Human MD2 Deficiency: A Pleiotropic Inborn Immune System Defect

Jun 7, 2023

The following is a summary of "Human MD2 deficiency—an inborn error of immunity with pleiotropic features," published in the MARCH 2023 issue of Allergy (& Immunology) by Li, et al.

For a study, researchers sought to investigate the mechanistic and phenotypic aspects of human MD2 deficiency. Toll-like receptors (TLRs) play a crucial role in sensing microbes and host defense, with Myeloid differentiation protein 2 (MD2) acting as a vital co-receptor for TLR4. MD2 facilitates the binding of TLR4 to the gram-negative bacterial cell wall component LPS, leading to downstream signaling activation.

The genetic cause of very early onset inflammatory bowel disease in a patient was elucidated by whole-exome sequencing, revealing a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del). Furthermore, the functional implications of the mutation in LY96, which encodes for MD2, were studied in genetically engineered induced pluripotent stem cell–derived macrophages with MD2 knockout or knockin of the patient-specific mutation.

The results showed that MD2-deficient macrophages had impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling, along with TLR4 endocytosis when challenged with LPS or bacteria. Additionally, cytokine expression (such as IL-6, TNF, and IL-10) was reduced in response to LPS or gram-negative bacteria, but not gram-positive bacteria.

The study concluded that human MD2 deficiency leads to defective TLR4 signaling when exposed to LPS or gram-negative bacteria, with variable clinical manifestations and expressivity due to unknown secondary risk factors. Since TLR4 is a therapeutic target for numerous inflammatory conditions, the findings of this study may provide insights into the potential side effects of pharmacological TLR4 targeting.

Source: jacionline.org/article/S0091-6749(22)01372-0/fulltext