TGFß signaling pathway is altered by HLA-B27 expression, resulting in pathogenic consequences relevant for spondyloarthritis.

BACKGROUND: Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-ß2 microglobulin (hß2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype. METHODS: Genetic interaction was studied between activin/transforming growth factor ß (TGFß) pathway and HLA-B27/hß2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hß2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFß pathways induced by its ligands, and the transcript level of target genes of the TGFß pathway, were evaluated. RESULTS: In HLA-B27/hß2m transgenic Drosophila, inappropriate signalling through the activin/TGFß pathway, involving Baboon (Babo), the type I activin/TGFß receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hß2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hß2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFß receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFß1 was increased in T cells from B27 rats, showing evidence for deregulated TGFß pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFß exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. CONCLUSIONS: This study shows that HLA-B27 alters the TGFß pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats.

HLA-B5 prevalence in patients with spondyloarthritis and impact on disease phenotype: a multicentric case-control study.

OBJECTIVE: The study aimed to estimate the prevalence of HLA-B51 and HLA-B52 in Lebanese patients with spondyloarthritis (SpA) compared to healthy controls (HC). We further aimed to evaluate the impact of HLA-B51 on phenotype and identify the distribution of the alleles in the HLA-B locus. METHODS: A case-control study enrolled consecutive SpA patients from three rheumatology clinics in Lebanon, including axial (axSpA), peripheral SpA (pSpA), and psoriatic arthritis (PsA) and HC from blood donors. Demographic and disease data were collected through interviews and file reviews, with testing of the entire HLA-B locus using molecular techniques. The prevalence of HLA-B51 and B52 was estimated in SpA patients versus controls. Prevalence comparisons were made, and logistic regression identified factors associated with HLA-B51 in patients. RESULTS: Data from 120 HC and 86 SpA patients (65 axSpA, 15 pSpA, 6 PsA), mean age 25.6 and 46.4 years, respectively, showed a higher HLA-B51 prevalence in SpA (25.6%), especially axSpA (29.2%) versus HC (12.5%), p = 0.016, and a numerically higher HLA-B52 prevalence (8.1% versus 4.2%, p = 0.230). HLA-B51 correlated with recurrent oral ulcerations (OR 7.99(95%CI 2.14-29.84) and radiographic juxta-articular erosions (OR 7.65(95%CI 1.14-38.03)). HLA-B35 was the most dominant allele in both groups (18.7%), followed by HLA-B27 (15.7%) and HLA-B51 (13.4%) in SpA. CONCLUSION: HLA-B51 was identified more frequently in patients with SpA compared to HC and was associated with recurrent oral ulcerations and juxta-articular radiographic erosions. Longitudinal studies are needed to determine whether this association indicates a disease overlap or might correlate with a specific SpA phenotype.

Choroidal and retinal vascular changes in HLA-B27-associated anterior uveitis.

PURPOSE: To quantitatively analyze choroidal and retinal vascular changes in HLA-B27-associated anterior uveitis. STUDY DESIGN: A retrospective study. METHODS: Medical records of 51 eyes with unilateral HLA-B27-associated anterior uveitis, their fellow eyes and 47 sex and age-matched healthy eyes were retrospectively reviewed. Their choroidal and retinal vasculature were analyzed using swept-source (SS) optical coherence tomography (OCT) and OCT angiography (OCTA) scans. RESULTS: Deep capillary plexus (DCP) vessel density (VD) (p < 0.001), choroidal vascularity index (CVI) (p = 0.012), and choriocapillary flow deficit (CCFD) (p < 0.001) of uveitic and fellow eye group were significantly higher than those of control group. On the contrary, superficial capillary plexus (SCP) VD (p < 0.001) of uveitic and fellow eye group were significantly lower than of control group. The vascular parameters of uveitis and fellow eye group showed no significant difference between uveitic and resolution period. CONCLUSION: Certain choroidal and retinal vascular parameters were significantly changed in both HLA-B27-associated anterior uveitis without posterior segment involvement and the quiet fellow eyes, suggesting their possible effects as a systemic inflammatory disorder.

Characterisation of the novel HLA-B*46:96 allele by next-generation sequencing.

HLA-B*46:96 differs from HLA-B*46:01:01:01 by a single nucleotide substitution at position 479 C>T.

Identification of eight new HLA class I alleles by next-generation sequencing.

Eight novel HLA class I alleles detected by next-generation sequencing.

The novel HLA-B*40:550 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*40:550 differs from HLA-B*40:01:02:01 by one nucleotide in exon 1.

The association between HLA-B variants and amoxicillin-induced severe cutaneous adverse reactions in Chinese han population.

Background: Amoxicillin (AMX) is among the most prescribed and the best tolerated antimicrobials worldwide. However, it can occasionally trigger severe cutaneous adverse reactions (SCAR) with a significant morbidity and mortality. The genetic factors that may be relevant to AMX-induced SCAR (AMX-SCAR) remain unclear. Identification of the genetic risk factor may prevent patients from the risk of AMX exposure and resume therapy with other falsely implicated drugs. Methodology: Four patients with AMX-SCAR, 1,000 population control and 100 AMX-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between AMX and risk HLA proteins. Results: Compared with AMX-tolerant controls, a significant association of HLA-B*15:01 with AMX-SCAR was validated [odds ratio (OR) = 22.9, 95% confidence interval (CI): 1.68-1275.67; p = 7.34 × 10-3]. Moreover, 75% carriers of HLA-B*15:01 in four patients with AMX-SCAR, and the carrier frequency of 10.7% in 1,000 control individuals and 11.0% in 100 AMX-tolerant controls, respectively. Within HLA-B protein, the S140 present in all cases and demonstrated the strongest association with AMX-SCAR [OR = 53.5, p = 5.18 × 10-4]. Molecular docking results also confirmed the interaction between AMX and S140 of the HLA-B protein, thus eliminating the false-positive results during in association analysis. Conclusion: Our findings suggest that genetic susceptibility may be involved in the development of AMX-SCAR in Han Chinese. However, whether the HLA-B variants observed in this study can be used as an effective genetic marker of AMX-induced SCAR still needs to be further explored in larger cohort studies and other ethnic populations.

Characterisation of the novel HLA-B*07:02:01:110 allele by next-generation sequencing.

HLA-B*07:02:01:110 differs from the HLA-B*07:02:01:01 allele by two nucleotide substitutions in the 3'UTR.

Anticipating the side effects of benznidazole: HLA-B*35 and patch test.

INTRODUCTION: Treatment of Chagas disease frequently causes distress to patients due to a high incidence of adverse effects. Different preemptive tests have been researched to prevent these effects and to allow focus to be given to certain predisposed patients. Benznidazole is the most prescribed Chagas disease treatment in Spain. In this work, we analyzed the genetic markers HLA-B*35 allele group and HLA-B*35:05 allele specifically, as well as an allergy patch test, as benznidazole's most frequent adverse effects are cutaneous. METHODS: HLA-B intermediate-resolution genotyping was performed followed by a high-resolution level analysis. Cutaneous allergies were tested using strips impregnated with a mixture of benznidazole and placed on the upper back of patients before starting treatment. RESULTS: In our sample of more than 400 patients, there was almost no relationship between any kind of side effect and either of the HLA-B alleles studied. The patch testing was quickly discarded as a preemptive test due to its low sensitivity (16.7%). CONCLUSION: In conclusion, we were unable to replicate and corroborate genetic markers identified by other groups and there is currently no test that can anticipate the adverse effects of benznidazole, therefore, more investigation should be carried out in this field.

Recognition of the HLA-B*40:400 allele and its associated HLA haplotype in a Taiwanese individual.

One nucleotide substitution in codon 81 of HLA-B*40:01:01 results in a novel allele, HLA-B*40:400.

Exploring the Pathogenesis of Spondylarthritis beyond HLA-B27: A Descriptive Review.

Spondylarthritis (SpA) is a chronic inflammatory condition that encompasses damage to the axial or peripheral skeleton, accompanied by specific extra-articular symptoms. Within this group, Ankylosing Spondylitis stands out as the hallmark member. Although the heritability of Ankylosing Spondylitis is estimated to be over 95%, only a portion of the heritability has been explained, with HLA-B27 accounting for 20.1% of it; therefore, ongoing research endeavors are currently concentrated on investigating the potential participation of different entities in the development of the disease. Genome-wide association studies have led to significant advances in our understanding of the genetics of SpA. In this descriptive review, we delve into the pathogenesis of Spondylarthritis beyond HLA-B27. We summarize the latest research on the potential participation of various entities in the development of the disease, including other genetic loci, immune dysregulation, microbiota, and environmental factors. The multifactorial nature of SpA and the complex interplay of genetic, immunological, and environmental factors are being increasingly recognized; therefore, it is of paramount importance to consider a holistic approach to comprehend the pathogenesis of SpA in order to identify novel therapeutic targets.

The possible protective role of HLA B27 and relevant immune markers in Juvenile Idiopathic Arthritis patients.

Background & Objectives: JIA is a disease with different immunological characteristics and a complicated genetic foundation. HLA B27 is a risk factor for the development of JIA, and its impact on immunopathogenesis of the disease is also an area of interest. To determine whether HLA B27 and immune markers varied between JIA patients and healthy population. Methods: This comparative cross-sectional study was conducted at Immunology Department of University of Health sciences (UHS), Lahore from February 2018 till August 2021. A total of (71) JIA patients and (34) healthy controls were enrolled. B cells were enumerated by flowcytometry, ELISA was used for serum cytokines estimation and HLA B27 allele was detected by SPSS polymerase chain reaction. Results: The HLA B27 allele was significantly more in the control group than in the patient group, suggesting it is a protective allele to prevent JIA. Peripheral blood B cell counts and percentages were significantly lower in the HLA B27 positive group than in the HLA B27 negative group of control population. Serum cytokine levels were not significantly different between the HLA B27 positive and HLA B27 negative allele of the two study populations. Conclusion: In this study B cells are different between the two groups of control population however; serum cytokines are comparable between the study groups. Though, it was indicated that HLA B27 may be a preventive allele in the onset of JIA.

Uveitis and Scleritis as a Risk Factor for Mortality.

PURPOSE: Uveitis and scleritis may be caused by local or systemic infection, or associated with noninfectious systemic inflammatory autoimmune disease. This study explored the all-cause mortality following an individual's first presentation with uveitis/scleritis. METHODS: A cross-sectional study was conducted on all uveitis/scleritis patients diagnosed by uveitis specialists and treated in a single tertiary referral center in New Zealand between 2006 and 2020(15y). Masquerade syndromes including intraocular lymphoma were excluded. Outcome measures: demographics, etiology of uveitis/scleritis, anatomical location and all-cause mortality. RESULTS: 2723 subjects were identified. Median age of onset of uveitis/scleritis was 44.9 years (Range:1.5-99.5 years). 49.6% were female. Median follow-up from diagnosis of uveitis/scleritis was 8.0 years (IQR 4.1-11.6 years) with a total follow-up of 24 443.3 subject-years. The most frequent diagnosis was idiopathic disease (30.9%), HLA-B27-positive uveitis (20.0%), and sarcoidosis (4.7%). Infectious etiologies (24.1%) were most commonly from herpes zoster virus (9.3%) and toxoplasmosis (4.3%). The age-adjusted mortality rate was higher in subjects with idiopathic disease, sarcoidosis, Fuchs' uveitis syndrome, granulomatosis with polyangiitis/ANCA-associated vasculitis, toxoplasmosis, and herpes zoster virus, when compared to HLA-B27-positive uveitis. Hazard of mortality peaked in the first seven years following diagnosis, then subsequently declined. Patients with uveitis/scleritis had a significantly higher rate of mortality compared to the general New Zealand population (IRR 1.656 p = 0.017). CONCLUSION: Infectious etiologies of uveitis/scleritis in this cohort were high when compared to other developed nations, attributable to data from a tertiary referral center treating inpatients. Potential shared inflammatory mechanisms in the eye and other organs can lead to concurrent non-ocular disease requiring systemic treatment, impacting an individual's longevity.

Clinical Characteristics of HLA-B27-Associated Anterior Uveitis in a Finnish Population-Based Cohort.

PURPOSE: To evaluate the clinical characteristics, treatment outcomes and ocular complications in patients with HLA-B27-associated AU compared to those without HLA-B27. METHODS: From the population-based data of all adult patients with AU during 2009-2020 (n = 413), 241 patients tested for HLA-B27 were included. Age of the initial onset, gender, etiology, course of uveitis, visual outcomes and complications were studied. RESULTS: 170 patients (71%) were HLA-B27+ and 71 (29%) HLA-B27-. Mean age at uveitis onset was 37 ± 13 in HLA-B27+ (95% CI, 35.4-39.3) and 43 ± 14 (95% CI, 40.3-46.4) in HLA-B27- patients (p = 0.001). Male:female ratio was 1.1:1 among HLA-B27+ and 0.58:1 (p = 0.024) in HLA-B27- patients. Most patients, 63% in HLA-B27+ and 68% in HLA-B27- had chronic uveitis. Recurrences were noted in 31% in HLA-B27+ group compared to 13%in HLA-B27-. 51% and 17% of HLA-B27+ and HLA-B27- patients, respectively, had systemic disease-associated uveitis. Etiology was Idiopathic in 44% and 69% of HLA-B27+ and HLA-B27- patients, respectively (p < 0.001). After the follow-up, +2 and -4 ETDRS letters changes were noted in HLA-B27+ and HLA-B27- patients (p = 0.005). Ocular complications developed in 43% and 47%, and surgical treatment of complications was required in 20% and 33% of patients in HLA-B27+ and HLA-B27- patients (p = 0.009). 1% (HLA-B27+) and 3% (HLA-B27-) developed visual impairment. CONCLUSION: Our results highlight the differences in the age of uveitis onset, gender distribution, course of uveitis, etiology, and treatment outcomes in HLA-B27+ and HLA-B27-uveitis. HLA-B27 seems to be associated with younger age at uveitis onset, more recurrences, systemic diseases, and better treatment outcomes with less complications.

Looking back on 51 years of the Carol Nachman Prize in Rheumatology-significance for the field of spondyloarthritis research.

The city and casino of Wiesbaden, capital of the German state Hessen, have endowed the Carol Nachman Prize to promote research work in the field of rheumatology since 1972. The prize, endowed with 37,500 €, is the second highest medical award in Germany and serves to promote clinical, therapeutic, and experimental research work in the field of rheumatology. In June 2022, the 50-year anniversary was celebrated. In the symposium preceding the award ceremony, an overview was given on the significance of spondyloarthritis for the work of the awardees in the past 30 years. This overview has now been put together to inform the interested community of the work performed, including the opinion of the awardees regarding what they consider to be their most important contribution.

The novel HLA-A*02:1152 and HLA-B*40:566 alleles identified in Russian bone marrow donors.

Identification of two novel HLA alleles in Russian bone marrow donors.

Characterisation of the novel HLA-B*18:243 allele using short- and long-read sequencing technologies.

The novel HLA-B*18:243 allele, first described in a potential bone marrow donor from Brazil.

Characterisation of the novel HLA-B*38:01:01:18 allele by next-generation sequencing.

HLA-B*38:01:01:18 differs from the HLA-B*38:01:01:01 allele by one nucleotide substitution in the 5'UTR.

Impact of HLA-B51 on Uveitis and Retinal Vasculitis: Data from the AIDA International Network Registries on Ocular Inflammatory Disorders.

PURPOSE: The clinical relevance of human leukocyte antigen (HLA) subtypes such as HLA-B51 on Behçet's disease (BD)-related uveitis and non-infectious uveitis (NIU) unrelated to BD remains largely unknown. METHODS: Data were prospectively collected from the International AIDA Network Registry for BD and for NIU. We assessed differences between groups (NIU unrelated to BD and positive for HLA-B51, BD-related uveitis positive for HLA-B51 and BD-related uveitis negative for HLA-B51) in terms of long-term ocular complications, visual acuity (VA) measured by best corrected visual acuity (BCVA), anatomical pattern, occurrence of retinal vasculitis (RV) and macular edema over time. RESULTS: Records of 213 patients (341 eyes) were analyzed. No differences in complications were observed (p = 0.465). With regard to VA, a significant difference was detected in median BCVA (p = 0.046), which was not maintained after Bonferroni correction (p = 0.060). RV was significantly more prevalent in NIU-affected patients who tested positive for HLA-B51, irrespective of the systemic diagnosis of BD (p = 0.025). No differences emerged in the occurrence of macular edema (p = 0.99). CONCLUSIONS: Patients with NIU testing positive for HLA-B51 exhibit an increased likelihood of RV throughout disease course, irrespective of a systemic diagnosis of BD. The rate of complications as well as VA are comparable between NIU cases unrelated to BD testing positive for HLA-B51 and uveitis associated with BD. Therefore, it is advisable to perform the HLA-B typing in patients with NIU or retinal vasculitis, even in the absence of typical BD features.

Anti-integrin αvß6 antibody in Takayasu arteritis patients with or without ulcerative colitis.

Background: It has been well documented that Takayasu arteritis (TAK) and ulcerative colitis (UC) coexist in the same patients. HLA-B*52 characterizes the co-occurrence, which is one of the common genetic features between these two diseases, indicating shared underlying pathologic mechanisms. Anti-integrin αvß6 antibody (Ab) is present in sera of UC patients in a highly specific manner. We investigated if there were any associations between anti-integrin αvß6 Ab and TAK, considering the risk HLA alleles. Methods: A total of 227 Japanese TAK patients were recruited in the current study and their serum samples were subjected to measurement of anti-integrin αvß6 Ab by ELISA. The clinical information, including the co-occurrence of UC, was collected. The HLA allele carrier status was determined by Luminex or genotype imputation. Results: The information about the presence of UC was available for 165 patients, among which eight (4.84%) patients had UC. Anti-integrin αvß6 antibody was identified in 7 out of 8 TAK subjects with UC (87.5%) while only 5 out of 157 (3.18%) TAK subjects without UC had the antibody (OR 121, p=7.46×10-8). A total of 99 out of 218 (45.4%) patients were HLA-B*52 carriers. There was no significant association between the presence of anti-integrin αvß6 Ab and HLA-B*52 carrier status in those without UC (OR 2.01, 95% CI 0.33-12.4, p = 0.189). Conclusions: The prevalence of anti-integrin αvß6 Ab was high in TAK patients with UC, but not in the absence of concomitant UC. The effect of HLA-B*52 on anti-integrin αvß6 Ab production would be minimal.