WHATS NEXT AFTER THE GENES FOR AUTOIMMUNITY?

Juan-Manuel Anaya, MD, PhDCentro de Estudio de Enfermedades AutoinmunesUniversidad del RosarioBogot, Colombia

Qu son las Enfermedades Autoinmunes y Por Qu son Importantes?De la hiptesis a la bsqueda del paradigma

El CREA es un Centro de Medicina TraslacionalDel laboratorio al Paciente y del Paciente al Laboratorio

Generacin y divulgacin de conocimiento Publicaciones cientficas, libros, simposios y congresosFormacin de recurso humano. Pregrado y posgrado Ejecucin de Proyectos. Internacionalizacin

Equipo Mdico (Especialistas)Enfermera Coordinacin de DatosCoordinacin de AnlisisLaboratorio InmunologaBiologa MolecularInvestigadores BsicosComit de ticaDireccin yAdministracinAtencin de Pacientes Asistentes de InvestigacinCoordinacin ClnicaPublicaciones & Divulgacin

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Anaya JM & Shoenfeld Y. IMAJ 2005;7:740

AR EAITLES SS UV

ARAR

AutoinmunidadQu son las enfermedades autoinmunes y cul es su impacto?Cules son las causas?Qu es la Tautologa Autoinmune y cul es su importancia?

Qu son las Enfermedades Autoinmunes y Por qu son Importantes?DefinicinFrecuentesIncurablesCostosasComorbilidadAgrupamientoTratables

Autoinmunidad y Enfermedad AutoinmuneLa autoreactividad es fisiolgicaLa enfermedad autoinmune es el proceso patolgico (dao tisular) producido por la prdida de la tolerancia (autoreactividad patolgica)Enfermedad causada por la activacin de linfocitos T o B, ambos.

Electroforesis de ProtenasCampuzano Maya G. Medicina&Laboratorio 2006;12:47-70.

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Dao Tisular en Enfermedad AutoinmuneMecanismo celular mediante lisis de la clula blanco por necrosis mediada por perforinas o por apoptosis inducida por Granzima B.Mecanismo humoral a travs de complejos inmunes, citolisis o fagocitosis de la clula blanco y mediante interferencia de la fisiologa celular

SSp-1SSp-2CTREl Sndrome de Sjgren es una Enfermedad Autoinmune

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Qu son las Enfermedades Autoinmunes y Por qu son Importantes?Auto agresin por parte del sistema inmuneFRECUENTES. Afectan al 5% de la poblacin

Qu son las Enfermedades Autoinmunes y Por qu son Importantes?INCURABLES

Qu son las Enfermedades Autoinmunes y Por qu son Importantes?Auto agresin por parte del sistema inmune Frecuentes. IncurablesCOSTOSASArtritis Reumatoide US$ 6.000 Paciente/AoEsclerosis MltipleUS$ 9.000-17.000 Paciente/Ao

Qu son las Enfermedades Autoinmunes y Por qu son Importantes?Auto agresin por parte del sistema inmune Frecuentes. Afectan cerca del 5% de la poblacinIncurablesCostosas. COMORBILIDADEnfermedad cardiovascularInfeccionesEnfermedades digestivasOsteoporosisDepresin

Qu son las Enfermedades Autoinmunes y Por qu son Importantes?Auto agresin por parte del sistema inmune FrecuentesIncurablesCostosas. ComorbilidadAGRUPAMIENTO Poliautoinmunidad y autoinmunidad familiar.

Agrupamiento de las Enfermedades AutoinmunesPoliautoinmunidad

Autoinmundad Familiar

Anaya JM et al Clin Dev Immunol. 2006 Anaya JM et al. Expert Rev Clin Immunol 2007Castiblanco J and Anaya JM. Ann NY Acad Sci 2007Rojas-Villarraga A, el al. Autoimmun Rev 2010Anaya JM. Arthritis Res Ther 2010Anaya JM, Rojas-Villarraga A. La Tautologa Autoinmune. 2012

Qu son las Enfermedades Autoinmunes y Por qu son Importantes?Auto agresin por parte del sistema inmuneFrecuentesIncurablesCostosasComorbilidadAgrupamientoTratables

AutoinmunidadQu son las enfermedades autoinmunes y cul es su impacto?Cules son las causas?Qu es la Tautologa Autoinmune y cul es su importancia?

A quin le da una enfermedad autoinmune?

Fenotipo

Genotipo

Medio Ambiente = E (t)Fenotipo

222EGPsss+=Fenotipo (P) = Genotipo (G) + Medioambiente (E)

21Interaccin entre genotipo, medio ambiente y mecanismos epigenticos en funcin del tiempo

Fisiopatologa de las Enfermedades Autoinmunes

Anaya JM. Autoimmun Rev 2014;13:423-6.

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Concordancia y Agregacin20-400.22-52-524-57LES200.13-50-525EM150.460-1330-50T1DFamiliares No-gemelosGemelos DicigotosGemelos MonocigotossPrevalencia en la poblacin general (%) Concordancia (%)

Enfermedad

Evidencia Gentica de las Enfermedades AutoinmunesWandstrat A, Wakeland E. Nature Immunol 2001;2:802-9.5-100.5-12-43-412-15AR

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Qu es la Tautologa Autoinmune?En retrica, tautologa (del griego , decir lo mismo) es una afirmacin obvia.

En lgica, una tautologa es una frmula que resulta verdadera en cualquier interpretacin.

En autoinmunidad, tautologa indica que las enfermedades autoinmunes (EAI) son similares unas a otras.

Vpq = EAI1~EAI2~EAI3

Una enfermedad autoinmune es similar a una segunda, a una tercera, y as sucesivamente.

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Preponderancia femenina Signos y sntomas compartidos (subfenotipos)PoliautoinmunidadCoagregacin Autoinmunidad familiar Severidad en funcin de la edad de inicio Fisiopatologa similar Agentes medioambientales similaresFactores genticos comunesInfluencia de la ancestra en el curso clnicoTratamiento similar

Mecanismos comunes de las enfermedades autoinmunesLa Tautologa Autoinmune

Preponderancia Femenina Mecanismos comunes de las enfermedades autoinmunesLa Tautologa Autoinmune

Quintero OL, et al. J Autoimmun 2012;38:J109-19

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Subfenotipos compartidos entre las enfermedades autoinmunesClnicosArtritis no erosivaFotosensibilidadFenmeno de RaynaudAlopeciaDepresinEnfermedad cardiovascular

LaboratorioAnticuerpos antinuclearesFactor reumatoideAnticuerpos anti-Ro

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Poliautoinmunidad

Autoinmunidad Familiar

Anaya et al Clin Dev Immunol. 2006Anaya et al. Expert Rev Clin Immunol 2007Castiblanco J and Anaya JM. Ann NY Acad Sci 2007Rojas-Villarraga et al. Autoimmun Rev 2010Anaya JM. Arthritis Res Ther 2010Rojas-Villarraga et al. Autoimmune Dis 2012Anaya et al. Autoimmune Dis 2012Crdenas-Roldan et al. BMC Medicine 2013

Semin Arthritis Rheum 2012;41:589-98.

After a mean of 7.9 years of disease, 57.9% of 161 patients still satisfied MCTD classification; 17.3% evolved into SSc, 9.1% into SLE, 2.5% into RA, 11.5% was reclassified as affected by undifferentiated connective tissue disease, and 1.7% as suffering from overlap syndrome. Las enfermedades autoinmunes son un espectro, que va desde las formas incompletas o frustras, pasando por formas poco severas y de lenta evolucin, hasta las formas rpidamente progresivas y fatales.

Fisiopatologa de las Enfermedades Autoinmunes

Anaya JM. Autoimmun Rev. 2012;11:781-4

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Poliautoinmunidad en 1.083 pacientes con cuatro enfermedades autoinmunesRojas-Villarraga et al. Autoimmune Dis. 2012 LESAREMESCN%N%N%N%N33530.930428.115414.229026,8Poliautoinmunidad13640.69832.22113.611840.7EAIT 6017.96421.1149.16723.1SS4714.03611.842.64314.8VIT 21.3SAP4814.382.6CBP155.2MAS 3911.6165.332289.7

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Sndrome de Sjogren 33% - 52%Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.Lockshin MD, et al. Lupus Sci Med. 2015;2:e000084.

Enfermedad Celaca 33%Demirezer Bolat A, et al. Digestion. 2015;92:185-91.

Cirrosis Biliar Primaria 32%Gershwin ME, et al. Hepatology 2005;42:1194-202.

Vitiligo 27%Amerio P, et al. Eur J Dermatol. 2010;20:354-8.

Enf. Autoinmune Tiroidea. 14%Boelaert K, et al. Am J Med 2010;123:183.e1-9.

Miastenia Gravis. 13%Mao ZF, et al. Int J Neurosci 2011;121:121-9.

Eclerosis Multiple. 8%Deretzi G, et al. Acta Neurol Scand 2015;131:225-30. Marrie RA, et al. Mult Scler. 2015;21:282-93.

PoliautoinmunidadLa Poliautoinmunidad es Frecuente!

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El agrupamiento de las enfermedades autoinmunes no es al azar

Anaya et al. Clin Rev Allergy Immunol. 2012;43:256-64.

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Poliautoinmunidad y SeveridadAlgunos informes de mayor severidad

Severidad compromiso erosivo en pacientes con AR y LES en presencia de anti-CCPIncidencia elevada de malignidad hematolgica en AR-SSNiveles bajos de remisin en Miastenia Gravis y EATInicio severo en diabetes Tipo 1 y E. CeliacaAlta actividad de LES y vasculitisMayor severidad del LES y SAF

Christensen et al. Acta Neurol Scand 1995;91:192-5.Valerio et al. Diabetologia 2002;45:1719-22.Ramos-Casals et al. Medicine (Baltimore). 2006;85:95-104.Chan et al. J Rheumatol. 2008 Jan;35:77-83.Kauppi et al. Cancer Causes Control 1997;8:201-4.Franco JS, et al. PLoS One. 2014;9:e110242.

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Poliautoinmunidad y SeveridadAlgunos informes de presentacin menos severa

Expresin clnica leve en EAT y MGEAI asociadas en SSc definen un subgrupo de menor severidadSS o EAT no influyen en la aparicin de nefritis lpica.

Marin et al. J Clin Endocrinol Metab 1997;82:438-43Avouac et al. J Rheumatol 2010;37:608-14 Rojas-Villarraga et al. Lupus 2010 19: 150Franco et al. EULAR 2014

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El estudio de la poliautoinmunidad, como un fenotipo extremo, es la mejor aproximacin para el estudio inmunogentico de la autoinmunidad y de los mecanismos comunes de las enfermedades autoinmunes (la tautologa autoinmune).

Genes PoliautoinmunesHLA-DRB1, HLA-DQB1, CD226, PTPN22, STAT4, GPR103, TNFAIP3, LRP1/STAT6

Enfermedad Autoinmune Familiar vs. Autoinmunidad Familiar Agregacin y Coagregacin Autoinmune

Cmo se agregan las enfermedades autoinmunes?

EA: enfermedad de Addison, ETAI: enfermedad tiroidea autoinmune, EII: enfermedad inflamatoria intestinal, ARJ: artritis reumatoide juvenil, EM: esclerosis mltiple, LES: lupus eritematoso sistmico, SS: sndrome de Sjgren, AR: artritis reumatoide, ES: esclerosis sistmica, DT1: diabetes tipo 1, VIT: vitiligo, PSO: psoriasis, Es An: espondilitis anquilosante, CBP: cirrosis biliar primaria, EC: enfermedad celaca, AP: anemia perniciosa, MG: miastenia gravis. 39

Preponderancia femenina Signos y sntomas compartidosPoliautoinmunidadAgregacin Severidad en funcin de la edad de inicio Fisiopatologa similar Agentes medioambientales similaresInfluencia de la ancestra en el curso clnicoFactores genticos comunesTratamiento similar

Mecanismos comunes de las enfermedades autoinmunesLa Tautologa Autoinmune

Amaya-Amaya et al. LACA 2013

Fisiopatologa de las enfermedades autoinmunes

Mecanismos comunesFenotipo en funcin del rgano blanco

Mecanismos comunes de las enfermedades autoinmunesLa Tautologa Autoinmune

Luu VP et al. Autoimmunity 2014;47:1-12.Vadasz Z et al FEBS Lett. 2013;587:2074-8.Yang M, Cell Mol Immunol 2013;10:122-32.Berthelot JM, et al. Joint Bone Spine 2013;80:18-22.

La funcin reguladora est disminuda en las enfermedades autoinmunes

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Singh RP, et al Autoimmun Rev. 2014La participacin de clulas Th17 es comn

Singh RP, et al Autoimmun Rev. 201444

El interfern Tipo 1 es un mediador comn en autoinmunidad

Ivashkiv LB, Donlin LT. Nat Rev Immunol 2014;14:36-49.Wahren-Herlenius M, Drner T. Lancet 2013;382:819-31.

It Enhances the interaction between innate and adaptive immunity And drives the positive feed forward loop in the autoimmune disease process.

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Preponderancia femenina Signos y sntomas compartidosPoliautoinmunidadCoagregacin Autoinmunidad familiar Severidad en funcin de la edad de inicio Fisiopatologa similar Agentes medioambientales similaresEcologa Autoinmune - Exposoma

Mecanismos comunes de las enfermedades autoinmunesLa Tautologa Autoinmune

Factores MedioambientalesElemento (s) identificable (s) en el entorno fsico, cultural, demogrfico, econmico, poltico, normativo o tecnolgico que afecta la supervivencia, las operaciones y el crecimiento de un individuo o poblacin:Agentes fsico-qumicos. Infecciones.Estilo de vida. Dieta, ejercicio, estrs.Factores sociales. Estrato socioeconmico, familia, amigos, servicios de salud, empleo.Factores psicolgicos. Autoestima, autoconcepto, relaciones con la familia y amistades, estrs, creencias culturales.

Anaya JM, et al. Front Immunol. 2016;7:139.

Infecciones.Agentes fsico-qumicos. Contaminacin, vecindarios seguros.Estilo de vida. Abuso de sustancias, la dieta, el ejercicio y el estrsFactores sociales y de la comunidad. Estrato socioeconmico, la familia, los amigos, los servicios de salud, empleo, la educacin y los ingresos.Factores psicolgicos. Autoestima, autoconcepto, relaciones con la familia y amistades, el estrs, las creencias culturales.

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Ecologa AutoinmuneFactores Medioambientales Compartidos

www.nature.com/clinicalpractice/rheum

7.Agentes medioambientales similares

IgG anti-EBV en pacientes ColombianosMecanismos comunes de las enfermedades autoinmunesLa Tautologa AutoinmuneAnaya et al. Autoimmunity. From bench to bedside. 2013

Cirrosis Biliar PrimariaLupus Eritematoso SistmicoEnf. Autoinmunes TiroideasArtritis ReumatoideEl Tabaquismo es un Factor Comn de Riesgo de Autoinmunidad

Esclerosis Mltiple

Brix TH, et al. Arch Intern Med. 2000;160:661-6.Belbasis L, et al. Lancet Neurol. 2015;14:263-73.Juran BD, et al. Semin Liver Dis. 2014;34:265-72.Costenbader KH, Karlson EW. Lupus 2006;15:737-45.Di Giuseppe D, et al. Arthritis Res Ther. 2013;15:R56.

Anaya JM, et al. Front Immunol. 2016;7:139.

In predisposed individuals carrying certain autoimmune alleles at HLA-DRB1, PTPN22, and PADI4 genes, cigarette smoke triggers citrullination by activating PAD enzyme, a mechanism that is estrogen dependent. Citrullinated proteins act as auto-antigens and induce the formation of anticitrullinated protein autoantibodies (ACPAs) by autoreactive B cells. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), released during cigarette smoking, acts as the best-known ligand for aromatic hydrocarbon receptor (AhR). AhR activation induces boosts T helper 17 (Th17) cells. Nicotine stimulates the 7-nicotine acetylcholine receptors (7nAChRs), and increases TNF, IL-6, IL-8, and IL-1 synthesis. The effect on T regulatory (Treg) function is controversial. All of these molecular pathways are responsible for the clinical manifestations listed on the right. PAD, peptidylarginine deiminase; SE, shared epitope; DC, dendritic cell; MS, multiple sclerosis; PBC, primary biliary cirrhosis; AITD, autoimmune thyroid disease; RA, rheumatoid arthritis; DMARD, disease-modifying antirheumatic drug; CVD, cardiovascular disease; ADs, autoimmune diseases; PolyA, polyautoimmunity; SLE, systemic lupus erythematosus; SS, Sjgren syndrome; aPL-abs, antiphospholipid antibodies.51

Preponderancia femenina Signos y sntomas compartidosPoliautoinmunidadCoagregacin Autoinmunidad familiar Severidad en funcin de la edad de inicio Fisiopatologa similar Agentes medioambientales similaresFactores genticos comunesInfluencia de la ancestra en el curso clnicoTratamiento similar

Mecanismos comunes de las enfermedades autoinmunesLa Tautologa Autoinmune

Artritis Reumatoide

Lupus Eritematoso Sistmico

Sndrome de Sjgren

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. Autoimmun Rev 2011

HLA-DRB1*0404TNF-308AIL1B +3953T#

TAP2*0201

PTPN22 +1858T

NOS3 i4b

HLA-DRB1*0301-DQB1*0201NFKBIL1 +738T#

CCR5 HHE and HHG*2

BAK1 GCA Haplotype

CCL3L1 CNV

STAT4 rs7574865T

TIRAP (MAL) 108L#

ITGAM rs1143679 ACD226 rs763361 T

Genes y Autoinmunidad Muchos son comunes y algunos son especficos para una determinada enfermedad

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 308A238G 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 TNF238A was protective (OR 0.04). In primary SS, both TNF- mRNA and its protein are significantly expressed in ducts and in mononuclear cells of salivary gland infiltrates (95), and TNF- 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 308A238G haplotype is a risk factor for pSS (OR: 3.6,p < 0.0001). Collectively, results indicate that the TNF308A238G 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-1 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.

DR4 OR: 3.9 (2.89-5.27)DRB1*0405 OR:7.2 (3.36-15.27)

DQ2 OR:1.93 (1.09-3.41) DQB1*0201 OR:2.32 (1.12-4.8)DRB1*0301 OR:3.63 (1.25-10.47)Alelos HLA comunes a diversas enfermedades autoinmunes en Amrica Latina

Cruz-Tapias et al. Autoimmune Dis. 2012

Artritis ReumatoideColombianosRamrez et al. Clin Exp Rheumatol 2012MexicanosTorres-Carrillo et al. Immunol Lett 2012

Lupus Eritematoso SistmicoColombianosAnaya et al. Genes Immun. 2005;6:628.Ramrez et al. Clin Exp Rheumatol 2012ArgentinosOrr et al. Hum Mol Genet 2009;18:569.PTPN22 (1858 T) es un Alelo Pleiotrpico Autoinmune en Latino-Americanos

Sndrome de SjgrenColombianosAnaya et al. Genes Immun. 2005;6:628.

Diabetes Tipo 1ColombianosAnaya et al. Genes Immun. 2005;6:628-31.BrasilerosChagastelles et al .Tissue Antigens 2010;76:144.Rassi et al. Ann N Y Acad Sci. 2008;1150:282.

VitiligoMexicanosGarca-Melendez et al. Exp Ther Med 2014

PTPN22 (Protein tyrosine phosphatase non-receptor 22) 1p13Lyp (Lymphoid-specific phosphatase)

PTP intracelular, 110 kdDominio cataltico N-terminalDominio no-cataltico C-teminalSe une a la kinasa Csk a travs de P1 (motivo rico en prolina)SNP 1858C T = R620W P1

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Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.Li YR, et al. Nat Med. 2015;21:1018-27.

Li YR, et al. Nat Med. 2015;21:1018-27.56

Preponderancia femenina Signos y sntomas compartidosPoliautoinmunidadCoagregacin Autoinmunidad familiar Severidad en funcin de la edad de inicio Fisiopatologa similar Agentes medioambientales similaresInfluencia de la ancestra en el curso clnicoFactores genticos comunesTratamiento similar

Mecanismos comunes de las enfermedades autoinmunesLa Tautologa Autoinmune

?

La heterogeneidad de las enfermedades autoinmunes se basa en los resultados epidemiolgicos, patolgicos y de diagnstico, pero en realidad, sus mecanismos inmunopatognicos son similaresLa Tautologa AutoinmuneConclusiones

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La identificacin de los mecanismos comunes de las enfermedades autoinmunes mejorar nuestra comprensin de estas enfermedades, facilitar una nueva taxonoma; permitir predecirlas, prevenirlas y descubrir nuevos blancos teraputicos.La Tautologa AutoinmuneConclusiones