Antigen receptor gene rearrangements immunoglobulin and TCR genes as molecular markers

Many hematopoietic malignancies have no detectable translocation suitable for PCR amplification, and in these cases an alternative strategy is required. In the lymphoid malignancies there is rearrangement of the antigen receptor at the immunoglobulin H (IgH) or TCR genes. The Ig and TCR molecules belong to a group of related proteins termed the immunoglobulin superfamily. Other members include CD8, N-CAM and MHC molecules. The Ig and TCR molecules have many similarities and have been shown to share common amino acid motifs. It is estimated that the immune system requires in excess of 1010 specific antibodies to respond to antigenic determinants encountered in the environment. If each Ig molecule were encoded separately in the germline, most of our genome would consist simply of Ig genes. Elegant work by Tonegawa has shown that Ig and TCR genes exist in the germline state as non-contiguous DNA segments that are rearranged during lymphocyte development (Table 6.4). Gene rearrangement involves recombination of germline gene segments that results in a permanently altered non-germline configuration (Figure 6.4). The process of Ig and TCR gene assembly ensures almost limitless variation of Ig and TCR molecules using only a limited amount of chromosomal DNA. Other features that ensure Ig and TCR variability include imprecise joining of individual V, D and J segments, duplication and inversion of segments, and somatic mutation (in Ig genes) of V, D and J.

Table 6.4 Immunoglobulin and T-cell receptor diversity is achieved through rearrangement of separate germline segments.

Diversity of immunoglobulin and TCR genes

Immunoglobulin

T-cell receptor

HK

X

a

ß

Y

e

V segments

2B0

100

100

60

B0

B

6

D segments

1B

0

0

0

2

0

S

J segments

6

B

4

B0

1S

B

S

VDJ recombination

104

B00

400

S000

2000

40

1B

N regions

2

0

0

1

2

1

4

N region additions

V-D, D-J

None

None

V-J

V-D, D-J

V-J

V-D1, D1-D2

V domains

1010

104

104

106

109

104

101S

V domain pairs

1014

101B

1017

Variable (VH) Diversity (D) Joining (JH)

Random nucleotide addition

Jcon

300-350 bp 250-300 bp 100-120 bp

Fig. 6.4 VDJ rearrangement

Rearrangement of non-contiguous germline V-, D- and J-region segments generates a complete V-D-J complex, which serves as a useful marker of malignancy. FR1, 2 and 3 refer to framework regions 1, 2 and 3, respectively; N, random N nucleotides; Jcon, JH consensus primer. The sizes of the various PCR products are shown (FR1 + Jcon generates a fragment of 300-350 bp, and so on).

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment