Monogenic form of autoimmune diabetes as a part of dysregulation of immune system


Authors: V. Straková;  P. Dušátková;  L. Elblová;  Š. Průhová
Authors‘ workplace: Pediatrická klinika 2. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice Motol, Praha
Published in: Čes-slov Pediat 2018; 73 (2): 104-109.
Category: Review

Věnováno významnému životnímu jubileu prof. MUDr. Lidky Lisé, DrSc.

Overview

Type 1 diabetes (T1D), a disease resulting from a combination of polygenic mode of inheritance and environmental factors accounts for 95% of all diabetes in children. Monogenic forms of autoimmune diabetes have been considered extremely rare. However, it has been shown recently that patients with autoimmune diabetes caused by a mutation in a single gene are hidden among children with „common“ T1D. Single gene defect leads to dysregulation of immune system and development of diabetes or other autoimmune diseases.

Candidate genes causing monogenic forms of autoimmune diabetes are the AIRE gene causing APS-1, the FOXP3 gene responsible for IPEX syndrome and the IL2RA gene for IPEX-like syndrome respectively. Mutations in the STAT3, CTLA4, LRBA or STAT1 genes are described in T1D occurring with autoimmune cytopenias (neutropenia, thrombocytopenia, autoimunne haemolytic anemia). Mutations in the ITCH gene causing multisystem autoimmune disease are extremely rare.

Correct early diagnosis of monogenic forms of autoimmune diabetes is essential for the causal treatment which also includes the allogenic bone marrow transplantation in some cases.

Key words:
autoimmune diabetes, APS-1, STAT3, CTLA4, AIRE, monogenic diabetes


Sources

1. Balazard F, Le Fur S, Valtat S, et al. Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study. BMC Public Health 2016; 16 (1): 1021.

2. Erlich H, Valdes AM, Noble J, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008; 57 (4): 1084–1092.

3. Gerstein HC. Making a difference with diabetes research and care. Diabetes Care 2016; 39 (8): 1309–1310.

4. Nagamine K, Peterson P, Scott HS, et al. Positional cloning of the APECED gene. Nat Genet 1997; 17 (4): 393–398.

5. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27 (1): 20–21.

6. Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014; 506 (7488): 376–381.

7. Flanagan SE, Haapaniemi E, Russell MA, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet 2014; 46 (8): 812–814.

8. Schreiner F, Plamper M, Dueker G, et al. Infancy-onset T1DM, short stature, and severe immunodysregulation in two siblings with a homozygous LRBA mutation. J Clin Endocrinol Metab 2016; 101 (3): 898–904.

9. Cetani F, Barbesino G, Borsari S, et al. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab 2001; 86 (10): 4747–4752.

10. Koskela HLM, Eldfors S, Ellonen P, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 2012; 366 (20): 1905–1913.

11. Alangari A, Alsultan A, Adly N, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol 2012; 130 (2): 481–488.e2.

12. Sediva H, Dusatkova P, Kanderova V, et al. Short stature in a boy with multiple early-onset autoimmune conditions due to a activating mutation: Could intracellular growth hormone signalling be compromised? Horm Res Paediatr 2017 March; 88 (2): 160–166.

13. Lee S, Moon JS, Lee C-R, et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy Clin Immunol 2016; 137 (1): 327–330.

14. Baud O, Goulet O, Canioni D, et al. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N Engl J Med 2001; 344 (23): 1758–1762.

15. Burroughs LM, Torgerson TR, Storb R, et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol 2010; 126 (5): 1000–1005.

16. Cheng MH, Shum AK, Anderson MS. What’s new in the Aire? Trends Immunol 2007; 28 (7): 321–327.

17. Abramson J, Husebye ES. Autoimmune regulator and self-tolerance – molecular and clinical aspects. Immunol Rev 2016; 271 (1): 127–140.

18. Li D, Zhao B, Luo Y, et al. Transplantation of Aire-overexpressing bone marrow-derived dendritic cells delays the onset of type 1 diabetes. Int Immunopharmacol 2017; 49: 13–20.

19. Bacchetta R, Barzaghi F, Roncarolo M-G. From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann N Y Acad Sci February 2016. doi: 10.1111/nyas.13011.

20. Murguia-Favela L, Hong-Diep Kim V, Upton J, et al. IPEX syndrome caused by a novel mutation in FOXP3 gene can be cured by bone marrow transplantation from an unrelated donor after myeloablative conditioning. LymhoSign J 2015; 2 (1): 31–38.

21. Horino S, Sasahara Y, Sato M, et al. Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome. Pediatr Transplant 2014; 18 (1): E25–E30.

22. Van Belle TL, Coppieters KT, Von Herrath MG. Type 1 diabetes: Etiology, immunology, and therapeutic strategies. Physiol Rev 2011; 91 (1). http://physrev.physiology.org/content/91/1/79.long. Accessed June 29, 2017.

23. Caudy AA, Reddy ST, Chatila T, et al. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol 2007; 119 (2): 482–487.

24. Abdelrahman HM, Sherief LM, Abd Elrahman DM, et al. The association of PTPN22 (rs2476601) and IL2RA (rs11594656) polymorphisms with T1D in Egyptian children. Hum Immunol 2016; 77 (8): 682–686.

25. Tang W, Cui D, Jiang L, et al. Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies. J Cell Mol Med 2015; 19 (10): 2481–2488.

26. Schwartz AM, Demin DE, Vorontsov IE, et al. Multiple single nucleotide polymorphisms in the first intron of the IL2RA gene affect transcription factor binding and enhancer activity. Gene 2017; 602: 50–56.

27. Friedline RH, Brown DS, Nguyen H, et al. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J Exp Med 2009; 206 (2): 421–434.

28. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+) CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192 (2): 303–310.

29. Zalloua PA, Abchee A, Shbaklo H, et al. Patients with early onset of type 1 diabetes have significantly higher GG genotype at position 49 of the CTLA4 gene. Hum Immunol 2004; 65 (7): 719–724.

30. Ligers A, Teleshova N, Masterman T, et al. CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2001; 2 (3): 145–152.

31. Slatter MA, Engelhardt KR, Burroughs LM, et al. Hematopoietic stem cell transplantation for CTLA4 deficiency. J Allergy Clin Immunol 2016; 138 (2): 615–619.e1.

32. Vogel TP, Milner JD, Cooper MA. The ying and yang of STAT3 in human disease. J Clin Immunol 2015; 35 (7): 615–623.

33. Milner JD, Vogel TP, Forbes L, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 2015; 125 (4): 591–599.

34. Huopio H, Miettinen PJ, Ilonen J, et al. Clinical, genetic, and biochemical characteristics of early-onset diabetes in the Finnish population. J Clin Endocrinol Metab 2016; 101 (8): 3018–3026.

35. Saikia B, Goel S, Suri D, et al. Novel mutation in SH2 domain of STAT3 (p.M660T) in hyper-IgE syndrome with sterno-clavicular and paravertebral abscesses. Indian J Pediatr 2017; 84 (6): 494–495.

36. Minakawa S, Tanaka H, Kaneko T, et al. Hyper-IgE syndrome with a novel mutation of the STAT3 gene. Clin Exp Dermatol 2016; 41 (6): 687–689.

37. Minegishi Y, Saito M, Tsuchiya S, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007; 448 (7157): 1058–1062.

38. Andersson E, Kuusanmäki H, Bortoluzzi S, et al. Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia. Leukemia 2016; 30 (5): 1204–1208.

39. Andersson EI, Rajala HLM, Eldfors S, et al. Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation. Blood Cancer J 2013; 3 (12): e168.

40. Lorenzini T, Dotta L, Giacomelli M, et al. STAT mutations as program switchers: turning primary immunodeficiencies into autoimmune diseases. J Leukoc Biol 2017; 101 (1): 29–38.

41. Uzel G, Sampaio EP, Lawrence MG, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation polyendocrinopathy enteropathy X-linked like syndrome. J Allergy Clin Immunol 2013; 131 (6): 1611–1623.e3.

42. Charbonnier L-M, Janssen E, Chou J, et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol 2015; 135 (1): 217–227.

43. Burns SO, Zenner HL, Plagnol V, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol 2012; 130 (6): 1428–1432.

44. Lopez-Herrera G, Tampella G, Pan-Hammarström Q, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet 2012; 90 (6): 986–1001.

45. Revel-Vilk S, Fischer U, Keller B, et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin Immunol 2015; 159 (1): 84–92.

46. Johnson MB, De Franco E, Lango-Allen H, et al. Recessively inherited Lrba mutations cause autoimmunity presenting as neonatal diabetes. Diabetes 2017 May; 66 (8): 2316–2322.

47. Bakhtiar S, Gámez-Díaz L, Jarisch A, et al. Treatment of infantile inflammatory bowel disease and autoimmunity by allogeneic stem cell transplantation in LPS-responsive beige-like anchor deficiency. Front Immunol 2017; 8: 52.

48. Matesic LE, Copeland NG, Jenkins NA. Itchy mice: the identification of a new pathway for the development of autoimmunity. Curr Top Microbiol Immunol 2008; 321: 185–200.

49. Johnson MB, Hattersley AT, Flanagan SE. Monogenic autoimmune diseases of the endocrine system. Lancet Diabetes Endocrinol 2016; 4 (10): 862–872.

Labels
Neonatology Paediatrics General practitioner for children and adolescents
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