title: Molecular analysis of IgA deficiency. Evidence for impaired switching to IgA.
abstract: The most common form of primary immunodeficiency is IgA deficiency (IgAD). However, the molecular basis of this disease remains elusive. Therefore, to address this issue we made a systematic analysis of the molecular events leading to IgA production. B lymphocytes that produce IgA have undergone somatic rearrangement that joins the switch (S) mu to S alpha region with deletion of the intervening sequences. Examination of the resulting S mu/S alpha junctions in unstimulated PBMC from IgAD patients by nested primer PCR revealed a significant decrease in the number of the S mu/S alpha fragments. To obtain the antisense primers to generate the S mu/S alpha fragments, we sequenced the human S alpha 1 and the downstream region extending to the C alpha 1 locus. Similar to previously reported switch sequences, we also found the S alpha 1 to be predominantly composed of pentameric repeats GAGCT and GGGCT. The decrease in the number of S mu/S alpha fragments is consistent with a profound decrease in the C alpha membrane mRNA expression in unstimulated PBMC, as well as in the C alpha mRNA levels and IgA production in PWM-stimulated PBMC. Sequence analysis of the switch junctions from IgA-producing cell lines, control donors, and an IgAD patient showed direct joining in 8 of 9 cases examined. TGF-beta 1, previously shown to be the switch factor for human and mouse IgA, was also examined. No difference in the TGF-beta 1 mRNA levels in unstimulated PBMC between the control subjects and the IgAD patients were detected. Our findings indicate that the failure to switch to IgA-producing B lymphocytes, or an impaired survival of such cells, may be an important molecular mechanism in IgAD.
authors.affiliation: Centre for BioTechnology, Karolinska Institute, Huddinge, Sweden.
authors.forename: K B
authors.initials: KB
authors.lastname: Islam
authors.forename: B
authors.initials: B
authors.lastname: Baskin
authors.forename: L
authors.initials: L
authors.lastname: Nilsson
authors.forename: L
authors.initials: L
authors.lastname: Hammarström
authors.forename: P
authors.initials: P
authors.lastname: Sideras
authors.forename: C I
authors.initials: CI
authors.lastname: Smith
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D005803:Genes, Immunoglobulin; D005812:Genes, Switch; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics*; D007137:Immunoglobulin alpha-Chains / Q000235:genetics*; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid
chemical_list: D017931:DNA Primers; D007137:Immunoglobulin alpha-Chains; D007148:Immunoglobulin mu-Chains; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell