Abstract
Absent in melanoma 2 (AIM2) has been reported to be a component of inflammasomes in innate immune cells. Surprisingly, AIM2 is expressed by B cells, and higher AIM2 expression is observed in the B cells from lupus patients. To date, the inflammasome-independent function of AIM2 in B cells remains unclear. Here, we report increased expression of AIM2 in human tonsil memory and germinal center (GC) B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients. Conditional knockout of AIM2 in B cells reduces the CD19+ B-cell frequency in lymph nodes and spleens, and dampens KLH-induced IgG1-antibody production. In a pristane-induced mouse model of lupus, AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells, T follicular helper (Tfh) cells, plasmablast cells, and plasma cells. Furthermore, the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6. However, the silencing of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression, indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6. In addition, IL-10 is found to upregulate AIM2 expression via DNA demethylation. Together, our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6–Blimp-1 axis, providing a novel target for SLE treatment.
Highlights
Absent in melanoma 2 (AIM2) is originally identified as a tumor suppressor of melanoma and named absent in melanoma 2.1AIM2 is a member of the interferon (IFN)-inducible PYHIN protein family.[2]
Increased AIM2 expression in B-cell subtypes from Systemic lupus erythematosus (SLE) patients To further investigate whether the AIM2 expression is associated with disease conditions, we detected the AIM2 expression in different B-cell subtypes in the peripheral blood from SLE patients (n = 56)
The frequency of AIM2+ plasma cells was positively correlated with the SLE disease activity index (SLEDAI) (r = 0.3137, p = 0.0186, Fig. 1g)
Summary
Absent in melanoma 2 (AIM2) is originally identified as a tumor suppressor of melanoma and named absent in melanoma 2.1AIM2 is a member of the interferon (IFN)-inducible PYHIN protein family.[2]. The AIM2-inflammasome can further promote either IL-18 and IL-1β production or gasdermin-D (GSDMD)-mediated pyroptosis.[3,4,5,6] In addition, the inflammasome-independent function of AIM2 is linked to the regulation of intestinal cell proliferation, apoptosis, and metastasis in colon cancer.[7] whether AIM2 exerts inflammasome-independent effects in immune cells, especially in adaptive immune cells, is unclear. Memory B cells are not capable of secreting antibodies, they can further undergo somatic hypermutation (SHM) and/or class switch DNA recombination (CSR) and differentiate into plasma cells upon subsequent antigen exposure.[10] This process is mainly regulated by the B lymphocyte-induced maturation protein 1 (Blimp-1)-Bcell lymphoma 6 protein (Bcl-6) axis
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