A TNIP1-driven human systemic autoimmune disorder with elevated IgG4

Abstract

The complex aetiology of human systemic autoimmune diseases presents a challenge for developing targeted and efficacious therapies. Greater insight into genetic factors that directly influence autoimmune pathogenesis can unveil underlying molecular defects that trigger disease in patient cohorts and inform the design of pathway-specific therapies. Whole genome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies and elevated serum IgG4 uncovered an identical ultrarare heterozygous missense variant in the gene encoding tumor necrosis factor alpha-induced protein 3 interacting protein 1 (TNIP1) segregating with disease. The pathogenic contribution of this human TNIP1 variant encoding a glutamine to proline amino acid substitution at residue 333 (Q333P) was investigated in a CRISPR-Cas9-edited mouse model dubbed vikala carrying the orthologous Tnip1 variant (vik). Homozygous vikala mice developed anti-nuclear antibodies, lymphocytic infiltration in the salivary glands and elevated serum IgG2c. Cellular abnormalities consistent with lupus-like autoimmune phenotypes were observed in vikala mice including the expansion of age-associated B cells, plasma cells, follicular and extrafollicular helper T cells and germinal center B cells. B cell abnormalities were cell-intrinsic, and the expansion of lymphoid subsets was rescued by the ablation of toll-like receptor 7 (Tlr7) or myeloid differentiation primary response protein 88 (Myd88) signalling. Investigation of the precise molecular mechanism of TNIP1Q333P revealed that the variant unexpectedly, impaired repression of type I interferon production without altering NF-κB signalling. TNIP1Q333P also decreased the recruitment of MYD88 and interleukin-1 receptor-associated kinase (IRAK1) to TNIP1-positive autophagosomes, thus inhibiting repression of TLR7 signalling. The unique molecular defects identified in the vikala mouse model provide a unique opportunity to explore emerging B cell tolerance paradigms related to autophagosome trafficking. This study is first to establish a direct causative role for TNIP1 variants in human autoimmunity. Our findings suggest that TLR7-targeting therapeutic agents may be effective in patients with ambiguous diagnoses of systemic autoimmunity featuring IgG4 elevation and TNIP1 dysregulation. Show more