Salivary gland B cell lymphoproliferative disorders in Sjögren's syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins's lymphomas.
Sjögren's syndrome (SS) represents a pathological model of the evolution from polyclonal B lymphocyte activation to oligoclonal/monoclonal B cell expansion, which may culminate in the development of a malignant lymphoproliferative disease. The different phases of this process are usually marked by the appearance of antigen-driven activated B cell clones, which are commonly IgM-positive and with rheumatoid factor (RF) activity. However, the agent(s) able to trigger B cell proliferation is still unknown. A similar pathogenetic mechanism exist in mixed cryoglobulinemia, another autoimmune disease that often evolves to non-Hodgkin's lymphoma (NHL) and in which hepatitis C virus (HCV) infection has been demonstrated to play an etiopathogenetic role. In the present study, we cloned and sequenced the antigen receptor (IgR) variable region genes of SS-associated monoclonal non-neoplastic lymphoproliferations and compared them with those of our previous reported HCV-associated NHL, to derive clues on the antigen(s) that sustains SS. The results obtained showed remarkable homologies between the antigen combinatory regions of the IgR expressed by both diseases. These homologies concern: a) the specific combinations of heavy and light variable region genes; b) the limited length of complementarity-determining regions (CDR3); c) the homology with antibodies with RF activity; d)the amino acid sequences of CDR3 in which common somatic mutations are present that possibly determine the antigen-binding specificity. In conclusion, although there are significant differences between SS and HCV-associated lymphoproliferative diseases, they share many molecular characteristics, which suggest an immunological cross-reactivity or molecular mimicry among the agents that underlie these disorders.
De Re
Valli
V
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCS, Aviano, Italy.
De Vita
Salvatore
S
Gasparotto
Daniela
D
Marzotto
Alessandra
A
Carbone
Antonino
A
Ferraccioli
Gianfranco
G
Boiocchi
Mauro
M
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000150:complications* / Q000276:immunology; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells / Q000276:immunology / Q000473:pathology; D022801:Complementarity Determining Regions / Q000235:genetics; D003429:Cross Reactions; D018450:Disease Progression; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D016174:Hepacivirus / Q000302:isolation & purification; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000276:immunology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010307:Parotid Neoplasms / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D016133:Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D012217:Rheumatoid Factor / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012793:Sialadenitis / Q000276:immunology / Q000473:pathology; D012859:Sjogren's Syndrome / Q000150:complications* / Q000276:immunology
D001323:Autoantibodies; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D011947:Receptors, Antigen, B-Cell; D012217:Rheumatoid Factor