Restrictive usage of monoclonal immunoglobulin light chain germline in POEMS syndrome

doi:10.1182/blood-2007-12-126979Prepublished online May 22, 2008;

Nishimura, Sonoko Misawa, Satoshi Kuwabara and Yasushi SaitoYusuke Takeda, Kayo Oda, Shinichi Ozawa, Naomi Shimizu, Shinichi Masuda, Ryuko Cho, Miki Daijiro Abe, Chiaki Nakaseko, Masahiro Takeuchi, Hiroaki Tanaka, Chikako Ohwada, Emiko Sakaida, in POEMS syndrome

light chain germlineΛRestrictive usage of monoclonal immunoglobulin

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Restrictive usage of monoclonal immunoglobulin λ light chain germline in POEMS

syndrome

Daijiro Abe,1 Chiaki Nakaseko,1 Masahiro Takeuchi,1 Hiroaki Tanaka,1 Chikako Ohwada,1

Emiko Sakaida,1 Yusuke Takeda,1 Kayo Oda,1 Shinichi Ozawa,1 Naomi Shimizu,1 Shinichi

Masuda,1 Ryuko Cho,1 Miki Nishimura,1 Sonoko Misawa,2 Satoshi Kuwabara,2 and Yasushi

Saito1

1 Division of Hematology, Department of Clinical Cell Biology, Chiba University Graduate

School of Medicine, Chiba, Japan; and 2 Department of Neurology, Chiba University

Graduate School of Medicine, Chiba, Japan

Corresponding author: Chiaki Nakaseko

Division of Hematology, Department of Clinical Cell Biology, Chiba University Graduate

School of Medicine

1-8-1, Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan

Phone: +81-43-222-7171, FAX: +81-43-225-6502

e-mail: [email protected]

Running head: Restricted λ light chain germline in POEMS

1

Blood First Edition Paper, prepublished online May 22, 2008; DOI 10.1182/blood-2007-12-126979

Copyright © 2008 American Society of Hematology


mailto:[email protected]



Abstract

POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy,

monoclonal gammopathy, and high levels of serum vascular endothelial growth factor

(VEGF), the pathogenesis of which remains unclear. A unique feature of this syndrome is that

the proliferating monoclonal plasma cells are essentially λ-restricted. Here, we determined

complete nucleotide sequences of monoclonal immunoglobulin λ light chain (IGL) variable

regions in 11 patients with POEMS syndrome. The V-region of the Igλ gene of all 11 patients

was restricted to the Vλ1 subfamily. Searching for homologies with IGL germlines revealed

that two germlines, IGLV1-44*01 (9/11) and IGLV1-40*01 (2/10) were identified, with an

average homology of 91.1%. The IGLJ3*02 gene was used in 11/11 rearrangements with an

average homology of 92.2%. These data suggest that the highly restricted use of IGL Vλ1

germlines plays an important role in the pathogenesis of POEMS syndrome.

2




Introduction

POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy,

monoclonal gammopathy, and other paraneoplastic features including organomegaly,

endocrinopathy, skin changes, edema and effusions.1-3 The pathogenesis of this disease is not

well understood, but overproduction of vascular endothelial growth factor (VEGF),

presumably secreted by plasmacytoma cells or platelets, is considered to be responsible for

the characteristic symptoms.4-6 Treatment for POEMS syndrome includes surgical resection or

radiation for plasmacytoma, and chemotherapy, especially high dose melphalan, followed by

autologous peripheral blood stem cell transplantation (auto-PBSCT).7-9 Recently,

thalidomide10,11, lenalidomide12 and anti-VEGF monoclonal antibodies have also been

used.13-15

A unique feature of this syndrome is that the proliferating monoclonal plasma cells are

essentially λ-restricted in most cases, and κ type is extremely rare.16 However, the

pathogenetic role of λ-type M protein in POEMS syndrome is unclear. Here, we determined

complete nucleotide sequences of monoclonal immunoglobulin λ light chain (IGL) variable

regions in patients with POEMS syndrome and found that Vλ germline usage is highly

restricted to the Vλ1 subfamily and very limited germlines.

Study design

This study was approved by the IRB of Chiba University Hospital.

3




Patients

A total of 15 patients (nine men and six women; median age at diagnosis, 54.7 years) were

included in the study (Table 1). All patients met the criteria for the diagnosis of POEMS

syndrome17 and had the five distinctive features of POEMS. The serum monoclonal

immunoglobulin light chain was λ-type in all patients. The serum monoclonal heavy chain

component was IgG in 7 patients and IgA in 8 patients. Informed consent was obtained from

the patients according to the Declaration of Helsinki.

Amplification of monoclonal λ chain gene and sequencing analysis

Total RNA was extracted from bone marrow mononuclear cells of patients with POEMS

syndrome using TRIzol (Invitrogen, Carlsbad, CA) and single-stranded cDNA was

synthesized using Superscript II (Invitrogen). The V-J region of the IGL gene was amplified

by RT-PCR using 5’ degenerate primers for the Vλ1−Vλ2−Vλ3 consensus leader lesion

(5’-ATGGCCKGSWYYSYTCTCCTC-3’) and 3’ primers matching the consensus upstream

part of the cλ exon (5’-CTCCCGGGTAGAGAAGTCACT-3’) as previously described.18 To

identify the amount of monoclonal PCR products, we utilized heteroduplex analysis in which

PCR products are denatured at 95℃ for 5 min and subsequently renatured at 4℃ for 1 hour

to induce homoduplex or heteroduplex formation.19 When sufficient monoclonal PCR product

was available for direct sequencing, PCR products were subjected to cycle sequencing using

the above primers. If the amount was small, homoduplex bands on the polyacrylamide gel

after heteroduplex analysis were excised and monoclonal PCR fragments were eluted from

the solubilized gel slice using QIAEX II (QIAGEN, Valencia, CA) and subjected to cycle

4




sequencing.

Sequence data were analyzed using the database of the International ImMunoGeneTics

information system (IMGT, http://imgt.cines.fr) and mutations were identified by comparison

with the germline sequence. The average mutation rate of the IGL gene was calculated as

previously described.20

Results and Discussion

Of 15 patients with POEMS syndrome who had λ-type M protein, nucleotide sequencing of

the IGL gene was successful in 11 (Table 1). The remaining 4 patients’ samples had none or

too little of the monoclonal band to sequence in heteroduplex analysis. Sequence analysis

revealed that the V-region of the monoclonal Igλ gene of all 11 patients was restricted to the

Vλ1 subfamily. Searching for homologies with IGL germlines revealed that they were derived

exclusively from IGLV1-44*01 (9 patients) or IGLV1-40*01 (2 patients). Complete

nucleotide and amino acid sequences are shown in Figure 1. IGLV rearrangements were

mutated with homologies to germline ranging from 81.5% to 96.1% (average homology:

91.1%). In the IGL-J region, the IGLJ3*2 gene was found in 11 of 11 patients. The

rearrangements were mutated with homologies to germline ranging from 84.1% to 100%

(average homology: 92.2%). All complementarity-determining region 3 (CDR3) were

composed of 11 amino acids, with identical acidic isoelectric point values of 13.0 and similar

molecular weights ranging from 1441.6.7 to 1552.8 (median, 1524.5). The average nucleotide

mutation rate was 8.6% with 7.5% in the framework regions (FWRs) and 11.8% in CDRs.

The ratio of replacement/silent (R/S) mutations was higher in the CDRs than in the FWRs.

In this study, the monoclonal IGL gene could not be analyzed in 4 patients’ samples. Two

5




cases had very small amounts of monoclonal band and the other two had no visible

monoclonal band at amplification by Vλ1-3 degenerate primers. The latter two cases might

have monoclonal IGL genes belonging to a Vλ subfamily other than Vλ1-3.

Analyses of monoclonal light chain genes have been extensively carried out in plasma

cell dyscrasias by others. González et al reviewed four reports of IGL gene usage in Ig-λ type

multiple myeloma and showed that mainly the Vλ1 (27%), Vλ2 (28%) and Vλ3 (41%)

subfamilies were used to a similar extent in λ-type myeloma, and that Vλ4 through Vλ10

subfamily usage was extremely rare (4%).21 Within these families, no clear preference for

individual gene segments was observed. Comenzo et al. reported the results of IGL germline

gene analysis in 39 patients with AL amyloidosis.22 The clonal AL gene subfamily belonged

to different subfamilies, including Vλ1 (26%), Vλ2 (13%), Vλ3 (15%), Vλ6 (28%) and Vκ1

(18%). Other germline genes were used, of which the IGLV6S1 germline of the Vλ6

subfamily was relatively dominant. We found that the monoclonal IGLV gene of all 11

POEMS patients belonged to the Vλ1 subfamily with only 2 germlines of Vλ1 represented.

There has been only one other report of IGLV gene analysis in POEMS syndrome by a French

group.18 In that study, Soubrier et al. found that both of the two cases analyzed were derived

from the Vλ1-IGLV1-40 germline, the same as in our study (Figure1A, C). Taken together

with our results, currently available data on thirteen cases indicate that IGLV genes are

restricted to the two Vλ1 germlines, IGLV1-44 in 9 and IGLV1-40 in 4 across two ethnically

different populations.

Why is the λ light chain germline repertoire so restrictive and what links exist between

germline gene use and VEGF in POEMS syndrome? Perfetti et al reported that amyloid V

regions were highly mutated in AL Amyloidosis and amyloidogenic light chains undergo

antigen-driven selection.23 Because the average nucleotide mutation rate and the R/S mutation

6




ratio were higher in the CDRs than in the FWRs, restricted light chains might undergo

antigen-driven selection in POEMS. These restricted λ chain might interact with

VEGF-related protein and play a role in VEGF secretion. In myeloma, interactions between

light-chain CDR3 sites and proteins such as Tamm-Horsfall proteins have been previously

described.24 However, the higher R/S mutation ratio in the CDRs and retention of cysteine

residues in FR1 and FR3 which were critical to structure suggest that these specific light

chains might interact with VEGF-related protein at FRWs but not CDRs like B-cell

superantigen.25

In conclusion, IGL-M protein in POEMS syndrome belongs to the Vλ1 subfamily and is

markedly restricted to a very limited number of germlines. Although exact mechanisms

responsible for this syndrome are still unclear, these data suggest that the restricted use of IGL

plays an important role in pathogenesis and may represent a new clinical entity. Further

studies are required to clarify the relationship between high VEGF levels and restricted usage

of Vλ genes in POEMS syndrome.

7




Acknowledgments

We thank Ms. Megumi Naito for technical assistance and Ms. Kimie Shibuya for secretarial

assistance. Also we thank Dr. Takeshi Tokuhisa and Dr. Akemi Sakamoto of Department of

Developmental Genetics, Chiba University Graduate School of Medicine for helpful

discussions.

Authorship

Contribution: D.A., C.N., M.T., H.T., C.O., and Y.S. designed the research. D.A., and C.N.

performed research, analyzed data, and wrote the paper. E.S., Y.T., K.O., S.O., N.S., S.M.,

R.C., and M.N. designed the research and analyzed data. S.M., and S.K. organized collection

of patient samples. All authors approved the final version of the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

8




References

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dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes:

the POEMS syndrome. Report on two cases and a review of the literature. Medicine

(Baltimore). 1980;59:311-322.

2. Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term

outcome. Blood. 2003;101:2496-2506.

3. Miralles GD, O'Fallon JR, Talley NJ. Plasma-cell dyscrasia with polyneuropathy. The

spectrum of POEMS syndrome. N Engl J Med. 1992;327:1919-1923.

4. Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular

endothelial growth factor (VEGF) in POEMS syndrome. Lancet. 1996;347:702.

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growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome.

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6. Hashiguchi T, Arimura K, Matsumuro K, et al. Highly concentrated vascular endothelial

growth factor in platelets in Crow-Fukase syndrome. Muscle Nerve. 2000;23:1051-1056.

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chemotherapy for POEMS syndrome. J Neurol Neurosurg Psychiatry. 1997;63:385-387.

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8. Dispenzieri A, Moreno-Aspitia A, Suarez GA, et al. Peripheral blood stem cell

transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood.

2004;104:3400-3407.

9. Kuwabara S, Misawa S, Kanai K, et al. Autologous peripheral blood stem cell

transplantation for POEMS syndrome. Neurology. 2006;66:105-107.

10. Sinisalo M, Hietaharju A, Sauranen J, Wirta O. Thalidomide in POEMS syndrome: case

report. Am J Hematol. 2004;76:66-68.

11. Kim SY, Lee SA, Ryoo HM, Lee KH, Hyun MS, Bae SH. Thalidomide for POEMS

syndrome. Ann Hematol. 2006;85:545-546.

12. Dispenzieri A, Klein CJ, Mauermann ML. Lenalidomide therapy in a patient with

POEMS syndrome. Blood. 2007;110:1075-1076.

13. Straume O, Bergheim J, Ernst P. Bevacizumab therapy for POEMS syndrome. Blood.

2006;107:4972-4973; author reply 4973-4974.

14. Badros A, Porter N, Zimrin A. Bevacizumab therapy for POEMS syndrome. Blood.

2005;106:1135.

15. Kanai K, Kuwabara S, Misawa S, Hattori T. Failure of treatment with anti-VEGF

monoclonal antibody for long-standing POEMS syndrome. Intern Med. 2007;46:311-313.

16. Dispenzieri A. POEMS syndrome. Blood Rev. 2007;21:285-299.

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17. Dispenzieri A. POEMS Syndrome. Hematology Am Soc Hematol Educ Program.

2005:360-367.

18. Soubrier M, Labauge P, Jouanel P, Viallard JL, Piette JC, Sauvezie B. Restricted use of

Vlambda genes in POEMS syndrome. Haematologica. 2004;89:ECR02.

19. Langerak AW, Szczepanski T, van der Burg M, Wolvers-Tettero IL, van Dongen JJ.

Heteroduplex PCR analysis of rearranged T cell receptor genes for clonality assessment in

suspect T cell proliferations. Leukemia. 1997;11:2192-2199.

20. Chang B, Casali P. The CDR1 sequences of a major proportion of human germline Ig

VH genes are inherently susceptible to amino acid replacement. Immunol Today.

1994;15:367-373.

21. Gonzalez D, van der Burg M, Garcia-Sanz R, et al. Immunoglobulin gene

rearrangements and the pathogenesis of multiple myeloma. Blood. 2007;110:3112-3121.

22. Comenzo RL, Wally J, Kica G, et al. Clonal immunoglobulin light chain variable region

germline gene use in AL amyloidosis: association with dominant amyloid-related organ

involvement and survival after stem cell transplantation. Br J Haematol. 1999;106:744-751.

23. Perfetti V, Ubbiali P, Vignarelli MC, et al. Evidence that amyloidogenic light chains

undergo antigen-driven selection. Blood. 1998;91:2948-2954.

24. Ying WZ, Sanders PW. Mapping the binding domain of immunoglobulin light chains for

Tamm-Horsfall protein. Am J Pathol. 2001;158:1859-1866.

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25. Levinson AI, Kozlowski L, Zheng Y, Wheatley L. B-cell superantigens: definition and

potential impact on the immune response. J Clin Immunol. 1995;15:26S-36S.

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13

Figure legend

Figure 1 Complete nucleotide and amino acid sequences of monoclonal IGL gene in

POEMS syndrome.

(A) Complete nucleotide sequences of two cases (No. 1 and 2) and previously reported two

cases by Soubrier et al (A and B)18 with the IGLV1-40*01 germline,

(B) Complete nucleotide sequences of nine cases with the IGLV1-44*01 germline,

(C) Complete amino acid sequences of these thirteen cases.

FR indicates framework; CDR, complementarity-determining region; Hyphens (-) show

nucleotide or amino acid identity and dots (.) represent gaps.




Table 1 Characteristics of patients and sequencing analysis of monoclonal IGL gene in POEMS syndrome

Patient Age at Sex M Bone marrow Serum Homoduplex Vλ IGLV gene IGLJ gene No. diagnosis, y protein plasma cells, VEGF, band subfamily

% pg/ml Germline Homology Germline Homology

1 31 F IgA-λ 6.2 >2,000 + Vλ1 IGLV1-44*01 90.4% IGLJ3*02 92.1% 2 37 M IgG-λ 1.0 >2,000 - ND ND ND 3 42 M IgG-λ 1.4 7,160 ± ND ND ND 4 57 F IgG-λ 0.4 1,920 + Vλ1 IGLV1-40*01 91.2% IGLJ3*02 84.1% 5 53 M IgA-λ 2.2 2,580 + Vλ1 IGLV1-44*01 92.9% IGLJ3*02 94.7% 6 49 M IgG-λ 1.4 1,640 + Vλ1 IGLV1-44*01 84.0% IGLJ3*02 89.2% 7 58 M IgG-λ 2.4 2,020 - ND ND ND 8 69 F IgA-λ 1.2 2,730 + Vλ1 IGLV1-44*01 96.1% IGLJ3*02 97.3% 9 69 F IgG-λ 1.4 1,750 + Vλ1 IGLV1-44*01 81.5% IGLJ3*02 81.1%

10 73 M IgG-λ 2.2 4,720 + Vλ1 IGLV1-40*01 91.6% IGLJ3*02 94.4% 11 66 F IgA-λ 1.6 >2,000 ± ND ND ND 12 40 M IgA-λ 2.2 5,110 + Vλ1 IGLV1-44*01 93.6% IGLJ3*02 97.3% 13 65 M IgA-λ 0.8 7,970 + Vλ1 IGLV1-44*01 95.4% IGLJ3*02 100% 14 53 F IgA-λ 0.1 2,440 + Vλ1 IGLV1-44*01 88.3% IGLJ3*02 89.2% 15 58 M IgA-λ 1.2 2,950 + Vλ1 IGLV1-44*01 96.9% IGLJ3*02 94.6% Median 54.7 1.4 ND indicates not determined; M, male; F, female; +, present; -, not present; and ±, slightly present.

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Figure 1A <------------------------------------ FR1------------------------------------>________________ CDR1 ______________

IGLV1-40*01 cagtctgtgctgacgcagccgccctca...gtgtctggggccccagggcagagggtcaccatctcctgcactgggagcagctccaacatcggggcaggttatgat.........

No.4 ---------------------g-----...-----------------t-----------------------g----c--at--g---t-----------------.........

No.10 --------a------------------...-------------t------c--a---------------t---------a-------c-------t----t----.........

A aga-----------------------g...-------a------------------------------t-------c-g--------------------------.........

B -cagtc------g--------------...-------------------------------------------------a---------g-------------g-.........

<---------------------- FR2 ---------------------->_____________ CDR2 ___________<-------------- FR3 -------------

IGLV1-40*01 gtacactggtaccagcagcttccaggaacagcccccaaactcctcatctatggtaacagc.....................aatcggccctcaggggtccct...gaccgattc

No.4 --ga----------a--cg---------------------------------------tt.....................g------------aa------...---------

No.10 ---a-------------a----------------------------------c-----t-.....................---------------a-----...---------

A ---a-t-----t------t---------g-------cg------------c-c---t-a-.....................---------------------...---------

B ---a----------a—-a--------gg---------g-----------------g—-a-.....................-t-------------------...---------

------------------------------------- FR3 ----------------------------------------->__________ CDR3 ________

IGLV1-40*01 tctggctccaag......tctggcacctcagcctccctggccatcactgggctccaggctgaggatgaggctgattattactgccagtcctatgacagcagcctgagt

No.4 ----------g-......---------------------------g----------------c--------ct------------------t-----a-gt---cct-

No.10 ------------......--------------------------------------------c------t--c-g----tt--t-----g-t-----a--tt----ac

A -----g------......--------t----g------------------------------a-----------c---------------------------------

B ------------......--------------------------------c----g----------------cg-----t-----------------a--------ct

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Figure 1B <------------------------------------ FR1 ----------------------------------->______________ CDR1 ________________ IGLV1-44*01 cagtctgtgctgactcagccaccctca...gcgtctgggacccccgggcagagggtcaccatctcttgttctggaagcagctccaacatcggaagtaatact............ No.1 --------c-----------t------...---------g------------------g---------c------gc--a----c--------gaa---c--............ No.5 ---------------------------...---------------------------------c-------c---g-----------------------g--............ No.6 ---------------------------...-----------------a------------t-g------------g--cc--t---tc-t---ct-t--t--............ No.8 ---------t---t-------------...------------------------a--------------------------------------------c--............ No.9 ------c-------------g------...-t-----c---------c---------t-------g-------------t-at-gga-ctcatg--.................. No.12 ---------t-----------------...---------g--------------a------------------------a----------------c--c--............ No.13 ------------------g---t----...----------------------------------------------------------------c-----t-............ No.14 --------t------------------...-t-------------------------------------------g--c-t-----tc---tt-cc---c--............ No.15 ---------------------------...---------------------------------------------------------------------ga-............ <---------------------- FR2 ---------------------->_____________ CDR2 ___________<--------------- FR3 ------------ IGLV1-44*01 gtaaactggtaccagcagctcccaggaacggcccccaaactcctcatctatagtaataat.....................cagcggccctcaggggtccct...gaccgattc No.1 --c----------g--------------------------------------a--c-g--.....................-t-------ca----------...--------- No.5 -cc--t-----------c----------------------------------a-g-c---.....................-gc------------------...--------- No.6 --c-----------a-ttg--a-g---t-----------g-------t--c-a-g--c--.....................g----------t---------...--------- No.8 -----t-----------a-------------------g---------g----c-------.....................---------------------...--------- No.9 -----t-----------at------------------g----g---------a--c----.....................g--a----------ca-a---...-g------t No.12 --c--------------c--------g------------------------ta-------.....................--------------------g...--------t No.13 ---c----------a--ca--t-------------------------t-------c-g--.....................g--------------------...--------- No.14 -----t----t-a----c--t---------------g----------------a------.....................--a--c---------------...------a—- No.15 --g--------t-----ct--------------------------------------g--.....................---------------------...--------- --------------------------------------- FR3 --------------------------------------->__________ CDR3 ________ IGLV1-44*01 tctggctccaag......tctggcacctcagcctccctggccatcagtgggctccagtctgaggatgaggctgattattactgtgcagcatgggatgacagcctgaat No.1 a-----------......--------t-----------------------------------c------------------------a------ta------------ No.5 --c-c-------......-----------ta---------------c-------------------------------------t--t----------------c--c No.6 ------------......-----------------------------c-c-----gc-----a--------c--a--c-t----t--t-c-------cgg-------- No.8 ------------......-------------------------------------------------------------------t---------g----a------- No.9 ------------......------t--------g--------c--------gc--t-g-------c------tt---c-tt----tga-----a-c---g----c--- No.12 ---------gc-......-------------------------------------------------------------t----t---t-----------t-----t- No.13 ------------......----------------------------------------------------------------------------------c------- No.14 -----g------......--------------------------------c----g-g-c--------------c---------t-tt-g-----a-----ta----- No.15 ------------......---------------------------------------------------------------------a-------------t------

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Figure 1C FR1 CDR1 FR2 CDR2 FR3 CDR3

(1-26) (27-38) (39-55) (56-65) (66-104) (105-)

__________________________ ____________ _________________ __________ _______________________________________ ___________

1 10 20 30 40 50 60 70 80 90 100 110

.........│.........│...... ...│........ .│.........│..... ....│..... ....│.........│.........│.........│.... .....│....

IGLV1-40*01 QSVLTQPPS.VSGAPGQRVTISCTGS SSNIGAGYD... VHWYQQLPGTAPKLLIY GNS....... NRPSGVP.DRFSGSK..SGTSASLAITGLQAEDEADYYC QSYDSSLSG

N0.4 -------A-.---------------T N--F-----... -N---HV---------- --I....... D---E--.------R..---------A----D---Y--- --F-NV-L-WV

No.10 ---------.----L-H------S-- N--L---F-... -N--------------- A-I....... -----I-.-------..--------------D--SQ-F- --F-NI-N-WV

A R--------.--E------------- G--------... –N----F--R--R---- A-N....... -------.-------..----G----------------- --------

B PV--A----.---------------- N--M----G... –N-------A--R---- -SN....... I------.-------..------------R-----R-F- ----N--T

IGLV1-44*01 QSVLTQPPS.ASGTPGQRVTISCSGS SSNIGSNT.... VNWYQQLPGTAPKLLIY SNN....... QRPSGVP.DRFSGSK..SGTSASLAISGLQSEDEADYYC AAWDDSLNG

No.1 ---------.---A-----S-----A N-H--E-P.... ----R------------ NTD....... L--Q---.---T---..--------------D------- -T-V----AWV

No.5 ---------.-----------P---G -------A.... A----H----------- ND-....... R------.----A--..----T----T------------ SS-------WV

No.6 ---------.----------L----G PF-L-LYS.... -----LVT-S---V--- NDH....... E------.-------..----------A-R-----E-F- SS--AG---WV

No.8 ----I----.--------I------- -------P.... ------------R--M- T--....... -------.-------..---------------------- V--E-N---WV

No.9 --L------.V-A------S------ IIGTHG...... ------F-----R-V-- NT-....... E----I-.G------..--S--A--L--ALA----F-F- VT-N-G---WV

No.12 ---------.---A----I------- N-----HP.... -----H----------- Y--....... -------.------A..--------------------F- SV---I-I-WV

No.13 ------AL-.---------------- -----T-I.... -H---HIS--------- -TD....... E------.-------..---------------------- -----T--AWV

No.14 ---------.V--------------G R--LVT-P.... ---FKH------E---- R--....... -------.--I----..------------RA-------- SS-E--M—WV

No.15 ---------.---------------- ----E—-D.... -----HF---------- --D....... -------.-------..---------------------- -T---I---

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Restrictive usage of monoclonal immunoglobulin light chain germline in POEMS syndrome

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