Tissue Antigens ISSN 0001-2815
LETTER TO THE EDITOR
A peculiar case of recombination at HLA–A locus M. N. Mishra1 , M. S. Bindra2 & V. Lal1 1 Department of Transplant Immunology, Dr Lal Path Labs Pvt. Ltd., National Reference Laboratory, New Delhi, India 2 Department of Pathology, Army Hospital R&R, New Delhi, India
Recombination of human leukocyte antigen (HLA) antigens during meiosis can lead to difficulty in haplotype construction which is mandatory for work up of patients for bone marrow transplantation. We report on a patient who showed recombination at A locus of his paternal chromosome. HLA typing at low resolution was performed as per the protocol by Luminex-Reverse sequence specific oligonucleotide probes using (Genprobe Lifecodes, Stanford, CA) kits for family members of a 4-year-old child diagnosed to be having acute lymphoblastic leukemia. Haplotype construction was performed manually as results of patient, his parents and siblings were available. The patient’s sample was retyped by sequence specific primers using Innotrain (Gmbh, Ketsch, Germany) as his haplotype could not be explained by the codominant inheritance of HLA molecules which follow Mendelian laws of inheritance. The paternal and maternal haplotypes were (a, b) and (c, d), respectively, and are shown in Table 1. The patient turned out to be (b/a, d) and his sibling was (b, d). The incidence of meiotic recombination is approximately 1% (1). We have previously reported on two cases of recombination (2). It may occur simultaneously at more than one locus (3) and sometimes lead to formation of novel alleles (4). Recombination should be distinguished from loss of heterozygosity in which will show as an undetected antigen and this can be confirmed by typing a sample from buccal mucosa or even a peripheral blood sample when the peripheral blast count is low (4). This should be specially thought of when the results of haplotype construction are unexpected. There may be undetected recombinations at the antigens not typed during the work of patients which also highlights the importance of typing for C and DQB1 antigens, as many centers requisition only ABDR typing and this may lead to significant graft versus host disease. If complete HLA typing has not been carried out this may be done when unexpected GVHD occurs in an apparently fully matched BMT.
The case report highlights the significance of recombination of HLA antigens and importance of ABCDRDQB1 typing even for related patients. Conflict of interests
The authors have declared no conflicting interests. Correspondence M. N. Mishra Department of Transplant Immunology Dr Lal Path Labs Pvt. Ltd. National Reference Laboratory New Delhi India Tel: +91 11 30244178 e-mail: [email protected] doi: 10.1111/tan.12353
References 1. Pandey JP. Major histocompatibility complex. In: Virella G, ed. Medical Immunology, 6th edn. USA: Informa Health Care, 2007, 23–34. 2. Mishra MN, Sharma A. Recombination in human leukocyte antigen region in two Asian Indian families. Indian J Hum Genet 2012: 18: 109–11. 3. Luo Y, Sun YY, Jin L et al. An unusual recombination event occurring between HLA-B and -Cw loci within a Chinese Han family. Zhonghua Yi Xue Za Zhi 2006: 86: 628–31(in Chinese). 4. Coppage M, Iqbal A, Ahmad A, Becker MW. Leukemia specific loss of heterozygosity of MHC in a CLL patient: disease state impacts timing of confirmatory typing. Hum Immunol 2013: 74: 41–4.
Table 1 Haplotypes of patient and family membersa
Father (a, b) Mother (c, d) Patient (b/a, d) Sibling (b, d) a The
234
A
B
C
DRB1
DQB1
DRB3/4/5
*03, *02 *02, *26 *02, *26 *02, *26
*37, *52 *08 *07 *37, *07 *52, *07
*06, *12 *07 *07 *06, *07 *12, *07
*10, *15 *03, *09 *10 *09 *15, *09
*05, *06 *02, *03 *05, *03 *06, *03
DRB5 DRB3, DRB4 DRB4 DRB5, *DRB4
first of the HLA A, B, C, DRB1 and DQB1 antigens comprise the first haplotype.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 234
LETTER TO THE EDITOR
A peculiar case of recombination at HLA–A locus M. N. Mishra1 , M. S. Bindra2 & V. Lal1 1 Department of Transplant Immunology, Dr Lal Path Labs Pvt. Ltd., National Reference Laboratory, New Delhi, India 2 Department of Pathology, Army Hospital R&R, New Delhi, India
Recombination of human leukocyte antigen (HLA) antigens during meiosis can lead to difficulty in haplotype construction which is mandatory for work up of patients for bone marrow transplantation. We report on a patient who showed recombination at A locus of his paternal chromosome. HLA typing at low resolution was performed as per the protocol by Luminex-Reverse sequence specific oligonucleotide probes using (Genprobe Lifecodes, Stanford, CA) kits for family members of a 4-year-old child diagnosed to be having acute lymphoblastic leukemia. Haplotype construction was performed manually as results of patient, his parents and siblings were available. The patient’s sample was retyped by sequence specific primers using Innotrain (Gmbh, Ketsch, Germany) as his haplotype could not be explained by the codominant inheritance of HLA molecules which follow Mendelian laws of inheritance. The paternal and maternal haplotypes were (a, b) and (c, d), respectively, and are shown in Table 1. The patient turned out to be (b/a, d) and his sibling was (b, d). The incidence of meiotic recombination is approximately 1% (1). We have previously reported on two cases of recombination (2). It may occur simultaneously at more than one locus (3) and sometimes lead to formation of novel alleles (4). Recombination should be distinguished from loss of heterozygosity in which will show as an undetected antigen and this can be confirmed by typing a sample from buccal mucosa or even a peripheral blood sample when the peripheral blast count is low (4). This should be specially thought of when the results of haplotype construction are unexpected. There may be undetected recombinations at the antigens not typed during the work of patients which also highlights the importance of typing for C and DQB1 antigens, as many centers requisition only ABDR typing and this may lead to significant graft versus host disease. If complete HLA typing has not been carried out this may be done when unexpected GVHD occurs in an apparently fully matched BMT.
The case report highlights the significance of recombination of HLA antigens and importance of ABCDRDQB1 typing even for related patients. Conflict of interests
The authors have declared no conflicting interests. Correspondence M. N. Mishra Department of Transplant Immunology Dr Lal Path Labs Pvt. Ltd. National Reference Laboratory New Delhi India Tel: +91 11 30244178 e-mail: [email protected] doi: 10.1111/tan.12353
References 1. Pandey JP. Major histocompatibility complex. In: Virella G, ed. Medical Immunology, 6th edn. USA: Informa Health Care, 2007, 23–34. 2. Mishra MN, Sharma A. Recombination in human leukocyte antigen region in two Asian Indian families. Indian J Hum Genet 2012: 18: 109–11. 3. Luo Y, Sun YY, Jin L et al. An unusual recombination event occurring between HLA-B and -Cw loci within a Chinese Han family. Zhonghua Yi Xue Za Zhi 2006: 86: 628–31(in Chinese). 4. Coppage M, Iqbal A, Ahmad A, Becker MW. Leukemia specific loss of heterozygosity of MHC in a CLL patient: disease state impacts timing of confirmatory typing. Hum Immunol 2013: 74: 41–4.
Table 1 Haplotypes of patient and family membersa
Father (a, b) Mother (c, d) Patient (b/a, d) Sibling (b, d) a The
234
A
B
C
DRB1
DQB1
DRB3/4/5
*03, *02 *02, *26 *02, *26 *02, *26
*37, *52 *08 *07 *37, *07 *52, *07
*06, *12 *07 *07 *06, *07 *12, *07
*10, *15 *03, *09 *10 *09 *15, *09
*05, *06 *02, *03 *05, *03 *06, *03
DRB5 DRB3, DRB4 DRB4 DRB5, *DRB4
first of the HLA A, B, C, DRB1 and DQB1 antigens comprise the first haplotype.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 234
