A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice

Abstract

We have found a new spontaneous autosomal recessive mutation in mice that causes a systemic absence of lymph nodes and Peyer's patches. The name "alymphoplasia", with the gene symbol "aly", is proposed for this mutant. The spleen of aly/aly mice is devoid of well-defined lymphoid follicles, and the thymus does not show a clear cortical-medullary distinction. The mutant homozygotes are deficient in both humoral and cell-mediated immune functions, and are highly susceptible to infections. They have a reduced level of IgM and severely depressed levels of IgG and IgA in their sera, and do not reject allogeneic skin grafts. However, they have mature T and B cells as determined from their cell surface antigens. The results of bone marrow transplantation experiments suggest a mesenchymal disorder as a possible cause of the lack of lymph nodes and of immunodeficiency in the aly mouse. The aly mutant mouse may be a useful animal model of primary immunodeficiency, as are the nu (nude) and scid (severe combined immunodeficiency) mice.

NF-κB and the immune response

“…Mice with a point mutation in nik (aly/aly mice) lack multiple secondary lymphoid organs (Miyawaki et al, 1994;Koike et al, 1996;Shinkura et al, 1999) and share several phenotypic similarities with lymphotoxin and IKKa single knockout animals (Mebius, 2003;Bonizzi and Karin, 2004). p52/RelB, which is activated downstream of NIK and IKKa, is thought to be the primary transcriptional mediator of several key organogenic factors including CXCL12, CXCL13, CCL19, CCL21 and MadCAM-1 (Yilmaz et al, 2003).…”

“…Mice in which non-canonical pathway components, RelB, NIK or IKKa, have been inactivated demonstrate severe defects in splenic architecture, similar to that seen in ltbr À/À spleens. These defects largely reflect deficiencies in splenic stromal cells (Miyawaki et al, 1994;Koike et al, 1996). Mice deficient in the non-canonical pathway fail to segregate B-cell-T-cell zones and FDC networks, and they fail to form GCs following immunization.…”

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

“…The alymphoplasia (aly) strain of mice carries a natural mutation of the NIK gene (5,6) in which a G855R substitution in the C terminus of the protein results in inability to bind to IKK-␣ (7). NIK aly/aly mice have provided a unique model for the abnormal development of lymphoid organs; NIK aly/aly mice lack all lymph nodes and Peyer's patches, and spleen architecture such as development of germinal centers and follicular dendritic cell clusters is disturbed (5,6,8). We and others have demonstrated that this is due to defective NF-B activation through the lymphotoxin (LT)-␤ receptor (LT␤R) (6,7,9), a receptor essential for the development of lymphoid organs (10).…”

“…We and others have demonstrated that this is due to defective NF-B activation through the lymphotoxin (LT)-␤ receptor (LT␤R) (6,7,9), a receptor essential for the development of lymphoid organs (10). Thymic structure is also disorganized in NIK aly/aly mice, which is not observed in mice deficient for LT-␣ or LT-␤ (10); the medulla in NIK aly/aly mice is smaller than that in NIK aly/ϩ mice, and the boundary of the cortex and medulla is unclear (5,6,11). In addition to this abnormal lymphoid organogenesis, NIK aly/aly mice also serve as a model of autoimmune disease, but of unknown etiology (12); histopathological analysis of NIK aly/aly mice has revealed chronic inflammatory changes in several organs, including the liver, pancreas, lung, salivary gland, and lacrimal gland (Refs.…”

Principles of tumor immunosurveillance and implications for immunotherapy

“…Alymphoplastic mice (aly /aly ) lack lymph nodes but possess a spleen with functionally normal CTL. 41,51 Although aly /aly mice generated detectable, but reduced, CTL responses after infection with vaccinia virus and LCMV, the elimination of these viruses was either delayed or virtually impossible; irrespective of the dose or the route of infection, aly /aly mice developed life -long LCMV persistence and splenectomized aly / aly mice did not mount a CTL response at all after infection with LCMV. 41 More recently, it was shown that aly /aly mice are immunologically ignorant of a cardiac allograft.…”