Strong HLA Association Research Articles

A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4+ T cell clones not only respond to proinsulin C-peptide (PI40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI40-47-IAPP74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognise self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4+ T cell clones reactive to native PI40-54 epitope and multiple HIPs fused at the same N-terminus (PI40-54) to the degradation products of two highly expressed pancreatic islet proteins, Neuropeptide Y (NPY68-74) and amyloid polypeptide (IAPP23-29 and IAPP74-80). We observed that five out of the selected SKW3 T cell lines expressing TCRs isolated from CD4+ T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI40-54 and HIP epitopes. Crystal structures of two TRAV26-1+-TRBV5-1+ T cell receptors (TCRs) in complex with PI40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI40-54 and HIPs determined that the P2, P7 and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8.

The Epidemiology of Newly Recognized Causes of Drug-Induced Liver Injury: An Update.

The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI.

Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.

Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

Epidemiology of myelin oligodendrocyte glycoprotein antibody-associated disease: a review of prevalence and incidence worldwide.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an inflammatory demyelinating disease of the central nervous system (CNS) with the presence of conformation-sensitive antibodies against MOG. The spectrum of MOGAD includes monophasic/relapsing optic neuritis, myelitis, neuromyelitis optica spectrum disorder (NMOSD) phenotype without aquaporin 4 (AQP4) antibodies, acute/multiphasic demyelinating encephalomyelitis (ADEM/MDEM)-like presentation, and brainstem and cerebral cortical encephalitis. There is no apparent female preponderance in MOGAD, and MOGAD can onset in all age groups (age at onset is approximately 30 years on average, and approximately 30% of cases are in the pediatric age group). While prevalence and incidence data have been available for AQP4+ NMOSD globally, such data are only beginning to accumulate for MOGAD. We reviewed the currently available data from population-based MOGAD studies conducted around the world: three studies in Europe, three in Asia, and one joint study in the Americas. The prevalence of MOGAD is approximately 1.3-2.5/100,000, and the annual incidence is approximately 3.4-4.8 per million. Among White people, the prevalence of MOGAD appears to be slightly higher than that of AQP4+ NMOSD. No obvious latitude gradient was observed in the Japanese nationwide survey. The data available so far showed no obvious racial preponderance or strong HLA associations in MOGAD. However, precedent infection was reported in approximately 20-40% of MOGAD cases, and this is worthy of further investigation. Co-existing autoimmune disorders are less common in MOGAD than in AQP4+ NMOSD, but NMDAR antibodies may occasionally be positive in patients with MOGAD. More population-based studies in different populations and regions are useful to further inform the epidemiology of this disease.

Primary sclerosing cholangitis-A long night's journey into day.

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Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.

Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.

Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies.

Our understanding of celiac disease and how it develops has evolved significantly over the last half century. Although traditionally viewed as a pediatric illness characterized by malabsorption, it is now better seen as an immune illness with systemic manifestations affecting all ages. Population studies reveal this global disease is common and, in many countries, increasing in prevalence. These studies underscore the importance of specific HLA susceptibility genes and gluten consumption in disease development and suggest that other genetic and environmental factors could also play a role. The emerging data on viral and bacterial microbe-host interactions and their alterations in celiac disease provides a plausible mechanism linking environmental risk and disease development. Although the inflammatory lesion of celiac disease is complex, the strong HLA association highlights a central role for pathogenic T cells responding to select gluten peptides that have now been defined for the most common genetic form of celiac disease. What remains less understood is how loss of tolerance to gluten occurs. New insights into celiac disease are now providing opportunities to intervene in its development, course, diagnosis, and treatment.

Skewing of the TCR V repertoire in SMX‐NO specific T cell responses

Background A role for drug-specific T cells has been demonstrated in many instances of drug hypersensitivity. In the case of -lactam antibiotics, such as flucloxacillin, we have shown that drug-protein conjugates are present in the plasma of all patients treated with this antibiotic, however only a small subset of patients develop hypersensitivity. Similarly, when a strong HLA association to drug hypersensitivity has been demonstrated such as for abacavir, not all patients with the risk allele will develop a hypersensitivity reaction. The mechanism underlying this variation in susceptibility is not fully understood. In carbamazepineinduced Stevens Johnson syndrome it is known that only patients with both the HLA risk allele and T cells with a specific TCR V will develop a reaction. This shows that an individual’s T cell repertoire may confer some susceptibility to drug hypersensitivity. Method In initial experiments, SMX-NO-specific CD4+ clones were generated from hypersensitive patients and analysed for TCR V expression. Nitroso sulfamethoxazole (SMXNO)-specific T cells were generated from 6 individuals by priming naive T-cells using drug-treated autologous dendritic cells. The responding cells were isolated using positive CD45RO magnetic bead selection. Naive and SMX-NO specific T cells were analysed by serology for 24 TCR Vs and by RT-PCR spectra-typing of the CDR3 region.

IL-17 Producing T Cells in Celiac Disease: Angels or Devils?

Celiac disease (CD) is a very common chronic condition in human beings, affecting approximately one in 100 individuals. It is an autoimmune disease with a defined environmental trigger, the gluten contained in dietary cereals, occurring in genetically susceptible individuals. The disease has a very strong HLA association. More than 90% of CD patients have HLA-DQ2, and almost all of the remaining celiac population possesses HLA-DQ8 molecules. Th17 cells seem to participate in the disease pathogenesis producing and secreting either proinflammatory or anti-inflammatory cytokines.

SP0010 Autoreactive B Cells in RA - What do Cloned ACPA Tell Us

Approximately 2/3 of RA patients develop antibodies towards a common posttranslational modification - citrullination. Such anti-citrullinated protein antibodies, ACPA, are strongly associated with the HLA-DR locus but consist of multiple...

A Missense Mutation in Myelin Oligodendrocyte Glycoprotein as a Cause of Familial Narcolepsy with Cataplexy

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

Delayed drug hypersensitivity: models of T‐cell stimulation

Drug-induced hypersensitivity reactions can cause a variety of serious diseases by involving drug-specific T-cells. Many of these reactions have been explained by the hapten concept, which postulates that small chemical compounds need to bind covalently to proteins to be recognized by the immune system. Due to their chemical reactivity, haptens stimulate the innate immunity by binding covalently to endogenous proteins and form so called hapten-carrier complexes, which are antigenic and induce T-cell responses. In recent years, a new concept has been developed since drug-induced hypersensitivity reactions were also observed with chemically unreactive drugs. This concept implies direct and reversible interactions of the drug between T-cell receptors (TCR) and major histocompatability complex (MHC) molecules. Therefore it was termed pharmacological interactions with immune receptors (p-i concept). Early observations on drug reacting T-cell clones (TCC) let believe that drugs bind first to the T-cell receptor since HLA molecules could be exchanged without affecting the drug reactivity. However, MHC molecules were always required for full activation of TCC. According to its strong HLA-B*5701 association, recent data on abacavir suggest that a drug could first bind to the peptide binding groove of the MHC molecule. The thereby modified HLA molecule can then be recognized by specific T-cells. Consequently, two types of reactions based on the p-i mechanism may occur: on the one hand, drugs might preferentially bind directly to the TCR, whereas in defined cases with strong HLA association, drugs might bind directly to the MHC molecule.

Personalized Medicine for Hla-Associated Drug-Hypersensitivity Reactions

Multiple genetic and nongenetic factors can modify the action of a drug, resulting in varied responses to a particular drug across different individuals. Personalized medicine incorporates the comprehensive knowledge of these factors to facilitate the selection of optimal therapy, reduce adverse drug reactions, increase patient compliance and increase the efficiency of therapy. Pharmacogenomics, which integrates the knowledge of an individual's genetic make-up for diagnostic decisions or therapeutic interventions is closely linked to personalized medicine, and is being increasingly used to prevent adverse drug reactions. There are various reports on genetic associations between particular HLA allotypes and drug hypersensitivities and the strongest associations reported thus far, are with the reverse transcriptase inhibitor, abacavir and HLA-B*5701, the gout prophylactic allopurinol and HLA-B*5801 and the antiepileptic carbamazepine and B*1502, providing a defined disease trigger and suggesting a general mechanism for these associations. Recognizing the strong HLA association, the US FDA has recommended genetic testing before starting abacavir and carbamazepine therapies. To incorporate HLA testing for other drug hypersensitivities and life-threatening reactions it is essential first to establish clear HLA associations, and second, to understand the immune-mechanism by which these drugs induce HLA-linked hypersensitivity. The latter will provide insight into the pathologic mechanisms of drug allergy allowing rational immunotherapy for these life-threatening reactions and the development of alternative drug therapies for hypersensitive patients.

New aspects in celiac disease

Celiac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA-DQ2 and HLA-DQ8 molecules, but human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. CD is caused by the lack of immune tolerance (oral tolerance) to wheat gluten. In this sense, the expression of soluble HLA-G in CD is of special interest because the molecule plays an important role in the induction of immune tolerance. The enhanced expression of soluble HLA-G found in CD may be part of a mechanism to restore the gluten intolerance. In this editorial, we review recent progress in understanding CD in relation to its prevalence, diagnosis and possible mechanisms of pathogenesis.

Autoimmunity in HLA-DQ8 transgenic mice expressing granulocyte/macrophage-colony stimulating factor in the beta cells of islets of langerhans

Type 1 diabetes (T1D) is a polygenic autoimmune disease with a strong HLA association particularly, HLA-DQ8. We investigated whether islet-specific expression of granulocyte/macrophage colony-stimulating factor (Ins.GM-CSF) in Aß°.NOD.DQ8 mice (HLA-DQ8 transgenic mice on a NOD background lacking endogenous mouse MHC class II molecules) would predispose to development of spontaneous autoimmune diabetes. Aß°.NOD.DQ8 mice expressing GM-CSF in the pancreatic ß cells (8+ G+) as well as litter mates lacking either HLA-DQ8 (8 − G+) or GM-CSF (8+ G − ) or both (8 − G − ) exhibited insulitis and sialadenitis of varying degrees. But none of the mice progressed to develop T1D. Other than the marked mononuclear cell infiltration in livers of mice expressing GM-CSF irrespective of HLA-DQ8 expression (8+ G+ or 8 − G+), no other changes were observed in the animals. Thus, we have shown for the first time that expression of HLA-DQ8 in the diabetes-predisposing mileu of NOD genetic background is not sufficient to predispose to development of autoimmune diabetes even when the potent immunostimulatory cytokine, GM-CSF is expressed in the pancreatic islets.

New advances in coeliac disease: serum and intestinal expression of HLA-G

Coeliac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA-DQ2 and HLA-DQ8, but as human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. Our aim was to investigate whether HLA-G, a gene located in the MHC class I region, and with important role in the induction of immunotolerance, may contribute to CD susceptibility. We demonstrated the expression of soluble HLA-G (sHLA-G) forms in intestinal biopsy and in serum of patients with CD. Indeed, all patients tested showed a positive expression of HLA-G in intestinal mucosa with different grade of immunoreaction. The serum levels of sHLA-G found in coeliac patients depend on the association with other diseases of autoimmune nature or genetics, and also depend on the transgressions in the diet with gluten ingested. The enhancer expression of sHLA-G in CD could be due as part of a mechanism to try restore the tolerance process towards oral antigens in a disease caused by loss of tolerance to dietary antigens and counteract the inflammation. In summary, in this paper, we demonstrate the association of CD with sHLA-G expression.

The genetics of psoriasis, psoriatic arthritis and atopic dermatitis.

Psoriasis and atopic dermatitis are chronic and relapsing inflammatory diseases of the skin associated with various immunologic abnormalities. Approximately 30% of psoriasis patients also have joint involvement, indicative of psoriatic arthritis. Genes and environment play a key role in the pathogenesis of these diseases. Genome-wide linkage scans have identified multiple loci linked to each disease and revealed overlap with psoriasis and atopic dermatitis susceptibility loci on chromosomes 1q21, 3q21, 17q25 and 20p12. The genes from these loci have not yet all been identified, or systematically tested for a role in psoriasis and atopic dermatitis; however, these locations suggest that some susceptibility factors lie within genes or gene families with common effects upon epithelial immunity. A strong HLA association is described for psoriasis, but not for atopic dermatitis. Knowledge of the genetic factors leading to these diseases will lead to an understanding of their variable age at onset, their waxing and waning and the variability of body surface environment. The effect of environmental triggers may also be understood once the altered pathways are elucidated. Genes implicated so far in atopic dermatitis are SPINK5, FcepsilonRI-beta and PHF11. Genes implicated in psoriasis so far are HLA-C, SLC9A3R1, NAT9, RAPTOR and SLC12A8. Genetic modifiers such as CARD15 may predispose to psoriatic arthritis.

Immunogenetics and genomics

Immunogenetic analysis of disease susceptibility has been encouraged by the identification of strong HLA associations with several diseases of uncertain cause. Weaker HLA associations exist with a large number of infectious and non-infectious diseases and the mechanisms of these effects are beginning to be uncovered. Extensive analyses of non-HLA immunogenetic variants have also been undertaken and associations with a variety of genes identified. Genetic linkage analysis of multicase families has recently identified new major susceptibility loci for a few immunologically determined common diseases. However, the greatest potential for the future lies in genome-wide searches for susceptibility genes that individually might have quite modest effects but cumulatively have a large impact on individual risk. This new era of immunogenomics promises to provide key insights into disease pathogenesis and identify multiple molecular targets for intervention strategies.

Major histocompatility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 *0401

To investigate the role of HLA class I in susceptibility to Felty's syndrome (FS) and large granular lymphocyte (LGL) syndrome. Fifty caucasoid FS patients, and 55 patients with LGL syndrome, of whom 26 had arthritis and 29 did not, were studied. Complete HLA class I and HLA-DR typing including, where relevant, DRB1*04 subtyping was carried out by molecular methods. Comparison was made with 78 unselected healthy caucasoid controls and a further 29 DRB1*0401+ individuals. A significant association was found between HLA-A*02 and FS [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 1.8-8.4, P = 0.0004]. At the B locus, there was an association between B*44 and LGL with arthritis [OR 3.5 (1.3-9.2), P = 0.01]. For HLA-Cw*0501, there was an association with FS [OR 4 (1. 7-9.2) P = 0.0008]. For both FS and LGL with arthritis, the extended haplotype HLA-A*02;B*44;Cw*0501;DRB1*0401 was significantly associated [OR 9.5 (2.6-35), P = 0.0001; OR 4.6 (1-22.4), P = 0.05, respectively]. There was no association between HLA class I or II and LGL without arthritis. All the allelic and haplotypic associations were lost on comparison with HLA-DRB1*0401+ controls. The strongest HLA association was with HLA-DRB1*0401 for FS [OR 27.9 (10.3-75.5), P = 10(-13)], and LGL with arthritis [OR 35.4 (9.6-131. 3), P = 10(-10)]. The major histocompatibility locus (MHC) associations with FS reported here are due to linkage disequilibrium with HLA-DRB1*0401. LGL syndrome with arthritis shows identical class II associations with FS, although there may be subtle immunogenetic differences between the two in the class I region. One of the extended haplotypes reported in a number of studies for FS and rheumatoid arthritis (summarized as HLA-A*02;Cw*0501; B*44;TNFb5;TNFa6;TNFd4;C4A*3;C4BQ*0;DRB1*0 401;DQB1*0301) is likely to be attributable to strong primary association with HLA-DRB1*0401, rather than to epistatic interaction between these loci.

Immunogenetics and rheumatic diseases: 25 years on from HLA‐B27

•. The strong HLA associations of many inflammatory arthropathies imply an underlying autoimmune pathology.•. The function of HLA molecules in the recognition of viral and bacterial antigens is now well described and has important implications for the pathogenesis of diseases such as ankylosing spondylitis, reactive arthritis and rheumatoid arthritis.•. HLA‐B27 is strongly associated with ankylosing spondylitis and has played an important role in defining a group of related spondyloarthropathies.•. HLA genes contribute less than half of the genetic basis of these diseases.•. Whole genome screening is a power tool to detect other genes relevant to these conditions.