Characterization of immunoglobulin variable regions of two human pathogenic monoclonal cryocrystalglobulins.
Cold-precipitating monoclonal immunoglobulins can rarely aggregate in form of crystals (cryocrystalglobulins) and cause serious clinical manifestations. The structural basis underlying this phenomenon remains to be defined. This study was undertaken to provide the first characterization of the heavy (VH) and light chain (VL) variable regions of two human pathogenic cryocrystalglobulins. The immunoglobulins used different heavy and light chain constant regions and germline gene fragments, underwent high degrees of somatic hypermutation, and showed distributions of replacement and silent nucleotide changes suggestive of antigenic selection. Primary sequences analyses and computer-generated modeling identified a positive charge and the introduction of unusual hydrophobic residues in exposed areas of VH and VL. In particular, a rare replacement of a polar residue with proline is shared at the beginning of the VH complementarity-determining region 2, and this residue might be involved in intermolecular contacts.
Navazza
Valentina
V
Department of Internal Medicine, Clinica Medica I, Fondazione IRCCS Policlinico San Matteo-University of Pavia, P.le Golgi 2, 27100 Pavia, Italy.
Gabba
Silvia
S
Alfieri
Andrea
A
Giorgetti
Sofia
S
Marchese
Loredana
L
Palladini
Giovanni
G
Mattevi
Andrea
A
Ascari
Edoardo
E
Caporali
Roberto
R
Montecucco
Carlomaurizio
C
Merlini
Giampaolo
G
Perfetti
Vittorio
V
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics*; D003080:Cold Temperature; D003460:Crystallization; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular
D000911:Antibodies, Monoclonal; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region