Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4873-4874
CORRESPONDENCE
Bone Marrow Transplantation, Fetal B-Cell Repertoire Development,
and the Mechanism of Immune Reconstitution
 |
LETTER |
To the Editor:
Studies of bone marrow (or stem cell) transplantation (BMT) provide
important insights in immunological and genetic mechanisms that form
the human immune system. Guillaume et al1 published an
excellent review of posttransplant B- and T-cell repertoires in the
context of therapeutic strategies that could enhance the outcome of
BMT. However, they suggested that immune reconstitution after BMT
follows a fetal program of development, and I think this warrants
further discussion.
The early post-BMT B-cell repertoire is usually characterized as fetal
because it appears to be dominated by VH elements that are
frequently detected in fetal liver (most particularly VH6). Formation of the human fetal VH repertoire has long been
thought to be guided by the location of the VH elements,
with JH-proximal VH segments (such as
VH6) rearranging most frequently. However, current evidence
contradicts this mechanism.2-4 For instance, analysis of
VH6 expression in fetal tissue with a monoclonal antibody failed to support increased VH6 levels as determined by
random sequencing and Northern blot analysis.2
Overexpression of the VH6 element can therefore no longer
be regarded as a characteristic of the fetal repertoire. In addition,
because the B-cell repertoire is dominated by (oligo)clonal expansions
early after BMT,5-7 measurement of VH family
expression levels may not be the most suitable marker to distinguish
fetal- or adult-type immune reconstitution. It is possible that
patterns of VH expression determined by Northern blotting,
random sequencing, or VH family-specific polymerase chain
reaction are skewed by dominant clones that express particular VH families.
What then defines a fetal repertoire? Fetal antigen receptors
characteristically contain antigen-binding pockets that are encoded by
relatively short third complementarity-determining regions
(CDR3).3,4,8 The importance of this characteristic is
reflected by the fact that it is conserved through evolution
it has
been described in species as diverse as frogs, rabbits, mice, and
humans and holds true for both B- and T-cell receptors. Prime determinants of CDR3 size are the usage pattern of diversity
(DH) elements and the length and frequency of
N-regionsstretches of DNA that are added by the enzyme terminal
deoxynucleotidyl-transferase during formation of the antigen receptor
gene. As compared with the situation in the adult, N-regions are
expressed at lower frequencies during fetal
development.3,4,8 For instance, an estimated 20% of CDR3
regions in 12- to 14-week-old fetal livers lack N-regions altogether.
In addition, up to 50% of fetal B-cell receptor CDR3 segments use the
DQ52 DH element (which is relatively small). By contrast to
this fetal pattern of CDR3 diversity, CDR3 regions in adult peripheral
blood are longer and more diverse; they rarely express DQ52, and they
contain extensive addition of N-regions in all instances.8
Given the clear difference between fetal-type and adult-type antigen
receptors, the pattern of CDR3 diversity is a more reliable marker for
distinction between fetal and adult repertoires.
To date, studies of the post-BMT repertoire5-7 demonstrated
that CDR3 regions of reconstituting B cells exhibit none of the characteristics that define a fetal repertoire: they rarely encode DQ52, they exhibit adult patterns of N-region addition, and their general size is indistiguishible from that in adult peripheral blood.
This pattern of diversity is identical to that in adult bone marrow
pre-B cells (which also produce adult-type CDR3
regions).7,9,10 In other words, there is no reason to
expect a recapitulation of fetal development after BMT, because the
graft, consisting of adult lymphoid progenitors, is placed in the adult
environment of the recipient.
In conclusion, immune reconstitution after BMT follows many established
ontogenetic patterns relating to the appearance of particular membrane
markers, Ig subclasses, and onset of antigen receptor rearrangements.
The sequence of events that occur during successful BMT can be regarded
as a blueprint for immune reconstitution in other clinical settings as
well. However, in the description and interpretation of these events,
it is important to realize that immune reconstitution does not appear
to recapitulate human fetal ontogeny.
F.M. Raaphorst
Department of Pathology
VU Academic
Hospital
Amsterdam, The Netherlands
| |
REFERENCES |
1.
Guillaume T, Rubinstein DB, Symann M:
Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation.
Blood
92:1471, 1998[Free Full Text]
2.
Raaphorst FM, Langlois-van den Bergh R, Waaijer JLM, Vossen JM, van Tol MJD:
Expression of the human immunoglobulin heavy chain VH6 gene element by fetal B lymphocytes.
Scand J Immunol
46:292, 1997[Medline]
[Order article via Infotrieve]
3.
Pascual V, Verkruyse L, Casey ML, Capra JD:
Analysis of Ig H chain gene segment utilization in human fetal liver. Revisiting the "proximal utilization hypothesis."
J Immunol
151:4164, 1993[Abstract]
4.
Raaphorst FM, Timmers E, Kenter MJH, van Tol MJD, Vossen JM, Schuurman RKB:
Restricted utilization of germ-line VH3 genes and short diverse third complementarity-determining regions (CDR3) in human fetal B lymphocyte immunoglobulin heavy chain rearrangements.
Eur J Immunol
22:247, 1992[Medline]
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5.
Näsman-Björk I, Lundkvist I:
Oligoclonal dominance of immunoglobulin VH3 rearrangements following allogeneic bone marrow transplantation.
Bone Marrow Transplant
21:1223, 1998[Medline]
[Order article via Infotrieve]
6.
Gokmen E, Raaphorst FM, Boldt D, Teale JM:
Immunoglobulin heavy chain third complementarity-determining regions (HCDR3s) post-stem cell transplantation do not resemble the developing human fetal HCDR3s in size distribution and immunoglobulin gene utilization.
Blood
92:2802, 1998[Abstract/Free Full Text]
7.
Näsman I, Lundkvist I:
Evidence for oligoclonal diversification of the VH6-containing immunoglobulin repertoire during reconstitution after bone marrow transplantation.
Blood
87:2795, 1996[Abstract/Free Full Text]
8.
Sanz I:
Multiple mechanisms participate in the generation of diversity of human H chain CDR3 regions.
J Immunol
147:1720, 1991[Abstract]
9.
Raaphorst FM, Raman CS, Tami J, Fischbach M, Sanz I:
Human Ig heavy chain CDR3 regions in adult bone marrow pre-B cells display an adult phenotype of diversity: Evidence for structural selection of DH amino acid sequences.
Int Immunol
9:1503, 1997[Abstract/Free Full Text]
10.
Milili M, Schiff C, Fougereau M, Tonnelle C:
The VDJ repertoire expressed in human preB cells reflects the selection of bona fide heavy chains.
Eur J Immunol
26:63, 1996[Medline]
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