The RAG1 Mutation Presenting as Early Onset SLE in an Iranian Patient
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Abstract
It has been established that mutations of the Recombinase activating genes (RAG1 and RAG2) are responsible for classic T-B-NK+ severe combined immunodeficiency (SCID). On the other hand, it has now become evident that certain mutations within these genes can also lead to other forms of combined immunodeficiency, antibody deficiency, and even autoimmunity.
In this report, we present a case involving a 9-month-old female patient who presents with clinical and laboratory findings indicative of systemic lupus erythematosus (SLE). Following the diagnosis of early-onset SLE and considering the presence of concurrent infections, it was considered necessary to investigate potential underlying monogenic disorders associated with inborn errors of immunity. Immunological evaluations demonstrated a combined immunodeficiency and whole exome sequencing confirmed that the patient has a mutation in the RAG1 gene.
1. Grimbacher B, Warnatz K, Yong PFK, Korganow ASPeter HH. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol. 2016;137(1):3-17.
2. Schmidt RE, Grimbacher BWitte T. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol. 2017;14(1):7-18.
3. Azizi G, Tavakol M, Yazdani R, Delavari S, Moeini Shad T, Rasouli SE, et al. Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity. Pediatr Allergy Immunol. 2021;32(6):1335-48.
4. Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015;125(11):4135-48.
5. Villa ANotarangelo LD. RAG gene defects at the verge of immunodeficiency and immune dysregulation. Immunol Rev. 2019;287(1):73-90.
6. Azizi G, Hesari MF, Sharifinejad N, Fayyaz F, Chavoshzadeh Z, Mahdaviani SA, et al. The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages. J Clin Immunol. 2023; 43(4):819-834.
7. Sharifinejad N, Azizi G, Chavoshzadeh Z, Mahdaviani SA, Alan MS, Tavakol M, et al. Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features. Front Immunol. 2022;13:1023127.
8. Krangel MS. Mechanics of T cell receptor gene rearrangement. Curr Opin Immunol. 2009;21(2):133-9.
9. Chi X, Li YQiu X. V(D)J recombination, somatic hypermutation and class switch recombination of immunoglobulins: mechanism and regulation. Immunology. 2020;160(3):233-47.
10. Abe T, Tsuge I, Kamachi Y, Torii S, Utsumi K, Akahori Y, et al. Evidence for defects in V(D)J rearrangements in patients with severe combined immunodeficiency. J Immunol. 1994;152(11):5504-13.
11. Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001;97(1):81-8.
12. Delmonte OM, Schuetz CNotarangelo LD. RAG Deficiency: Two Genes, Many Diseases. J Clin Immunol. 2018;38(6):646-55.
13. Niehues T, Perez-Becker RSchuetz C. More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135(2):183-92.
14. Notarangelo LD, Kim MS, Walter JELee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234-46.
15. Villa A, Santagata S, Bozzi F, Imberti LNotarangelo LD. Omenn syndrome: a disorder of Rag1 and Rag2 genes. J Clin Immunol. 1999;19(2):87-97.
16. Gennery A. Recent advances in understanding RAG deficiencies. F1000Res. 2019;8.
17. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-507.
18. Walter JE, Lo MS, Kis-Toth K, Tirosh I, Frugoni F, Lee YN, et al. Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol. 2015;135(1):272-3.
19. Kato T, Crestani E, Kamae C, Honma K, Yokosuka T, Ikegawa T, et al. RAG1 deficiency may present clinically as selective IgA deficiency. J Clin Immunol. 2015;35(3):280-8.
20. Min Q, Csomos K, Li Y, Dong L, Hu Z, Meng X, et al. B cell abnormalities and autoantibody production in patients with partial RAG deficiency. Front Immunol. 2023;14:1155380.
21. Delmonte OM, Villa ANotarangelo LD. Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency. Blood. 2020;135(9):610-19.
22. Geier CB, Piller A, Linder A, Sauerwein KM, Eibl MMWolf HM. Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens. PLoS One. 2015;10(7):e0133220.
23. Chen K, Wu W, Mathew D, Zhang Y, Browne SK, Rosen LB, et al. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J Allergy Clin Immunol. 2014;133(3):880-2 e10.
24. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97-9.
25. Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, et al. Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT. Blood. 2023;141(7):713-24.
2. Schmidt RE, Grimbacher BWitte T. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat Rev Rheumatol. 2017;14(1):7-18.
3. Azizi G, Tavakol M, Yazdani R, Delavari S, Moeini Shad T, Rasouli SE, et al. Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity. Pediatr Allergy Immunol. 2021;32(6):1335-48.
4. Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015;125(11):4135-48.
5. Villa ANotarangelo LD. RAG gene defects at the verge of immunodeficiency and immune dysregulation. Immunol Rev. 2019;287(1):73-90.
6. Azizi G, Hesari MF, Sharifinejad N, Fayyaz F, Chavoshzadeh Z, Mahdaviani SA, et al. The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages. J Clin Immunol. 2023; 43(4):819-834.
7. Sharifinejad N, Azizi G, Chavoshzadeh Z, Mahdaviani SA, Alan MS, Tavakol M, et al. Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features. Front Immunol. 2022;13:1023127.
8. Krangel MS. Mechanics of T cell receptor gene rearrangement. Curr Opin Immunol. 2009;21(2):133-9.
9. Chi X, Li YQiu X. V(D)J recombination, somatic hypermutation and class switch recombination of immunoglobulins: mechanism and regulation. Immunology. 2020;160(3):233-47.
10. Abe T, Tsuge I, Kamachi Y, Torii S, Utsumi K, Akahori Y, et al. Evidence for defects in V(D)J rearrangements in patients with severe combined immunodeficiency. J Immunol. 1994;152(11):5504-13.
11. Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001;97(1):81-8.
12. Delmonte OM, Schuetz CNotarangelo LD. RAG Deficiency: Two Genes, Many Diseases. J Clin Immunol. 2018;38(6):646-55.
13. Niehues T, Perez-Becker RSchuetz C. More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135(2):183-92.
14. Notarangelo LD, Kim MS, Walter JELee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234-46.
15. Villa A, Santagata S, Bozzi F, Imberti LNotarangelo LD. Omenn syndrome: a disorder of Rag1 and Rag2 genes. J Clin Immunol. 1999;19(2):87-97.
16. Gennery A. Recent advances in understanding RAG deficiencies. F1000Res. 2019;8.
17. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-507.
18. Walter JE, Lo MS, Kis-Toth K, Tirosh I, Frugoni F, Lee YN, et al. Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol. 2015;135(1):272-3.
19. Kato T, Crestani E, Kamae C, Honma K, Yokosuka T, Ikegawa T, et al. RAG1 deficiency may present clinically as selective IgA deficiency. J Clin Immunol. 2015;35(3):280-8.
20. Min Q, Csomos K, Li Y, Dong L, Hu Z, Meng X, et al. B cell abnormalities and autoantibody production in patients with partial RAG deficiency. Front Immunol. 2023;14:1155380.
21. Delmonte OM, Villa ANotarangelo LD. Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency. Blood. 2020;135(9):610-19.
22. Geier CB, Piller A, Linder A, Sauerwein KM, Eibl MMWolf HM. Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens. PLoS One. 2015;10(7):e0133220.
23. Chen K, Wu W, Mathew D, Zhang Y, Browne SK, Rosen LB, et al. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J Allergy Clin Immunol. 2014;133(3):880-2 e10.
24. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97-9.
25. Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, et al. Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT. Blood. 2023;141(7):713-24.
| Files | ||
| Issue | Vol 6, No 4 (2023) | |
| Section | Case Report | |
| DOI | https://doi.org/10.18502/igj.v6i4.17101 | |
| Keywords | ||
| Systemic Lupus Erythematosus RAG1 SCID Immunodeficiency | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Cheraghi T, Mir Emarati A, Moradkhani A. The RAG1 Mutation Presenting as Early Onset SLE in an Iranian Patient. Immunol Genet J. 2023;6(4):137-140.
