Autoinmunidad dr. anaya

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  • Venn diagram in which results are display to show how a polymorphism, TNF2 allele, was associated with three different AIRD while others, such as haplotype DRB1*0302-DQB1*0201 and PTPN22 eighteen fifty-eight T allele were associated with two: SLE and pSS. There was some disease specific polymorphims such as the intron 4b allele from the endothelial nitric oxide synthase gene. Otherwise, some polymorphism were protective for two diseases. This was the case of NFKBIL1 gene. The HLA-DRB1*0404 allele was associated with RA [17]. As discussed extensively elsewhere [2], this association is consistent with other reports from Latin-America (Table 8). We also found that haplotype HLA-DRB1*0301-DQB1*0201 was associated with pSS and SLE [18,19], as has been observed in Caucasians [2]. TAP2 locus influences the susceptibility to SLE and RA in Colombians (45). The frequencies of TAP1 and TAP2 variants found in controls were similar to those observed in white, Brazilian, and African populations (85). This result suggests that from an evolutionary point of view TAP genes are relatively ancient. TAP molecules have an essential role in antigen processing and presentation to cytotoxic T lymphocytes. The TAP heterodimer is composed of TAP1 and TAP2 subunits which may function together or independently as homodimers, transporting antigenic peptides from the cytoplasm into the lumen of the endoplasmic reticulum (86). The association of the TAP2 molecule with the selected peptide may depend on specific positions inside such peptide(s), which will link to positions 2, 3, 6, and 7 as well as the C-terminal extreme in TAP2 (87). Thus the role of TAP2 in SLE and RA may correspond to a particular selection of peptides (auto-antigens). We observed that TNF-308A (TNF2) allele was a predisposing factor for RA (OR 1.8), while TNF-238A was protective (OR 0.01). The TNF GG –238 genotype has been associated with RA severity independently of the presence of HLA-DR4 (88-90). In our population the genotype as well as the TNF –308A–238G haplotype was associated with RA. Similarly, the –308A allele has been associated with susceptibility to SLE in Caucasian populations, in linkage disequilibrium with HLA-DR3 (91, 92), as well as in an HLA-independent manner (93, 94). Our findings support the association of this allele with disease (OR 2.4), while TNF–238A was protective (OR 0.04). In primary SS, both TNF-α mRNA and its protein are significantly expressed in ducts and in mononuclear cells of salivary gland infiltrates (95), and TNF-α has been suggested to participate in the proteolysis of glandular acini (96). Our results show that, as it occurs in RA and SLE, the TNF –308A–238G haplotype is a risk factor for pSS (OR: 3.6,p < 0.0001). Collectively, results indicate that the TNF–308A–238G haplotype constituted a common susceptibility factor for autoimmune diseases (RA, SLE, and pSS) in our population. We also investigate the role of eNOS locus ( NOS3 ) in SLE and observed that this gene clearly influences the susceptibility to disease (21). First, a misbalance in intron 4 was clearly seen between patients and controls. The 4b allele and 4bb genotype were associated with SLE. The intron 4 VNTR has been found to have a consistent influence on eNOS mRNA expression, protein concentration, and enzyme activity (97, 98). In cultured human umbilical vein endothelial cells, intron 4bb genotype was responsible for higher levels of eNOS synthesis, while intron 4 ab genotype was associated with reduced synthesis (97). Accordingly, these results might have a functional explanation for the elevated levels of nitric oxide, as well as the endothelial dysfunction observed in SLE patients. The effect of intron 4 on eNOS protein synthesis could be indirectly linked to additional variation in its gene structure that produces direct effects (97). PTPN22 gene was investigated because its product, Lyp, is a key regulator of inflammation. We observed that 1858T allele is a high risk factor for pSS and SLE and might be a lower risk factor for T1D in our population (22). Signaling aberration and abnormalities in tyrosine phosphorylation might act as a central defect in the pathogenesis of SLE (99, 100). Our results confirm previous findings in independent SLE cohorts (64, 101, 102) and suggest that down-regulation of T-cell activation plays an important role in T-cell-mediated response in disease. The observed association between PTPN22 polymorphism and pSS is new. Two previous negative results in Caucasian patients with pSS have been published. The first was carried out by Criswell et al (64) in families with 16 affected subjects. Recently, Itaah et al (103) reported a lack of association in 183 French patients with pSS and 172 healthy controls. Differences in ethnicity and patient selection may explain the results. Nevertheless, based upon animal models, PTPN22 might play a role in diseases characterized by lymphoproliferation such as pSS. PTPN22 knockout mice display rather subtle changes in a number of immune parameters, such as enlargement of the spleen and the lymph nodes and is accompanied by spontaneous formation of germinal centers and higher levels of antibodies that appeared to be largely secondary to lower thresholds for signaling in T cells (104). No significant influence of this polymorphism was observed in RA, which could be explained by clinical heterogeneity and a lower allelic frequency of T allele in our healthy control group compared with healthy Caucasians in whom this polymorphism has a low susceptibility risk for RA [22]. Interleukin-1 beta (IL-1b) exerts a range of inflammatory and immunomodulatory activities that are important in host defense and autoimmune response. The IL-1b gene ( IL1B ), located on chromosome 2 (2q13), is polymorphic. Thus, we were also interested into examine the influence of this polymorphism on AIDs. Results disclosed that allele +3953T is protective for SLE as was the haplotype -511C +3953T (24), which was associated with a lower LPS-stimulated-PBM IL-1β secretion (24), explaining the protective association. No association with pSS and RA was observed (24). Evidence indicating a linkage of the IL-1 cluster genes to RA and a possible role for this region in erosive disease was reported by Cox et al (105) who examined 195 nuclear families with RA. However, association studies of IL-1b polymorphism in RA are controversial. While some studies have found that +3953T SNP is associated with severe RA in French, Chinese, and Sweden patients (106-109), others have failed to confirm this association in RA patients from Netherlands (110) and also from China (111, 112) . Our study fails to observe any influence of IL1B -511 and +3953 SNPs on RA susceptibility. A few studies of IL1B polymorphism in patients with SLE and pSS are available. Huang et al (112) observed no association between IL1B polymorphisms and SLE in Chinese patients. On the contrary, the IL1B -511CT genotype and -511T allele were shown to be associated with SLE in African Americans but not in Whites from the South-eastern US (113). IL1B +3953 polymorphism was not associated with pSS in Finnish patients (114). In Japanese, genotypes -511 CC and -31 TT were significantly less frequent in pSS patients than in healthy controls and SLE patients (115). The diverse results summarized above may be due to differences in the origin of the studied populations and linkage disequilibrium with other IL1 cluster genes (24). The CCR5 gene encodes a member of the beta chemokine receptor family, which is expressed by T cells and macrophages, and is known to be an important co-receptor for macrophage-tropic virus, including HIV, to enter host cells (Table 1). It has been previously shown that variation in CCR5 is complex and can be organized into nine major haplogroups designated as human haplogroups (HH) A, B, C, D, E, F*1, F*2, G*1 and G*2 (Figure 1) (47). Although there is some inter-cohort variability, findings from multiple HIV-1 natural history cohorts indicate that possession of genotypes that contain the CCR5 HHE haplotype are associated with an increased risk of acquiring HIV-1 and an accelerated disease course (116-118). By contrast, the CCR5-D32 -bearing HHG*2 and CCR2 -64I-bearing HHF*2 haplotypes are associated with HIV disease-retardation (116, 117, 119). However, these CCR5 genotype-phenotype associations are also complex because their phenotypic effects are dependent both on ethnicity and on the specific pairing of the partner CCR5 haplotypes (116, 117). The latter concept is perhaps best illustrated by studies pertaining to the CCR5-D32 -bearing HHG*2 haplotype. Homozygosity for the HHG*2 haplotype confers near absolute protection against HIV acquisition, and heterozygosity is associated with a delayed rate of HIV disease progression (116, 117, 120). For this reason, there has been intense interest in defining the association between the CCR5-D32 -bearing HHG*2 haplotype and different diseases, including AIDs (121-126). Unfortunately, most of these association studies have been largely restricted to examining the effects of CCR5-D32 heterozygosity, without consideration to the partner CCR5 haplotype. This study, the first to consider such haplotypes, indicates that CCR5 HHE and the CCR5-D32 bearing HHG*2 haplotypes are associated with an increased risk of acquiring SLE, but not RA and pSS in our population. Taken together, our results clearly indicate that in a single, carefully-characterized population, some polymorphisms are common risk factors for the development of ADs while others are disease specific.
  • Autoinmunidad dr. anaya

    1. 1. Juan-Manuel Anaya, MD, DrSc Centro de Estudio de Enfermedades Autoinmunes Universidad del Rosario, Bogotá.
    2. 2. Anaya JM & Shoenfeld Y. IMAJ 2005;7:740
    3. 3. Origen Común de las Enfermedades Autoinmunes AR hT LES SS UV AR AR
    4. 4. <ul><li>¿Qué son las Enfermedades Autoinmunes? </li></ul><ul><li>Las Enfermedades Autoinmunes tienen un Origen Común </li></ul>
    5. 5. <ul><li>La autoinmunidad (autoreactividad) es fisiológica. </li></ul><ul><li>La enfermedad autoinmune es el proceso patológico (daño tisular) producido por la pérdida de la tolerancia (autoreactividad patológica). </li></ul><ul><li>Enfermedad causada por la activación de linfocitos T o B, ó ambos, en ausencia de causa discernible (ej. infección, cáncer, medicamentos). </li></ul>
    6. 6. <ul><li>Mecanismo Celular mediante lisis de la célula blanco por necrosis mediada por perforinas o por apoptosis inducida por Granzima B. </li></ul><ul><li>Mecanismo Humoral a través de complejos inmunes, citolisis o fagocitosis de la célula blanco, o mediante interferencia de la fisiología celular. </li></ul>
    7. 7. El Síndrome de Sjögren (resequedad de mucosas por compromiso inflamatorio de éstas) es una Enfermedad Autoinmune SSp-1 SSp-2 CTR
    8. 8. Enfermedades Autoinmunes
    9. 9. Las Enfermedades Autoinmunes son Frecuentes 3.5% de la población sufre de al menos una Enfermedad Autoinmune
    10. 10. Las Enfermedades Autoinmunes son Multifactoriales Genes Medio Ambiente Neuroendocrino ?
    11. 11. Anticuerpos Individuos Susceptibles Pérdida de la Tolerancia HA 8.1, TNF PTPN22 , CTLA4 ,BAK1, IRF5, CD226 Apoptosis de Célula Blanco Antígenos Crípticos Neo-antígenos Inflamación Local y Sistémica Respuesta Inflamatoria  Calidad de Vida Citoquinas CCR,CCL,ON,MMP,PRL,… Clínica: Signos Síntomas Daño Tisular Local Virus ? Toxinas ? Fisiopatología de las Enfermedades Autoinmunes Anaya JM, et al. Autoinmunidad y Enfermedad Autoinmune. CIB. 2005
    12. 12. Fisiopatología de las Enfermedades Autoinmunes <ul><li>Mecanismos comunes </li></ul><ul><li>Fenotipo distinto </li></ul><ul><li>en función del </li></ul><ul><li>órgano (sistema) </li></ul><ul><li>blanco </li></ul>
    13. 13. Origen Común de las Enfermedades Autoinmunes Anaya JM et al. Expert Rev Clin Immunol 2007;3:623-35 Castiblanco J, Anaya JM. Ann NY Acad Sci 2007;1109:1-8 Variantes Comunes / Múltiples Enfermedades Poliautoinmunidad Autoinmundad Familiar
    14. 14. Anaya et al. Clin Dev Immunol 2006:13:185-95
    15. 15. Origen Común de las Enfermedades Autoinmunes Artritis Reumatoide Lupus Eritematoso Sistémico Síndrome de Sjögren Correa PA, et al . J Rheumatol 2005 Anaya JM, et al . Genes Immun 2005 Anaya JM et al . Clin Dev Immunol 2006 Mamtani M et al . Ann Rheum Dis 2007 Castiblanco J, Anaya JM. Hum Immunol 2008 Palomino-Morales RJ et al. Genes Immun 2008 Delgado-Vega AM et al . 2009 Anaya JM, et al . J Autoimm 2009 Anaya JM, et al . Submitted # Indica protección HLA-DRB1*0404 TNF-308A IL1B +3953T # TAP2*0201 PTPN22 +1858T NOS3 i4b HLA-DRB1*0301-DQB1*0201 NFKBIL1 +738T # CCR5 HHE and HHG*2 BAK1 GCA Haplotype CCL3L1 CNV STAT4 rs7574865T TIRAP (MAL) 108L # ITGAM rs1143679 A CD226 rs763361 T
    16. 16. <ul><li>Preponderancia femenina </li></ul><ul><li>Fisiopatología similar </li></ul><ul><li>Signos y síntomas compartidos </li></ul><ul><li>Severidad inversamente relacionada con la edad de inicio </li></ul><ul><li>Efecto medioambiental similar (Ej. Tabaco, EBV). </li></ul><ul><li>Factores genéticos similares ( HLA, STAT4, BAK1, IRF5, CTLA4) </li></ul><ul><li>Autoinmunidad familiar </li></ul><ul><li>Poliautoinmunidad </li></ul><ul><li>Mismo tratamiento (Ej. Rituximab, Tocilizumab) </li></ul>
    17. 17. Adriana Rojas-Villaraga Paola Cruz Lina M. Amezquita Diana Botello Rubén D. Mantilla Yesid Muñoz Edwin Jauregui Colciencias Fundación para la Promoción de la Investigación y Tecnología Universidad del Rosario Riesgo de Fractura –CAYRE IPS Asociación Colombiana de Reumatología Fundación Marshfield, USA Fundación TCC

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