Name: Immunodeficiency 98 with autoinflammation | Acronym: IMD98
Alt. names: TLR8-GOF | TLR8 gain of function

Gene: TLR8 | MOI: X-linked recessive | Mechanism of action: Gain of Function

No. of cases in DB: 3 | First reported in: 2021

Last updated on: 2023-03-31 06:19:58 by Xiao P. Peng

OMIM: 301078

Orphanet: -

MONDO: 0024777

DOID: -

ClinGen:

Germline X-linked TLR8 gain-of-function has been described in 3 patients from 2 families thus far (PMID: 33512449, 34981838). It is characterized by immunodeficiency, autoimmunity, and autoinflammation. Patients present with non-malignant lymphoproliferation recurrent sinorespiratory and GI infections, autoimmune cytopenias, oral ulcers, and inflammatory CNS, skin and joint involvement in the first decade of life. Immunophenotyping is notable for elevated proinflammatory serum cytokines, activated T cells and monocytes, and evidence of T-cell dysregulation, with inverted CD4:CD8 ratios, skewed naive to memory ratio of CD4+ T cells, and increased double-negative T cells. Patients also show hypogammaglobulinemia, nonspecific auto-antibody production, and B cell maturation defects leading to reduced class-switch memory B cells. Additionally, patients have increased peripheral blood type I IFN signatures, albeit lower than for patients with primary IFNopathies.

Some patients received immunoglobulin replacement therapy for hypogammaglobulinemia and all patients received immunosuppression for autoimmune/autoinflammatory complications (i.e. sirolimus, rituximab, cyclosporine A, anakinra) including steroids. In general, patients with neutropenia had a poor response to therapeutic or high doses of G-CSF. Thus far, one patient receiving hematopoietic stem cell transplant was able to engraft with complete donor chimerism and no signs of graft-versus-host disease (PMID: 34981838).