Enfermedad antimembrana basal glomerular en hermanos no gemelos con HLA idéntico / Anti-glomerular basement membrane disease in HLA-identical non-twin siblings

La enfermedad antimembrana basal glomerular (EMBG) es un trastorno autoinmune caracterizado por la presencia de anticuerpos antimembrana basal glomerular (AMBG), hemorragia pulmonar, glomerulonefritis necrotizante y depósito lineal de inmunoglobulinas en inmunofluorescencia directa. La predisposición genética, entre otros factores, posee un papel importante en el desarrollo de la enfermedad. Estudios previos han demostrado que el antígeno leucocitario humano (HLA), HLA-DR15 y HLA- DR4, se asocian con mayor riesgo de presentarla, mientras que el HLA-DR1 y HLA-DR7 han demostrado ser factor de protección frente a su desarrollo.Describimos el primer caso de dos hermanos no gemelos con EMBG con tipaje HLA idéntico, con factor de riesgo HLA-DR4 y factor de protección HLA-DR7. Planteamos la importancia de analizar el tipaje de histocompatibilidad en hermanos de pacientes con EMBG, para determinar el grado de susceptibilidad genética y plantear en ellos un seguimiento estrecho, con el objetivo de lograr un diagnóstico y tratamiento precoces en caso de presentar la enfermedad. (AU)

Anti-glomerular basement membrane disease (AGBM) is an autoinmune disorder characterized by the presence of anti-glomerular basement membrane (anti-GBM) antibodies, alveolar hemorrhage, necrotizing glomerulonephritis, and linear deposition of immunoglobulins through direct inmunofluorescence. Genetic predisposition, among other factors, plays an important role in the development of the disease. Previous studies have shown that HLA-DR15 and HLA-DR4 increase the risk of presenting it, while HLA-DR1 and HLA-DR7 protect against its development.We describe the first case of two non-twin siblings with AGBM and identical HLA, with HLA-DR4 as risk factor and HLA-DR7 as protection factor. We propose the importance of analyzing HLA in siblings of patients with AGBM, to determine the degree of genetic susceptibility and to carry out a close follow-up on them, with the aim of achieving an early diagnosis and treatment in case of presenting the disease. (AU)

Concurrent use of two independent methods prevents erroneous HLA typing of deceased organ donors - An important strategy for patient safety and accurate virtual crossmatching for broader sharing.

Comprehensive and accurate human leukocyte antigen (HLA) typing within a short turnaround time is a crucial initial step for allocating deceased donor organs for transplantation. Erroneous HLA typing of deceased donors can be catastrophic and result in recipient death, failed transplant, and organ wastage due to inappropriately matched donors. The real-time polymerase chain reaction method is widely used as the sole method for HLA typing of deceased donors because of its simplified workflow. Herein, we have reported cases of four deceased donors showing discrepant HLA typing discovered using two independent methods concurrently. The HLA typing of these donors could have been erroneously reported if a single method had been used, which would have profound patient safety implications. In one case, the drop out of HLA-DR7 using a single method could have resulted in harmful organ allocation if the organ was transplanted after a virtual crossmatch to a sensitized candidate showing strong donor-specific HLA-DR7 antibodies. In conclusion, this case series suggests that concurrent dual typing is essential for accurate HLA typing of deceased donors. This strategy is vital because precise HLA typing is critical for accurate virtual crossmatching, which facilitates continuous distribution and broader geographic sharing of the deceased donor organ.

Anti-glomerular basement membrane disease in HLA-identical non-twin siblings.

Anti glomerular basement membrane disease (AGBM) is an autoinmune disorder characterised by the presence of anti-glomerular basement membrane (Anti-GBM) antibodies, alveolar hemorrhage, necrotizing glomerulonephritis, and linear deposition of immunoglobulins through direct inmunofluorescence. Genetic predisposition, among other factors, plays an important role in the development of the disease. Previous studies have shown that HLA-DR15 and HLA-DR4 increase the risk of presenting it, while HLA-DR1 and HLA-DR7 protect against its development. We describe the first case of two non-twin siblings with AGBM and identical HLA, with HLA-DR4 as risk factor and HLA-DR7 as protection factor. We propose the importance of analysing HLA in siblings of patients with AGBM, to determine the degree of genetic susceptibility and to carry out a close follow-up on them, with the aim of achieving an early diagnosis and treatment in case of presenting the disease.

Chronic Active Antibody-Mediated Rejection Following COVID-19 Infection in a Kidney Transplant Recipient: A Case Report.

Kidney transplant recipients who develop coronavirus disease 2019 (COVID-19) are at increased risk of life-threatening illness, which often requires reducing immunosuppression despite the potential risk of causing an allograft rejection. Herein, we describe the clinical presentation and course of a kidney transplant recipient who acquired COVID-19 and was hospitalized with severe symptoms and hypoxemia. Upon admission, the patient was found to have elevated de novo donor-specific antibodies (DSA) yielding a positive cytotoxicity crossmatch and concurrent elevated plasma donor-derived cell-free DNA (dd-cfDNA) level, indicating a possible ongoing rejection despite improvement in his serum creatinine. Because of persistent positive COVID-19 tests and stable serum creatinine, a kidney allograft biopsy was initially deferred and his dd-cfDNA and DSA were monitored closely postdischarge. Three months later, because of persistent elevated dd-cfDNA and positive DSA, a kidney allograft biopsy was performed, which showed chronic active antibody-mediated rejection. Accordingly, the patient was treated with intravenous immunoglobulin and his maintenance immunosuppressive regimen was increased.

Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects.

Select CMV epitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope-specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in coinfected HLA-DR7+ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared with those from an HIV- HCMV+ HLA-DR7+ cohort or with HLA-DR7-restricted CD4+ T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4+ T cells consisted of effector memory or effector memory-RA+ subsets with restricted TCRß usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38+ and HLA-DR+ The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.

HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity.

The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immune-mediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202,-DQA1*0201) were created. These two lines were crossed with a human (h)CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a pre-clinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.

Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4.

Leucine-rich glioma-inactivated1 (LGI1) encephalitis is an antibody-associated inflammation of the limbic area. An autoimmune etiology is suspected but not yet proven. We performed human leukocyte antigen (HLA) analysis in 25 nontumor anti-LGI1 patients and discovered a remarkably strong HLA association. HLA-DR7 was present in 88% compared to 19.6% in healthy controls (p = 4.1 × 10-11 ). HLA-DRB4 was present in all patients and in 46.5% controls (p = 1.19 × 10-7 ). These findings support the autoimmune hypothesis. An exploratory analysis was performed in a small group of 4 tumor-LGI1 patients. The strong HLA association seems not applicable in these patients. Therefore, the absence of HLA-DR7 or HLA-DRB4 could raise tumor suspicion in anti-LGI1 patients. Ann Neurol 2017;81:193-198.

Paediatric celiac patients carrying the HLA-DR7-DQ2 and HLA-DR3-DQ2 haplotypes display small clinical differences.

AIM: The aim of this study was to determine the relevance of HLA-DR7-DQ2 typing in a prospective cohort of paediatric coeliac disease patients from Southern Europe. METHODS: This cross-sectional study tested 249 paediatric patients with coeliac disease. HLA-DR3-DQ2 was typed in combination with HLA-DR7-DQ2 to screen for the HLA-DQ2 haplotype. The histological, analytical and clinical characteristics of the subjects were recorded. RESULTS: A total of 91 coeliac patients were diagnosed: 96.7% carried HLA-DQ2 and 4.4% carried HLA-DQ8. In percentage terms, 80.2% of patients carried HLA-DR3-DQ2 and 34.1% carried HLA-DR7-DQ2. We did not find significant differences between HLA-DR7-DQ2 and HLA-DR3-DQ2 paediatric patients with respect to histological damage and clinical characteristics, except for irritability and weight loss. These characteristics were more frequent in HLA-DQ2trans than in HLA-DQ2cis (22.2% vs. 0.0% [p = 0.035] and 55.6% vs. 21.4% [p = 0.017], respectively). Coeliac-specific autoantibody levels were higher in HLA-DQ2cis than one half of HLA-DQ2trans patients (105.5 vs. 19.2 U/mL, p = 0.014). CONCLUSION: Small clinical differences were found between paediatric coeliac patients carrying HLA-DR7-DQ2 and HLA-DR3-DQ2. For a correct screening of HLA-DQ2, at least in our geographical population, the HLA-DR7-DQ2 haplotype should be typed due to its frequency and clinical presentation.

Isolation of human CD4/CD8 double-positive, graft-versus-host disease-protective, minor histocompatibility antigen-specific regulatory T cells and of a novel HLA-DR7-restricted HY-specific CD4 clone.

Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T cell alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4(+)/CD8(+) double-positive; 2) specific for an HLA class I-restricted autosomal Ag; 3) expressed a Tr1 profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I-restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7-restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease-protective, minor H Ag-specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target.

HLA-DR and HLA-DP restricted epitopes from human cytomegalovirus glycoprotein B recognized by CD4+ T-cell clones from chronically infected individuals.

PURPOSE: Helper CD4(+) T cells presumably play a major role in controlling cytomegalovirus (CMV) by providing help to specific B and CD8(+) cytotoxic T cells, as well as through cytotoxicity-mediated mechanisms. Since CMV glycoprotein B (gB) is a major candidate for a subunit vaccine against CMV, we searched for gB-epitopes presented by human leukocyte antigen (HLA)-class II molecules. METHODS: Dendritic cells obtained from CMV-seropositive donors were loaded with a recombinant gB and co-cultured with autologous CD4(+) T cells. Microcultures that specifically recognized gB were cloned by limiting dilution using autologous Epstein-Barr virus (EBV)-immortalized B cells pulsed with gB as antigen-presenting cells. To pinpoint precisely the region encoding the natural epitope recognized by a given CD4(+) clone, we assessed the recognition of recombinant Escherichia coli expressing gB-overlapping polypeptides after their processing by autologous EBV-B cells. RESULTS: We isolated several gB-specific CD4(+) T-cell clones directed against peptides gB(190-204), gB(396-410), gB(22-36) and gB(598-617) presented by HLA-DR7, HLA-DP10 and HLA-DP2. While their precise role in controlling CMV infection remains to be established, gB-specific CD4(+) T cells are likely to act by directly targeting infected HLA-class II cells in vivo, as suggested by their recognition of EBV-B cells infected by the Towne CMV strain. CONCLUSIONS: The characterization of such gB-epitopes presented by HLA-class II should help to understand the contribution of CD4(+) T-cell responses to CMV and may be of importance both in designing a vaccine against CMV infection and in immunomonitoring of subjects immunized with recombinant gB or with vectors encoding gB.

Race-specific type 1 diabetes risk of HLA-DR7 haplotypes.

The aim of this study was to test the hypothesis that closely related human leukocyte antigen (HLA) haplotypes containing the DRB1*07:01 gene ['DR7' (DRB1*07:01-DQA1*02:01-DQB1*02:01g or DRB1*07:01-DQA1*03:01-DQB1*02:01g) haplotypes] derived from European and African populations differ in their genetic susceptibility for type 1 diabetes (T1D) depending on the DQ-α molecule present. A combined total of 98 African American T1D patients from the Type 1 Diabetes Genetics Consortium and from Children's Hospital and Research Center Oakland were genotyped for the HLA class II loci DRB1, DQA1, and DQB1. DNA samples extracted from newborn blood spot cards from African Americans born in California (n = 947) were used as a population-based control group. Among African American cases, the European-derived DRB1*07:01-DQA1*02:01-DQB1*02:01g haplotype was protective for T1D risk (odds ratio (OR) = 0.34; 95% confidence interval (CI) 0.14-0.78; P < 0.011), but the African-derived DRB1*07:01-DQA1*03:01-DQB1*02:01g haplotype increased T1D risk (OR = 3.96; 95% CI 1.94-8.08; P < 5.5E-05). The effect of DRB1*07:01-DQB1*02:01g on T1D susceptibility depends on the DQA1 allele. DRB1*07:01-DQA1*02:01-DQB1*02:01g is protective for T1D; however, the presence of DQA1*03:01 on the DRB1*07:01-DQB1*02:01g haplotype not only renders the DR7 haplotype not protective but also creates a haplotype with significant T1D risk. These data underscore the importance of assessing genetic effects within ethnic context.

Linfocitosis B policlonal persistente: estudio de 35 casos / Persistent polyclonal B-cell lymphocytosis: study of 35 cases

Fundamento y objetivo: La linfocitosis B policlonal persistente (LBPP) es una entidad muy poco frecuente que se relaciona con el tabaquismo e incide especialmente en mujeres. Cursa con aumento de IgM sérica, asociación al haplotipo HLA-DR7, anomalías citogenéticas y múltiples reordenamientos de IgH/BCL-2. Todavía no está clara su naturaleza premaligna o benigna. El objetivo de este trabajo fue analizar las características de la LBPP con especial interés en su evolución. Pacientes y método: Se han estudiado retrospectivamente 35 LBPP de 5 hospitales catalanes. Se realizó una valoración morfológica de las extensiones de sangre por los miembros del Grup Català de Citologia Hematològica (GCCH) en un microscopio de 16 cabezales y se analizaron los datos clínicos y biológicos. Resultados: La LBPP se presentó, en la mayoría de los casos, como linfocitosis en mujeres fumadoras. El distintivo morfológico es la presencia de linfocitos de aspecto activado, en ausencia de enfermedades víricas recientes, y de linfocitos bilobulados y/o hendidos, y algunos con bolsillos nucleares observados por ultraestructura. En la mayoría de los casos estudiados se detectó: aumento policlonal de IgM, expresión del haplotipo HLA-DR7, anomalías cromosómicas como i(3)(q10) y múltiples reordenamientos de IgH/BCL-2. Con una mediana de seguimiento de 70,7 meses, 34 de los 35 pacientes permanecen asintomáticos y vivos, uno falleció por un adenocarcinoma de pulmón y otro desarrolló un linfoma folicular, sin demostración de relación alguna entre éste y la LBPP. Conclusiones: La LBPP presenta un curso estable y asintomático, y se acompaña con frecuencia de alteraciones genéticas. Se desconoce si es una situación premaligna, a semejanza de las gammapatías monoclonales de significado incierto. Por ello, es fundamental una correcta interpretación de la linfocitosis y un seguimiento evolutivo (AU)

Background and objectives: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare entity, presenting especially in adult smoker women. It is characterized by an increase of serum IgM, DR7-HLA haplotype,cytogenetic abnormalities and multiple IgH/BCL-2 earrangements. To date, it has not been elucidatedwhether this is a benign or premalignant disorder. We analyzed the PPBL characteristics with especial attention to its evolution.Patients and methods: Thirty-five PPBL patients from 5 hospitals in Catalonia were retrospectivelyanalyzed. A simultaneous morphologic review of the blood smears was performed by members of the GCCH in a 16 multiple-observer optic microscope. Clinical and biological data were also analyzed. Results: PPBL presents in the majority of cases with persistent polyclonal B-cell lymphocytosis and affects primarily smoker women. The morphologic hallmark, in absence of viral infections, is the presence of activated lymphocytes with bilobulated and/or cleaved nuclei, and nuclear pockets in theultrastructural study. Increased serum IgM, HLA-DR7 haplotype, chromosomal abnormalities such asi(3)(q10) and multiple IgH/BCL-2 rearrangements were detected. Thirty-four out of 35 patients are alive after a median follow up of 70.7 months. One patient died because of lung adenocarcinoma and another developed a follicular lymphoma without relation to PPBL.Conclusions: PPBL has an asymptomatic and stable evolution, although it frequently presents genetic abnormalities. It remains unknown whether it is a premalignant entity, similar to monoclonal gammopathies of unknown significance. Hence, accurate cytologic diagnosis and follow-up are essential (AU)

Linfocitosis B policlonal persistente. ¿Una enfermedad benigna o un pre-linfoma? / Persistent polyclonal B-cell lymphocytosis: Benign disease or prelymphoma?

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Autism spectrum disorders are associated with an elevated autoantibody response to tissue transglutaminase-2.

We report that a significant number of autistic children have serum levels of IgA antibodies above normal to the enzyme tissue transglutaminase II (TG2), and that expression of these antibodies to TG2 is linked to the (HLA)-DR3, DQ2 and DR7, DQ2 haplotypes. TG2 is expressed in the brain, where it has been shown to be important in cell adhesion and synaptic stabilization. Thus, these children appear to constitute a subpopulation of autistic children who fall within the autism disease spectrum, and for whom autoimmunity may represent a significant etiological component of their autism.

Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care.

Host immunogenetic variations strongly influence the severity of group A streptococcus sepsis by modulating responses to streptococcal superantigens (Strep-SAgs). Although HLA-II-DR15/DQ6 alleles strongly protect against severe sepsis, HLA-II-DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome. We found that, regardless of individual variations in TCR-Vß repertoires, the presentation of Strep-SAgs by the protective HLA-II-DR15/DQ6 alleles significantly attenuated proliferative responses to Strep-SAgs, whereas their presentation by the high-risk alleles augmented it. Importantly, HLA-II variations differentially polarized cytokine responses to Strep-SAgs: the presentation of Strep-SAgs by HLA-II-DR15/DQ6 alleles elicited significantly higher ratios of anti-inflammatory cytokines (e.g., IL-10) to proinflammatory cytokines (e.g., IFN-γ) than did their presentation by the high-risk HLA-II alleles. Adding exogenous rIL-10 significantly attenuated responses to Strep-SAgs presented by the high-risk HLA-II alleles but did not completely block the response; instead, it reduced it to a level comparable to that seen when these superantigens were presented by the protective HLA-II alleles. Furthermore, adding neutralizing anti-IL-10 Abs augmented Strep-SAg responses in the presence of protective HLA-II alleles to the same level as (but no higher than) that seen when the superantigens were presented by the high-risk alleles. Our findings provide a molecular basis for the role of HLA-II allelic variations in modulating streptococcal sepsis outcomes and suggest the presence of an internal control mechanism that maintains superantigen responses within a defined range, which helps to eradicate the infection while attenuating pathological inflammatory responses that can inflict more harm than the infection itself.

Does HLA-DR7 differentiate the overlap syndrome of auto-immune hepatitis-primary biliary cirrhosis (AIH-PBC) from those with auto-immune hepatitis type 1?

INTRODUCTION: Autoimmune hepatitis (AIH) and overlap-syndrome (OS) are autoimmune liver diseases of unknown etiology. Although HLA-DR3/DR4 plays a susceptibility role in AIH but there is limited information in regard to OS. OBJECTIVE: Determine the genetic expression of HLA-DR among patients with AIH versus OS in order to establish susceptibility alleles in comparison to healthy controls (HC). METHODS: 26 patients with AIH and 15 patients with OS were studied. Ninety-nine healthy historical controls without autoimmunity were evaluated. Patients with AIH and OS were selected based on the international group for the study of AIH criteria and the Chazouilleres criteria for OS. Patients had at least one liver biopsy. Characterization of HLA-DR was extracted from peripheral blood leukocytes. Alleles were obtained for AIH, OS and HC and comparisons were made between groups. RESULTS: There was a significant increase in HLADR3 and DR1 in AIH compared with the HC group (p = 0.04, OR 2.6, 0.87-7.9, 95% CI). In the AIH group there was a decreased frequency in allele HLA-DR8 when compared with HC (p = 0.04, OR 3.2). There were no statistical differences between the genetic frequencies in the OS group compared with HC. However, HLA-DR7 was able to distinguish between OS patients from those with AIH (p = 0.02, OR 9.8, 1.02-233.6, 95% CI). CONCLUSIONS: HLA-DR1/DR3 is increased in AIH, but contrary to data reported in AIH, HLA-DR7 frequency is increased in OS, suggesting increased susceptibility which distinguishes patients with AIH from those with OS.