disequilibrium) were those most associated with CARD9 expression. CARD9 is a plausible candidate for AS given its central role in the innate immune response.

Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis.

OBJECTIVES: To assess the possible association of killer immunoglobulin-like receptor (KIR) genes, specifically KIR3DL1, KIR3DS1 and KIR3DL2, with ankylosing spondylitis (AS). METHODS: 14 KIR genes were genotyped in 200 UK patients with AS and 405 healthy controls using multiplex polymerase chain reaction. Sequence-specific oligonucleotide probes were used to subtype 368 cases with AS and 366 controls for 12 KIR3DL2 alleles. Differences in KIR genotypes and KIR3DL2 allele frequencies were assessed using the chi(2) test. RESULTS: KIR3DL1 and KIR3DS1 gene frequencies were very similar in cases with AS and controls (odds ratio = 1.5, 95% confidence interval 0.8 to 3.0, and odds ratio = 1.02, 95% confidence interval 0.2 to 5.3, respectively). KIR3DL2 allele frequencies were not significantly different between cases with AS and controls. CONCLUSIONS: Neither the KIR gene content of particular KIR haplotypes nor KIR3DL2 polymorphisms contribute to AS.

An antibody combination that targets activated T cells extends graft survival in sensitized recipients.

Memory T cells are the very essence of adaptive immunity with their rapid and efficient response to antigen rechallenge and long-term persistence. However, it is becoming increasingly evident that when primed with self or transplanted tissue, these cells play a key role in causing and perpetuating tissue damage. Furthermore, current treatments, which efficiently control the naive response, have limited effects on primed T cells. We have used a treatment based on a combination of antibodies specific for molecules expressed by activated T lymphocytes to selectively remove these cells. This approach, which we termed multi-hit therapy, leads to cumulative binding of antibodies to the target T cells and a striking prolongation of skin graft survival in presensitized recipients in a stringent skin transplant model. The findings are consistent with the depletion of graft-specific CD4+ and CD8+ T cells, although other modes of action, such as T-cell regulation and altered migration could play a role. In conclusion, our therapeutic strategy controls primed T cells which are a major driving force in the pathology of many autoimmune diseases and in transplant rejection.

MHC2TA promoter polymorphism (-168*G/A, rs3087456) is not associated with susceptibility to rheumatoid arthritis in British Caucasian rheumatoid arthritis patients.

OBJECTIVE: To investigate the association of a single-nucleotide polymorphism (SNP) in the promoter region of MHC2TA gene (-168*G/A, rs3087456), which has previously been described in a Swedish rheumatoid arthritis (RA) cohort, in British Caucasian RA patients. METHODS: We genotyped 733 RA patients and 613 healthy controls for MHC2TA -168*G/A SNP by amplification-refractory mutation system (ARMS). Data were analysed using SPSS version 13.0 software and the chi-square test was applied where appropriate. RESULTS: The MHC2TA -168*G/A SNP was not associated with increased susceptibility to RA in our patients. Stratifying the patients according to the presence or absence of rheumatoid factor (RF) showed the SNP to be more common in RF negative patients, but this did not reach statistical significance. CONCLUSION: We did not confirm the previously reported association of this MHC2TA polymorphism with RA in our UK population despite its ethnic similarities with the Swedish population in which it was first described.

Effects of PTPN22 C1858T polymorphism on susceptibility and clinical characteristics of British Caucasian rheumatoid arthritis patients.

OBJECTIVES: To confirm the association of a functional single-nucleotide polymorphism (SNP), C1858T (rs2476601), in the PTPN22 gene of British Caucasian rheumatoid arthritis (RA) patients and to evaluate its influence on the RA phenotype. METHODS: A total of 686 RA patients and 566 healthy volunteers, all of British Caucasian origin, were genotyped for C1858T polymorphism by PCR-restriction fragment length polymorphism assay. Data were analysed using SPSS software and the chi 2 test as applicable. RESULTS: The PTPN22 1858T risk allele was more prevalent in the RA patients (13.9%) compared with the healthy controls (10.3%) (P = 0.008, odds ratio 1.4, 95% confidence interval 1.09-1.79). The association of the T allele was restricted to those with rheumatoid factor (RF)-positive disease (n = 524, 76.4%) (P = 0.004, odds ratio 1.5, 95% confidence interval 1.1-1.9). We found no association between PTPN22 and the presence of the HLA-DRB1 shared epitope or clinical characteristics. CONCLUSIONS: We confirmed the previously reported association of PTPN22 with RF-positive RA, which was independent from the HLA-DRB1 genotype.

Functional group characterization of indoor, outdoor, and personal PM: results from RIOPA.

UNLABELLED: Fourier transform infrared (FTIR) spectra of outdoor, indoor, and personal fine particulate matter (PM(2.5)) samples were collected during the Relationship of Indoor, Outdoor, and Personal Air (RIOPA) study. FTIR spectroscopy provides functional group information about the entire PM(2.5) sample without any chemical preparation. It is particularly important to characterizing the poorly understood organic fraction of PM(2.5). To our knowledge this is the first time that FTIR spectroscopy has been applied to a PM(2.5) exposure study. The results were used to chemically characterize indoor air and personal exposure. Sulfate was strongest in outdoor samples, which is consistent with the generally accepted understanding that sulfate is of outdoor origin. Absorbances attributed to soil dust were also seen in many outdoor and some indoor and personal samples. Inorganic nitrate absorbances were a common feature of many California and some New Jersey samples. Carbonyl absorbances showed substantial variation in strength, number of peaks, and wave number shift between samples, indicating variability in composition and sources. Absorbances attributed to aliphatic hydrocarbon and amide functional groups were enhanced in many personal and indoor samples, which suggested the influence of indoor sources in these homes. We speculate that meat cooking is one possible source of particulate amides. PRACTICAL IMPLICATIONS: To our knowledge this is the first time that FTIR spectroscopy has been used to characterize the composition of indoor and personal PM(2.5). The presence of sulfate, nitrate, ammonium, soil dust and a number of organic functional groups are all detected in one analysis on filter samples without extraction or other sample preparation. Differences between indoor and outdoor spectra are used to identify spectral features due to indoor-generated PM(2.5). Particularly interesting are the much larger aliphatic absorbances, shifts in carbonyl absorbances, and occasional small amide absorbances found in indoor and personal spectra but rarely in outdoor spectra. These observations are important because organics make up a large portion of PM(2.5) mass and their composition and properties are poorly characterized. The properties and behavior of organic compounds in airborne particles are often predicted based on their functional group composition. This analysis begins the development of a better understanding of the functional group composition of indoor and personal PM(2.5) and how it differs from that of outdoor PM(2.5). Eventually this will lead to an improved understanding of the properties, behavior and effects of PM(2.5) of indoor and outdoor origin.

Dynamic nuclear polarization at 9T using a novel 250GHz gyrotron microwave source.

In this communication, we report enhancements of nuclear spin polarization by dynamic nuclear polarization (DNP) in static and spinning solids at a magnetic field strength of 9T (250 GHz for g=2 electrons, 380 MHz for 1H). In these experiments, 1H enhancements of up to 170+/-50 have been observed in 1-13C-glycine dispersed in a 60:40 glycerol/water matrix at temperatures of 20K; in addition, we have observed significant enhancements in 15N spectra of unoriented pf1-bacteriophage. Finally, enhancements of approximately 17 have been obtained in two-dimensional 13C-13C chemical shift correlation spectra of the amino acid U-13C, 15N-proline during magic angle spinning (MAS), demonstrating the stability of the DNP experiment for sustained acquisition and for quantitative experiments incorporating dipolar recoupling. In all cases, we have exploited the thermal mixing DNP mechanism with the nitroxide radical 4-amino-TEMPO as the paramagnetic dopant. These are the highest frequency DNP experiments performed to date and indicate that significant signal enhancements can be realized using the thermal mixing mechanism even at elevated magnetic fields. In large measure, this is due to the high microwave power output of the 250 GHz gyrotron oscillator used in these experiments.

Papular acantholytic dyskeratosis of the vulva.

We describe two patients with unusual asymptomatic, papular lesions on the vulva, clinically resembling lichen planus, the histology of which revealed unexpected findings of suprabasilar clefting, acantholysis and dyskeratotic cells giving rise to corps ronds and grains together with hyperkeratosis and parakeratosis, features originally associated with a diagnosis of Darier's disease. Focal acantholytic dyskeratosis has been described in a wide variety of inflammatory and neoplastic processes including those involving mucous membranes and has been attributed various diagnostic labels. We feel that the findings in our patients are consistent with a diagnosis of papular acantholytic dyskeratosis of the vulva, a rare condition, which was first described in 1984.