David H. Verity

Natural killer cell immunoglobulin-like receptor (KIR) locus profiles in African and South Asian populations

Natural killer (NK) and some T cells express killer cell immunoglobulin-like receptors (KIRs), which interact with HLA class I expressed by target cells and consequently regulate cytolytic activity. The number of KIR loci can vary and so a range of genetic profiles is observed. We have determined the KIR genetic profiles from one African (n = 62) and two South Asian (n = 108, n = 78) populations. Several of the KIRs are present at significantly different frequencies between the two major ethnic groups (eg KIR2DS4 gene frequency 0.82 African, 0.47 S Asian. Pc < 1 × 10−6) and this is due to uneven distribution of two KIR haplotype families ‘A’ and ‘B’. All three populations described here displayed a greater degree of diversity of KIR genetic profiles than other populations investigated, which indicates further complexity of underlying haplotypes; in this respect we describe two individuals who appear homozygous for a large deletion including the previously ubiquitous 2DL4. We have also reanalysed three populations that we studied previously, for the presence of a KIR which is now known to be an indicator of the ‘B’ haplotype. South Asians had the highest overall frequencies of all KIR loci characteristic of ‘B’ haplotypes (Pc < 0.0001 to < 0.004). Furthermore, gene frequency independent deviances in the linkage disequilibrium were apparent between populations.

Behçet’s disease: from Hippocrates to the third millennium

Behçet’s disease (BD) is characterised by recurrent episodes of orogenital aphthae, systemic vasculitis, and systemic and retinal venous thrombosis. An association between HLA-B51 and BD was first identified over 20 years ago, but recently identified gene associations implicate regions both within and without the MHC in the immunological events underlying the lesions in BD. These include allelic variants within the tumour necrosis factor gene region and within the MHC class I chain related gene region, the factor V Leiden mutation, which is associated with retinal vascular occlusion, and alleles of the intercellular adhesion molecule gene. No single causative gene for BD has emerged; the evidence indicates that the underlying immune events in BD are triggered by a microbial antigen and subsequently driven by genetic influences which control leucocyte behaviour and the coagulation pathways. Knowledge of these risk factors may permit a more accurate prognosis for a given patient, and identify new pathways for more targeted intervention than is currently available.

MIC-A allele profiles and HLA class I associations in Behçet's disease

Abstract Recently a new family of non-classical MHC molecules, the MHC class I chain-related protein (MIC), encoded by genes located in the major histocompatability complex have been identified. On the basis of the location of MIC genes and the structure and expression of MIC molecules it has been postulated that MIC may be a susceptibility factor in Behçets disease (BD). We investigated the association of the 16 described external domain alleles and the transmembrane triplet repeats of MIC-A with BD in a Middle Eastern population. DNA from ninety-five patients and 102 age- and sex-matched controls were analyzed by polymerase chain reaction using allele specific primers. Our results show an increase of MIC-A*009 in the BD patient group 44/95 (46%) compared with controls 24/102 (24%) (χ2=11.3, OR=2.8, P=0.00078). MIC-A*009 was also found to be strongly associated with HLA-B51 in the patients 39/44 (88%) when compared with controls 10/24 (42%) (χ2=4, P=0.04). MIC-A*009 was also found in linkage disequilibrium with HLA-B52, but only in controls. The A6 form of a MIC-A transmembrane triplet repeat was found to be significantly raised in the patients (80/95; 84%;) compared with controls (58/102, 57%) (χ2=17.5, OR=4, P=0.000028). Although the MIC-A associations described are highly significant, the association with HLA-B51 independently remains the most significant factor (χ2=56.8, P<10–6). The data suggests that as both MIC-A*009 and A6 are in strong linkage disequilibrium with HLA-B51, they are unlikely to be the susceptibility gene for BD but may be markers for additional risk factors.

SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex

The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson’s F: P=0.001). In contrast, there was a high inter-population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright’s FST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.

Eyelid reconstruction: the state of the art.

Purpose of reviewThe goals of eyelid reconstruction are corneal protection, restoration of the integrity of the lid lamellae, and improvement of facial symmetry. Inadequate reconstruction may lead to corneal exposure and sight-threatening keratopathy; in the younger patient, visual deprivation and amblyopia may also follow. The purpose of this review is to describe new materials and approaches used in reconstructing the damaged eyelid. Recent findingsAlthough the surgical principles of lid reconstruction remain unchallenged, new materials and techniques have emerged. These include the use of both autogenous and cadaveric acellular dermis in the management of lower eyelid retraction, and amniotic membrane transplantation in the management of tarsal conjunctival disease. Recent work on upper facial nerve branch reinnervation in the animal model may also offer hope for eyelid reanimation after facial palsy. SummaryThe lid surgeon requires a sound knowledge of the principles involved in reconstructing the respective lamellae of the lid. Anterior lamellar reconstruction carries a significant risk of ectropion, and large defects may require several interposition flaps for optimum skin texture and color reconstruction. New materials (autogenous and cadaveric) for posterior lid reconstruction may reduce donor site morbidity and surgical time, but they may contract significantly after surgery. Recent experience with amniotic membrane transplantation may improve the prognosis for patients with entropion and symblepharon caused by conjunctival cicatricial changes.

Behçet’s disease in patients of west African and Afro-Caribbean origin

Aim: To report the presence of Behçet’s disease with ocular involvement in patients of west African or Afro-Caribbean origin. Methods: Case series of eight patients reporting to a tertiary uveitis service. Results: Eight patients with typical features of the disease are presented. Six of the eight patients were tested and found to be HLA-B51 negative. Conclusion: Behçet’s disease has only been reported in sporadic case reports in the indigenous west African and Afro-Caribbean populations, in whom the incidence of HLA B51 is also very low. A series of patients from the London region presented with the typical symptoms and signs of disease, most of whom were also HLA B51 negative. The presence of disease in this population, when absent in the indigenous population, suggests either that ascertainment of disease is poor in the indigenous population or that acquired factors may be important in the aetiology of the disease.

Bicanalicular Obstruction in Lichen Planus: A Characteristic Pattern of Disease

PURPOSE Lichen planus, an idiopathic mucocutaneous inflammatory disease, has only once been reported to cause lacrimal drainage obstruction. The authors present a series of patients with epiphora resulting from systemic lichen planus and describe the characteristic pattern of lacrimal canalicular blockage. DESIGN Retrospective noninterventional case series. PARTICIPANTS Eight patients (5 women, 3 men) with a median presenting age of 49 years (range, 39-60 years). METHODS A retrospective review of case notes for patients attending the lacrimal clinic between 1998 and 2005 was performed to identify patients with nontraumatic lacrimal canalicular obstruction. In addition to demographic information, the data collected included a history of periocular herpetic infection, administration of systemic 5-fluorouracil, other causes of canalicular obstruction, the extent of proximal and distal canalicular obstruction (noted during surgery), the type of surgery, and the surgical outcomes. MAIN OUTCOME MEASURES Identification of patients with biopsy-proven systemic lichen planus who had conjunctival and canalicular disease and documentation of the extent and severity of canalicular obstruction. RESULTS Of the 184 patients with canalicular obstruction identified during the study period, 8 had lichen planus. Bilateral, bicanalicular involvement was present in 7 of 8 lichen planus patients, with 3 of 8 patients having completely obstructed canaliculi. Primary dacryocystorhinostomy (DCR) with retrograde canaliculostomy was performed in 4 of 8 patients, but all required secondary placement of Lester Jones canalicular bypass tubes. The other 4 patients had either primary DCR alone (both eyes in 1 patient, with solely canalicular stenosis) or DCR with primary placement of Jones tubes (6 eyes in 3 patients). Histologic examination of pericanalicular tissues in 2 patients showed features consistent with lichen planus. CONCLUSIONS Lacrimal involvement in lichen planus is characterized by severe bilateral bicanalicular occlusion involving most of the length of affected canaliculi, and placement of a Jones canalicular bypass tube is generally required to control symptoms.

Discoid lupus erythematosus of the periorbita: clinical dilemmas, diagnostic delays

PurposeUntreated periocular discoid lupus erythematosus (DLE), though very rare, may lead to significant morbidity with lid deformities, trichiasis, and symblepharon formation. We present the largest reported cohort of patients with biopsy-proven DLE solely affecting the periorbital region.MethodsObservational case series of patients managed over a 7-year period (2004–10).ResultsSeven patients (one male) presented to the Adnexal Service at Moorfields Eye Hospital at a median age of 47 years (range 23–71 years); median interval from symptom onset to biopsy-proven diagnosis was 38 months (range 6–86 months). Changes in peripheral skin were present in 1 patient (occurring after the initial eyelid presentation) and the presenting periocular features were dissimilar across the group, these included: chronic blepharo-conjunctivitis, madarosis, atypical chalazia, depigmentation of the eyelid margin, or marked, persistent periocular oedema with dacryoadenitis.Two cases settled spontaneously, but five required systemic hydroxychloroquine or intralesional corticosteroid injections.ConclusionPeriorbital DLE is rare and very varied in its presentation, the protean manifestations often resulting in significant diagnostic delay. All patients with unusual periocular skin disease and those with a refractory inflammatory dermopathy, should undergo biopsy of involved tissue(s), thus leading to earlier diagnosis and prevention of permanent cicatricial periocular changes.

Natural history of periocular capillary haemangiomas: changes in internal blood velocity and lesion volume

AimAlthough the clinical characteristics of childhood periocular capillary haemangiomas are well known, serial measurements of blood velocity and lesion size are unknown. This investigation was designed to measure the changes in maximum blood velocity and estimated size of lesion in children with capillary haemangioma not requiring active intervention.Study designRetrospective case-note review for a cohort of children with capillary haemangioma involving the eyelid and orbit.Patients and methodsChildren with periocular capillary haemangioma, under the care of the Orbital unit at Moorfields Eye Hospital between 1996 and 2005, were monitored clinically and with repeated ultrasonographic examination. Volume estimates were calculated as an ovoid based on the three maximum orthogonal measurements for the haemangioma, and blood velocity was assessed by Colour Flow Mapping, Colour Doppler Energy Imaging, and Spectral Doppler techniques using a Sequoia 512 Acuson scanner.ResultsTwenty-four children (12 boys) had initial assessment by 18 months of age, and the haemangioma increased in size in 14/24 (58%), the increase being between 4 and 931% of initial volume estimate. The largest measured size for an individual haemangioma appears inversely related to the childs age at measurement, this mirroring a similar trend in measurements for the maximum blood velocity. Blood velocity measurements also tend to decrease with time, the peak velocity being before 1 year of age in the majority (15/24; 62%). In many children, both volume estimates and blood velocities show a cyclic variation—this occurring with increasing intervals between the maxima, before a final decay in both parameters.Although, for the whole group, there was no correlation (correlation coefficient=0.29) between estimated size and measured blood velocity, some individual children showed a significant correlation between the two parameters. The age at maximum blood velocity appeared to precede the age at maximum volume in most children, and in many there was an orbital anomaly detectable on ultrasonographic examination, even with complete clinical resolution of the haemangioma.ConclusionsUltrasonographic examination of periocular capillary haemangiomas show that these lesions have a very high blood velocity in feeding vessels—about 2–3 orders of magnitude greater than normal capillary beds—and that the velocity and volume of such lesions undergo a cyclic variation during their natural history. Evidence suggests that both velocity and volume decrease with time, although often not returning to zero on ultrasonography (unlike the clinical resolution of the lesions). In most children, blood velocity peaks before volume estimates and this might suggest that decreasing perfusion leads to later tissue atrophy and involution of the haemangioma.

The effect of intralesional steroid injections on the volume and blood flow in periocular capillary haemangiomas.

Aim: To examine the effect of steroid therapy on the volume estimates and blood flow characteristics of childhood periorbital capillary haemangiomas. Patients and Methods: Children at risk of amblyopia due to periorbital haemangiomas were treated with intralesional steroid injections (between 1 and 4 courses) and serial assessment of the volume and blood—flow characteristics of the lesions measured using colour Doppler ultrasonography. The characteristics of the haemangiomas in these children were compared with a cohort of untreated cases. Results: Eight of nine treated children were female, this proportion being significantly different from the equal sex distribution of an untreated cohort (p < 0.05). All children in the steroid-treated group presented within 1 month of birth, compared to the untreated children, who presented at an average of 2.1 months of age (range 0—14, median 2.9 months) (p = 0.04) and they required significantly longer follow-up in the Orbital service (mean 65 months, range 26—105), compared with an average of 35 months (range 4—92, median 23) in the untreated group (p = 0.002). The maximum estimated volume of the lesions were significantly larger in the treated group (treated group mean 8.9 ml, untreated group mean 4.1 ml; p = 0.016), with a trend towards higher maximum measured blood velocities in the treated group (treated mean 64 cm compared with untreated mean 52 cm; p = 0.1). Steroid injections appear to reduce the volume and blood flow of haemangiomas, this suppression persisting for several months (between 5 and 20) before the lesion later displays the cyclic fluctuations in volume and flow seen with untreated lesions. All treated haemangiomas had some residual vascular anomaly, detectable on ultrasonography, at last follow-up—this being despite absence of clinical signs in most cases. Conclusion: Periorbital capillary haemangiomas requiring steroid therapy for risk of amblyopia were significantly commoner in females, were larger lesions and presented at an earlier age. Intralesional steroids appear to cause a reduction of blood flow, with a transient reduction in volume and a suppression of the natural cyclic variation seen without treatment. The changes after a course of steroid therapy appear to last for between 5 and 20 months, this period of suppression of the lesion probably being particularly useful during infancy and early childhood when the child is at greatest risk of amblyopia.