Transcriptomic signatures of classical monocytes reveal pro-inflammatory modules and heterogeneity in polyarticular juvenile idiopathic arthritis.

Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.

Genome Sequencing in an Individual Presenting with 22q11.2 Deletion Syndrome and Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial etiology. 22q11.2 proximal deletion syndrome is a multisystemic disease with over 180 manifestations already described. In this report, the authors describe a patient presenting with a short stature, neurodevelopmental delay, and dysmorphisms, who had an episode of polyarticular arthritis at the age of three years and eight months, resulting in severe joint limitations, and was later diagnosed with 22q11.2 deletion syndrome. Investigation through Whole Genome Sequencing revealed that he had no pathogenic or likely-pathogenic variants in both alleles of the MIF gene or in genes associated with monogenic arthritis (LACC1, LPIN2, MAFB, NFIL3, NOD2, PRG4, PRF1, STX11, TNFAIP3, TRHR, UNC13DI). However, the patient presented 41 risk polymorphisms for juvenile idiopathic arthritis. Thus, in the present case, arthritis seems coincidental to 22q11.2 deletion syndrome, probably caused by a multifactorial etiology. The association of the MIF gene in individuals previously described with juvenile idiopathic arthritis and 22q11.2 deletion seems unlikely since it is located in the distal and less-frequently deleted region of 22q11.2 deletion syndrome.

Using the attract method to identify core pathways in juvenile idiopathic arthritis.

The aim of this study was to identify core pathways associated with juvenile idiopathic arthritis (JIA) using the attract method. Kyoto Encyclopedia of Genes and Genomes pathways were determined using the GSEA-ANOVA method, based on the gene expression data of JIA. Syn-expression groups within core attractor pathways were identified by hierarchical clustering. Correlated sets of genes exhibiting highly similar profiles to the syn-expression groups were identified and each correlated set was subjected to a gene ontology functional enrichment analysis to discover potentially shared biological themes. Based on a false-discovery rate < 0.05, we identified 11 significant pathways were identified as potential attractors. Flag genes or uninformative genes were removed and 5 discriminative pathways: the proteasome, ribosome, protein export, spliceosome, and Parkinson's disease pathways were identified. A final set of syn-expression groups with a consistent trend of relative expression of pathway-related genes was obtained; that is, the proteasome, ribosome, protein export, spliceosome, and Parkinson's disease pathways were composed of 2, 2, 1, 2, and 3 clusters, respectively. Genes in each correlated set shared common roles, and changes at the pathway level were more likely to be real. In light of these, the attract method was able to on expand important context to find distinguishing expression patterns within pathways. This paper predicted that the functional themes involved in protein synthesis (such as proteasome, ribosome, spliceosome) were closely related to the progression of JIA, which might contribute to the detection of therapy target for JIA.

Diagnostic performance of anti-citrullinated protein/peptide antibodies in juvenile idiopathic arthritis.

The prevalence rates of anti-citrullinated protein/peptide antibodies (ACPAs) were investigated in a cohort of juvenile idiopathic arthritis (JIA) patients, and their diagnostic performances were compared. ACPAs, including anti-cyclic citrullinated peptide IgG (anti-CCP), anti-CCP IgG/IgA (anti-CCP3.1), citrullinated recombinant rat filaggrin antibodies (CPA), anti-mutated citrullinated vimentin (anti-MCV), and antibodies to citrullinated human IgG-derived peptides (RA/CP), were measured in the sera from 81 JIA patients. Serum samples from 55 children with other joint diseases or viral infections and 49 healthy donors were tested as controls. Of the 81 JIA patients, 7 (8.6%), 8 (9.9%), 17 (21.0%), 23 (28.4%), and 18 (22.2%) were found to be positive for anti-CCP, anti-CCP3.1, CPA, anti-MCV, and RA/CP, respectively, with specificities of 98.1, 95.1, 93.3, 84.6, and 86.5%. Analysis by subtype revealed that 7/7 (100%) of RF-positive polyarticular JIA patients tested positive at high serum levels for anti-MCV or RA/CP, and 5/7 (71.4%) were positive for anti-CCP, anti- CCP3.1, or CPA (P < 0.001, compared with controls). Eighteen of 81 JIA patients demonstrated joint erosions on radiographs and erosive arthritis occurred more often in ACPAs positive patients (P < 0.01). Our findings indicate that although ACPAs are not satisfactory screening biomarkers for JIA due to low sensitivity, ACPA measurement can aid in diagnosing RF-positive polyarticular JIA and identifying JIA patients with severe bone involvement. The diagnostic performance of each ACPA in JIA is different, and the careful selection of assays is necessary.

Dois pares de irmãos com artrite idiopática juvenil (AIJ): relato de casos / Two pairs of brothers with juvenile idiopathic arthritis (JIA): case reports

Relato de casos de ocorrência de Artrite Idiopática Juvenil (AIJ) em dois pares de irmãos acompanhados no serviço de reumatologia pediátrica da Universidade Federal da Bahia. O envolvimento genético na patogênese da AIJ está claro e o risco de recorrência entre irmãos corrobora esta contribuição. Um importante marco dessa descoberta envolve a confirmação da contribuição dos polimorfismos do complexo principal de histocompatibilidade (MHC) na susceptibilidade ao desenvolvimento da AIJ. Apesar de muitos progressos, os inúmeros estudos existentes ainda não são capazes de explicar diversos mecanismos implícitos na patogênese da AIJ.

This is a case report of juvenile idiopathic arthritis in two pairs of brothers followed in the Department of Pediatric Rheumatology, Universidade Federal da Bahia. Genetic involvement in juvenile idiopathic arthritis pathogenesis is clear and the risk of recurrence among siblings supports this contribution. An important landmark of this discovery involves the acknowledgment of major histocompatibility complex polymorphism contribution to juvenile idiopathic arthritis development susceptibility. Despite many advances, the numerousavailable studies cannot explain several implicit mechanisms in juvenile idiopathic arthritispathogenesis yet.

[Two pairs of brothers with juvenile idiopathic arthritis (JIA): case reports]. / Dois pares de irmãos com artrite idiopática juvenil (AIJ): relato de casos.

This is a case report of juvenile idiopathic arthritis (JIA) in two pairs of brothers followed in the department of pediatric rheumatology, Universidade Federal da Bahia. Genetic involvement in JIA pathogenesis is clear and the risk of recurrence among siblings supports this contribution. An important landmark of this discovery involves the acknowledgment of major histocompatibility complex (MHC) polymorphism contribution to JIA development susceptibility. Despite many advances, the numerous available studies cannot explain several implicit mechanisms in JIA pathogenesis yet.

Juvenile rheumatoid arthritis and asthma, but not childhood-onset systemic lupus erythematosus are associated with FCRL3 polymorphisms in Mexicans.

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.

MiR-146a polymorphism is associated with asthma but not with systemic lupus erythematosus and juvenile rheumatoid arthritis in Mexican patients.

Extensive research has shown that aberrant expression of microRNAs (miRNAs) plays an important role in innate and adaptive immune responses. The rs2910164 polymorphism has been identified as a functional variant, which affects the transcription and expression level of miR-146a and, thereby, contributes to the pathogenesis of several inflammatory and autoimmune diseases. To investigate whether the rs2910164 G/C polymorphism was associated with asthma, systemic lupus erythematosus (SLE) or juvenile rheumatoid arthritis (JRA), we performed an association study in a pediatric Mexican cohort. We included 979 pediatric patients (asthma: 402, SLE: 367 and JRA: 210) and 531 control subjects without inflammatory or immune diseases. Genotyping was performed using the 5' exonuclease technique. The genotype distribution of the rs2910164 polymorphism was in Hardy-Weinberg equilibrium in each group. No significant differences were detected in the distribution of this polymorphism between cases and controls (P = 0.108, 0.609 and 0.553 for subjects with asthma, JRA and SLE, respectively). However, stratification by gender showed a statistically significant difference between asthmatic and control females, where the C allele was significantly associated with protection to asthma (odds ratio = 0.694, 95% confidence interval 0.519-0.929, P = 0.0138). Our results provide evidence that rs2910164 may play a role in the susceptibility to childhood-onset asthma, but not SLE or JRA in Mexicans. Further association studies may contribute to determining the role of miR-146a single-nucleotide polymorphisms in immune-mediated diseases.

HMOX1 promoter (GT)n polymorphim is associated with childhood-onset systemic lupus erythematosus but not with juvenile rheumatoid arthritis in a Mexican population.

OBJECTIVES: The heme oxigenase 1 (HO-1), a rate-limiting enzyme for heme degradation, is an important cytoprotective protein. Transcriptional activity of HO-1 coding gene (HMOX1) can be regulated by the presence of a dinucleotide repeat polymorphism (GT)n at its promoter region. Accordingly, length of (GT)n repeat has been associated with susceptibility to several diseases. We investigated whether the HMOX1 (GT)n polymorphism was associated with childhood-onset systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA) susceptibility. METHODS: We studied 207 and 333 unrelated Mexican patients with JRA and childhood-onset SLE, respectively. The control population consisted of 653 individuals ethnically matched with cases. The HMOX1 (GT)n polymorphism was genotype by PCR and fluorescence technology. RESULTS: We found 27 different alleles, with the 22 and 29 repeats as the most common alleles. Distribution of short allele (n<25) and SS genotype was not statistically associated with JRA subjects. Interestingly, the frequency of both short allele and SS genotype was significantly associated with SLE susceptibility (OR=1.47, 95%CI [1.14-1.89], p=0.002; and OR=2.79, 95%CI [1.24-6.24], p=0.01, respectively). CONCLUSIONS: The distribution pattern of HMOX1 (GT) alleles was different in the Mexican population than those reported elsewhere. Our results suggest that HMOX1 (GT)n polymorphism was associated with susceptibility to childhood-onset SLE but not with JRA in Mexican individuals.

Association of HLA DRB1 alleles with juvenile idiopathic arthritis in Mexicans.

OBJECTIVE: The aim of the study was to investigate association between HLA class II alleles and juvenile idiopathic arthritis (JIA) in Mexican patients. PATIENTS AND METHODS: We typed 120 patients with JIA and 99 healthy controls for HLA class II alleles were performed by PCR-SSO. Differences between the whole group of JIA and its subtypes and controls were calculated by using the Xi2; p-values were corrected (pc) with Bonferroni's test. RESULTS: The alleles HLA-DRB1*01 (pc= 0.00083) and HLA-DRB1*04 (pc=0.0049) were strongly associated with systemic JIA, while HLA-DRB1*11 and HLA-DRB1*14 were found to have decreased frequencies in the patients with systemic JIA compared to the controls. Two alleles were found to have increased frequencies with JIA oligoarthritis subgroup, HLA-DRB1*11 (p=0.01, pc=NS) and HLA-DRB1*13 (p=0.01, pc=NS). The HLA-DRB1*04 was found increased frequencies with susceptibility for RF negative and RF positive polyarthritis JIA subgroups (p correction resulted in loss of significance). In contrast two alleles HLA-DRB1*07 and HLA-DRB1*14 were found decreased frequencies only patients RF positive polyarthritis JIA subgroup compared to the controls (pc=NS). CONCLUSION: The profile of HLA-DRB1 alleles associations in Mexican with JIA were somewhat distinct from association typically found in Caucasians.

Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population.

There is a great deal of evidence that points to the association of the tumor necrosis factor-alpha (TNF-alpha) gene as a common genetic factor in the pathogenesis of diseases that are caused by inflammatory and/or autoimmune etiologies. Two single nucleotide polymorphisms (SNPs) identified in the TNF-alpha promoter region have been associated with disease susceptibility and severity. We investigated whether -308G/A and -238G/A TNF-alpha polymorphisms were associated with asthma, systemic lupus erythematosus (SLE), and juvenile rheumatoid arthritis (JRA) in a pediatric Mexican population. In a case-control study of 725 patients (asthma: 226, JRA: 171, and SLE: 328) and 400 control subjects, the participants were analyzed using the allelic discrimination technique. The genotype distribution of both TNF-alpha polymorphisms was in Hardy-Weinberg equilibrium in each group. However, there were significant differences in the allele frequency of TNF-alpha-308A between the patients and the healthy controls. This allele was detected in 2.9% of the controls, 6.0% of asthmatic and JRA patients (p = 0.002 and p = 0.0086), and 6.7% of SLE patients (p = 0.00049); statistical significance was maintained after ancestry stratification (asthma: p = 0.0143, JRA: p = 0.0083, and SLE: p = 0.0026). Stratification by gender showed that the risk for the -308A allele in asthma and JRA was greater in females (OR = 4.16, p = 0.0008 and OR = 4.4, p = 0.0002, respectively). The TNF-alpha -238A allele showed an association only with JRA in males (OR = 2.89, p = 0.004). These results support the concept that the TNF-alpha gene is a genetic risk factor for asthma, SLE, and JRA in the pediatric Mexican population.

GSTT1, GSTM1 and GSTP1 polymorphisms and susceptibility to juvenile idiopathic arthritis.

OBJECTIVE: In this study we have analyzed GSTM1, GSTT1 and GSTP1 polymorphisms in patients with juvenile idiopathic arthritis (JIA), to investigate a possible role of these genes as genetic components of the disease. METHODS: A total of 103 individuals (49 oligoarticular, 41 polyarticular and 13 systemic) were analyzed for the three polymorphisms, using a PCR/RFLP methodology. RESULTS: We have observed significantly increased frequencies of individuals with GSTT1 null genotype in JIA patients comparing to controls (37% x 21%; p=0.0183). There was a 2-fold increased risk (OR 2.2, 95% CI 1.2-4.1) associating the disease with the GSTT1 null genotype. Considering the subgroups (oligoarticular, polyarticular and systemic), the results indicated an association between polyarticular and systemic patients and the GSTT1 null genotype. There was a 2-fold increased risk for polyarticular patients (OR 2.4, 95%, CI 1.1-5.4), and a 4-fold increased risk for systemic patients (OR 4.4, 95%, 1.3-14.5). CONCLUSION: The GSTT1 null genotype seems to be involved in polyarticular and systemic JIA.

Association of the HLA-G 14-bp insertion/deletion polymorphism with juvenile idiopathic arthritis and rheumatoid arthritis.

We tested the possible association of the 14-bp polymorphism of the HLA-G gene in the course of two inflammatory diseases, rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Patients and controls were genotyped for the 14-bp polymorphism by polymerase chain reaction with specific primers for the exon 8 of the human leukocyte antigen (HLA)-G gene and the amplified fragment was visualized in a 6% polyacrylamide gel. A total of 106 JIA patients, 265 RA patients, 356 healthy adults and 85 healthy children were genotyped for the 14-bp polymorphism. Female JIA patients presented a higher frequency of the -14 bp allele when compared with female healthy children (0.743 and 0.500, corrected P=0.003), which reflected in the JIA group as a whole. This increased frequency of the -14-bp allele was observed in all JIA subtypes. In RA patients, no differences in allelic and genotypic frequencies were observed between patients and controls. No correlations were observed among genotype and disease severity or clinical manifestations. Our data suggest that the HLA-G -14 bp allele is probably a risk factor for JIA, mainly in females. Considering the differences observed in relation to gender, we suggest that hormonal differences can interfere with the development of JIA. Considering the RA patients, our data agree with results from the literature and highlight the differences in the etiology of RA and JIA.

Differential CCR5Delta32 allelic frequencies in juvenile idiopathic arthritis subtypes: evidence for different regulatory roles of CCR5 in rheumatological diseases.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood and is characterized by persistent arthritis for at least 6 weeks. Its aetiopathogenesis is unknown but there is strong evidence that there is a substantial genetic component. Chemokine receptors genes are among the candidate genes for association with arthritis and other inflammatory diseases. The CC chemokine receptor 5 (CCR5)Delta32 polymorphism has been associated with rheumatoid arthritis (RA), conferring a protective effect. OBJECTIVE: To determine whether the CCR5Delta32 polymorphism is associated with JIA and RA in Brazilian patients. METHODS: We investigated 203 RA patients, 101 JIA patients, and 104 healthy individuals by amplification of the CCR5Delta32 deletion. We compared the allelic frequencies among these groups, as well as among different JIA subtypes. RESULTS: The frequency of the Delta32 allele was higher in JIA patients (9.4%) as compared to control subjects (3.8%) and RA patients (3.2%). Grouping the patients according to JIA subtypes, we observed a higher CCR5Delta32 allelic frequency in the subtypes with a greater inflammatory component: 4.1% in oligoarticular (n = 49), 11.2% in polyarticular (n = 40) [9.5% in rheumatoid factor negative (RF-) and 33.3% in RF positive (+)], and 25% in systemic JIA (n = 12). CONCLUSIONS: This study suggests that in JIA, unlike in RA, CCR5Delta32 does not have a protective effect, but instead it could be a factor associated with more inflammatory forms of the disease. These observations give rise to new questions about the mechanism and the cellular types involved in JIA as well as about the aetiology of JIA.

HLA-DRB1 alleles and HLA-DRB1 shared epitopes are markers for juvenile rheumatoid arthritis subgroups in Colombian mestizos.

We studied the association of human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 alleles and HLA haplotypes with juvenile rheumatoid arthritis (JRA) in 65 patients and 65 controls from Colombia. The JRA subsets were distinguished on the basis of criteria established by the American College of Rheumatology. Two alleles were associated with protection, HLA-DRB1*1501 (p = 0.002) and HLA-DRB1*1402 (p = 0.01). HLA-DRB1*1602 (p = 0.0000002) was associated with susceptibility for systemic JRA and HLA-DRB1*1104 (p = 0.0002) for pauciarticular JRA. Amino acid sequences at residues 70-74 of DRB1 chain shared by HLA-DRB1 alleles (shared epitomes) were also informative. The polyarticular JRA subset revealed association with (70)QRRAA(74), which includes HLA-DRB1*04, 01, and (70)DRRAA(74), which includes DRB1*1601, 1602, 1101, and 1104. Two new findings of interest were the association of the haplotypes DRB1*1104, DQB1*0301(p = 0.0002) with pauciarticular JRA and DRB1*1602, DQB1*0301 (p = 0.0000002) association with systemic JRA. The DRB1 alleles of these two haplotypes share the epitope (70)DRRAA(74)and were associated with both the pauciarticular and the systemic subset of JRA. Our results suggest that studies of disease susceptibility in populations of admixed genetic background should take into account the contribution of different ethnic groups or nationalities in the recruitment of controls and patients studied in order to rule out genetic stratification.

[Polymorphism of human HLA-DRB1 leukocyte antigen alleles and its association to juvenile rheumatoid arthritis in a sample of Colombian mestizo children]. / Polimorfismo de los alelos de los antígenos de leucocitos humanos HLA-DRB1 y su asociación con la artritis reumatoidea juvenil en una muestra de niños mestizos colombianos.

Oligotypes of the human leukocyte antigen HLA Class II, DRB1 alleles were characterized at the molecular level in a group of Colombian children suffering juvenile rheumatoid arthritis (JRA). The distribution of these alleles was examined in a group of Colombian mestizo children (genetic admixture of Amerindians, Europeans and Africans) suffering from clinically distinct JRA subsets in order to detect HLA allele frequency differences in patients with different JRA subsets. A group of 65 patients with JRA and 65 controls were characterized for the subtypes of the HLA-DRB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR-SSOP). The oligotyping protocol recommended by the 12th International Histocompatibility Workshop held in St. Malo, Paris, in 1996, was used. Subtype HLA-DRB1*1104 was the allele most strongly associated with susceptibility to JRA (Fisher's p = 0.013, odds ratio (OR) = 16.79, etiologic fraction (EF) = 0.93). HLA-DRB1*1602 was also associated with susceptibility to a lesser degree (Fisher's p = 0.016, OR = 8.98, EF = 0.88). HLA-DRB1 alleles participating in JRA protection were HLA-DRB1*1501 (preventive fraction (PF) = 0.466, p = 0.005) and HLA DRB1*1402 (PF = 0.49, p = 0.009). The relationship between some HLA-DRB1 alleles and clinical features was also compared. The presence of rheumatic factor was associated with the alleles HLA-DRB1*0407 (p = 0.05, OR = 11.2, EF = 0.45) and HLA-DRB1*1302 (p = 0.02, OR = 22.8, EF = 0.63). There was also an association between HLA-DRB1*0701 (p = 0.001, OR = 58, EF = 0.73) with expressing ANA +. We found that in the oligoarticular subset, the allele HLA-DRB1*1104 (p = 0.0034, OR = 41.53, EF = 0.97) was the one expressed most commonly. In the poliarticular group, the alleles most frequently expressed were HLA-DRB1*0404 (Fisher's p = 0.012, OR = 8.75, EF = 0.88). In patients with systemic JRA, the HLA-DRB1*1602 allele (p = 0.005, OR = 21.33, EF = 0.95) was most frequent. These results suggested that the MHC genes of mestizo children influence not only the clinical expression of the disease, but also the susceptibility to its development.

Hyperzincemia with systemic inflammation: a heritable disorder of calprotectin metabolism with rheumatic manifestations?

A boy had infantile-onset systemic inflammation, growth failure, hepatosplenomegaly, anemia, leukocytopenia, progressive muscular dystrophy, and hypercalprotectinemia, resulting in marked hyperzincemia. His mother had a history of chronic arthritis since childhood and also showed hypercalprotectinemia/hyperzincemia. We postulate an inherent defect in calprotectin metabolism.

Juvenile rheumatoid arthritis-like polyarthritis in Nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease (8q21) from the family of the genetically determined chromosomal instability syndromes. The disorder is characterized by microcephaly, growth retardation, immunodeficiency, and high incidence of cancer. Several noninflammatory anomalies of the musculoskeletal system have been described in patients with this syndrome. We describe an Argentinian girl with all the clinical, immunological, and cytogenic characteristics described for NBS plus a juvenile rheumatoid arthritis-like syndrome. To our knowledge this is the first report of a patient with the NBS who presented with a symmetric chronic polyarthritis resembling JRA.

Caracterización inmunogenética de pacientes adultos y niños argentinos con enfermedades del tejido conectivo / Immunogenetic characterization of argentinian child and adult patients with connective tissue diseases

El descubrimiento a principios de la década del 70 de la fuerte asociación entre el antígeno de histocompatibilidad HLA-B27 con la espondilitis anquilosante (EA) sugirió que componentes del complejo mayor de histocompatibilidad podrían contribuir a la susceptibilidad a padecer ciertas enfermedades. Desde entonces los antígenos HLA han sido hallados estar asociados con más de 100 afecciones, muchas de las cuales pertenecen a la esfera reumatológica. Algunas enfermedades comprometen genes de la región del HLA que están ligados a alelos específicos de Clase I o Clase II, o a combinaciones de alelos (haplotipos). También se ha observado que algunos genes del HLA pueden modular la expresión clínica y la severidad de algunas enfermedades. La función del sistema HLA tiene efectos muy amplios, no solamente por el papel que juega en la respuesta inmune adaptativa sino también por su complejidad genética, la cual puede variar de acuerdo a los diferentes grupos étnicos estudiados. En nuestro país la caracterización inmunogenética de los pacientes con diversas enfermedades del tejido conectivo no ha sido ampliamente estudiada. En el presente trabajo se focaliza en la influencia que tienen ciertos antígenos del HLA en la susceptibilidad, expresión clínica y severidad de algunas enfermedades reumáticas, principalmente la EA, la artritis reumatoidea tanto del adulto (AR) como las diferentes formas que la misma presenta en los niños (ARJ), como también en las miopatías inflamatorias idiopáticas de la infancia, en la predominante población caucásica de pacientes en nuestro país... (TRUNCADO)

Caracterización inmunogenética de pacientes adultos y niños argentinos con enfermedades del tejido conectivo / Immunogenetic characterization of argentinian child and adult patients with connective tissue diseases

El descubrimiento a principios de la década del 70 de la fuerte asociación entre el antígeno de histocompatibilidad HLA-B27 con la espondilitis anquilosante (EA) sugirió que componentes del complejo mayor de histocompatibilidad podrían contribuir a la susceptibilidad a padecer ciertas enfermedades. Desde entonces los antígenos HLA han sido hallados estar asociados con más de 100 afecciones, muchas de las cuales pertenecen a la esfera reumatológica. Algunas enfermedades comprometen genes de la región del HLA que están ligados a alelos específicos de Clase I o Clase II, o a combinaciones de alelos (haplotipos). También se ha observado que algunos genes del HLA pueden modular la expresión clínica y la severidad de algunas enfermedades. La función del sistema HLA tiene efectos muy amplios, no solamente por el papel que juega en la respuesta inmune adaptativa sino también por su complejidad genética, la cual puede variar de acuerdo a los diferentes grupos étnicos estudiados. En nuestro país la caracterización inmunogenética de los pacientes con diversas enfermedades del tejido conectivo no ha sido ampliamente estudiada. En el presente trabajo se focaliza en la influencia que tienen ciertos antígenos del HLA en la susceptibilidad, expresión clínica y severidad de algunas enfermedades reumáticas, principalmente la EA, la artritis reumatoidea tanto del adulto (AR) como las diferentes formas que la misma presenta en los niños (ARJ), como también en las miopatías inflamatorias idiopáticas de la infancia, en la predominante población caucásica de pacientes en nuestro país... (TRUNCADO)(AU)