Missense Immune Disruption

WRITTEN BY: Nicholas Breehl

Many of the early onset immune deficiencies that are observed stem from genetic mutations. On the other end of the spectrum, immune diseases with onsets later in life tend to be less severe, include patients with no prior family history, and are not as well understood.

A novel human immunodeficiency syndrome is revealed from work done by a team of researchers including Matthew C. Cook from Australian National University in Canberra and Hirokazu Kanegane from Tokyo Medical and Dental University. The research is published in the Journal of Experimental Medicine.

By comparing whole genomes of patients with immune deficiencies, the team discovered two patients with no familial relation have the same mutation in the IKBKB gene. The IKBKB gene is involved in encoding an enzyme called IKK2 that controls the development and activation of white blood cells by regulating the NF-kB cell signaling pathway. The patients suffer from excessive inflammation, increased susceptibility to recurrent infections, and the loss of both T cells and B cells.

The NF-kB is a family of transcription factors that regulate gene expression in many tissues as well as influence critical actions on white blood cell development, homeostasis, activation and maintenance of self-tolerance.

The study reports how combined phenotyping of patients carrying a de novo (new) gain-of-function mutation in IKBKB gene, and a mouse engineered to take the orthologous gene helped to describe a novel immune syndrome.

The mouse models were created to confirm the mutation was responsible for the disease pathogenesis. The gene editing tool CRISPR/Cas9 was utilized to generate the mouse model mutation. Mice and humans with this single nucleotide mutation share similar cellular and biochemical phenotypes.

It has previously been shown that early onset immune deficiencies are caused by mutations inhibiting the IKK2 and NF-kB signaling. However, the team discovered that the specific mutation observed in the two patients caused an over-activation of IKK2 resulting in NF-kB cell signaling increases.

“Now that there is empirical evidence that single-gene variants can cause complex immune phenotypes, it is important that we explore rare and novel variants in cases where the disease remains unexplained,” shares authors of the paper.

Kanegane explains the results “show that a de novo mutation IKBKB increases the function of IKK2 and results in a combined immune deficiency syndrome affecting both T and B cells.”

As a result of the mutation the patients both had low levels of antibody-producing B cells and T cells; the cells that help to stave off infections. Interestingly, one type of T cell that recorded sensitivity to increased activation.

The team remarked that their work might aid in future studies investigating therapeutic interventions for personalized therapy. The Authors describe that “methods for determining function of precise human mutations that might account for a novel syndrome is a high priority.”