The influence of CD40-CD154 interactions on the expressed human V(H) repertoire: analysis of V(H) genes expressed by individual B cells of a patient with X-linked hyper-IgM syndrome.
Analysis of the V(H)DJ(H) repertoire of peripheral blood IgM(+) B cells from a patient with X-linked hyper-IgM syndrome (X-HIgM) was undertaken to determine whether the distribution of V(H) families in the productive repertoire might be regulated by in vivo CD40-CD154 interactions. The distribution of V(H) genes in the non-productive repertoire of IgM(+) B cells was comparable in X-HIgM and normals. Unlike the normal productive V(H) repertoire, however, in the X-HIgM patient the V(H)4 family was found at almost the same frequency as the V(H)3 family. This reflected a diminution in the positive selection of the V(H)3 family observed in normals and the imposition of positive selection of the V(H)4 family in the X-HIgM patient. Unique among the V(H)3 genes, V(H)3-23/DP-47 was positively selected in both normals and the X-HIgM patient. No major differences in the usage of J(H) or D segments or the complementarity-determining region (CDR) 3 were noted, although the foreshortening of the CDR3 noted in the mutated V(H) rearrangements of normals was absent in the X-HIgM patient. Finally, a minor degree of somatic hypermutation was noted in the X-HIgM patient. These results have suggested that specific influences on the composition of the V(H) repertoire in normals require CD40-CD154 interactions.
Brezinschek
H P
HP
Department of Internal Medicine and Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas TX 75235, USA.
Dörner
T
T
Monson
N L
NL
Brezinschek
R I
RI
Lipsky
P E
PE
D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D002675:Child, Preschool; D005803:Genes, Immunoglobulin; D008040:Genetic Linkage; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007075:Immunoglobulin M / Q000097:blood*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D009154:Mutation; D014960:X Chromosome
D019013:CD40 Antigens; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; D023201:CD40 Ligand