Precision Therapy for the Treatment of Primary Immunodysregulatory Diseases

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Key points

  • Primary immunodysregulatory disorders are an expanding group of molecularly defined primary immunodeficiency diseases in which autoimmunity and hyperinflammation are hallmarks.

  • Cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig fusion proteins serve as a functional replacement of CTLA-4, successfully treating patients with CTLA4 haploinsufficiency and LRBA deficiency.

  • Leniolisib (CDZ173), a potent inhibitor of the p110δ subunit of PI3Kδ, has successfully treated lymphoproliferation in patients with

Cytotoxic T lymphocyte antigen-4 haploinsufficiency

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a key negative immune regulator crucial for the function of regulatory T (Treg) cells that are responsible for maintaining self-tolerance and immune homeostasis.1 CTLA4 competes with the costimulatory receptor CD28 for its ligands CD80 and CD86 on antigen-presenting cells (APCs). Upon binding, CTLA4 reduces the expression of CD28, resulting in reduction of APC-mediated activation of T cells, thereby downregulating the immune response.

CTLA4

Lipopolysaccharide-responsive beige-like anchor deficiency

Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency leads to an autosomal-recessive form of combined immunodeficiency, caused by biallelic mutations in LRBA gene.12,13 LRBA is a ubiquitously expressed cytosolic protein that regulates the traffic of intracellular vesicles and is involved in the endocytosis of ligand-activated receptors. CTLA-4 undergoes endocytosis within T cells, where it is either recycled back to the plasma membrane or degraded within lysosomes. LRBA normally

Activated PI3K deficiency syndrome

Activated P13K deficiency syndrome (APDS) is a combined immunodeficiency syndrome associated with multiple noninfectious complications such as nonmalignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly, nodular mucosal lymphoid hyperplasia), increased risk for lymphoma and other malignancies, developmental delay, and autoimmune and inflammatory diseases.24 Phosphoinositide-3-kinase δ (PI3Kδ) is a class IA lipid kinase that phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2)

Signal transduction and activator of transcription 1 and 3 – gain of function

The signal transducer and activator of transcription (STAT) family is composed of several transcription factors involved in activation of Janus kinase (JAK) signaling (Fig. 1).

Cellular signaling begins with cytokine and/or growth factor association to a transmembrane receptor, which stimulates the activation of receptor-bound JAKs. Cytosolic STATs are then tyrosine-phosphorylated by activated JAKs, prompting STAT dimerization, and such conformational change allows STAT nuclear translocation.

STAT 1 – gain of function

STAT1 is specifically activated by type I and II interferons (IFN), interleukin (IL) 6, γ chain cytokines, IL-10, and IL-23, promoting an upregulation of IFN-γ-dependent genes. The overdrive in STAT1 GOF is in part thought to be caused by lack of STAT1 dephosphorylation and is characterized by increased expression of PDL-1, INF-α/INF-β, IL-27, IL-6, and IL-21. These factors are associated with inhibition of the development of IL-17-producing T cells (TH17). Deficiency in IL-17 dependent

STAT3 – gain of function

STAT3 modulates the intracellular signaling of several cytokines (IFNs, IL-2, IL-6, IL-7, IL-10, IL-12, IL-15, IL-21, IL-23, and IL-27) and growth factors. STAT3 activation favors Th17cell response by increasing the expression of orphan nuclear receptors (RORγ/RORα), which are important transcription factors for Th17 cell activation and expansion. Activation of STAT3 also leads to restriction of regulatory T cell development.52, 53, 54

GOF germline mutations in STAT3 cause an immunodeficiency

Inflammasome disorders

Inflammasomes are intracellular multiprotein complexes serving as a key component of the innate immune system. Inflammasomes are responsible for regulating the immunologic response to exogenous and endogenous factors, thereby crucial in protecting the host.59 The rapid availability of proinflammatory cytokines like IL-1, IL-18, and IL-33 in response to danger signals represents a key mechanism of inflammation. Mutations in 2 of the IL-1 regulating genes, NLRP3 and IL1RN, cause early onset

Summary

Understanding of disease mechanisms of primary immunodysregulatory disorders has offered the opportunity to alter the abnormal immune response interfering with mechanism of disease normalizing the immune response. Mechanism-based therapy has been effective at reversing disease-related manifestations in primary immunodysregulatory disorders, offering the most precise therapy to patients.

Disclosure

The authors have nothing to disclose.

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