RESUMO
Darwinian theory requires that mutations be produced in a nonanticipatory manner; it is nonetheless consistent to suggest that mutations that have repeatedly led to nonviable phenotypes would be introduced less frequently than others-if under appropriate genetic control. Immunoglobulins produced during infection acquire point mutations that are subsequently selected for improved binding to the eliciting antigen. We and others have speculated that an enhancement of mutability in the complementarity-determining regions (CDR; where mutations have a greater chance of being advantageous) and/or decrement of mutability in the framework regions (FR; where mutations are more likely to be lethal) may be accomplished by differential codon usage in concert with the known sequence specificity of the hypermutation mechanism. We have examined 115 nonproductively rearranged human Ig sequences. The mutation patterns in these unexpressed genes are unselected and therefore directly reflect inherent mutation biases. Using a chi2 test, we have shown that the number of mutations in the CDRs is significantly higher than the number of mutations found in the FRs, providing direct evidence for the hypothesis that mutations are preferentially targeted into the CDRs.
Assuntos
Genes de Imunoglobulinas , Região Variável de Imunoglobulina/genética , Mutação , Artrite/genética , Artrite/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , DNA Complementar/genética , Evolução Molecular , Frequência do Gene , Humanos , Seleção Genética , Serina/genéticaRESUMO
The role of cytokines in leukemic arthritis is unknown. The presentation of a patient with B cell chronic lymphocytic leukemia and destructive arthritis of the wrist joints prompted us to study the synovial cytokine pattern by immunohistologic analysis. In addition, rearranged V(H) and V(L) immunoglobulin genes were sequenced to assess B cell clonality. Heavy infiltrations of CD20+ cells with lambda light chain restriction were found in the synovial tissue. Sequencing demonstrated overexpansion of a single B cell clone (DP58/D/J(H)4b and IGLV3S2/Jlambda2-Jlambda3 for V(H) and V(L), respectively) in the peripheral blood. Identical V(H) and V(L) rearrangements were found in the synovial infiltrates. Somatic mutations were found in both the peripheral blood and the synovial clone. Immunohistologic study revealed the presence of abundant interleukin-1beta (IL-1beta) and, to a lesser degree, tumor necrosis factor beta (TNFbeta) (lymphotoxin). In contrast, TNFalpha, interferon-gamma, IL-4, IL-6, and IL-10 were rarely found in the synovial infiltrates. Therefore, IL-1beta secreted in great amounts by leukemic B cells appears to be the major cytokine that mediates joint destruction in leukemic arthritis.
