MHC class II deficiency: Report of a novel mutation and special review
Main Article Content
Keywords
MHC class II deficiency, CIITA, RFXANK, RFX5, RFXAP
Abstract
The MHC II deficiency is a rare autosomal recessive primary immunodeficiency syndrome with increased susceptibility to respiratory and gastrointestinal infections, failure to thrive and early mortality. This syndrome is caused by mutations in transcription regulators of the MHC II gene and results in development of blind lymphocytes due to the lack of indicatory MHC II molecules. Despite homogeneity of clinical manifestations of patients with MHC II deficiency, the genetic defects underlying this disease are heterogeneous. Herein, we report an Iranian patient with MHC II deficiency harbouring a novel mutation in RFXANK and novel misleading clinical features. He had ataxic gait and dysarthria from 30 months of age. Epidemiology, clinical and immunological features, therapeutic options and prognosis of patients with MHC II are reviewed in this paper.
References
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2. Dimitrova D, Ong PY, O’Gorman MR, Church JA. Major histocompatibility complex class II deficiency complicated by Mycobacterium avium complex in a boy of mixed ethnicity. J Clin Immunol. 2014;34:677-80.
3. Devaiah BN, Singer DS. CIITA and its dual roles in MHC gene transcription. Front Immunol. 2013;4:476.
4. Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Proc ICI Milan. 2013;2014:164.
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8. Djidjik R, Messaoudani N, Tahiat A, Meddour Y, Chaib S, Atek A, et al. Clinical, immunological and genetic features in eleven Algerian patients with major histocompatibility complex class II expression deficiency. Allergy Asthma Clin Immunol. 2012;8:14.
9. Ben-Mustapha I, Ben-Farhat K, Guirat-Dhouib N, Dhemaied E, Largueche B, Ben-Ali M, et al. Clinical, immunological and genetic findings of a large tunisian series of major histocompatibility complex class II deficiency patients. J Clin Immunol. 2013;33:865-70.
10. Ouederni M, Vincent QB, Frange P, Touzot F, Scerra S, Bejaoui M, et al. Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients. Blood. 2011;118:5108-18.
11. Kallen ME, Pullarkat ST. Type II bare lymphocyte syndrome: role of peripheral blood flow cytometry and utility of stem cell transplant in treatment. J Pediatr Hematol Oncol. 2015;37:e245-9.
12. Alyasin S, Abolnezhadian F, Khoshkhui M. A case of probable MHC class II deficiency with disseminated BCGitis. Iran J Immunol. 2015;12:219---25.
13. Steimle V, Otten LA, Zufferey M, Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell. 1993;75:135-46.
14. Dziembowska M, Fondaneche MC, Vedrenne J, Barbieri G, Wiszniewski W, Picard C, et al. Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. Immunogenetics. 2002;53:821-9.
15. Bontron S, Steimle V, Ucla C, Eibl MM, Mach B. Two novel mutations in the MHC class II transactivator CIITA in a second patient from MHC class II deficiency complementation group A. Hum Genet. 1997;99:541-6.
16. Schmetterer KG, Seidel MG, Kormoczi U, Rottal A, Schwarz K, Matthes-Martin S, et al. Two newly diagnosed HLA class II-deficient patients identified by rapid vector-based complementation analysis reveal discoordinate invariant chain expression levels. Int Arch Allergy Immunol. 2010;152:390-400.
17. Wiszniewski W, Fondaneche MC, Lambert N, Masternak K, Picard C, Notarangelo L, et al. Founder effect for a 26-bp deletion in the RFXANK gene in North African major histocompatibility complex class II-deficient patients belonging to complementation group B. Immunogenetics. 2000;51:261-7.
18. Wiszniewski W, Fondaneche MC, Louise-Plence P, ProchnickaChalufour A, Selz F, Picard C, et al. Novel mutations in the RFXANK gene: RFX complex containing in-vitro-generated RFXANK mutant binds the promoter without transactivating MHC II. Immunogenetics. 2003;54:747-55.
19. Gladstone Pious D. Stable variants affecting B cell alloantigens in human lymphoid cells. Nature. 1978;271:459-61.
20. Siepermann M, Gudowius S, Beltz K, Strier U, Feyen O, Troeger A, et al. MHC class II deficiency cured by unrelated mismatched umbilical cord blood transplantation: case report and review of 68 cases in the literature. Pediatr Transplant. 2011;15:E80-6.
21. Al-Herz W, Alsmadi O, Melhem M, Recher M, Frugoni F, Notarangelo LD. Major histocompatibility complex class II deficiency in Kuwait: clinical manifestations, immunological findings and molecular profile. J Clin Immunol. 2013;33:513-9.
22. Antoine C, Muller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003;361:553-60.
23. Renella R, Picard C, Neven B, Ouachee-Chardin M, Casanova JL, Le Deist F, et al. Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections. Br J Haematol. 2006;134:510-6.
24. Small TN, Qasim W, Friedrich W, Chiesa R, Bleesing JJ, Scurlock A, et al. Alternative donor SCT for the treatment of MHC class II deficiency. Bone Marrow Transplant. 2013;48:226-32.
25. Al-Mousa H, Al-Shammari Z, Al-Ghonaium A, Al-Dhekri H, Al-Muhsen S, Al-Saud B, et al. Allogeneic stem cell transplantation using myeloablative and reduced-intensity conditioning in patients with major histocompatibility complex class II deficiency. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2010;16:818-23.
26. Kuo CY, Chase J, Garcia Lloret M, Stiehm ER, Moore T, Aguilera MJ, et al. Newborn screening for severe combined immunodeficiency does not identify bare lymphocyte syndrome. J Allergy Clin Immunol. 2013;131:1693-5.
27. Wiszniewski W, Fondaneche MC, Le Deist F, Kanariou M, Selz F, Brousse N, et al. Mutation in the class II trans-activator leading to a mild immunodeficiency. J Immunol. 2001;167:1787-94 (Baltimore, Md: 1950).
28. Peijnenburg A, Van den Berg R, Van Eggermond MJ, Sanal O, Vossen JM, Lennon AM, et al. Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene. Immunogenetics. 2000;51:42-9.
29. Quan V, Towey M, Sacks S, Kelly AP. Absence of MHC class II gene expression in a patient with a single amino acid substitution in the class II transactivator protein CIITA. Immunogenetics. 1999;49:957-63.
30. Fondaneche MC, Villard J, Wiszniewski W, Jouanguy E, Etzioni A, Le Deist F, et al. Genetic and molecular definition of complementation group D in MHC class II deficiency. Hum Mol Gen. 1998;7:879-85.
31. Mannhalter JW, Wolf HM, Gadner H, Potschka M, Eibl MM. Cellmediated immune functions in a patient with MHC class II deficiency. Immunol Invest. 1991;20:151-67.
32. Steimle V, Otten LA, Zufferey M, Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). J Immunol. 1993;178:6677-88 (Baltimore Md: 1950) 2007.
33. Guirat-Dhouib N, Baccar Y, Mustapha IB, Ouederni M, Chouaibi S, El Fekih N, et al. Oral HPV infection and MHC class II deficiency (A study of two cases with atypical outcome). Clin Mol Allergy: CMA. 2012;10:6.
34. Prod’homme T, Dekel B, Barbieri G, Lisowska-Grospierre B, Katz R, Charron D, et al. Splicing defect in RFXANK results in a moderate combined immunodeficiency and long-duration clinical course. Immunogenetics. 2003;55:530-9.
35. Lennon-Dumenil AM, Barbouche MR, Vedrenne J, Prod’Homme T, Bejaoui M, Ghariani S, et al. Uncoordinated HLA-D gene expression in a RFXANK-defective patient with MHC class II deficiency, J Immunol. 2001;166:5681-7 (Baltimore, Md: 1950).
36. Nagarajan UM, Peijnenburg A, Gobin SJ, Boss JM, van den elsen PJ. Novel mutations within the RFX-B gene and partial rescue of MHC and related genes through exogenous class II transactivator in RFX-B-deficient cells. J Immunol. 2000;164:3666-74 (Baltimore, Md: 1950).
37. Lisowska-Grospierre B, Fondaneche MC, Rols MP, Griscelli C, Fischer A. Two complementation groups account for most cases of inherited MHC class II deficiency. Hum Mol Gen. 1994;3:953-8.
38. Nagarajan UM, Louis-Plence P, DeSandro A, Nilsen R, Bushey A, Boss JM. RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity. 1999;10:153-62.
39. Masternak K, Barras E, Zufferey M, Conrad B, Corthals G, Aebersold R, et al. A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nature Genet. 1998;20:273-7.
40. Nekrep N, Jabrane-Ferrat N, Wolf HM, Eibl MM, Geyer M, Peterlin BM. Mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome. Nature Immunol. 2002;3:1075-81.
41. Peijnenburg A, Van Eggermond MJ, Gobin SJ, Van den Berg R, Godthelp BC, Vossen JM, et al. Discoordinate expression of invariant chain and MHC class II genes in class II transactivator-transfected fibroblasts defective for RFX5. J Immunol. 1999;163:794-801 (Baltimore, Md: 1950).
42. Peijnenburg A, Van Eggermond MC, Van den Berg R, Sanal O, Vossen JM, Van den Elsen PJ. Molecular analysis of an MHC class II deficiency patient reveals a novel mutation in the RFX5 gene. Immunogenetics. 1999;49:338-45.
43. Villard J, Reith W, Barras E, Gos A, Morris MA, Antonarakis SE, et al. Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency. Human Mut. 1997;10:430-5.
44. Steimle V, Durand B, Barras E, Zufferey M, Hadam MR, Mach B, et al. A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev. 1995;9:1021-32.
45. van Eggermond MC, Tezcan I, Heemskerk MH, van den Elsen PJ. Transcriptional silencing of RFXAP in MHC class II-deficiency. Mol Immunol. 2008;45:2920-8.
46. Villard J, Mach B, Reith W. MHC class II deficiency: definition of a new complementation group. Immunobiology. 1997;198:264-72.
47. Villard J, Lisowska-Grospierre B, van den Elsen P, Fischer A, Reith W, Mach B. Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency. N Engl J Med. 1997;337:748-53.
2. Dimitrova D, Ong PY, O’Gorman MR, Church JA. Major histocompatibility complex class II deficiency complicated by Mycobacterium avium complex in a boy of mixed ethnicity. J Clin Immunol. 2014;34:677-80.
3. Devaiah BN, Singer DS. CIITA and its dual roles in MHC gene transcription. Front Immunol. 2013;4:476.
4. Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Proc ICI Milan. 2013;2014:164.
5. Durand B, Sperisen P, Emery P, Barras E, Zufferey M, Mach B, et al. RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. EMBO J. 1997;16:1045-55.
6. Klein C, Lisowska-Grospierre B, LeDeist F, Fischer A, Griscelli C. Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome. J Pediatr. 1993;123:921-8.
7. Naamane H, El Maataoui O, Ailal F, Barakat A, Bennani S, Najib J, et al. The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population. Eur J Pediatr. 2010;169:1069-74.
8. Djidjik R, Messaoudani N, Tahiat A, Meddour Y, Chaib S, Atek A, et al. Clinical, immunological and genetic features in eleven Algerian patients with major histocompatibility complex class II expression deficiency. Allergy Asthma Clin Immunol. 2012;8:14.
9. Ben-Mustapha I, Ben-Farhat K, Guirat-Dhouib N, Dhemaied E, Largueche B, Ben-Ali M, et al. Clinical, immunological and genetic findings of a large tunisian series of major histocompatibility complex class II deficiency patients. J Clin Immunol. 2013;33:865-70.
10. Ouederni M, Vincent QB, Frange P, Touzot F, Scerra S, Bejaoui M, et al. Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients. Blood. 2011;118:5108-18.
11. Kallen ME, Pullarkat ST. Type II bare lymphocyte syndrome: role of peripheral blood flow cytometry and utility of stem cell transplant in treatment. J Pediatr Hematol Oncol. 2015;37:e245-9.
12. Alyasin S, Abolnezhadian F, Khoshkhui M. A case of probable MHC class II deficiency with disseminated BCGitis. Iran J Immunol. 2015;12:219---25.
13. Steimle V, Otten LA, Zufferey M, Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell. 1993;75:135-46.
14. Dziembowska M, Fondaneche MC, Vedrenne J, Barbieri G, Wiszniewski W, Picard C, et al. Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. Immunogenetics. 2002;53:821-9.
15. Bontron S, Steimle V, Ucla C, Eibl MM, Mach B. Two novel mutations in the MHC class II transactivator CIITA in a second patient from MHC class II deficiency complementation group A. Hum Genet. 1997;99:541-6.
16. Schmetterer KG, Seidel MG, Kormoczi U, Rottal A, Schwarz K, Matthes-Martin S, et al. Two newly diagnosed HLA class II-deficient patients identified by rapid vector-based complementation analysis reveal discoordinate invariant chain expression levels. Int Arch Allergy Immunol. 2010;152:390-400.
17. Wiszniewski W, Fondaneche MC, Lambert N, Masternak K, Picard C, Notarangelo L, et al. Founder effect for a 26-bp deletion in the RFXANK gene in North African major histocompatibility complex class II-deficient patients belonging to complementation group B. Immunogenetics. 2000;51:261-7.
18. Wiszniewski W, Fondaneche MC, Louise-Plence P, ProchnickaChalufour A, Selz F, Picard C, et al. Novel mutations in the RFXANK gene: RFX complex containing in-vitro-generated RFXANK mutant binds the promoter without transactivating MHC II. Immunogenetics. 2003;54:747-55.
19. Gladstone Pious D. Stable variants affecting B cell alloantigens in human lymphoid cells. Nature. 1978;271:459-61.
20. Siepermann M, Gudowius S, Beltz K, Strier U, Feyen O, Troeger A, et al. MHC class II deficiency cured by unrelated mismatched umbilical cord blood transplantation: case report and review of 68 cases in the literature. Pediatr Transplant. 2011;15:E80-6.
21. Al-Herz W, Alsmadi O, Melhem M, Recher M, Frugoni F, Notarangelo LD. Major histocompatibility complex class II deficiency in Kuwait: clinical manifestations, immunological findings and molecular profile. J Clin Immunol. 2013;33:513-9.
22. Antoine C, Muller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003;361:553-60.
23. Renella R, Picard C, Neven B, Ouachee-Chardin M, Casanova JL, Le Deist F, et al. Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections. Br J Haematol. 2006;134:510-6.
24. Small TN, Qasim W, Friedrich W, Chiesa R, Bleesing JJ, Scurlock A, et al. Alternative donor SCT for the treatment of MHC class II deficiency. Bone Marrow Transplant. 2013;48:226-32.
25. Al-Mousa H, Al-Shammari Z, Al-Ghonaium A, Al-Dhekri H, Al-Muhsen S, Al-Saud B, et al. Allogeneic stem cell transplantation using myeloablative and reduced-intensity conditioning in patients with major histocompatibility complex class II deficiency. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2010;16:818-23.
26. Kuo CY, Chase J, Garcia Lloret M, Stiehm ER, Moore T, Aguilera MJ, et al. Newborn screening for severe combined immunodeficiency does not identify bare lymphocyte syndrome. J Allergy Clin Immunol. 2013;131:1693-5.
27. Wiszniewski W, Fondaneche MC, Le Deist F, Kanariou M, Selz F, Brousse N, et al. Mutation in the class II trans-activator leading to a mild immunodeficiency. J Immunol. 2001;167:1787-94 (Baltimore, Md: 1950).
28. Peijnenburg A, Van den Berg R, Van Eggermond MJ, Sanal O, Vossen JM, Lennon AM, et al. Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene. Immunogenetics. 2000;51:42-9.
29. Quan V, Towey M, Sacks S, Kelly AP. Absence of MHC class II gene expression in a patient with a single amino acid substitution in the class II transactivator protein CIITA. Immunogenetics. 1999;49:957-63.
30. Fondaneche MC, Villard J, Wiszniewski W, Jouanguy E, Etzioni A, Le Deist F, et al. Genetic and molecular definition of complementation group D in MHC class II deficiency. Hum Mol Gen. 1998;7:879-85.
31. Mannhalter JW, Wolf HM, Gadner H, Potschka M, Eibl MM. Cellmediated immune functions in a patient with MHC class II deficiency. Immunol Invest. 1991;20:151-67.
32. Steimle V, Otten LA, Zufferey M, Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). J Immunol. 1993;178:6677-88 (Baltimore Md: 1950) 2007.
33. Guirat-Dhouib N, Baccar Y, Mustapha IB, Ouederni M, Chouaibi S, El Fekih N, et al. Oral HPV infection and MHC class II deficiency (A study of two cases with atypical outcome). Clin Mol Allergy: CMA. 2012;10:6.
34. Prod’homme T, Dekel B, Barbieri G, Lisowska-Grospierre B, Katz R, Charron D, et al. Splicing defect in RFXANK results in a moderate combined immunodeficiency and long-duration clinical course. Immunogenetics. 2003;55:530-9.
35. Lennon-Dumenil AM, Barbouche MR, Vedrenne J, Prod’Homme T, Bejaoui M, Ghariani S, et al. Uncoordinated HLA-D gene expression in a RFXANK-defective patient with MHC class II deficiency, J Immunol. 2001;166:5681-7 (Baltimore, Md: 1950).
36. Nagarajan UM, Peijnenburg A, Gobin SJ, Boss JM, van den elsen PJ. Novel mutations within the RFX-B gene and partial rescue of MHC and related genes through exogenous class II transactivator in RFX-B-deficient cells. J Immunol. 2000;164:3666-74 (Baltimore, Md: 1950).
37. Lisowska-Grospierre B, Fondaneche MC, Rols MP, Griscelli C, Fischer A. Two complementation groups account for most cases of inherited MHC class II deficiency. Hum Mol Gen. 1994;3:953-8.
38. Nagarajan UM, Louis-Plence P, DeSandro A, Nilsen R, Bushey A, Boss JM. RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity. 1999;10:153-62.
39. Masternak K, Barras E, Zufferey M, Conrad B, Corthals G, Aebersold R, et al. A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nature Genet. 1998;20:273-7.
40. Nekrep N, Jabrane-Ferrat N, Wolf HM, Eibl MM, Geyer M, Peterlin BM. Mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome. Nature Immunol. 2002;3:1075-81.
41. Peijnenburg A, Van Eggermond MJ, Gobin SJ, Van den Berg R, Godthelp BC, Vossen JM, et al. Discoordinate expression of invariant chain and MHC class II genes in class II transactivator-transfected fibroblasts defective for RFX5. J Immunol. 1999;163:794-801 (Baltimore, Md: 1950).
42. Peijnenburg A, Van Eggermond MC, Van den Berg R, Sanal O, Vossen JM, Van den Elsen PJ. Molecular analysis of an MHC class II deficiency patient reveals a novel mutation in the RFX5 gene. Immunogenetics. 1999;49:338-45.
43. Villard J, Reith W, Barras E, Gos A, Morris MA, Antonarakis SE, et al. Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency. Human Mut. 1997;10:430-5.
44. Steimle V, Durand B, Barras E, Zufferey M, Hadam MR, Mach B, et al. A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev. 1995;9:1021-32.
45. van Eggermond MC, Tezcan I, Heemskerk MH, van den Elsen PJ. Transcriptional silencing of RFXAP in MHC class II-deficiency. Mol Immunol. 2008;45:2920-8.
46. Villard J, Mach B, Reith W. MHC class II deficiency: definition of a new complementation group. Immunobiology. 1997;198:264-72.
47. Villard J, Lisowska-Grospierre B, van den Elsen P, Fischer A, Reith W, Mach B. Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency. N Engl J Med. 1997;337:748-53.
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Farrokhi, S., Shabani, M., Aryan, Z., Zoghi, S., Krolo , A., Boztug, K., & Rezaei, N. (2018). MHC class II deficiency: Report of a novel mutation and special review. Allergologia Et Immunopathologia, 46(3), 263-275. https://all-imm.com/index.php/aei/article/view/412
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Farrokhi, S., Shabani, M., Aryan, Z., Zoghi, S., Krolo , A., Boztug, K., & Rezaei, N. (2018). MHC class II deficiency: Report of a novel mutation and special review. Allergologia Et Immunopathologia, 46(3), 263-275. https://all-imm.com/index.php/aei/article/view/412