Defective secretion of an immtmoglobulln caused by mutations in the heavy chain complementarity determining region 2

Ching Chen, Tammy M. Martin, Susan Stevens, Marvin B. Kittenberg

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We have investigated four secretion-deficient antibodies (Abs) derived from a panel of 46 mutant T15 anti-phosphocholine Abs, all of which have point mutations in the heavy chain (H) complementarity determining region 2 (CDK2). The level of secretion for these four Abs was < 10% of wild type when expressed together with the T15 light chain (L) in either SP2/0 or P3X63Ag8.653 myeloma cells although normal levels of H and L chain mRNA were produced. Moreover, abundant intracellular H and L chain proteins were detected. Three of the four mutants had little or no assembled H and L complexes intracellularly whereas one had a significant amount of intraceUular immunoglobulin (Ig) which was shown to be capable of binding Ag. Thus, we demonstrate for the first time that point mutations confined to CDK2 of the H chain variable (V) region can impede Ab assembly and secretion. We then introduced the same CDK2 mutations into a related H chain which is encoded by the same T15 VH gene but different diversity (D) and joining (J) genes. When these H chains were expressed with a non-T15 L chain, the resulting Abs were secreted normally. The results thus suggest that the effects of the CDK2 mutations on Ab secretion are dependent on their interactions with L and/or H chain D-J sequences. These results also reveal a novel mechanism that could contribute to B cell wastage.

Original languageEnglish (US)
Pages (from-to)577-586
Number of pages10
JournalJournal of Experimental Medicine
Volume180
Issue number2
DOIs
StatePublished - Aug 1 1994

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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