The MYD88 gene encodes a cytosolic adapter protein, MyD88, which is involved in signaling for both the innate and adaptive immune response. The MyD88 adapter protein is essential for transducing signals in the interleukin-1 (IL-1) and toll-like receptor (TLR) pathways, which regulate activation of proinflammatory genes, and stimulating signaling molecules that activate interacting proteins called nuclear factor-kappa-B (NF-κB).
Two rare diseases are associated with the MYD88 gene: MyD88 deficiency and Waldenström macroglobulinemia (WM) [also known as lymphoplasmacytic lymphoma].
MyD88 deficiency is a primary immunodeficiency disorder (PID) - inherited in an autosomal recessive manner - that affects the innate immune response. This rare disorder leads to increased susceptibility to severe and frequent infections by pyogenic bacteria (such as Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa). These infections can be life-threatening in infancy and childhood, becoming less frequent after the age of 10. Despite this, patients afflicted with Myd88 deficiency present a normal immune response to other common bacteria, viruses, fungi, and parasites. Children with MyD88 deficiency develop invasive bacterial infections, which could lead to septicemia, meningitis, joint inflammation and arthritis, and even cause abscesses on internal organs.
Waldenström macroglobulinemia is a chronic lymphoproliferative disorder that is classified as a rare disease by the NIH. Over 90% of people with Waldenström macroglobulinemia have been found to have a mutation in the MYD88 gene that replaces the amino acid leucine with proline at position 265 (Leu265Pro or L265P). This genetic change is not inherited, but instead acquired during the person’s lifetime and only present in abnormal white blood cells (WBCs) – also known as a somatic mutation. The altered MyD88 protein is overactive, stimulating the signaling molecules that activate NF-κB. This abnormally active NF-κB has been suggested to allow survival of abnormal cells that should undergo apoptosis, potentially contributing to the accumulation of lymphoplasmacytic cells in Waldenström macroglobulinemia. The root cause of the condition has yet to be determined, but environmental, genetic, and viral factors have been suggested.
The same MYD88 L265P somatic mutation is also found in other cases of blood cell cancers, such as diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma. This mutation contributes to the development of the condition through the same mechanism as Waldenström macroglobulinemia, as previously described. The L265P mutation may be one of many genetic changes involved in the development of these cancers – different cancers may develop depending on the type of cell that acquires the somatic mutation.
Cyagen developed MyD88 knockout C57BL/6 mice (C57BL/6 MyD88-/-) for use in studying the effects of IL-33 on tumor immune response in lung cancer-bearing mice. The establishment of animal model is as follows: wild type and MyD88-/- were inoculated with Lewis cells (LLC), mouse lung adenocarcinoma cells, under the armpit of the forelimb. Recombinant PBS IL-33 (rIL-33) was used as treatment via intraperitoneal injection, with the following results:
These results have a provided a greater understanding of the molecular mechanisms of IL-33 inhibiting tumor survival through regulating anti-tumor cellular immunity. It has been shown that intraperitoneal injection of IL-33 showed a dose-dependent manner of inhibiting tumor growth in wild-type tumor-bearing mice but had no effect on tumor growth in MyD88-/- mice. Additionally, IL-33 could significantly upregulate cellular immunity in wild type mice, it had no effect on cell immunity in MyD88-/- mice. While IL-33 promoted differentiation and maturation of DC cells in local tumor microenvironment for wild type mice, this was inhibited among MyD88-/- mice – indicating that IL-33 induced immune response acts through the MyD88 signaling pathway. Additional studies of IL-33 as a potential anti-tumor cytokine would be needed to evaluate its immune effects across tumor type, immune response stage, and animal model.
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