Inmunopatogénesis de la Diabetes 1

Autores/as

  • Mario Sánchez Medina Academia Nacional de Medicina

Palabras clave:

Diabetes 1, epidemiología, fisiopatología, Inmunología, Genética

Resumen

La diabetes 1 es una enfermedad incurable, devastadora por sus complicaciones locales y sistémicas que no tienen tratamiento electivo hasta el presente, sino el riguroso control, mediante múltiples dosis diarias de insulina o bombas de infusión, no sin riesgos, que detienen el progreso de las lesiones vasculares y neurológicas Se considera un proceso órgano específico (1,2,3,4,5) en el cual las células b se destruyen, por mecanismos mediados por autoanticuerpos y por productos de células T auto reactivas que desencadenan inflamación y alteraciones anatómicas y funcionales en el órgano afectado. Así mismo, debe cumplir con los criterios (6) para definir a una enfermedad auto inmune que son:

1. Ser transferible por anticuerpos o células T del paciente.
2. Su curso debe demorarse o prevenirse mediante inmunosupresores.
3. Estar asociada a signos de autoinmunidad humoral o mediada por la célula, dirigidas contra el órgano blanco.
4. La enfermedad debe ser experimentalmente inducida por sensibilización contra un antígeno presente en el órgano blanco.

Inmunológicamente hasta hoy, en la diabetes 1 hay una susceptibilidad hereditaria y se ha encontrado una asociación con los alelos HLA-DR3-DR4 del complejo mayor de histocompatibilidad (MHC) (7). Además cada día aparecen nuevos locis (8), que se asocian con predisposición a la enfermedad. Basados en la tasa de concordancia, 35-50%, en gemelos homocigóticos (9) y por los estudios epidemiológicos,(10) factores ambientales (11), infecciosos (12), químicos (13) y nutricionales,(14) inician o precipitan el progreso de la diabetes (1).

Tiene como base una falla central y periférica en la tolerancia de la b células a moléculas específicas como ocurre en diversos procesos autoinmunes,(4) en que hay sobreproducción de citoquinas,(15) en el caso de la diabetes el interferon a (IFN-a),(16) el factor de necrosis tumoral (TNF-a) (17), cuya fuente son los macrófagos y las células dendríticas (3,18) localizados en el infiltrado del islote, y la interleuquina-1a (IL-a)(19) también elaborada por la célula presentadora del antígeno (APC) Además hay un desequilibrio en la respuesta inmune, entre los linfocitos Th-1/Th-2 presentes en el momento de la insulitis (20,21)...

Biografía del autor/a

Mario Sánchez Medina, Academia Nacional de Medicina

Doctor en Medicina y Cirugía de la Universidad Nacional de Colombia. Fundador de la Asociación Colombiana de Diabetes, y la Asociación Colombiana de Alergia, Asma e Inmunología.

Referencias bibliográficas

Bach J.F.: ¡nsulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev 15:516-542, 1994.

Eisenbarth G.S.: Molecular aspects of the etiology of type I diabetes mellitus. Journal of Diabetes and its implications 7:142-150,1993.

Arnush M. et al: Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. J. Clin. Inves!. 102:2684-2691, 1998.

Mandrup-Poulsen et al: Cytokines and the endocrine system. 11. Roles in substrate metabolism, modulation ofthyroidal and

pancreatic endocrine cell functions and autoimmune endocrine diseases. Eur. Journal of Endocrinology 134:21-30, 1996.

Yamada K. et al: Mouse islet celllysis mediated by interleukin- 1-induced Fas. Diabetologia 39:1306-1312,1996.

Rose N.R., Bona C.: Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol. Today 14: 426-430, 1993.

Rotter J.I., Valdheim C.M., Rimoin D.L.: Genetics of diabetes mellitus. In Rifkin H., Porte D (eds) Diabetes Mellitus. Theory and practice 4. Elsevier, Amsterdam, pp. 378-413, 1990.

Thomson Gabriel: Mapping disease genes: Family-based association studies. Am. J. Hum. Gene!. 57:487-498, 1995

Lo S.S., Tun RY., Hawa M., Leslie RD: Studies of diabetic twins. Diabetes Metab. Rev 7:223-238, 1999.

Laakso M., ReunanenA., Klaukka T., et al: Changes in the prevalence and incidence of diabetes mellitus in Finnish adults, 1970-1987. Am. J. Epidemiol. 133:850-857, 1991.

Songini M., Muntoni S.: High incidence of type I diabetes in Sardinia, Lancet 337:1047,1991.

King M.L., Shaiakh A., Bidwell D. et al: Coxsackie-B-virus-specific IgM responses in children with insulin dependent Uuvenileonset;

type 1) diabetes mellitus. Lancet 1: 1397-1399, 1983.

Kaufman D.L., Erlander M.G., Clare-Salzler M., et al: Autoimmunity to two forms of glutamate decarboxylase in ¡nsulin-dependent

diabetes mellitus. J. Clin. Inves!. 89:283-292, 1985.

Elliot RB., Martin J.M: Dietary proteins: a trigger of insulin-dependent diabetes in the BB rat? Diabetologia 26:297-299, 1984.

Corbett JA, Wang J.L, et al: Interleukin 1b induces the formation of nitric oxide by B-cells purified from rodent islets of Langerhans. J. Clin. Inves!. 90:2384-2391, 1992.

Rose N.R: Autoimmune Diseases: Tracing the shared threads. Hospital Practice. 1997.

Lacy P.E: The intraislet macrophage and type I diabetes. The Mount Sinai Journal of Medicine 61(2):170-174,1994.

Lee W.C., Zhong C., Quian S. et al: Phenotype function and in vivo migration and survival of allogenic dendritic cell progenitors

genetically engineered to express TGF-b. Transplantation 66:1810-1817,1998.

Bendtzen K., Mandrup-Poulsen T., et al: Cytotoxicity of human interleukin-1 or pancreatic islets of Langerhans. Science 232:1545-1547,1986.

Hanenberg H., Kolb-Bachofen, Kantwerk-Funke G., Kolb H.: Macrophage infiltration precedes and is prerequisite for Iymphocytic

insulilis in pancreatic islets of prediabetic BB rats. Diabetologia 32: 126-134, 1989.

Yagi N., Yokono K., Amano K. et al: Expression of intercellular adhesion molecule 1 on pancreatic b-cells destruction by cytotoxic T-cells in murine autoimmune diabetes. Diabetes

:744-751,1995.

Harrison L.C., Chu S.X., de Aixpurua H.J., et al: Islet reactive T celis are a marker of preclinical insulin-dependent diabetes. J. Clin. Inves!. 89: 1161-1165, 1992.

Haskins K., McDuffie M.: Acceleration of diabetes in young NaD mice with a CD4+ islet-specific T-cell clone. Science 249:1433-1436,1990.

Garcia K.C., Teyton L., Wilson lA: Structural basis ofT-cell recognition. Annu. Rev. Immunol. 17:369-397, 1999.

Moretta A., Biassoni R., Bottino C. et al: Major histocompatibility complex class I-specific receptors on human natural killer and T Iyrnphocytes. Immunol. Rev. 155:105-117, 1997

Mag W.J., Bersani L. and Mantovani A.: Tumor necrosis factor is chemotactic for mOhocytes and polymorpholeucocytes. J. Immunol. 138:1069, 1997.

Weber M., Deng S. et at: Adenoviral transfection of isolated pancreatic islets:A study of programmed cell death (Apoptosis) and islet function. Journal of Surgical Research 69:23-32, 1997.

Kanets H., Fuji J., Seo H., et al: Apoptopic cell death triggered by nitric oxide in pancreatic ~ cells. Diabetes 44:733, 1995. 29. McDaniel M.L., Kwon G., et al: Cy10kines and nitric oxide in islet inflammation and diabetes. Proc. Soco Exp. Biol. Med. 211:24-32, 1996.

Corbett J.A., et al: Nitric oxide mediates 11-1b-1 induced islet dysfunction and destruction: Prevention by dexamethasone. Autoimmunity 15:145-153, 1993.

Dahlen E., Dawe K. et al. Dendritic cells and macrophages are the first and major producers of TNF-a in pancreatic islets in the nonobese diabetic mouse. Journal of Immunology 160:3585-3593, 1998.

Baldwin A.S. Jr.: The NF-kappa B and 1kappa B proteins: New discoveries and insights. Annu. Rev. Immunol. 14:649- 683, 1996.

Giannoukakis N., Rudert WA., Robbins P. and Trucco M.: Targeting autoimmune diabetes with gene therapy. Diabetes 48:2107-21211, 1999.

Suda T, Takahashi T. et al: Molecular cloning and expression of the fas ligand, a novel member of the tumor necrosis factorfamily. CeIl75:1169-1178, 1993.

Suda T, Hashimoto H. et al: Membrane fas ligand kills human peripheral blood T Iymphocytes, and soluble fas ligand blocks the killing. J. Exped. Med. 186(12):2045-2050, 1997

Hale AJ., Smith C.A. et al: Apoptosis: molecular regulation of cell death. Eur. J. Biochem. 236:1-26,1996.

Scarim AL., Arnush M. et al: Evidence for the presence of type I IL-1 receptors on b-cells of islets of Langerhans. Biochimica et Biophysica Aeta 1361 :313-320, 1997.

Kagi D., Vignaux F. et al: Fas and perforing pathways as major mechanisms of T Cell-mediated cytotoxicity. Science 265:528-530,1994.

Trauth B.C., Klas C. et al: Monoclonal antbody-mediated tumor regression by inductionof apoptosis.Science 245:301-305,1989.

Shigekazu N. and Suda T: Fas and fas ligand: Ipr and gld mutations. Immunol. Today 16(1):39-43, 1995.

Stassi G. et al: Nitric oxide primes pancreatic b cells for fasmediated destruction in insulin-dependent diabetes mellitus. J. Exp. Med. 186:1193-1200, 1997.

PosseltAM., Naji A., Roark J.H., et al: Intrathymic islet transplantation in the spontaneously diabetic BB rat. Ann. Surg. 214:363-373,1991.

Charlton B., Taylor-Edwards C., Tisch R, Fathman C.G: Prevention of diabetes and insulitis by neonatal intrathymic islet administration in NOD mice. J.Autoimmun. 7:549-560,1994.

Arnush M., Scarim A.L. et al: Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. J. Immunol. 160:2684-2691, 1998.

Hunger RE., Carnaud C., Garcia l., Vasalli P., Mueller C: Prevention of autoimmune diabetes mellitus in NOD mice by transgenic expression of soluble tumor necrosis factor receptor p55. Eur. J. Immunol. 27:255-261, 1997.

Thomson AW, Lu L., et al: Microchimerism, dendritic cell progenitors and transplantation tolerance. Stem. CeI113:622- 639,1995.

Lenschow D.J., Zeng 1.et at: Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 257:789-792,1992.

Weber C.J., Hagler M.K., Chryssochoos J.T, et al: CTLA4- Ig prolongs survival of microencapsulated neonatal porcine islets xenografts in diabetic NOD mice. Cell transplant 6:505- 508,1997.

Smith D.K., Korbut G.S., Suarez-Pinzon WL., et al: Interleukin- 4 or interleukin-1 O expressed from adenovirus- transduced syngeneic islet grafts fails to prevent beta cell destruction in diabetic NOD mice. Transplantation 64:1030-

, 1997.

Tripp C.S., Wolf S.F., Unanue E.R: Interleukin 12 and tumor necrosis factor are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with Iisteriosis, and interleukin 10 is a physiologic

antagonist. Proc. Nat. Acad. Sci. USA 90:3725- 3729,1993.

Yang X., Michie S., et al: The role of ce11adhesion molecules in the development of IDDM. Diabetes 45:705-710, 1996.

Tafuri A, Bowers WE., et al: High stimulatory activity of dendritic cells from diabetes-prone BioBreeding/Worcester rats exposed to macrophage-derived factors. J. Clin. Invest. 91 :2040-2048, 1993.

Vives M., Soldevila G., et al: Adhesion molecules in human islet [i cells: de novo induction of ICAM-1 but not LFA-3. Diabetes 40: 1382-1390, 1991.

Martin S., Heidenthal E. et al: Soluble forms of intercellular adhesion molecule-1 inhibit insulitis and onset of autoimmune diabetes. Diabetologia 41:1298-1303,1998.

Steptoe R.J., Thomson A.W.: Dendritic cells and tolerance induction. Clin. Exp. Immunol. 105:397-402, 1996.

Lu L., Lee A. et al. Transduction of dentritic cells with adenoviral vectors encoding CTLA4-lg markedly reduces their allostimulatory activity. Transplantation Proceedings 31:797, 1999.

Linsley P.S., et al: Immunosupression in vivo by a soluble form ofthe CTLA-4 cell activation molecule. Science 257:793- 795, 1992.

Starzl TE., Murase N., et al: Regulation of immune reactivity and tolerance migration and localization: With particular reference to allo- and xenotransplantation. Transp!antation Proceedings 31 :763-768, 1999.

Pratt J.C., Sadwasdikosol S. et al: Positive and negative signaling pathways. Transplantation Proceedings 31:772-774, 1999.

Kenyon N.S., et al: Long-term survival and funetion of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc. Natl.Acad. Sci. 96:8132-817,1999.

Kenyon N.S., Fernandez L.A., et al: Long-term survival and funetion of intrahepatic islet allograft in baboons treated with humanized anti-CD 154. Diabetes 48: 1473-1481, 1999.

Stuart P.M., Grifith TS, Usui N., Pepose J., Yu X., Ferguson TA.: CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J. Clin. Invest. 99:396-402, 1997.

Fandrick F., Lin X., Zhu X., Kloppel G., Parwaresch R, Kremer B: CD95L confers immune privilege to liver which are spontaneously accepted. Transplant Proc. 30:1057-1058,1998.

Schneider P., Thome M., Burns K., Bodmer I.L., Hofmann K., Kataoka T, Holler N. Tschopp J.: Trail receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappa~. Immunity 7:831-836,1997.

Wajant H., Johannes F.J., Haas E., Siermienski K, et al: Dominant-negative FADD inhibits TNFR60, Fas/Apol and TRAIL-RA/Ap02-mediated cell death but not gene induction. Curro BioI8:113-116, 1998.

Cómo citar

[1]
Sánchez Medina, M. 2001. Inmunopatogénesis de la Diabetes 1. Medicina. 23, 2 (ago. 2001), 88–92.

Descargas

Los datos de descargas todavía no están disponibles.

Descargas

Publicado

2001-08-03

Número

Sección

Artículo Científico