Immunoglobulin Allotypes

The products of allelic forms of the same gene are known as allotypes. Allotypes are now known for all mouse heavy chains (Stall, 1995). There are no known serologically detectable allotypes of mouse k chains. The constant regions of XI chains of mice show a single amino acid difference between BALB/c and SJL mice (Arp et al., 1982). In the rat, the k chains show extensive polymorphism, and variants have also been described for a, y2b and ylc chains (Gutman, 1986; Bazin etal., 1990).

Immunoglobulin allotypes are important for several reasons. They allow genetic linkage studies to be carried out, and the origin of immunoglobulins to be determined in cell transfer experiments. They were central in demonstrating allelic exclusion (see later), in showing that variable and constant region genes were linked, and in showing that all the heavy chain genes are linked to each other. However, a detailed account of the esoteric world of immunoglobulin allotypes is beyond the scope of this book. A comprehensive review of mouse immunoglobulin allotypes is given by Stall (1995).

The heavy chain locus in the mouse is designated Igh, and the constant region loci are designated Igh-C. The genes are named in order of discovery Igh-1 to Igh-8 (Table 6.1). (Note that the order of the genes on the chromosome is completely different; see Fig. 6.1.) Alleles at each locus are designated by superscripts (e.g. Igh-lb). The combination of Igh-C alleles in a particular mouse strain is known as a haplotype. In many cases the haplotype designation is the same letter as the allele for that strain at the Igh-1 (y2a) locus (Table 6.2).

The structural basis for immunoglobulin allotypes is now well understood. The variation appears to fall into two categories. In some cases, there are single point mutations, such as for mouse IgM (Schreier et al., 1986). These are known as 'simple' allotypes. Some allotypes are classified as 'complex', because there are multiple amino acid substitutions at several different regions of the chain (Sheppard and Gutman, 1981a, b; Olio and Rougeon, 1983). In the former case, the variation can be explained by simple point mutations, but in the case of allotypes with multiple substitutions between alleles, more complex genetic mechanisms such as gene conversion have probably been responsible (Sheppard and Gutman, 1981a, b; Olio and Rougeon, 1983).

Table 6.1 Locus symbols for mouse immunoglobulin heavy chains

Constant region Igh-C

Constant region loci lgh-1 (y2a)

lgh-2 (a) lgh-3 (y2b) lgh-4 (y1) lgh-5 (6) lgh-6 (n) lgh-7 (e) lgh-8 (y3)

Table 6.2 Distribution of alleles of the Igh-C loci in the Igh-C haplotypes Haplotype Prototype lgh-6 lgh-5 lgh-8* lgh-4 lgh-3 lgh-1 lgh-7 lgh-2

Strain

M-

5

V3

Y1

y2b

Y2a

e

a

a

BALB/c

a

a

a

a

a

a

a

a

b

C57BL10/J

b

b

a

b

b

b

b

b

c

DBA/2

a

a

a

a

a

c

?

c

d

AKR/J

n(df

a

a

d

d

d

a

d

e

A/J

e

e

a

a

e

e

a

d

f

CE/J

a

a

a

a

f

f

?

f

g

Rill/)

a

a

a

a

g

g

?

g

h

SEA/J

a

a

a

a

a

h

?

a

i

CBA/H

a

a

a

a

a

j

a

k

KH-1*

?

?

a

a

a

k

?

c

1

KH-2f

?

?

a

a

a

1

?

c

m

Kyf

?

?

a

b

b

m

?

b

n

NZB

n{d)

a

a

d

e

e

?

d

o

AL/N

e

e

a

a

d

d

?

?

P

SWR/J

?

?

?

?

f

c

?

?

* Allelic forms of y3 chains have only been found in wild mice and the SPE strain of Mus spretus (Huang et a/., 1984; Amor eta/., 1984).

' Haplotypes derived from wild mice.

* This allele was first identified in NZB mice and is thus given the designation lgh-6n. However, recent studies indicate that it is common to both AKR and NZB and should be designated lgh-6d.

I am grateful to Dr Alan Stall for providing me with updated information for this table. For further information, see Stall (1995).

* Allelic forms of y3 chains have only been found in wild mice and the SPE strain of Mus spretus (Huang et a/., 1984; Amor eta/., 1984).

' Haplotypes derived from wild mice.

* This allele was first identified in NZB mice and is thus given the designation lgh-6n. However, recent studies indicate that it is common to both AKR and NZB and should be designated lgh-6d.

I am grateful to Dr Alan Stall for providing me with updated information for this table. For further information, see Stall (1995).

Allotypic variation can affect many properties of antibodies. Heterologous antisera (e.g. rabbit anti-mouse IgG) may have a pronounced bias towards a particular haplotype. For example, one such antiserum reacted about 20-fold more strongly against IgG2a of the a haplotype than the b haplotype (Stall, 1995). If this difference is not appreciated, it could potentially cause serious errors in experimental measurements of antibody levels. Allotypic variation can also affect physical properties such as solubility, binding to staphylococcal protein A (Seppala et al., 1981) and electrophoretic mobility (Herzenberg et al., 1967). Mouse IgG of the b allotype (i.e. from C57BL and related strains) is less soluble than IgG of the a allotype (from BALB/c).

In BALB/c mice, the light chains of myeloma IgA are disulfide-bonded to each other and not to the heavy chains, while the conventional IgA structure is seen in myelomas from NZB mice (Warner and Marchalonis, 1972). A similar genetic variation is seen in human IgA2 (Grey et al., 1968). The different arrangement of disulfide bonds seen in BALB/c and NZB IgA myeloma proteins could have reflected the known allotypic difference, but it has been shown that each strain produces both forms of IgA, and that in each strain both forms share the serological allotypic characteristics of that strain (Stanisz et al., 1983). It would therefore appear that the myeloma proteins are not necessarily typical of the structure of all IgA molecules produced by these strains. These mouse strains have a single a chain gene (Lai et al., 1989), so the dimorphism in mouse IgA structure is probably not a consequence of the known allotypic differences in a chain (see Stanisz et al., 1983, for further discussion).

By a process of repeated backcrossing, a number of 'allotype congenic' partner strains of mice have been produced, in which the heavy chain locus derived from one strain is transferred to the other strain (see Stall, 1995). These pairs are histocompatible, and allow the transfer of lymphoid cells between them. The use of anti-allotype antibodies can then allow the identification and quantification of cells and antibodies derived from the donor and the recipient.

Allotypes of membrane immunoglobulin are particularly useful in tracing the origin of lymphocytes in cell transfer experiments. Allelic variation has been described for membrane IgD (Goding etal., 1976) and IgM (Black et al., 1978), and numerous monoclonal antibodies have been described that recognize allotypic determinants membrane immunoglobulin (Oi et al., 1978; Stall and Loken, 1984; Schuppel etal, 1987; reviewed by Stall, 1995).

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