RESUMEN
Analysis of chimerism in blood post-HCT using STR-PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. RQ-PCR chimerism is 10- to 100-fold more sensitive, but clinical studies in children are sparse. We analyzed IMC in blood samples following transplantation for acute lymphoblastic or myeloid leukemia in 56 children. IMC was defined as a minimum increase of (a) 0.1% or (b) 0.05% recipient DNA between two samples. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (HR 12.8 [95% CI: 3.9-41.4; P < .0001] and 7.6 [95% CI: 2.2-26.9; P < .01], respectively). The first IMC was detected at a median of 208 days prior to relapse. The 5-year cumulative incidence of relapse for children with a single IMC was 45.5% (CI 12.3-74.4) and 41.0% (14.2-66.6) for IMC above 0.1% and 0.05%, respectively. However, in 47 and 38 children never attaining IMC > 0.1% and >0.05%, 10 and 8 children relapsed, respectively. In a landmark analysis, no association was found between IMC prior to 90 days post-HCT and subsequent relapse by either classification of IMC and AUC for RQ-PCR chimerism was 54.2% (95 CI 27.7- 84.8). Although limited by a retrospective design, these results indicate that monitoring of RQ-PCR chimerism in peripheral blood may have a role in early detection of relapse in acute childhood leukemia.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Quimera por Trasplante , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/sangre , Estudios Longitudinales , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Trasplante HomólogoRESUMEN
The main aim of this study was to evaluate the impact of early T-cell chimerism status on the incidence and clinical course of acute graft-versus-host disease (aGVHD) in allogeneic transplant recipients after myeloablative conditioning. Of 62 patients, 38 (61%) had complete T-cell donor chimerism (DC), and 24 (39%) had mixed T-cell chimerism (MC). The incidence of early death (before day 100) with steroid-resistant aGVHD was significantly higher in patients with complete DC compared to patients with MC (6/38 vs. 0/24, p = 0.04). The time from aGVHD diagnosis to nonrelapse death was markedly different in patients with complete DC versus MC [53 days (range 12183) vs. 238 days (range 135 550), p = 0.005]. Conditioning with Etopophos/total body irradiation (TBI) resulted in significantly more patients with MC compared to conditioning with cyclophosphamide/TBI. In conclusion, early complete T-cell DC was associated with a high incidence of early death in patients receiving highdose steroids for the treatment of aGVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/uso terapéutico , Prednisolona/uso terapéutico , Subgrupos de Linfocitos T/inmunología , Quimera por Trasplante/inmunología , Enfermedad Aguda , Adolescente , Adulto , Aloinjertos , Ciclofosfamida/uso terapéutico , Etopósido/análogos & derivados , Etopósido/uso terapéutico , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Histocompatibilidad , Humanos , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Compuestos Organofosforados/uso terapéutico , Prednisolona/farmacología , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Adulto JovenRESUMEN
To investigate whether polymorphisms in genes coding for mannose-binding lectin (MBL) and surfactant protein-D (SP-D) are associated directly or by interaction with smoking with rheumatoid arthritis (RA), anti-citrullinated peptide antibody (ACPA) positive RA, and erosive RA. MBL2 genotypes, SFTPD genotype at codon 11, and HLA-shared epitope were determined in 456 patients with rheumatoid arthritis and 533 sex- and age-matched controls. Patients were grouped according to the presence of ACPA antibodies and RA-associated bone erosions and sub-stratified according to smoking status as never or ever smokers. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated using multiple logistic regression analyses controlling for shared epitope. The low-producing SFTPD genotype was not associated with risk of RA or ACPA positive RA, but with erosive disease in the RA patients (OR = 1.8; 95% CI 1.1-3.0) particularly in RA ever smokers (OR = 2.4; 95% CI 1.3-4.3). The high-producing MBL2 genotype YA/YA was associated with ACPA positive RA (OR = 1.4; 95% CI 1.0-1.9) and erosive joint disease in RA ever smokers (OR = 1.8; 95% CI 1.1-3.0). Genetic disposition for low SP-D was not associated with RA but with erosive RA by interaction with smoking. The genetic disposition for high MBL production was associated with ACPA positive RA irrespective of shared epitope. The findings need to be replicated but do as such offer further explanations for the clinical heterogeneity of RA.
Asunto(s)
Artritis Reumatoide/genética , Lectina de Unión a Manosa/genética , Polimorfismo Genético/genética , Proteína D Asociada a Surfactante Pulmonar/genética , Fumar/genética , Adolescente , Adulto , Anciano , Anticuerpos Antiidiotipos/sangre , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Epítopos/genética , Femenino , Genotipo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/genética , Péptidos Cíclicos/inmunología , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
t(12;21)(p13;q22)[ETV6-RUNX1] is the most common chromosomal translocation in childhood acute lymphoblastic leukemia, and it can often be backtracked to Guthrie cards supporting prenatal initiation and high levels of circulating t(12;21)-positive cells at birth. To explore the prevalence of ETV6-RUNX1-positive cells in healthy neonates, mononuclear cells from 1417 umbilical cord blood samples were isolated within 24 hours from birth and subsequently screened for ETV6-RUNX1 transcripts using a highly sensitive real-time reverse transcription polymerase chain reaction assay. In first-run polymerase chain reaction, 14 samples were positive at levels below 10(-5), of which specific hybridization reflecting the relevant genetic region was positive in 9 cases. Repeated analyses using stored mRNA and flowcytometric sorting of a CD19(+), CD8(+), and CD19(-)/CD8(-) subpopulations from cryopreserved mononuclear cells from the same cord blood samples (mean sorted: 18 × 10(6) cells) revealed no positive findings, which demonstrates that the level and/or frequency of ETV6-RUNX1-positive cells is markedly lower than suggested in previous studies.
Asunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 21/genética , Sangre Fetal/metabolismo , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Translocación Genética/genética , Adulto , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Estudios Transversales , Femenino , Sangre Fetal/citología , Humanos , Lactante , Recién Nacido , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Sensibilidad y EspecificidadRESUMEN
Next-generation sequencing (NGS) methods have been introduced for immunoglobulin (IG)/T-cell receptor (TR) gene rearrangement analysis in acute lymphoblastic leukemia (ALL) and lymphoma (LBL). These methods likely constitute faster and more sensitive approaches to analyze heterogenous cases of ALL/LBL, yet it is not known whether gene rearrangements constituting low percentages of the total sequence reads represent minor subpopulations of malignant cells or background IG/TR gene rearrangements in normal B-and T-cells. In a comparison of eight cases of B-cell precursor ALL (BCP-ALL) using both the EuroClonality NGS method and the IdentiClone multiplex-PCR/gene-scanning method, the NGS method identified between 29% and 139% more markers than the gene-scanning method, depending on whether the NGS data analysis used a threshold of 5% or 1%, respectively. As an alternative to using low thresholds, we show that IG/TR gene rearrangements in subpopulations of cancer cells can be discriminated from background IG/TR gene rearrangements in normal B-and T-cells through a combination of flow cytometry cell sorting and multiple displacement amplification (MDA)-based whole genome amplification (WGA) prior to the NGS. Using this approach to investigate the clonal evolution in a BCP-ALL patient with double relapse, clonal TR rearrangements were found in sorted leukemic cells at the time of second relapse that could be identified at the time of diagnosis, below 1% of the total sequence reads. These data emphasize that caution should be exerted when interpreting rare sequences in NGS experiments and show the advantage of employing the flow sorting of malignant cell populations in NGS clonality assessments.
RESUMEN
The multi-hit hypothesis for paediatric leukemogenesis states that an initial genetic hit (often occurring prenataly) must be followed by one or more hit(s) before a cell become leukeamic. Studies have demonstrated the presence of pre-leukaemic t(12;21)-positive cells at levels 10(-3) to 10(-4) in 1% of newborns (i.e. 100-fold their risk of t(12;21)-positive ALL), but only at levels of 10(-5) to 10(-6) in 0.5% adults. As the risk of developing ALL is inversely associated to the gestational age at birth, we investigated if this increased risk could be explained by an increase in prevalence and quantity of pre-leukaemic t(12;21)-positive children born prematurely. Using a sensitive qRT-PCR assay, we screened messenger RNA from fresh umbilical cord-blood samples from 256 premature children. In none of the neonates, t(12;21)-positive cells could be demonstrated. Therefore, no increase in the prevalence and magnitude of preleukaemic t(12;21)-positive cells compared to previously published data from mature children could be demonstrated. This indirectly supports the theory that prevalence and quantity of preleukaemic t(12;21)-positive cells peaks at term or early childhood and that exogenous factors are necessary to initiate their clearance.
Asunto(s)
Sangre Fetal/citología , Recien Nacido Prematuro/sangre , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Enfermedad Aguda , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Estudios Transversales , Humanos , Recién Nacido , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prevalencia , ARN Mensajero/genética , Factores de RiesgoRESUMEN
Chimerism analysis following hematopoietic stem cell transplantation (HSCT) for leukemia is routinely applied in parallel with quantification of minimal residual disease (MRD) to identify imminent relapse. In the past decades, new methods with a lower limit of detection compared to standard methods have been developed, so-called microchimerism analysis. Microchimerism analysis is fast, simple, applicable across pre-HSCT disease-type and can be applied on peripheral blood allowing frequent testing during follow-up. Monitoring of microchimerism in blood could replace repeated bone marrow analysis for MRD and allow earlier detection of imminent relapse or graft failure. Clinical studies in single center cohorts have shown conflicting but promising results. There is currently no consensus on the interpretation of microchimerism analysis and heterogeneity of studies remains a major obstacle for inter-study comparisons and meta-analysis in this field. We have conducted a systematic review of studies investigating associations between microchimerism and relapse of leukemia post-HSCT. We summarize current evidence and provide suggestions for future research.
Asunto(s)
Quimerismo , Trasplante de Células Madre Hematopoyéticas , Leucemia/genética , Leucemia/terapia , Trasplante Homólogo , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/genética , Trasplante Homólogo/métodosRESUMEN
Ficolin-2 is a serum opsonin, which has been shown to be a pattern recognition molecule in the lectin complement activation pathway. Because innate immune mechanisms are involved in maintaining tissue homeostasis we hypothesized that Ficolin-2 also participate in the clearance of dying host cells. We found that Ficolin-2 binds to late apoptotic cells, as well as to apoptotic bodies and necrotic cells, but not to early apoptotic cells. We demonstrated that Ficolin-2 binds DNA in a calcium dependent manner and that DNA inhibits the binding to late apoptotic and necrotic cells, suggesting that DNA on permeable dying cells is a plausible ligand. Reconstituting serum deficient of Ficolin-2, C1q and mannose-binding lectin with Ficolin-2 augmented deposition of complement C4 on necrotic cells. Opsonization leads to an enhanced attachment/uptake of necrotic cells by macrophages. In conclusion dying host cells expose ligands with the capacity of binding Ficolin-2, which in turn leads to increased attachment and engulfment. Binding of Ficolin-2 to DNA points at nucleic acid exposed by permeable late apoptotic and necrotic cells as one of the ligands for Ficolin-2. Ficolin-2 may therefore be a scavenger molecule participating in the removal of host cells and maintenance of tissue homeostasis.
Asunto(s)
Apoptosis/inmunología , ADN/metabolismo , Lectinas/farmacología , Necrosis/inmunología , Proteínas Opsoninas/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Células CHO , Activación de Complemento/efectos de los fármacos , Cricetinae , Cricetulus , Humanos , Células Jurkat , Lectinas/genética , Lectinas/metabolismo , Monocitos/efectos de los fármacos , Monocitos/inmunología , Proteínas Opsoninas/genética , Proteínas Opsoninas/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , FicolinasRESUMEN
Pyrosequencing represents one of the most thorough methods used to analyze polymorphisms. One advantage of using pyrosequencing for genotyping is the ability to identify not only single-nucleotide polymorphisms (SNPs) but also tri-allelic variations, insertions and deletions (InDels). In contrast to most other genotyping assays the sequence surrounding the polymorphism provides an internal control making this method highly reliable.
Asunto(s)
Técnicas de Genotipaje , Lectinas/genética , Lectina de Unión a Manosa/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Humanos , Reacción en Cadena de la Polimerasa/métodos , Análisis de Secuencia de ADN/métodos , FicolinasRESUMEN
BACKGROUND: HIV-infected controllers control viral replication and maintain normal CD4+ T cell counts. Long Term Non-Progressors (LTNP) also maintain normal CD4+ T cell counts, but have on-going viral replication. We hypothesized that different immunological mechanisms are responsible for preserved CD4+ T cell counts in controllers and LTNP. METHODS: 25 HIV-infected controllers and 14 LTNP were included in this cross-sectional study. For comparison, 25 progressors and 34 healthy controls were included. Production and destruction of T cells were addressed by determination of T cell receptor excision circles (TREC), recent thymic emigrants, naïve cells, immune activation, senescence and apoptosis. Furthermore, telomere length was determined, and the amount of lymphoid tissue in tonsil biopsies was quantified. RESULTS: Controllers presented with partly preserved thymic output, preserved expression of the IL-7 receptor and IL-7 receptor density, and lower levels of destruction of cells than progressors resembling HIV-negative healthy controls. In contrast, LTNP appeared much like progressors, and different from controllers in immune activation, senescence, and apoptosis. Interestingly, CD8+ RTE, TREC and telomere length were partly preserved. Finally, both controllers and LTNP displayed decreased amounts of lymphoid tissue compared to healthy controls. CONCLUSIONS: Controllers presented with an immunological profile different from LTNP. While controllers resembled healthy controls, LTNP were similar to progressors, suggesting different immunological mechanisms to be responsible for preserved CD4+ T cell counts in LTNP and controllers. However, both controllers and LTNP presented with reduced amounts of lymphoid tissue despite preserved CD4+ T cell counts, indicating HIV to cause damage even in non-progressors.
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Infecciones por VIH/inmunología , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios Transversales , Femenino , Citometría de Flujo , Infecciones por VIH/genética , Seropositividad para VIH , Humanos , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/inmunología , Telómero/genética , Carga ViralRESUMEN
Our aim was to elucidate the relative amount of the different splice forms of FoxP3 mRNA in CD4+ T cells in peripheral blood (PB) compared to synovial fluid (SF) in RA and PsA patients. FoxP3 mRNA was measured using a quantitative real-time PCR method. CD4+ T cells were isolated from 17 paired samples of PB and SF from RA and PsA patients, and PB from 10 controls. FoxP3fl and FoxP3Δ2 mRNA was significantly increased (6.7 and 2.1-fold, respectively) in PB CD4+ T cells from RA patients compared to controls. FoxP3fl and Δ2 mRNA in SF CD4+ T cells was increased compared to controls in sero-negative RA and PsA, but not in sero-positive RA patients, who had a high FoxP3 expression in both PB and SF. The FoxP3Δ2Δ7 mRNA was barely detectable in patient samples, and not at all in healthy individuals. We provide evidence of an increased expression of FoxP3 splice forms in synovial CD4+ T cells from RA patients. A skewed, high expression profile of FoxP3, but not CTLA-4, in sero-negative RA and PsA, indicates that synovial CD4+ T cells may represent unique subsets of T cells which have been induced locally or selectively recruited to the joint.
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Artritis Psoriásica/genética , Artritis Reumatoide/genética , Linfocitos T CD4-Positivos/fisiología , Factores de Transcripción Forkhead/genética , Isoformas de Proteínas/inmunología , Líquido Sinovial/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Empalme Alternativo , Artritis Psoriásica/sangre , Artritis Psoriásica/inmunología , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Linfocitos T CD4-Positivos/inmunología , Femenino , Factores de Transcripción Forkhead/inmunología , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/química , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Discordances between minimal residual disease estimates obtained by different methods are a problem in childhood acute lymphoblastic leukemia. We aimed to optimize methods allowing the biological exploration of such discrepancies, i.e. the combination of flow-sorting of small immunophenotypically defined cell populations with subsequent analyses of leukemia-associated cytogenetic and molecular marker. The approaches described here optimize the use of the same tube of unfixed, antibody-stained BM cells for flow-sorting of small cell populations and subsequent exploratory FISH and PCR-based analyses.
Asunto(s)
Médula Ósea/química , Separación Celular/métodos , Citogenética/métodos , Citometría de Flujo/métodos , Hibridación Fluorescente in Situ/métodos , Reacción en Cadena de la Polimerasa/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Médula Ósea/inmunología , Niño , Humanos , Inmunoglobulina G/inmunología , Neoplasia Residual/química , Neoplasia Residual/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
OBJECTIVE: To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). RESULTS: Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. CONCLUSION: The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.
Asunto(s)
Artritis Reumatoide/genética , Artritis Reumatoide/fisiopatología , Autoanticuerpos/inmunología , Lectina de Unión a Manosa/genética , Péptidos Cíclicos/inmunología , Polimorfismo Genético , Adulto , Anciano , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Autoanticuerpos/sangre , Evaluación de la Discapacidad , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVE: Patients with rheumatoid arthritis (RA) have excess morbidity and mortality due to ischemic heart disease. It has been suggested that high serum levels of mannose-binding lectin (MBL) and agalactosyl IgG (IgG-G0) are associated with increased inflammation in RA. MBL also enhances inflammation-mediated tissue injury during postischemic reperfusion. This study was undertaken to examine whether these factors are associated with increased risk of ischemic heart disease in RA. METHODS: MBL alleles were genotyped in 229 Danish patients with RA. In addition, serum levels of MBL and IgG-G0 were measured. Incidences of ischemic heart disease, myocardial infarction, and death due to ischemic heart disease after the diagnosis of RA were assessed in a prospective study. RESULTS: During a median followup of 9.5 years, ischemic heart disease was diagnosed in 8 of 27 patients with genetically determined high serum levels of MBL, as compared with 24 of the remaining 192 patients (data not available on 10 patients). After correction for other known risk factors, the hazard ratio (HR) was 3.6 (95% confidence interval [95% CI] 1.4-9.2). The corrected HR for myocardial infarction was 9.0 (95% CI 2.2-36.4). High serum levels of MBL also conferred an increased risk of death due to ischemic heart disease (age- and sex-adjusted HR 10.5, 95% CI 2.7-41.3). However, further analyses showed that these associations were present only in patients with high serum levels of IgG-G0. CONCLUSION: Genetically determined high serum levels of MBL and high serum levels of IgG-G0 are associated with increased risk of ischemic heart disease, myocardial infarction, and premature death in patients with RA.
Asunto(s)
Artritis Reumatoide/genética , Inmunoglobulina G/genética , Lectina de Unión a Manosa/genética , Isquemia Miocárdica/genética , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/sangre , Artritis Reumatoide/mortalidad , Comorbilidad , Dinamarca/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Inmunoglobulina G/sangre , Masculino , Lectina de Unión a Manosa/sangre , Persona de Mediana Edad , Isquemia Miocárdica/sangre , Isquemia Miocárdica/mortalidad , Polimorfismo Genético , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To determine whether variant alleles of the mannose-binding lectin (MBL) gene causing low serum concentrations of MBL and/or polymorphisms of HLA-DRB1 are associated with increased susceptibility to polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) or particular clinical phenotypes of PMR/GCA. METHODS: MBL and HLA-DRB1 alleles were determined by polymerase chain reaction in 102 Danish patients with PMR (n = 37) or GCA (n = 65). Two hundred fifty and 193 healthy individuals served as controls for MBL and HLA genotyping, respectively. RESULTS: The prevalence of MBL variant alleles in controls, patients with PMR only, and patients with GCA was 37, 32, and 53% (p = 0.01), respectively. HLA-DRB1*04 was found in 47% of patients with PMR only and in 54% of patients with GCA, which differed significantly from the 35% found in controls (p = 0.01). HLA-DR4 alleles were not associated with any clinical phenotypes of PMR/GCA, whereas MBL variant alleles were associated with cranial arteritis, high erythrocyte sedimentation rate, and low B-hemoglobin. CONCLUSION: We found MBL variant alleles and HLA-DR4 alleles to be weak susceptibility markers for GCA. In patients with PMR/GCA, MBL variant alleles were associated with signs of increased inflammatory activity and clinical signs of arteritic manifestations. This was not found for HLA-DR4 alleles. These findings indicate that HLA-DR4 and MBL are contributing to the pathophysiology of GCA at different levels in the disease process.
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Predisposición Genética a la Enfermedad , Arteritis de Células Gigantes/genética , Antígeno HLA-DR4/genética , Lectina de Unión a Manosa/genética , Polimorfismo Genético , Anciano , Anciano de 80 o más Años , Alelos , ADN/análisis , Femenino , Marcadores Genéticos , Genotipo , Arteritis de Células Gigantes/metabolismo , Arteritis de Células Gigantes/patología , Humanos , Masculino , Lectina de Unión a Manosa/metabolismo , Persona de Mediana Edad , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimialgia Reumática/genética , Polimialgia Reumática/metabolismo , Polimialgia Reumática/patologíaRESUMEN
Epidemiological data indicate that acute lymphoblastic leukemia (ALL) could be induced by interactions between the immune system and early childhood infections. Mannose-binding lectin (MBL) plays a critical role in the immune response in early childhood before specific immune protection develops. We investigated whether there may be an association between childhood ALL and low-producing MBL genotypes. Serum MBL levels depend on normal (A) or defective (O) alleles, and on normal (Y) or reduced (X) promoter activities. For this study, 137 noninfants with ALL and 250 controls were classified into 3 MBL genotype groups according to their influence on the serum level of functional MBL: group I, YA/YA and YA/XA (higher levels); group II, XA/XA and YA/O (intermediate levels); and group III, MBL insufficiency with XA/O or O/O (MBL-deficient) genotypes. Compared with controls, cases more often had low-level genotypes (I/II/III: 63 [46%]/44 [32%]/30 [22%] vs 145 [58%]/65 [26%]/40 [16%]; P =.02) and MBL deficiency (8.8% vs 2.8%; P =.009). Thus, the ALL odds ratio for MBL-deficient versus nondeficient individuals was 3.3 (95% CI, 1.3-8.7), whereas the ALL odds ratio for group I versus group II/III genotypes was 0.62 (95% CI, 0.41-0.94). MBL group III patients were significantly younger at diagnosis than patients in group I/II (median, 3.9 vs 5.2 years; P =.04). The study shows that the presence of low-level MBL genotypes is associated with an increased risk of childhood ALL, particularly with early age at onset.