Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease.

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (p c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/HLA-Bw4i from gait difficulties (p c = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (pc = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.

Carbon Fiber-Based Twisted and Coiled Artificial Muscles (TCAMs) for Powered Ankle-Foot Orthoses.

Ankle foot orthoses (AFOs) control the position and motion of the ankle, compensate for weakness, and correct deformities. AFOs can be classified as passive or powered. Powered AFOs overcome the limitations of passive AFOs by adapting their performance to meet a variety of requirements. However, the actuators currently used to power AFOs are typically heavy, bulky, expensive, or limited to laboratory settings. Thus, there is a strong need for lightweight, inexpensive, and flexible actuators for powering AFOs. In this technical brief, carbon fiber/silicone rubber (CF/SR) twisted and coiled artificial muscles (TCAMs) are proposed as novel actuators for powered AFOs. CF/SR TCAMs can lift to 12,600 times their weight with an input power of only 0.025 W cm-1 and are fabricated from inexpensive materials through a low-cost manufacturing process. Additionally, they can provide a specific work of 758 J kg-1 when an input voltage of 1.64 V cm-1 is applied. Mechanical characterization of CF/SR TCAMs in terms of length/tension, tension/velocity, and active-passive length/tension is presented, and results are compared with the performance of skeletal muscles. A gait analysis demonstrates that CF/SR TCAMs can provide the performance required to supplement lower limb musculature and replicate the gait cycle of a healthy subject. Therefore, the preliminary results provided in this brief are a stepping stone for a dynamic AFO powered by CF/SR TCAMs.

A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10-4; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.

Satisfaction with ankle foot orthoses in individuals with Charcot-Marie-Tooth disease.

BACKGROUND: Ankle foot orthoses (AFOs) are commonly prescribed to individuals with Charcot-Marie-Tooth disease (CMT). The aim of this study was to evaluate patient reported satisfaction with orthotic devices and services in individuals with CMT to provide preliminary data for advancing AFO development and improving clinical care. METHODS: The Orthotics and Prosthetics Users Survey was distributed via e-mail through the Inherited Neuropathy Consortium (INC) Contact Registry and includes 11 device-specific questions and 10 service-related questions. Participants were also asked open-ended questions about their experiences with AFOs. RESULTS: Three hundred and fourteen individuals completed the survey. Over one-third of participants provided negative responses, including dislike of AFO appearance, discomfort, abrasions or irritations, and pain. Ratings of orthotic services were generally positive. CONCLUSIONS: Lower scores related to discomfort, abrasions and pain identified areas for AFO improvement. Continued research in these areas will be beneficial to informing and advancing AFO development and improving clinical care.

Access to HIV Pre-exposure Prophylaxis in Practice Settings: a Qualitative Study of Sexual and Gender Minority Adults' Perspectives.

BACKGROUND: Sexual and gender minority (SGM) populations remain at disproportionate risk of HIV infection. Despite the effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV, PrEP uptake has been slow. OBJECTIVE: To identify barriers and facilitators of PrEP access by examining SGM patients' experiences with accessing health care systems and engaging with providers about PrEP in a variety of practice settings. DESIGN: Semi-structured, individual, qualitative interviews. PARTICIPANTS: Twenty-seven sexual and gender minority adults residing in Oregon. APPROACH: Interviews were audio-recorded, transcribed, and analyzed using thematic analysis. KEY RESULTS: We identified three main themes. Participants described the centrality of patient-provider relationships to positive experiences around PrEP, the necessity of personally advocating to access PrEP, and the experience of system-level barriers to PrEP access. Participants also made several suggestions to improve PrEP access including improving provider engagement with SGM patients, encouraging providers to initiate conversations about PrEP, and increasing awareness of medication financial support. CONCLUSIONS: In order to reduce HIV disparities, improving PrEP access will require additional efforts by providers and resources across health care settings to reduce barriers. Interventions to improve provider education about PrEP and provider communication skills for discussing sexual health are needed. Additionally, there should be system-level improvements to increase coordination between patients, providers, pharmacies, and payers to facilitate PrEP access and uptake.

Arthritogenic peptide binding to DRB1*01 alleles correlates with susceptibility to rheumatoid arthritis.

Genetic susceptibility to rheumatoid arthritis (RA) is often defined by the presence of a shared epitope (QKRAA, QRRAA, or RRRAA) at positions 70-74 in HLA-DRß1. However, DRß1*01:01 and 01:02 contain the same QRRAA epitope, but differ considerably in their susceptibility to RA. The purpose of this study was to determine if this difference could be explained by their ability to bind three arthritogenic peptides that we have previously shown to bind to the archetypal RA-susceptible allele, DRß1*04:01, but not to the resistant DRß1*08:01 allele. Binding of type II collagen(258-272), citrullinated and native vimentin(66-78), and citrullinated and native α-enolase(11-25) were measured on cell lines expressing either DRß1*01:01, *01:02 or *01:03 in association with DRα1*01:01. DRß1*01:01 and *01:02 both exhibited a 6.5-fold preference for citrullinated vimentin(66-78) compared to native vimentin. However, DRß1*01:01 also exhibited a 1.7-fold preference for citrullinated α-enolase(11-25) and bound collagen(258-272), while DRß1*01:02 bound neither of these peptides. Consistent with its known resistance to RA, DRß1*01:03 preferentially bound native vimentin(66-78) and α-enolase(11-25) over the citrullinated forms of these peptides, and also failed to bind collagen(258-272). Site-directed mutagenesis was performed to determine which amino acid residues were responsible for the differences between these alleles. Mutating position 86 in DRß1*01:01 from glycine to the valine residue found in DRß1*01:02 eliminated binding of both citrullinated α-enolase(11-25) and collagen(258-272), thereby recapitulating the peptide-binding profile of DRß1*01:02. The difference in susceptibility to rheumatoid arthritis between DRß1*01:01 and *01:02 thus correlates with the effect of position 86 on the binding of these arthritogenic peptides. Consistent with their association with RA resistance, positions I67, D70 and E71 all contributed to the inability of DRß1*01:03 to bind these arthritogenic peptides.

Foot offloading associated with carbon fiber orthosis use: A pilot study.

BACKGROUND: Traumatic lower limb injuries can result in chronic pain. Orthotic interventions are a leading conservative approach to reduce pain, manage loading, and protect the foot. Robust carbon fiber custom dynamic orthoses (CDOs) designed for military service members have been shown to reduce foot loading. However, the effect of carbon fiber orthosis design, including designs widely used in the civilian sector, on foot loading is unknown. RESEARCH QUESTION: Determine if carbon fiber orthoses alter foot loading during gait. METHODS: Loadsol insoles were used to measure peak forces and force impulse acting on the forefoot, midfoot, hindfoot, and total foot. Nine healthy, able-bodied individuals participated. Force impulse was quantified as cumulative loading throughout stance phase. Participants walked without an orthosis and with three carbon fiber orthoses of differing designs: a Firm stiffness CDO, a Moderate stiffness CDO, and a medial and lateral strut orthosis (MLSO). RESULTS: There were significant main effects of orthosis condition on peak forefoot forces as well as forefoot and hindfoot force impulse. Peak forefoot forces were significantly lower in the Moderate and Firm CDOs compared to no orthosis and MLSO. Compared to walking without an orthosis, forefoot force impulse was significantly lower and hindfoot force impulse was significantly greater in all carbon fiber orthoses. Additionally, hindfoot force impulse in the Firm CDO was significantly higher than in the MLSO and Moderate CDO. SIGNIFICANCE: The three carbon fiber orthosis designs differed regarding foot loading, with more robust orthoses providing greater forefoot offloading. Orthosis-related changes in forefoot loading suggest that carbon fiber orthoses could reduce loading-associated pain during gait. However, increased hindfoot force impulse suggests caution should be used when considering carbon fiber orthoses for individuals at risk of skin breakdown with repetitive loading.

The effect of carbon fiber custom dynamic orthosis use and design on center of pressure progression and perceived smoothness in individuals with lower limb trauma.

BACKGROUND: Carbon-fiber custom dynamic orthoses are used to improve gait and limb function following lower limb trauma in specialty centers. However, the effects of commercially available orthoses on center of pressure progression and patient perception of orthosis smoothness during walking are poorly understood. METHODS: In total, 16 participants with a unilateral lower extremity traumatic injury underwent gait analysis when walking without an orthosis, and while wearing monolithic and modular devices, in a randomized order. Device alignment, stiffness, participant rating of perceived device smoothness, center of pressure velocity, and ankle zero moment crossing were assessed. FINDINGS: The modular device was approximately twice as stiff as the monolithic device. Alignment, smoothness ratings, peak magnitude of center of pressure velocity, and zero moment crossing were not different between study devices. The time to peak center of pressure velocity occurred significantly later for the modular device compared to the monolithic and no orthosis conditions, with large effect sizes observed. INTERPRETATION: Commercially available orthoses commonly used to treat limb trauma affect the timing of center of pressure progression relative to walking without an orthosis. Despite multiple design differences, monolithic and modular orthoses included in this study did not differ with respect to other measures of center of pressure progression. Perceived smoothness ratings were approximately 40% greater with the study orthoses as compared to previous studies in specialty centers, which may be due to a more gradual center of pressure progression, as indicted by lower peak magnitude of center of pressure velocity with both study orthoses.

Novel testing system to determine shoe mechanical properties.

BACKGROUND: Shoes play an important role in ankle foot orthosis (AFO) function and alignment. Despite this, shoe mechanical testing systems are rarely colocated with gait analysis systems, limiting their availability and use during AFO-related studies. OBJECTIVE: The purpose of this study was to evaluate a novel mechanical testing system used to measure shoe heel stiffness and change in height with loading using equipment available in most gait analysis laboratories. The novel testing system will allow for shoe assessment during AFO studies at little additional cost. STUDY DESIGN: Shoes were tested to determine initial stiffness, terminal stiffness, and total stiffness, and whether these measures changed with repeated compressions (early vs. late). TECHNIQUE: The novel testing system consists of a baseplate for counterweights, uprights that support a low-friction hinge, and a lever arm with a heel-shaped indenter to apply force to the shoe. Minimal detectable change values were calculated using the standard error of measurement. Intraclass correlation coefficients were calculated in SPSS using a (2, k) model. RESULTS: No significant differences in mean values, or interactions, were observed between rounds of testing and early and late compressions (P > .05). Intraclass correlation coefficient values were greater than 0.98, and minimal detectable change values were less than 20% of the average for each measure. CONCLUSIONS: The novel mechanical testing system, combined with pre-existing gait analysis equipment, can be used to reliably assess shoe stiffness and change in height.

Custom Dynamic Orthoses and Physical Therapist Intervention for Bilateral Midfoot Amputation: A Case Report.

OBJECTIVE: Partial foot amputation is often associated with decreased mobility and function. Recent advances in custom carbon-fiber dynamic ankle-foot orthoses (CDOs) have improved gait, pain, and function following musculoskeletal trauma and can benefit individuals with partial foot amputation. However, limited information is available related to CDO use outside the military. The purpose of this case report is to describe the course of care and outcomes of a civilian provided with CDOs after bilateral transmetatarsal amputation. CASE DESCRIPTION: A 72-year-old man had a blood-borne bacterial infection (septicemia) of unknown origin at 68 years of age, developed limb-threatening necrosis of the hands and feet, and received bilateral transmetatarsal amputations with skin grafting. The patient initially used foam toe fillers and cushioned shoes but was functionally limited and experienced recurrent ulceration. He was fitted with bilateral CDOs 39 months after amputation and completed device-specific training with a physical therapist. RESULTS: After 1 week with the CDOs, ankle range of motion during gait was reduced, but greater than 40% increases were observed in bilateral ankle plantarflexor moments and ankle plantarflexion push-off power compared with the toe fillers. With additional therapist-directed training focused on gait and activity performance, ankle plantarflexor moments and plantarflexion push-off power further increased when compared with results after 1 week of CDO use. The patient reported marked improvement in quality of life with the CDOs due to improved walking ability on level and uneven terrain, marked improvement in confidence, and reduced pain. CONCLUSION: This case reflects the lessons learned and outcomes of a civilian using bilateral CDOs after bilateral transmetatarsal amputation and with poor skin quality. The results from this case study suggest that carbon-fiber CDOs and focused training by a physical therapist can result in improved gait biomechanics, mobility, and quality of life.

A Sexual Health Promotion App for Transgender Women (Trans Women Connected): Development and Usability Study.

BACKGROUND: HIV severely impacts the transgender communities in the United States, and transgender women have the highest HIV incidence rates among any identified risk group. Guided by formative research with transgender women and by an expert advisory panel of transgender women, we designed a prototype mobile app to promote HIV prevention among transgender women. OBJECTIVE: This study aimed to develop and test the usability and acceptability of the prototype Trans Women Connected mobile app. METHODS: We engaged in a 3-phase prototype development process. After conducting formative research about the health needs of this population, we outlined a theory-based app framework and developed three prototype activities (ie, a vision board, a pre-exposure prophylaxis [PrEP] education activity, and an interactive map). We then tested the usability and acceptability of the mobile app and activities with 16 transgender women using pre- and posttests, think-aloud protocols, and open-ended questions. RESULTS: Participants reported high acceptability for the mobile app; the mean rating across all usability and likability questions was 5.9 out of 7. Service utilization intention, goal setting, and social support increased at posttest compared with pretest. Increases in self-efficacy in finding lesbian, gay, bisexual, transgender, and queer-friendly services; intention to seek online social support; and PrEP knowledge were statistically significant. Participants described the app as attractive and useful and perceived all three activities positively. CONCLUSIONS: This study describes the development and usability and acceptability evaluation of a prototype mobile app designed for and with transgender women for HIV prevention. The usability testing findings provided important insights toward refining and the further development of the Trans Women Connected mobile app. The results suggest that a mobile health intervention can support positive changes. The remaining development and efficacy randomized trial of the Trans Women Connected mobile app is currently underway.

Findings from Formative Research to Develop a Strength-Based HIV Prevention and Sexual Health Promotion mHealth Intervention for Transgender Women.

Purpose: Transgender women experience significant health disparities, including increased risk of HIV infection. In this study, we examined the sexual health needs of transgender women in the context of their overall health and well-being and to identify overarching content framing strategies and content for a mobile health intervention. Methods: We conducted four focus groups and 20 individual in-depth interviews in the United States with racially and geographically diverse transgender women. Results: Four key themes were identified: structural factors as a central part of health; prioritization of transition-related care and mental health; the need for sexual health beyond preventing sexually transmitted infections and HIV; and the importance of connection and community. Conclusions: These themes can help inform the development of HIV prevention and sexual health promotion interventions for transgender women. The results suggest that the HIV and sexual health needs of transgender women should be addressed within the context of structural factors with a focus on resilience, community connection, and social support.

"Little Tablets of Gold": An Examination of the Psychological and Social Dimensions of PrEP Among LGBTQ Communities.

There are significant psychological, social, and cultural dimensions to the HIV epidemic in the United States, especially among lesbian, gay, bisexual, transgender, and queer (LGBTQ) communities. Biomedical HIV treatment has been shown to impact these dimensions. However, there is little understanding of the real-world psychosocial and sociocultural effects of the latest biomedical HIV prevention strategy, HIV pre-exposure prophylaxis (PrEP). This study explored the psychosocial and sociocultural dimensions of PrEP use among LGBTQ adults. We interviewed 23 LGBTQ adults who were current or former users of PrEP. Results included that PrEP users' experiences were shaped by multiple forms of stigma. Participants were highly motivated to challenge PrEP stigma and to support PrEP use among other community members. Lastly, participants described positive impacts on their individual well-being and their sexual partnerships. Findings suggest that PrEP has significant impacts beyond biomedical outcomes for both the individuals who use PrEP and their communities.

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop.

The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3 ∼ KIR3DL1/S1 ∼ KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

A Molecular Analysis of the Shared Epitope Hypothesis: Binding of Arthritogenic Peptides to DRB1*04 Alleles.

OBJECTIVE: The shared epitope hypothesis posits that amino acids QR/KRAA in positions 70-74 of the DRΒ1 chain are responsible for rheumatoid arthritis susceptibility. However, even DRB1*04 alleles containing the shared epitope vary greatly with respect to degrees of susceptibility. This study was undertaken to conduct a molecular examination of the shared epitope hypothesis by measuring binding of arthritogenic peptides to susceptibility and resistance alleles. METHODS: We measured binding of native and citrullinated forms of vimentin(66-78) and α-enolase(11-25) and noncitrullinated type II collagen(258-272) to 88 class II alleles on Luminex beads (which includes alleles of many varying degrees of susceptibility and resistance). We expressed DRΒ1*04:01, *04:02, and *08:01 in T2 cells and mutated DRΒ1*04:01 at positions 67, 70, 71, 74, and 86 to corresponding residues in DRB1*04:02, *04:03, *04:04, *04:05, and *08:01. Finally, we measured responses of 4 DRΒ1*04:01 restricted collagen(258-272) T cell hybridomas against wild-type DRΒ1*04:01, *04:02, and all mutated alleles. RESULTS: The most susceptible allele, DRΒ1*04:01, preferentially bound citrullinated vimentin(66-78) and citrullinated α-enolase(11-25) over the native forms. DRΒ1*04:02 exhibited no preference for citrullinated peptides, and *08:01 preferred native peptides. Similarly, DRB1*04:01 bound collagen(258-272) , but *04:02 and *08:01 did not. Mutating DRΒ1*04:01 at positions 70, 71, 74, and 86 to the corresponding residues in DRΒ1*04:02 or *08:01 dramatically reduced the specificity for citrullinated peptides and collagen(258-272) binding. CONCLUSION: These observations demonstrate that while amino acids at positions 70, 71, and 74 within the shared epitope in DRΒ1 mediate binding and T cell responses of arthritogenic peptides, position 86 outside the shared epitope also plays a critical role.

Multiple HLA epitopes contribute to type 1 diabetes susceptibility.

Disease susceptibility for type 1 diabetes is strongly associated with the inheritance of specific HLA alleles. However, conventional allele frequency analysis can miss HLA associations because many alleles are rare. In addition, disparate alleles that have similar peptide-binding sites, or shared epitopes, can be missed. To identify the HLA shared epitopes associated with diabetes, we analyzed high-resolution genotyping for class I and class II loci. The HLA epitopes most strongly associated with susceptibility for disease were DQB1 A(57), DQA1 V(76), DRB1 H(13), and DRB1 K(71), whereas DPB1 YD(9,57), HLA-B C(67), and HLA-C YY(9,116) were more weakly associated. The HLA epitopes strongly associated with resistance were DQB1 D(57), DQA1 Y(80), DRB1 R(13), and DRB1 A(71). A dominant resistance phenotype was observed for individuals bearing a protective HLA epitope, even in the presence of a susceptibility epitope. In addition, an earlier age of disease onset correlated with significantly greater numbers of susceptibility epitopes and fewer resistance epitopes (P < 0.0001). The prevalence of both DQ and DR susceptibility epitopes was higher in patients than in control subjects and was not exclusively a result of linkage disequilibrium, suggesting that multiple HLA epitopes may work together to increase the risk of developing diabetes.

Lack of HLA predominance and HLA shared epitopes in biliary Atresia.

UNLABELLED: Biliary atresia (BA) is characterized by progressive inflammation and fibrosis of bile ducts. A theory of pathogenesis entails autoimmune-mediated injury targeting bile duct epithelia. One of the strongest genetic associations with autoimmunity is with HLA genes. In addition, apparently dissimilar HLA alleles may have similar antigen-binding sites, called shared epitopes, that overlap in their capacity to present antigens. In autoimmune disease, the incidence of the disease may be related to the presence of shared epitopes, not simply the HLA allelic association. AIM: To determine HLA allele frequency (high-resolution genotyping) and shared epitope associations in BA. RESULTS: Analysis of every allele for HLA-A, -B, -C, -DRB1, -DPB1 and -DQB1 in 180 BA and 360 racially-matched controls did not identify any significant HLA association with BA. Furthermore, shared epitope analysis of greater than 10 million possible combinations of peptide sequences was not different between BA and controls. CONCLUSIONS: This study encompasses the largest HLA allele frequency analysis for BA in the United States and is the first study to perform shared epitope analysis. When controlling for multiple comparisons, no HLA allele or shared epitope association was identified in BA. Future studies of genetic links to BA that involve alterations of the immune response should include investigations into defects in regulatory T cells and non-HLA linked autoinflammatory diseases.