Toll-like-receptor-8 deficiency syndrome

Very rare monogenic autoinflammatory immune deficiency syndrome first described in 2021 by Aluri J et al. and caused by a heterogeneous pathogenic TLR8 variant. The clinical picture was described in 6 unrelated men with clinical pictures including neutropenia, infections, lymphoproliferation and humoral immunodeficiencies. In some cases, bone marrow failure was associated with 3 different variants in the X-linked gene TLR8, which codes for the endosomal Toll-like receptor 8 (TLR8/Xp22.2).

The mechanism of neutropenia, the main feature of TLR8-GOF, appears to be multifactorial and involves both production and destruction mechanisms based on antineutrophil antibodies, direct cytotoxicity and/or Fas ligand-mediated destruction of neutrophils and progenitor cells, and impaired neutrophil differentiation and survival by proinflammatory mediators.

Most patients suffer from infections caused by both common and rare microorganisms, apparently due to abnormal adaptive immunity and the consequences of prolonged neutropenia (e.g. Aspergillus).

Several patients have been diagnosed with ALPS based on signs of lymphoproliferative disease (e.g. splenomegaly), cytopenias and laboratory findings commonly seen in ALPS (autoimmune lymphoproliferative syndrome) (e.g. double negative T cells (DNTs), autoantibodies and elevated vitamin B12 levels].

Autoantibodies against blood cells are not a consistent finding. Importantly, the neutropenia was by and large unresponsive to the standard immunosuppressants commonly used in interface diseases with autoimmunity, highlighting its multifactorial cause with similar features to BMF entities. Persistent and/or refractory neutropenia is an indication for hematopoietic stem cell transplantation (HSCT).

5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism as the cause of the clinical phenotype. Mosaicism was also detected in skin fibroblasts from 3 patients, indicating that the mutations were not restricted to the hematopoietic compartment (Aluri J et al. 2021).

All variants led to a GOF (gain of function) in the TLR8 protein. Clinically, a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B cell maturation was also found. The differentiation of myeloid cells from patient-derived induced pluripotent stem cells showed increased responsiveness to TLR8.

In a new case (57-year-old Asian woman), sharply bordered, large brownish plaques had been present on the trunk and extremities since the age of 14. Furthermore, periodic fever, exophthalmos, anticardiolipin antibody syndrome with positive rheumatoid factor and other inflammatory parameters (ESR, CRP) were diagnosed, and a heterogeneous pathological variant of c.1715G>A in Toll-like receptor 8 was detected.

Hyperkeratosis with follicular horn plugs, elongated retele ridges, moderate infiltration of histiocytes and foam cells as well as pronounced fibrosis in the dermis and in the subcutaneous fatty tissue.

TLR8-GOF is still a relatively young entity. From a genetic perspective, TLR8-GOF joins a growing list of (interface) diseases that can be caused by both germline and somatic (mosaic) genetic variants. The phenotype of this new disease has probably not yet been definitively determined (Bleesing J 2022)

1. Aluri J et al. (2021) Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood 137:2450-2462.
2. Bleesing J (2022) Gain-of-function defects in toll-like receptor 8 shed light on the interface between immune system and bone marrow failure disorders. Front Immunol13:935321.
3. Lee YH et al. (2012) Associations between TLR polymorphisms and systemic lupus erythematosus: a systematic review and meta-analysis. Clin Exp Rheumatol 30:262-265. https://www.ncbi.nlm.nih.gov/pubmed/22325161
4. Liu JW et al. (2025)Toll-like receptor 8 deficiency syndrome result in diffuse pigmented skin rash and autoinflammatory syndrome. J Dtsch Dermatol Ges 23:763-765.