La ecografía de glándulas salivales en el diagnóstico del síndrome de Sjögren / Ultrasound of the salivary glands in the diagnosis of Sjögren´s syndrome

Objetivo: describir los hallazgos ecográficos en las glándulas salivares para el diagnóstico del síndrome de Sjögren primario. Metodología: se realizó una revisión narrativa de la literatura, con búsqueda en bases de datos seleccionando los principales artículos de revisión e investigaciones originales en español e inglés publicados en los últimos 20 años. Resultados: los hallazgos confirman el valor diagnóstico de la ecografía como estudio no invasivo de las glándulas salivares. Conclusión: la ecografía de glándulas salivares es un método útil y confiable para el diagnóstico del síndrome de Sjögren.

Objective: to describe salivary glands ultrasonography findings for the diagnosis of primary Sjögren ́s syndrome. Methodology: a narrative review of the literature by a database search selecting the main original review and research articles published in the last 20 years in Spanish and English. Results: findings confirm ultrasonography diagnostic value as a non-invasive method for salivary glands evaluation. Conclusion: sonographic evaluation of the salivary glands is a useful and reliable method for diagnosing Sjögren ́s syndrome.

Ecografía de la glándula salival mayor en pacientes con síndrome seco: descripción de una cohorte colombiana, reporte preliminar / Major salivary gland ultrasound in patients with dry syndrome: Description of a Colombian cohort, and a preliminary report

RESUMEN Introducción: El síndrome de Sjögren (SS) es una enfermedad autoinmune que afecta a las glándulas exocrinas condicionando síndrome seco. Los criterios diagnósticos se basan en pruebas serológicas, oftalmológicas, histopatológicas y flujo salival. Se ha propuesto el uso de la ecografía glandular salival como prueba diagnóstica. Escasos estudios se han realizado en Latinoamérica. Objetivo: Describir las alteraciones ecográficas en las glándulas salivales en una población colombiana que asiste al servicio de reumatología con síntomas secos. Materiales y métodos: Estudio de corte transversal; análisis preliminar de 50 pacientes que asisten por consulta externa (agosto de 2019 a enero de 2020). Evaluación sociodemográfica y clínica a través de cuestionario estructurado, pruebas paraclínicas y oftalmológicas, biopsia de glándula salival menor y valoración ecográfica de las glándulas salivales mayores (puntuación 0-6 basada en De Vita). Análisis univariado y bivariado (Chi-cuadrado y prueba de Fischer). Resultados: El 94% de la población eran mujeres y el 38% tenían SS. El promedio de edad fue de 55,9 ± 9,6 arios. La proporción de pacientes con ecografía positiva para el SS y diagnóstico por criterios del SS es mayor respecto a los pacientes con ecografía negativa (p< 0,0001). Los pacientes con ecografía positiva presentaron mayor proporción de anti-La (p = 0,002), ANA (p = 0,008), anti-Ro (p< 0,0001), linfopenia (p = 0,007), xerostomía objetiva (p = 0,019) y subjetiva (p = 0,041). Conclusiones: La ecografía podría considerarse una herramienta útil en el diagnóstico del SS, dado que los pacientes que presentan alteraciones ecográficas glandulares tienen una mayor proporción de perfil inmunológico positivo (anti-Ro, ANA, anti-La) y su positividad se encuentra asociada al SS por criterios. Se requieren nuevos estudios para evaluar las características operativas de la prueba.

ABSTRACT Introduction: Sjögren's syndrome (SS) is an autoimmune disease affecting the exocrine glands causing dry syndrome. The diagnostic criteria are based on serological, ophthalmological, histopathological, and salivary flow tests. The use of salivary gland ultrasound has been proposed as a diagnostic test. Few studies have been carried out in Latin America. Objective: To describe the ultrasound patterns in the salivary glands in the Colombian population seen in the Rheumatology Department due to dry symptoms. Materials and methods: Cross-sectional study; a preliminary analysis was performed on 50 patients attending the Outpatient Clinic (August-January 2020). A sociodemographic and clinical evaluation was made using a questionnaire. Paraclinical and ophthalmological tests, minor salivary gland biopsy, and ultrasound assessment of the major salivary glands (De Vita score 0-6) were the main items to evaluate. Univariate and bivariate analyses (Chi-squared, Fischer test) were performed. Results: Most (94%) of the population were women, and 38% had SS. The mean age was 55.9±9.6 years old. The proportion of patients with positive ultrasound for SS and a diagnosis using SS criteria was higher compared to patients with negative ultrasound (p<.0001). Patients with positive ultrasound had a higher proportion of anti-La (p=.002), ANAS (p=.008), anti-Ro (p<.0001), lymphopenia (p=.007), and objective and subjective xerostomia (p=.019 and p=.041, respectively). Conclusions: Ultrasound assessment could be considered a useful tool in the diagnosis of SS, since more patients presenting with glandular ultrasound abnormalities have a higher positive immunological profile (anti-Ro, ANAS, anti-La) and their positivity is associated with SS criteria. New studies are required to evaluate the operational characteristics of the test.

[Tuberculosis in the era of anti-TNF-alpha therapy: Why does the risk still exist?]

Rheumatoid arthritis is an autoimmune systemic disease characterized mainly by inflammatory compromise of diarthrodial joints. Multiple drug therapies have been developed to control the activity of rheumatoid arthritis, among them, the first line of disease-modifying antirheumatic drugs (DMARD), and novel drug therapies such as the anti-TNF alpha therapy, with satisfactory clinical outcomes.Despite this positive fact, the use of this therapy implies the risk of producing negative effects due to its mechanism of action, which has been associated with multiple infections, especially tuberculosis, making it necessary to use screen tests before resorting to this kind of drugs.We present the case of a 58-year-old female patient, with a six-year history of rheumatoid arthritis.The patient developed disseminated tuberculosis with compatible radiological and histological findings after receiving treatment with infliximab (anti-TNF therapy). No test was performed to screen for latent tuberculosis infection prior to the administration of infliximab.The performance of routine screenings tests for tuberculosis prior to anti-TNF alpha therapy plays an essential role in the detection of asymptomatic patients with latent tuberculosis. This is the only way to identify those patients who would benefit from anti-tuberculosis drugs before the initiation of anti-TNF alpha therapy, which makes the difference in the search of a significant reduction in the incidence of tuberculosis and its associated morbidity and mortality.

Tuberculosis in the era of anti-TNF-alpha therapy: Why does the risk still exist? / La tuberculosis en la era del tratamiento con fármacos inhibidores del factor de necrosis tumoral alfa: ¿por qué persiste el riesgo?

Abstract Rheumatoid arthritis is an autoimmune systemic disease characterized mainly by inflammatory compromise of diarthrodial joints. Multiple drug therapies have been developed to control the activity of rheumatoid arthritis, among them, the first line of disease-modifying antirheumatic drugs (DMARD), and novel drug therapies such as the anti-TNF alpha therapy, with satisfactory clinical outcomes. Despite this positive fact, the use of this therapy implies the risk of producing negative effects due to its mechanism of action, which has been associated with multiple infections, especially tuberculosis, making it necessary to use screen tests before resorting to this kind of drugs. We present the case of a 58-year-old female patient, with a six-year history of rheumatoid arthritis. The patient developed disseminated tuberculosis with compatible radiological and histological findings after receiving treatment with infliximab (anti-TNF therapy). No test was performed to screen for latent tuberculosis infection prior to the administration of infliximab. The performance of routine screenings tests for tuberculosis prior to anti-TNF alpha therapy plays an essential role in the detection of asymptomatic patients with latent tuberculosis. This is the only way to identify those patients who would benefit from anti-tuberculosis drugs before the initiation of anti-TNF alpha therapy, which makes the difference in the search of a significant reduction in the incidence of tuberculosis and its associated morbidity and mortality.

Resumen La artritis reumatoidea es una enfermedad crónica de carácter autoinmunitario caracterizada principalmente por el compromiso inflamatorio de las articulaciones cartilaginosas. Se han desarrollado múltiples tratamientos farmacológicos para controlar el avance de la artritis reumatoidea, entre ellos, los fármacos antirreumáticos modificadores de la enfermedad, además de nuevos esquemas terapéuticos con inhibidores del factor de necrosis tumoral alfa, con resultados clínicos satisfactorios. Sin embargo, el uso de tales medicamentos no resulta inocuo, ya que se los ha asociado con diversos efectos secundarios, especialmente, infecciones como la tuberculosis, lo cual exige la aplicación de pruebas de tamización antes de utilizarlos. Se reporta el caso de una paciente de 58 años de edad con artritis reumatoidea de seis años de evolución, que después de recibir tratamiento con uno de estos fármacos, el infliximab, desarrolló tuberculosis diseminada, cuyo diagnóstico se confirmó mediante radiología e histopatología. No se emplearon pruebas de detección de la tuberculosis latente antes de prescribirle el infliximab. Las pruebas de tamización para tuberculosis deben emplearse de forma rutinaria, con el fin de detectar aquellos pacientes con tuberculosis latente, ya que es la única manera de determinar si se requiere profilaxis antituberculosa antes de administrar dichos fármacos, hecho que marca la diferencia cuando se busca disminuir la incidencia de tuberculosis y la consecuente morbimortalidad.

Personalized medicine. Closing the gap between knowledge and clinical practice.

Personalized medicine encompasses a broad and evolving field informed by a patient distinctive information and biomarker profile. Although terminology is evolving and some semantic interpretations exist (e.g., personalized, individualized, precision), in a broad sense personalized medicine can be coined as: "To practice medicine as it once used to be in the past using the current biotechnological tools." A humanized approach to personalized medicine would offer the possibility of exploiting systems biology and its concept of P5 medicine, where predictive factors for developing a disease should be examined within populations in order to establish preventive measures on at-risk individuals, for whom healthcare should be personalized and participatory. Herein, the process of personalized medicine is presented together with the options that can be offered in health care systems with limited resources for diseases like rheumatoid arthritis and type 1 diabetes.

Familial Aggregation and Segregation Analysis in Families Presenting Autoimmunity, Polyautoimmunity, and Multiple Autoimmune Syndrome.

Studies documenting increased risk of developing autoimmune diseases (ADs) have shown that these conditions share several immunogenetic mechanisms (i.e., the autoimmune tautology). This report explored familial aggregation and segregation of AD, polyautoimmunity, and multiple autoimmune syndrome (MAS) in 210 families. Familial aggregation was examined for first-degree relatives. Segregation analysis was implemented as in S.A.G.E. release 6.3. Data showed differences between late- and early-onset families regarding their age, age of onset, and sex. Familial aggregation of AD in late- and early-onset families was observed. For polyautoimmunity as a trait, only aggregation was observed between sibling pairs in late-onset families. No aggregation was observed for MAS. Segregation analyses for AD suggested major gene(s) with no clear discernible classical known Mendelian transmission in late-onset families, while for polyautoimmunity and MAS no model was implied. Data suggest that polyautoimmunity and MAS are not independent traits and that gender, age, and age of onset are interrelated factors influencing autoimmunity.

Genetics and vaccines in the era of personalized medicine.

Vaccines represent the most successful and sustainable tactic to prevent and counteract infection. A vaccine generally improves immunity to a particular disease upon administration by inducing specific protective and efficient immune responses in all of the receiving population. The main known factors influencing the observed heterogeneity for immune re-sponses induced by vaccines are gender, age, co-morbidity, immune system, and genetic background. This review is mainly focused on the genetic status effect to vaccine immune responses and how this could contribute to the development of novel vaccine candidates that could be better directed and predicted relative to the genetic history of an individual and/or population. The text offers a brief history of vaccinology as a field, a description of the genetic status of the most relevant and studied genes and their functionality and correlation with exposure to specific vaccines; followed by an inside look into autoimmunity as a concern when designing vaccines as well as perspectives and conclusions looking towards an era of personalized and predictive vaccinology instead of a one size fits all approach.

What is next after the genes for autoimmunity?

Clinical pathologies draw us to envisage disease as either an independent entity or a diverse set of traits governed by common physiopathological mechanisms, prompted by environmental assaults throughout life. Autoimmune diseases are not an exception, given they represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. Although they are pleiotropic outcomes of non-specific disease genes underlying similar immunogenetic mechanisms, research generally focuses on a single disease. Drastic technologic advances are leading research to organize clinical genomic multidisciplinary approaches to decipher the nature of human biological systems. Once the currently costly omic-based technologies become universally accessible, the way will be paved for a cleaner picture to risk quantification, prevention, prognosis and diagnosis, allowing us to clearly define better phenotypes always ensuring the integrity of the individuals studied. However, making accurate predictions for most autoimmune diseases is an ambitious challenge, since the understanding of these pathologies is far from complete. Herein, some pitfalls and challenges of the genetics of autoimmune diseases are reviewed, and an approximation to the future of research in this field is presented.

The rs1024611 regulatory region polymorphism is associated with CCL2 allelic expression imbalance.

CC chemokine ligand 2 (CCL2) is the most potent monocyte chemoattractant and inter-individual differences in its expression level have been associated with genetic variants mapping to the cis-regulatory regions of the gene. An A to G polymorphism in the CCL2 enhancer region at position -2578 (rs1024611; A>G), was found in most studies to be associated with higher serum CCL2 levels and increased susceptibility to a variety of diseases such as HIV-1 associated neurological disorders, tuberculosis, and atherosclerosis. However, the precise mechanism by which rs1024611influences CCL2 expression is not known. To address this knowledge gap, we tested the hypothesis that rs1024611G polymorphism is associated with allelic expression imbalance (AEI) of CCL2. We used haplotype analysis and identified a transcribed SNP in the 3'UTR (rs13900; C>T) can serve as a proxy for the rs1024611 and demonstrated that the rs1024611G allele displayed a perfect linkage disequilibrium with rs13900T allele. Allele-specific transcript quantification in lipopolysaccharide treated PBMCs obtained from heterozygous donors showed that rs13900T allele were expressed at higher levels when compared to rs13900C allele in all the donors examined suggesting that CCL2 is subjected to AEI and that that the allele containing rs1024611G is preferentially transcribed. We also found that AEI of CCL2 is a stable trait and could be detected in newly synthesized RNA. In contrast to these in vivo findings, in vitro assays with haplotype-specific reporter constructs indicated that the haplotype bearing rs1024611G had a lower or similar transcriptional activity when compared to the haplotype containing rs1024611A. This discordance between the in vivo and in vitro expression studies suggests that the CCL2 regulatory region polymorphisms may be functioning in a complex and context-dependent manner. In summary, our studies provide strong functional evidence and a rational explanation for the phenotypic effects of the CCL2 rs1024611G allele.

The multiple autoimmune syndromes. A clue for the autoimmune tautology.

The multiple autoimmune syndromes (MAS) consist on the presence of three or more well-defined autoimmune diseases (ADs) in a single patient. The aim of this study was to analyze the clinical and genetic characteristics of a large series of patients with MAS. A cluster analysis and familial aggregation analysis of ADs was performed in 84 patients. A genome-wide microsatellite screen was performed in MAS families, and associated loci were investigated through the pedigree disequilibrium test. Systemic lupus erythematosus (SLE), autoimmune thyroid disease (AITD), and Sjögren's syndrome together were the most frequent ADs encountered. Three main clusters were established. Aggregation for type 1 diabetes, AITD, SLE, and all ADs as a trait was found. Eight loci associated with MAS were observed harboring autoimmunity genes. The MAS represent the best example of polyautoimmunity as well as the effect of a single genotype on diverse phenotypes. Its study provides important clues to elucidate the common mechanisms of ADs (i.e., autoimmune tautology).

Influence of variations in CCL3L1 and CCR5 on tuberculosis in a northwestern Colombian population.

We investigated the association of polymorphisms in CCR5, the major human immunodeficiency virus (HIV)-1 coreceptor, and copy number of its potent ligand CCL3L1 with tuberculosis in 298 individuals from Colombia. The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. Furthermore, CCR5-HHD was associated with higher CCR5 gene and surface expression. These results substantiate the strong link between the pro-inflammatory effects of CCR5 and its ligands with active tuberculosis and suggest that chemokine-chemokine receptor genetic determinants may influence tuberculosis in addition to HIV/AIDS.

Duffy-null-associated low neutrophil counts influence HIV-1 susceptibility in high-risk South African black women.

BACKGROUND: The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)-1 infection among Africans is unknown. METHODS: The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty-seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity. RESULTS: Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm(3) had a ∼3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC -46T > C) was significantly associated with neutrophil counts (P = 7.9 × 10(-11)). DARC -46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm(3). The risk of acquiring HIV infection was ∼3-fold greater in those with the trait of Duffy-null-associated low neutrophil counts, compared with all other study participants. CONCLUSIONS: Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null-associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa.

Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes.

PURPOSE OF REVIEW: It is unknown whether biomarkers simply correlate with or are causal for HIV-associated outcomes. Mendelian randomization is a genetic epidemiologic approach used to disentangle causation from association. Here, we discuss the potential use of Mendelian randomization for differentiating whether biomarkers are correlating with or causal for HIV-associated outcomes. RECENT FINDINGS: Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. A formal Mendelian randomization study using a genetic marker as a proxy for the biomarker has not been conducted in the HIV field. However, in the postgenomic era, this approach is being used increasingly. Examples are evidence for the causal role of BMI in blood pressure and noncausal role of C-reactive protein in coronary heart disease. We discuss the conceptual framework, uses, and limitations of Mendelian randomization in the context of HIV infection as well as specific biomarkers (IL-6, C-reactive protein) and genetic determinants (e.g., in CCR5, chemokine, and DARC genes) that associate with HIV-related outcomes. SUMMARY: Making the distinction between correlation and causality has particular relevance when a biomarker (e.g., IL-6) is potentially modifiable, in which case a biomarker-guided targeted treatment strategy may be feasible. Although the tenets of Mendelian randomization rest on strong assumptions, and conducting a Mendelian randomization study in HIV infection presents many challenges, it may offer the potential to identify causal biomarkers for HIV-associated outcomes.

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry.

Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm(3) during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The African-specific -46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4(+) T-cell counts, such that leukopenic but not nonleukopenic HIV(+) AAs with DARC -46C/C had a survival advantage compared with all Duffy-positive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIV-infected AAs, despite immunodeficiency.

HIV-1 disease-influencing effects associated with ZNRD1, HCP5 and HLA-C alleles are attributable mainly to either HLA-A10 or HLA-B*57 alleles.

A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis.

TIRAP (MAL) S180L polymorphism is a common protective factor against developing tuberculosis and systemic lupus erythematosus.

BACKGROUND AND AIM: The involvement of Toll-like receptor (TLR)-mediated pathways in infectious and autoimmunity has been suggested. The MyD88 adaptor-like (Mal) protein, also known as the TIR domain-containing adaptor protein (TIRAP), is implicated in the TLR2- and TLR4-mediated MyD88-dependent signaling pathway. The aim of this study was to investigate the influence of the functional TIRAP (MAL) S180L polymorphism on tuberculosis (TB) and four autoimmune diseases namely: rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1D). METHODS: This was a case-control and family based association study in which 1325 individuals from a well-defined Colombian population were involved. TIRAP (MAL) S180L genotyping was done by using a polymerase chain reaction-restriction fragment length polymorphism technique and by direct sequencing. RESULTS: Leu180 allele was found to be a protective factor against developing TB (odd ratio (OR): 0.53, 95% confidence interval (CI): 0.29-0.97) and SLE (OR: 0.29, 95% CI: 0.14-0.61) while no significant influence on RA, pSS and T1D was observed. CONCLUSION: These results support the influence of TIRAP (MAL) S180L polymorphism on TB and indicate that TB and SLE might share a common immunogenetic pathway in the innate immune response.

The IkappaBL gene polymorphism influences risk of acquiring systemic lupus erythematosus and Sjögren's syndrome.

The human inhibitory kappaB-like gene (IkappaBL) maps to a chromosomal region approximately 25 kb telomeric of the TNF gene at 6p21.3. IkappaBL encodes a protein related to IkappaBalpha that may interact with members of the NF-kappaB/Rel family. We evaluated the role of IkappaBL gene polymorphism in systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). Genomic DNA isolated from individuals with SLE (n = 134), pSS (n = 67) and from individuals matched for age, sex, and ethnicity (n = 423) was genotyped for Delta-473, -62T/A and +738T/C polymorphisms. The -62A allele was associated with a decrease in the risk of acquiring SLE in a recessive manner; whereas the +738C allele was associated with a more than twofold and threefold increase in the risk of SLE and pSS respectively, relative to the +738T allele. Four haplotypes were observed for the IkappaBL polymorphisms. Haplotype -62A+738T (AT) was associated with a 37% decrease in the risk of SLE, whereas AC tended to increase the risk of developing pSS. Using previously reported TNF data, an almost twofold increased in the risk of SLE was observed between haplotypes IKBL-62T+738T/TNF-308G-238G (TTGG) and TTAG because of linkage disequilibrium between IKBL-62T and TNF-308A. Our findings indicate that the IkappaBL gene influences the risk of developing SLE and pSS.

The nature and nurture of common autoimmunity.

Autoimmune diseases are a heterogeneous group of disorders where multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Although their heterogeneity is due to a collection of diverse conditions based on epidemiology, pathology, or diagnostic criteria, the underlying immunogenetic mechanism might be similar. Herein the nature and nurture of autoimmune diseases considered as a trait are reviewed, and a discussion is given on their multifactorial characteristics.

The kaleidoscope of autoimmunity: multiple autoimmune syndromes and familial autoimmunity.

Three related lines of evidence sustain the common origin for autoimmune diseases (ADs). First, the clinical evidence corresponding to the kaleidoscope of autoimmunity, which is the co-occurrence of various ADs within an individual or co-occurrence within members of a nuclear family. Second, the physiopathologic evidence indicating that the pathologic mechanisms might be similar among ADs. Last, the genetic evidence indicating that autoimmune phenotypes could represent pleiotropic outcomes of nonspecific disease genes. The two conditions that better illustrate the kaleidoscope of autoimmunity are multiple autoimmune syndromes and familial autoimmunity. The multiple autoimmune syndromes consist of the presence of three or more well-defined autoimmune conditions in a single patient. The familial autoimmunity is defined as the presence of diverse ADs on multiple members of a nuclear family. Herein, both the multiple autoimmune syndromes and familial autoimmunity are discussed and various epidemiological factors considered in the context of the common genetic background of autoimmunity.