A polymorphism in the coding region of Il12b promotes IL-12p70 and IL-23 heterodimer formation

Interleukin (IL)-12 and IL-23 are heterodimeric cytokines involved in the induction of Th1 and Th17 immune responses. Previous work indicated that a region on chromosome 11 encoding the IL-12 p40 subunit regulates strain differences in susceptibility to murine trinitrobenzene sulfonic acid (TNBS)-induced colitis. In addition, this region determines strain differences in LPS induced IL-12 responses. Here we investigated how polymorphisms in the coding region of murine Il12b influence IL-12 and IL-23 heterodimer formation. Transfection studies using constructs containing IL-12p35 linked to either IL-12p40 from the colitis-resistant C57Bl/6 strain or to the polymorphic p40 variant from the colitis-susceptible SJL/J strain demonstrated that SJL/J-derived p40 constructs synthesized significantly more IL-12p70 than constructs harboring the C57Bl/6-p40 variant. This could not be attributed to differences in synthesis rate or secretion implicating a higher affinity of SJL/J derived IL-12p40 for its IL-12p35 subunit. This higher affinity is also associated with increased IL-23 synthesis. In addition, C57Bl/6 mice transgenic for the SJL/J 40 variant synthesized significantly more IL-12p70 and were more prone to develop colonic inflammation than did C57Bl/6 mice transgenic for the C57Bl/6-p40 variant upon LPS challenge. The more efficient binding of the polymorphic Il12b variant to p35 and p19 is most likely due to conformational changes following differential glycosylation as a consequence of the polymorphism. The high synthesis rate of the mature cytokines resulting from this efficient binding can lead to rapid pro-inflammatory skewing of immune responses and distortion of the homeostatic balance underlying the higher susceptibility for colitis

Abnormal lymphoid organ development in immunodeficient mutant mice.

Development of the primary and secondary lymphoid organs is a tightly controlled process. These tissues are highly organized to maximize efficiency of the immune response. Spontaneous and targeted mutations in laboratory mice have led to better understanding of the molecular interactions and signaling pathways essential to the development and organization of lymphoid tissues, and the functional consequences of loss or disruption of the normal structures. On the basis of studies of mutations in mice and other species, it has been determined that a wild-type allele of the Foxn1 gene is required for normal thymic development and function. The Tlx1, Bapx1, Tcf21, Wt1 and Dh genes are essential for development of the spleen, while mutations of Nkx2-3, Lta, Ltb, Ltbr, Map3k14, Relb, Tnf, Tnfrsf1a, Cxcl13, Blr1 (Cxcr5), or cpdm genes result in disruption of normal splenic microarchitecture. The requirements for organized lymph nodes vary according to anatomic location, but most rely on Id2 (Idb2) and Rorc, in addition to lymphotoxins and Tnfrsf11a, Tnfsf11, Relb, Map3k14, Cxcl13, and Blr1 genes. Development of Peyer\u27s patches is dependent on Id2 and Rorc genes, lymphotoxins, and Relb, Map3k14, Il7r, and cpdm genes. Less is known about the requirements for nasal-associated lymphoid tissues (NALT), but Id2 is a requirement. Here we review abnormalities of lymphoid organ development in immunodeficient mutant mice, including spontaneous and targeted mutations of Id2, Rorc, Tnf, Tnfrsf1a, Lta, Ltb, Ltbr, Tnfrsf11a, Tnfsf11, Relb, Map3k14, IL7r, Blr1, and Cxcl13 genes