RESUMEN
BACKGROUND: Peripheral blood B cells include lymphocytes at various stages of differentiation, each with a specific function in the immune response. All these stages show variations in percentage and absolute number throughout human life. The numbers and proportions of B subpopulation are influenced by factors such as gender, age, ethnicity, and lifestyle. This study establishes reference values according to age of peripheral blood B cell subtypes in healthy Mexican population. METHODS: Peripheral blood from healthy new-borns and adults were analysed for total B cell subpopulations, using surface markers such as CD19, IgM, IgD, CD21, CD24, CD27, and CD38, to identify naïve, memory with and without isotype switch, double-negative, transitional, and plasmablast cells. RESULTS: We observed a significant variation in terms of frequency and absolute counts between all groups analysed. Values from each B cell subpopulation show variations according to age. CONCLUSIONS: In order to attempt to elucidate reference values for B cell subpopulation, the present study evaluated a population sample of healthy blood donors from this region. Values reported here can also be used as a tool for diagnosis of diseases in which B cell maturation is affected.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Síndromes de Inmunodeficiencia/diagnóstico , Adolescente , Adulto , Distribución por Edad , Antígenos CD/metabolismo , Circulación Sanguínea , Niño , Preescolar , Humanos , Memoria Inmunológica , Inmunofenotipificación , Lactante , Activación de Linfocitos , Masculino , México , Valores de Referencia , Adulto JovenRESUMEN
X-linked agammaglobulinemia (XLA) is caused by BTK mutations, patients typically show <2% of peripheral B cells and reduced levels of all immunoglobulins; they suffer from recurrent infections of bacterial origin; however, viral infections, autoimmune-like diseases, and an increased risk of developing gastric cancer are also reported. In this work, we report the BTK mutations and clinical features of 12 patients diagnosed with XLA. Furthermore, a clinical revision is also presented for an additional cohort of previously reported patients with XLA. Four novel mutations were identified, one of these located in the previously reported mutation refractory SH3 domain. Clinical data support previous reports accounting for frequent respiratory, gastrointestinal tract infections and other symptoms such as the occurrence of reactive arthritis in 19.2% of the patients. An equal proportion of patients developed septic arthritis; missense mutations and mutations in SH1, SH2 and PH domains predominated in patients who developed arthritis.
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Agammaglobulinemia/genética , Agammaglobulinemia/patología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Mutación Missense/genética , Agammaglobulinemia/complicaciones , Agammaglobulinemia/diagnóstico , Artritis/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/genética , Inmunoglobulina G/sangre , Inmunoglobulina G/genética , Inmunoglobulina M/sangre , Inmunoglobulina M/genética , MéxicoRESUMEN
Hyper-IgE syndrome (HIES) is an immunodeficiency disorder that is characterized by distinctive immunologic and non-immunologic manifestations. Although mutations in signal transducer and activator of transcription 3 (STAT3) have been associated with HIES, the exact nature of the relationship is unknown. Here, we characterized the functional activity of STAT3 and its mutations in 11 Mexican patients with autosomal dominant HIES. STAT3 phosphorylation was evaluated by flow cytometry, and in silico analyses were performed to estimate the impact of allelic mutations on the DNA binding and SH2 domains of the STAT3 protein. Electrophoretic mobility shift assays were used to assess whether the STAT3 mutants could bind to the consensus oligonucleotide target in vitro. Two novel mutations [g.58891A>T (Asn395Tyr) and g.59078A>T (Asn425Tyr)] as well as one possible somatic mosaicism were found in several of the patients who bore some remarkable features. However, there were no direct correlations between genotypes and HIES clinical features. STAT3 phosphorylation was found to be lower in the patient cohort than in healthy controls. Moreover, the mutated STAT3 proteins could bind to the Sp1, but not to the STAT3, consensus sequence. From these functional studies, the STAT3 mutations found in our patient cohort were concluded to be deleterious for normal STAT3 function.
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Síndrome de Job/genética , Mutación/genética , Factor de Transcripción STAT3/genética , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Cohortes , Secuencia de Consenso , Demografía , Ensayo de Cambio de Movilidad Electroforética , Femenino , Heterogeneidad Genética , Humanos , Masculino , México , Fosforilación , Fosfotirosina/metabolismo , Unión Proteica , Factor de Transcripción STAT3/químicaRESUMEN
Primary immunodeficiencies (PID) are genetic diseases that affect the immune system and for the last 20 years, the Latin American Society for Immunodeficiencies (LASID) has been promoting initiatives in awareness, research, diagnosis, and treatment for the affected patients in Latin America. These initiatives have resulted in the development of programmes such as the LASID Registry (with 4900 patients registered as of January 2014), fellowships in basic and clinical research, PID summer schools, biannual meetings, and scientific reports, amongst others. These achievements highlight the critical role that LASID plays as a scientific organisation in promoting science, research and education in this field in Latin America. However, challenges remain in some of these areas and the Society must envision additional strategies to tackle them for the benefit of the patients. In June 2013, a group of experts in the field met to discuss the contributions of LASID to the initiatives of PID in Latin America, and this article summarises the current state and future perspectives of this society and its role in the advance of PIDs in Latin America.
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Síndromes de Inmunodeficiencia , Sociedades Médicas/organización & administración , Investigación Biomédica/organización & administración , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/terapia , América Latina , Sistema de RegistrosRESUMEN
BACKGROUND: There are two inheritance patterns, the X-linked recessive (XL) pattern and the autosomal recessive pattern. There is no information on the predominant inheritance pattern of male patients with chronic granulomatous disease (CGD) in Mexico. OBJECTIVE: The aim of this study was to determine the inheritance pattern in a cohort of Mexican male patients with CGD by means of the detection of an XL status carrier among their female relatives, and to describe the frequency of discoid lupus (DL) among carriers. METHODS: We detected the female relatives within the families of male patients with CGD, and carried out the 123 dihydrorhodamine (DHR) assay in all female participants. All carriers were questioned for current or past established DL diagnosis. RESULTS: We detected 33 families with one or more CGD male patients; we found an XL-CGD in 79% of the relatives from at least one female relative with a bimodal pattern. For the remaining seven relatives we were not able to confirm a carrier status by means of a DHR assay. Moreover, we detected one mother with CGD secondary to skewed X-chromosome inactivation. We also found 47 carriers, and only one carrier with DL among them. CONCLUSION: We concluded that XL-CGD is the most frequent form of CGD in a cohort of CGD male patients in Mexico. DHR assay is a fast and practical tool to determine the CGD form in the Latin-American countries. Finally, DL frequency in Mexico is lower than that reported in the literature for other regions of the world.
Asunto(s)
Cromosomas Humanos X/genética , Enfermedad Granulomatosa Crónica/genética , Patrón de Herencia , Lupus Eritematoso Discoide/genética , Rodaminas , Separación Celular , Estudios de Cohortes , Femenino , Citometría de Flujo/métodos , Pruebas Genéticas , Enfermedad Granulomatosa Crónica/diagnóstico , Heterocigoto , Humanos , Patrón de Herencia/genética , Lupus Eritematoso Discoide/diagnóstico , Masculino , México , LinajeRESUMEN
BACKGROUND AND AIMS: Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by decreased antibody production and low or normal B-cell numbers. To elucidate the clinical and immunological heterogeneity of CVID, we studied 16 patients diagnosed with CVID. METHODS: We analysed B, T and NK cell populations. We also assessed CD27 expression to define B-cell subsets and examined the expression of molecules important in B-cell proliferation and differentiation, such as the transmembrane activator and CALM interactor (TACI), inducible costimulator (ICOS), CD154 and CD40. RESULTS: We observed reduced B and T-cell numbers in CVID patients; this reduction was more pronounced in adults. While one group of patients (group I) showed a significant reduction in CD27+ memory B-cells, another group (group II) of patients exhibited numbers of CD27+ memory B-cells similar to the healthy donor. The frequency of B-cells and T-cells expressing CD40 and ICOS, respectively, was significantly lower in all CVID patients compared with healthy donors. Finally, a correlation between the frequency of CD27+ memory B-cells and clinical features was observed in CVID patients. CONCLUSION: These results suggest that in some patients, the combined defects in both T and B-cells may account for CVID. Additionally, patients in group I exhibited an increased frequency of pneumonia and chronic diarrhoea.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Inmunodeficiencia Variable Común/inmunología , Células Asesinas Naturales/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Antígenos CD40 , Ligando de CD40/metabolismo , Niño , Preescolar , Femenino , Humanos , Memoria Inmunológica , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Masculino , México , Persona de Mediana Edad , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Common variable immunodeficiency (CVID) is characterised by hypogammaglobulinaemia and a broad clinical spectrum, mainly showing recurrent bacterial infections accompanied sometimes by increased susceptibility to chronic lung disease, autoimmunity, and neoplastic diseases. OBJECTIVES: To evaluate the clinical and immunological characteristics of patients with CVID in Mexico. METHODS: This is a retrospective analysis of 43 patients with CVID from the Immunology Division of seven different reference centres in Mexico. Patients were diagnosed according to the diagnostic criteria of the European Society for Immunodeficiency Diseases. We collected demographics, clinical and immunological data from each patient and a statistical analysis was performed. RESULTS: There were 23 (53.5%) male and 20 (46.5%) female patients. Median age at onset of disease was 13.7 years, and median age at diagnosis was 19 years. Average delay in diagnosis was 12.5 years. The median total serum levels of IgG, IgM, and IgA at diagnosis were 175, 18, and 17.8mg/dL, respectively. The mean percentage of CD19+ B cells was 8.15%. Sinusitis (83%), pneumonia (83%), gastrointestinal infection (70%), and acute otitis media (49%) were the most common manifestations. Bronchiectasis was present in 51% of the patients, 44% manifested non-infectious chronic diarrhoea, and 70% experienced weight loss. Autoimmunity was present in 23% of the patients; haemolytic anaemia and autoimmune thrombocytopenic purpura were the most common presentations. Allergy was present in 30.2% of patients, with allergic rhinitis and asthma being the most frequent types. Two patients developed malignancy. All the patients received Intravenous immunoglobulin (IVIG) as a fundamental part of the treatment at a mean dose of 408mg/kg. CONCLUSION: This is the first cohort of CVID reported in Mexico We found that infection diseases were the most frequent presentations at onset. Moreover, patients had an average diagnosis delay of twelve years and thus a major prevalence of bronchiectasis. We suggest performing an extended analysis of patients with CVID patients in other Latin American countries.
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Asma/inmunología , Linfocitos B/inmunología , Bronquiectasia/inmunología , Inmunodeficiencia Variable Común/inmunología , Infecciones/inmunología , Adolescente , Adulto , Antígenos CD19/metabolismo , Autoinmunidad , Niño , Estudios de Cohortes , Inmunodeficiencia Variable Común/fisiopatología , Inmunodeficiencia Variable Común/terapia , Femenino , Humanos , Inmunoglobulinas/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , México , Estudios Retrospectivos , Adulto JovenRESUMEN
Autosomal recessive interleukin-12 receptor ß1 (IL-12Rß1) deficiency has been described as the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), characterized by clinical disease due to weakly virulent mycobacteria such as Bacille Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM) in children who are normally resistant to most infectious agents. Here, we report the cases of five patients with mycobacterial infection, including one with systemic lupus erythematosus (SLE). Blood samples from patients and healthy controls were activated in vitro with BCG, BCG+IL-12, and BCG+IFN-γ. The results showed reduced or no production of IFN-γ after IL-12 stimulation in all samples. IL-12Rß1 expression on the cell surface was negligible or absent. Genetic analysis showed five novel mutations.
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Receptores de Interleucina-12/deficiencia , Receptores de Interleucina-12/genética , Adolescente , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Resultado Fatal , Humanos , Lactante , Interleucina-12/sangre , Masculino , Datos de Secuencia Molecular , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Over the past three decades, there has been a remarkable improvement in the outcome of children diagnosed with systemic lupus erythematosus (SLE). In general, paediatric-onset SLE has been associated with higher mortality rates and more disease damage than adults with SLE. The objective was to determinate the impact of clinical, laboratory, and electroencephalographic findings on survival amongst patients with paediatric-onset SLE. METHODS: Charts of Mexican patients with paediatric-onset SLE diagnosed between 1970 and 2001 were analysed retrospectively; univariate and multivariate analyses were used for analysing associations between clinical and laboratory features and death; Kaplan-Meier tests were used to estimate survival curves. RESULTS: 159 patients were included, 105 were female, with a median age of 12.7 years at diagnosis and a median duration of symptoms prior to diagnosis of 8.4 months. Univariate analysis showed that haematuria, leukocyturia, proteinuria, presence of urine cast, <60% glomerular filtration rate, haemolytic anaemia, and abnormal electroencephalogram, were all poor prognostic factors (p<0.05). Multivariate analysis showed that the presence of proteinuria and abnormal electroencephalograms (p<0.05) were independent factors associated with death. The overall survival rate was 82.9% at five years and 77.4% at ten years upon follow-up. Infection and high disease activity were the most common causes of death. CONCLUSIONS: Survival of paediatric-onset SLE patients was lower compared to that reported for patients in wealthier countries. Amongst the patients who died, the presence of proteinuria and abnormal electroencephalograms were found to be determinant for survival. Infection and activity were the most common causes of death.
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Electrocardiografía/estadística & datos numéricos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/mortalidad , Adolescente , Edad de Inicio , Niño , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , México/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
A regulatory single nucleotide polymorphism located in the 5' region (-169T/C) of the Fc receptor-like 3 (FCRL3_3) gene has been associated with both susceptibility and protection in immune diseases. This case-control study aimed to evaluate the association between FCRL3 polymorphisms and juvenile rheumatoid arthritis (JRA), asthma, and childhood-onset systemic lupus erythematosus (SLE) in a Mexican population. We performed PCR-based genotyping to identify four FCRL3 single nucleotide polymorphisms (FCRL3_3 to FCRL3_6) in patients with JRA (n=202), asthma (n=239), or childhood-onset SLE (n=377), and healthy controls (n=400). The case-control analysis showed a male-gender dependent association between the FCRL3_3C, FCRL3_5C, and FCRL3_6A alleles and either JRA (OR=0.57, p=0.003; OR=0.55, p=0.002; OR=0.53, p=0.0007, respectively) or asthma (OR=0.72, p=0.04; OR=0.74, p=0.05; OR=0.70, p=0.02, respectively). As expected, minor alleles of these SNPs with the CGCA haplotype were also significantly associated with JRA (OR=0.35, p=0.00005) and asthma (OR=0.61, p=0.007). We found no association between FCRL3 SNPs or haplotypes and childhood-onset SLE. These results supported the notion that FCRL3 is involved in the etiology of several immune diseases. Our results also suggested that SNPs located in the FCRL3 gene were protective against JRA and asthma in male Mexican patients.
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Artritis Juvenil/genética , Asma/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos/genética , Adolescente , Adulto , Alelos , Artritis Juvenil/epidemiología , Asma/epidemiología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Técnicas de Genotipaje , Haplotipos , Humanos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico/epidemiología , Masculino , México/epidemiología , Factores SexualesRESUMEN
Primary immunodeficiency diseases (PIDD) are associated with significant morbidity and mortality and result in a significant public health burden. This is in part due to the lack of appropriate diagnosis and treatment of these patients. It is critical that governments become aware of this problem and provide necessary resources to reduce this impact on health care systems. Leading physicians in their respective countries must be supported by their own governments in order to implement tools and provide education and thus improve the diagnosis and treatment of PIDD. The Latin American Society of Primary Immunodeficiencies (LASID) has initiated a large number of activities aimed at achieving these goals, including the establishment of a PIDD registry, development of educational programmes and guidelines, and the introduction of a PIDD fellowship programme. These initiatives are positively impacting the identification and appropriate treatment of patients with PIDD in Latin America. Nevertheless, much remains to be done to ensure that every person with PIDD receives proper therapy.
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Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/terapia , Congresos como Asunto , Humanos , América Latina , Sociedades MédicasRESUMEN
Experts from six Latin American countries met to discuss critical issues and needs in the diagnosis and management of primary immunodeficiency diseases (PIDD). The diagnosis of PIDD is generally made following referral to an immunology centre located in a major city, but many paediatricians and general practitioners are not sufficiently trained to suspect PIDD in the first place. Access to laboratory testing is generally limited, and only some screening tests are typically covered by government health programmes. Specialised diagnostic tests are generally not reimbursed. Access to treatment varies by country reflecting differences in healthcare systems and reimbursement policies. An online PIDD Registry Programme for Latin America has been available since 2009, which will provide information about PIDD epidemiology in the region. Additional collaboration across countries appears feasible in at least two areas: a laboratory network to facilitate the diagnosis of PIDD, and educational programmes to improve PIDD awareness. In total, these collaborations should make it possible to advance the diagnosis and management of PIDD in Latin America.
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Manejo de la Enfermedad , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/terapia , Alergia e Inmunología/educación , Conocimientos, Actitudes y Práctica en Salud , Accesibilidad a los Servicios de Salud , Humanos , Inmunoglobulinas Intravenosas/economía , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/economía , Cobertura del Seguro , Reembolso de Seguro de Salud , América Latina , Sistema de RegistrosRESUMEN
X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency in which affected patients have very low levels of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Mutations in the gene encoding for Bruton's tyrosine kinase (Btk) are responsible for most of the agammaglobulinemia. In this work, 14 Btk mutations responsible of causing XLA are described; eight of which are novel and six are mutations previously reported. Seven of the mutations were due to deletions and insertions of exons and introns, respectively, which suggest splicing defects. The others were missense mutations, five of which affect arginine residues and have been described, and two new which affect leucine and glutamine residues (L111P and E605G). Most of these mutations were located at the kinase domain of Btk and, less frequently, they were found in PH and SH2 domains. Protein expression was also affected since most of the patients did not express or express very low Btk.
Asunto(s)
Agammaglobulinemia/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Ligamiento Genético , Proteínas Tirosina Quinasas/genética , Adolescente , Agammaglobulinemia Tirosina Quinasa , Niño , Preescolar , Humanos , México , Mutación , Proteínas Tirosina Quinasas/sangreRESUMEN
BACKGROUND: Acute respiratory tract infections (ARTIs) are a major cause of childhood morbidity and mortality. Immunostimulants (IS) may reduce the incidence of ARTIs. OBJECTIVES: To determine the efficacy and safety of IS in preventing ARTIs in children. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005); MEDLINE (January 1966 to January 2006); and EMBASE (January 1990 to January 2006); PASCAL (up to January 2006); SciSearch (up to January 2006); and IPA (up to January 2006) for reports of trials. Investigators in the field were also contacted. Ongoing studies were searched in the trial registration web site, metaRegister of Controlled Trials. SELECTION CRITERIA: All comparative trials which enrolled patients less than 18 years of age were included. The intervention of interest was the use of an IS medication administered by any method for preventing ARTIs. Clinical trials using random or quasi-random allocation and comparing IS medication or medications to placebo were included. DATA COLLECTION AND ANALYSIS: The outcome on ARTIs was analyzed both as the mean number of ARTIs by group and as a percent change in the rate of ARTIs. Meta-analysis was undertaken using a random-effects model and results were presented as weighted mean differences (WMD) with 95% confidence intervals (CI). The trials search, quality assessment and data extraction were undertaken independently by two authors. A funnel plot suggested there may be publication bias in the trials identified. MAIN RESULTS: Thirty-four placebo controlled trials (3877 participants) provided data in a form suitable for inclusion in the meta-analysis. When compared with placebo, the use of IS was shown to reduce ARTIs measured as the total numbers of ARTIs (WMD -1.27; 95% CI -1.58 to -0.97) and the difference in ARTIs rates (WMD -39.68%; 95% CI -47.27% to -32.09%). The trial quality was generally poor and a high level of statistical heterogeneity was evident. The subgroup analysis of bacterial IS studies produced similar results, with lower heterogeneity. No difference in adverse events was evident between the placebo and IS groups AUTHORS' CONCLUSIONS: This review showed that IS reduces the incidence of ARTIs in children, by 40% on average. However, due to significant heterogeneity and the poor quality of the trials this positive result should be interpreted with caution. The safety profile of IS appears to be good. Further high-quality trials are needed and we encourage national health authorities to conduct large, multicenter, double-blind, placebo-controlled trials on the role of IS in the prevention of ARTIs.
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Adyuvantes Inmunológicos/uso terapéutico , Infecciones del Sistema Respiratorio/prevención & control , Adolescente , Niño , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Several studies have identified a functional single nucleotide polymorphism 1858C/T in the PTPN22 gene to be associated with several autoimmune diseases. Association studies of this polymorphism with familial and sporadic systemic lupus erythematosus (SLE) have shown some discrepancies. To our knowledge, this is the first study that includes only pediatric-onset SLE patients. We performed a case-control association study in 250 unrelated Mexican patients with childhood-onset SLE consisting of 228 cases with sporadic SLE and 22 cases with familial SLE and 355 healthy controls. We observed a statistically significant difference in the frequency of the PTPN22 1858T allele between SLE patients (3.4%) and healthy controls (1.1%) (P=0.0062, odds ratio (OR) 3.09 (95% confidence interval 1.32-7.21)). The association was also observed when only sporadic cases were analyzed (OR=3.19). Our results support the association of the PTPN22 1858T allele with sporadic childhood-onset SLE in Mexican population.