IMMUNOLOGY TODAY

Ghetie, V., Hubbard, J.G., Kim, J.K., Tsen, M.F., Lee, Y. and Ward, E.S. (I 996) Abnormally short

serum half-lives of IgG in P2-microglobulin-

deficient mice. Eur. J. Immuol. 26, 690-696

Two important and seemingly separate

areas of research regarding IgG function

have been brought together by a recent

publication demonstrating that the neona-

tal IgG Fc receptor termed FcRn may have

another important role throughout life in

mainlaining plasma IgG Ieve!!. IgG is a

very unusual plasma protein in that it has a

biological halt-life measured in weeks com-

pared with one of days for 1gM and IgA.

This is important in that high-titre IgG re-

sponses to antigen can be sustained for

many months following infection. In the

mid-1960s, a hypothesis was proposed to

explain this extended half-life: a receptor

was suggested to be responsible for pro-

tecting IgG from degradation, recycling tl!e

antibody back to the plasma. Saturation of

this receptor would thus maintain a homeo-

static balance between IgG synthesis and

degradation. However, the nature of the re-

ceptor has proved elusive.

In parallel, the observation that maternal

IgG is transported to the neonate prompted

the identification of a candidate transport

receptor, termed FcRn, that was homolo-

gous to major histocompatibility complex

(MHC) class 1 molecules. F&n has an 01-

heavy chain and a &-microglobulin (m)-

light chain; it can bind to a highly conserved

region of IgG with high avidity at low pH,

but releases it again at neutral pH. Mice de-

ficient for this receptor Q&-m knockout) are

incapable of acqniring maternal IgG as

neonates. In this paper it is shown that these

same mice have lower plasma IgG levels

and a shorter plasma half-life for !gG

throughout life. It seems most likely that the

same receptor is involved in both of these

properties of I$ and it points to important

new avenues of work to pursue with regard

to understanding the role of FcRn ii? uizn.

Mike Clark (mrc7@cam.ac.uk) is at the Dept of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK CB2 1YP.

No;vrli, A. and Monroe, J.G. (1996) Acquisition of surface IgD fails to protect from rolerance

induction: both surface IgM- and igD-mediated signals induce apoptosis of immature murine 6

lymphocytes.]. Immunol. 156, i328-1332

Immature B cells go through a window of

development in which thiy ale exquisitely

sensitive to alttigen-reccpto; i;l,!-ccd tolcr-

ante. This period correlates very closely

with expression of surface immunoglobulin

(sIg) M but little or no sIgD. The level of

sIgD gradually rises until expression is five-

to tenfold more than slgM, during which

time the maturing B cell becomes resistant

to tolerization. These circumstantial associ-

ations have led to a general paradigm that

antigen-induced signalling through slghl

alone resulted in deletion or ancrgy of im-

mature B cells, whereas hgation ot slgU

provided a dominant positive signal, pro-

tecting the cell from negatitpe selection.

Years of work have failed to confirm this

hypothesis directly, although data have sug-

gested that qualitahvelp different signals are

generated through slgM and slgD. Here,

Norvell and Munroe revisit this conundrum

by examining the new bone-marrow em,-

grant B cells from BALB/c mice 14 days

after sublethal irradiation. These highly

tolerance-sensitive cells coexpress slgD and

slgM, arc l&Ah’ and express the marker

BP-1 -all the hallmarks of immature B ceils.

So, do they show differential effects of

ligation of slgD \‘s. slgM! Apparently not.

Ligation of both isotypey, alone or together,

did not lead to proliferation. In fact, ligation

of either sIgD or slgM produced the same

effect - induction of apoptosis, 2s measured

by propidium iodide staining. II: co*:!r,~$c-

lion of this long-standing prenlise, ligation

of slgD at the same time as slgM did not

inhibit induction of cell death.

Naturally, it may be argued that the pres-

ence and activity of costimulatorl/ molecules

such as CD40 or B7 can modifv the effect5 of

ligating these slg isotypes, such that the roles

ascribed to slgM and slgD on immature B

sells might still become evident, as envis-

aSed by the ‘tolrrogc!lic vs. protective’ hy-

pothrsis. If not, then some new thinking ~11

the real functiorl ot IgD is .~gently required.

Schilham. M., Oosterwegel. M.A., Moerer, P. et al. (I 996) Defects In cardiac outflow tract formatlon

and pro-B-lymphocyte expansion in mice lacking Sax-4. Nature 380, 7 I l-7 I4

The so called SOS genes encode a large fam-

ily of DNA-binding proteins of which the

prototypic member is the Y-chromosomal

sex-determining gene Sr!/. Another member,

SOS-~, is expressed widely during murine

embryogenesis but in the adult is restricted

to immature B and T cells.

As reported here by Schilham ct 171.,

gene-targeted mice deficient for 51~J

(SO.P--) die at embryonic day 14 (El&l as a

result of a failure of cardiac development.

However, the fetal liver is sufficiently de-

veloped by El3 for haematopoietic cells to

be recovered and used in adoptixre transfer

experiments. Thus, E 13 SOS-X- fetal liver

cells were transferred into lethally irradi-

ated recipients and the emergence of lym-

phoid cells was evaluated eight weeks later.

El3 fetal liver cells from heterozygous or

wild-type littermates were used in control

transfer experiments. Sor-J fetal liver cells

could reconstitute the monocytc, granulocyte

and T-cell compartments to a level compa-

rable with those in the controls. However,

CD43- 82X- pre-B cells Ivere almost com-

plctely absent and CDJ3a B22O‘ pro-B cells

were greatly reduced. Moreover, the pro-B-

ce!l response to interleukin 7 (IL-7) was much

slowrer than that in comparable controls, in-

dicating that this prc.liferative capacity

compartment is impaired in 50.X-d- mice.

Overail. the So::-4 deficiency resembles

the phenotype of mice defective for either

the IL-7 receptor or the IL-2 receptor y cham,

suggesting that 5J.V~4 is integral to the

patli~vny regul,ltii?g pro-B-0211 clp‘insion

Interestingly, a few mature surface immuno-

globin (s1g)’ I3 cells do develop in thcsjc ~nl-

mals, adding the caveat that the pla5ticitv of

the developing immune bystern cdn, ior J

limited number of B cells, o\‘crcome Ihis %c-

rious ontogenic block.

UNE 1996