Modern view on LRBA deficiency
Facilities of molecular genetic methods allow to distinguish several monogenic deficiencies in the general group of primary immunodeficiencies, including common variable immune deficiency (CVID), which have peculiarities of the natural course, therapy, and prognosis. One of these nosologies is LRBA deficiency. In this article a number of foreign sources were reviewed, systematized and classified to define a comprehensive understanding of the LRBA deficiency phenomenon . The most relevant scientific studies of North America and Europe and publications from various ranking medical journals were analyzed.
LRBA deficiency is a PID caused by mutations in LRBA gene that disrupt the immune system regulation. It is characterized by lymphoproliferation, autoaggression, hypogammaglobulinemia and recurrent infections. Sometimes LRBA deficiency is called LATAIE disease (LRBA deficiency with autoantibodies, regulatory T-cell defects, autoimmune infiltration, and enteropathy).
Special attention was given to the mutation of LRBA gene and the connection to the defects caused in T- and B-lymphocytes, the clinical picture and diagnostics. It was suggested that LRBA protein reduces the level of autophagy, leading to increased apoptosis, impared T- and B-cell immune response, lymphoproliferation and autoimmune disorders. LRBA protein is especially expressed in the immune cells, its deficiency leads to defects of B-cells differentiation. However, LRBA deficiency does not affect T-regulatory cells differentiation. Main approaches to the treatment of patients with LRBA deficiency are presented in the article.
Methods of systemic and content analysis of Russian and foreign sources were used when writing the article.
Tatyana V. LatyshevaNRCI Institute of Immunology FMBA of Russia
head of the Immunopathology and Intensive Care Department, NRC Institute of Immunology FMBA of Russia, MD, PhD, professor
Elena A. LatyshevaNRCI Institute of Immunology FMBA of Russia
chief researcher of the Immunopathology and Intensive Care Department, NRC Institute of Immunology FMBA of Russia, MD, PhD
Nailya Kh. SetdikovaNRCI Institute of Immunology FMBA of Russia
senior researcher of the Immunopathology and Intensive Care Department, NRC Institute of Immunology FMBA of Russia, MD, PhD
Daria R. EsaulovaNRCI Institute of Immunology FMBA of Russia
medical resident of the Immunopathology and Intensive Care Department, NRC Institute of Immunology FMBA of Russia
- Joyce EY, Jordan S, Yesim YD. New primary immunodeficiency diseases: context and future. Pediatriia. 2019;98(3):8–23 (In Russ.). doi: 10.24110/0031-403X-2019-98-3-8-23
- Vasilieva MM. Primary immunodeficiencies: general variable immunodeficiency (GVID). Dal’nevostochnyi meditsinskii zhurnal. 2019;4:101–106 (In Russ.). doi: 10.35177/1994-5191-2019-4-101-106
- Shcherbina AYu. Masks of primary immunodeficiency disorders: diagnostic and therapeutic problems. Rossiiskii zhurnal detskoi gematologii i onkologii. 2016;3(1):52–58 (In Russ.). doi: 10.17650/2311-1267-2016-3-1-52-58
- Suspitsyn EN, Yanus GA, Makhova MA, Khamidulina AA, Guseva MN, Preobrazhenskaya EV, et al. Estimation of efficiency of ising target miltigene sequencing in children with recurrent infections. Meditsina: teoriya i praktika. 2019;4(3):20–27 (In Russ.).
- Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the international union of immunological societies expert committee. J Clin Immunol. 2020;40(1):24–64. doi: 10.1007/s10875-020-00763-0
- niaid.nih.gov [Internet]. LRBA Deficiency. National Institute of Allergy and Infectious Diseases. September [cited 2020 Apr 04]. Available from:https://www.niaid.nih.gov/sites/default/files/LRBAFactSheet.pdf
- Ochs HD, Hitzig WH. History of primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. 2012;12(6):577–587. doi: 10.1097/ACI.0b013e32835923a6
- Kuzmenko NB, Shcherbina AYu. Classification of primary immunodeficiencies as a reflection of modern ideas about their pathogenesis and therapeutic approaches. Rossiiskii zhurnal detskoi gematologii i onkologii. 2017;4(3):51–57 (In Russ.). doi: 10.17650/2311-1267-2017-4-3-51-57
- Lopez-Herrera G, Tampella G, Pan-Hammarström Q, Herholz P, Trujillo-Vargas CM, Phadwal K, 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. doi: 10.1016/j.ajhg.2012.04.015
- Rodina YuA, Horeva AL, Abramova IN, Shvets OA, Burlakov VI, Tereshenko GV, et al. Therapy features of interstitial lymphocytic lung disease (ILLD) in patients with immune dysregulation syndromes: case report. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2018;17(3):103–110 (In Russ.). doi: 10.24287/1726-1708-2018-17-3-103-110
- Alangari A, Alsultan A, Adly N, Massaad MJ, Kiani IS, Aljebreen A, 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. doi: 10.1016/j.jaci.2012.05.043
- Wang JW, Howson J, Haller E, Kerr WG. Identification of a novel lipopolysaccharide-inducible gene with key features of both A kinase anchor proteins and chs1/beige proteins. J Immunol. 2001;166(7):4586–4595. doi: 10.4049/jimmunol.166.7.4586
- Gebauer D, Li J, Jogl G, Shen Y, Myszka DG, Tong L. Crystal structure of the PH–BEACH domains of human LRBA/BGL. Biochemistry. 2004;43(47):14873–14880. doi: 10.1021/bi049498y
- Dyomin VG, Chaganti SR, Dyomina K, Palanisamy N, Murty VV, Dalla-Favera R, Chaganti RS. BCL8 is a novel, evolutionarily conserved human gene family encoding proteins with presumptive protein kinase A anchoring function. Genomics. 2002;80(2):158–165. doi: 10.1006/geno.2002.6822
- Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, 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. doi: 10.1016/j.jaci.2014.10.019
- Moreau K, Ravikumar B, Renna M, Puri C, Rubinsztein DC. Autophagosome precursor maturation requires homotypic fusion. Cell. 2011;146(2):303–317. doi: 10.1016/j.cell.2011.06.023
- Jaramillo CM, Vargas CM. Dissecting the localization of lipopolysaccharide-responsive and beige-like anchor protein (LRBA) in the endomembrane system. Allergol Immunopathol (Madr). 2020;48(1):8–17. doi: 10.1016/j.aller.2019.07.011
- Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–440. doi: 10.1126/science.aaa1663
- Yang L, Xue X, Chen X, Wu J, Yang X, Xu L, et al. Abatacept is effective in Chinese patients with LRBA and CTLA4 deficiency. Genes Dis. Forthcoming 2020. doi: 10.1016/j.gendis.2020.03.001
- Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol. 2012;130(6):1428–1432. doi: 10.1016/j.jaci.2012.07.035