Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα.
Bottom Line: Mice heterozygous for the IκBα S32I mutation found in patients exhibited typical features of ED-ID.Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-κB signaling.IκBα mutant → Rag2(-/-), but not WT→IκBα mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs.
Affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.Show MeSH
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Mentions: Gross examination revealed no visible cervical, axillary, inguinal, or mesenteric LNs in >15 IκBα mutant mice examined (Fig. 2 A and not depicted). No LN tissue could be detected in hematoxylin and eosin (H&E)–stained serial sections of the inguinal fat pad in IκBα mutant mice (not depicted). To confirm the absence of LNs, we injected mice in the footpad with Evan’s blue dye. Blue-colored lymphatic vessels were readily apparent in both mutant and WT mice. Blue-colored LNs could be detected in the popliteal, inguinal, and paraaortic area in WT mice, but were absent in the mutants (Fig. 2 B and not depicted). Examination of H&E-stained sections of the small intestine revealed no detectable PPs in seven mutant mice compared with 7.1 ± 2.3 PPs in seven WT littermates examined (Fig. 2 C). However, nasal-associated lymphoid tissue (NALT) was present in IκBα mutant mice, although it was less abundant than in WT mice (Fig. 2 D). The numbers of circulating lymphocytes were significantly increased in the IκBα mutant mice (Fig. 3 A), a finding also reported in patients with the S32I IκBα mutation (Courtois et al., 2003; Janssen et al., 2004) and in LTα−/−, LTβ−/−, and LTβR−/− mice that lack both LNs and PPs but have detectable NALT (De Togni et al., 1994; Ware et al., 1995; Alimzhanov et al., 1997; Matsumoto et al., 1997; Fütterer et al., 1998; Tumanov et al., 2003).
Affiliation: Division of Allergy and Immunology and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics, Division of Transfusion Medicine, and Department of Pathology, Harvard Medical School, Boston, MA 02115.