AIMing 2 promote lupus by targeting helpers

The immune system defends the body against foreign or dangerous invaders while protecting the self. If it mistakes self for non-self, then it attacks the body’s own tissues, causing autoimmune disorders, such as systemic lupus erythematosus (SLE). SLE is the most common type of lupus. Many organs, including the skin, joint, lung, kidney and brain, can be affected andmanifested with widespread inflammation and tissue damage. The accumulation of a wide spectrum of autoantibodies against self-nuclear components is a hallmark of SLE.1 Follicular helper T (TFH) cells, a subset of CD4 T helper (TH) cells, are required for the precise control of antibody production by germinal centre (GC) B cells.2,3 It is well-recognised that overexpansion or dysregulation of TFH cells is the root of the aberrant production of self-reactive antibodies that promote lupus pathogenesis.4 Thus, a deeper understanding of the mechanisms controlling TFH cell differentiation and function may facilitate the development of therapies to treat SLE. Wu et al. have presented a newmechanism bywhich the TFH response is potentially dysregulated in SLE patients. The expression of Absent in melanoma 2 (human AIM2 andmurineAim2) is found to be increased in TFH-like cells (CD4Bcl6PD1) in the peripheral blood and skin lesions of lupus patients, compared to healthy controls. The elevated AIM2 level is attributed to the increased recruitment of the hydroxymethyltransferase ten-eleven translocation

The immune system defends the body against foreign or dangerous invaders while protecting the self. If it mistakes self for non-self, then it attacks the body's own tissues, causing autoimmune disorders, such as systemic lupus erythematosus (SLE). SLE is the most common type of lupus. Many organs, including the skin, joint, lung, kidney and brain, can be affected and manifested with widespread inflammation and tissue damage. The accumulation of a wide spectrum of autoantibodies against self-nuclear components is a hallmark of SLE. 1 Follicular helper T (T FH ) cells, a subset of CD4 + T helper (T H ) cells, are required for the precise control of antibody production by germinal centre (GC) B cells. 2,3 It is well-recognised that overexpansion or dysregulation of T FH cells is the root of the aberrant production of self-reactive antibodies that promote lupus pathogenesis. 4 Thus, a deeper understanding of the mechanisms controlling T FH cell differentiation and function may facilitate the development of therapies to treat SLE.
Wu et al. have presented a new mechanism by which the T FH response is potentially dysregulated in SLE patients. The expression of Absent in melanoma 2 (human AIM2 and murine Aim2) is found to be increased in T FH -like cells (CD4 + Bcl6 + PD1 + ) in the peripheral blood and skin lesions of lupus patients, compared to healthy controls. The elevated AIM2 level is attributed to the increased recruitment of the hydroxymethyltransferase ten-eleven translocation 2 (TET2) driven by the cytokine interleukin (IL)-21 to the AIM2 promoter region, leading to reduced AIM2 methylation. AIM2 interacts with the T FH -promoting transcription factor c-MAF, 3 enhancing and sustaining IL-21 production and T FH cell differentiation. Accordingly, deletion of Aim2 or Tet2 in murine T cells results in reduced T FH and GC B cells as well as antigen-specific antibody production. Serum autoantibody levels and renal immunoglobulin G deposition are also expectedly reduced in mice with T-cell-specific ablation of Aim2 in both pristane-induced and chronic graft-versus-host disease lupus models. The increased expression of IL21, TET2, AIM2 and c-MAF and the positive correlation of AIM2 with IL21 or c-MAF in SLE patients support the potential contribution of the IL-21-TET2-AIM2-c-MAF axis to lupus development. Nevertheless, TET2, as a DNA demethylating factor, has various target genes. In fact, IL-21 increases the recruitment of TET2 to the BCL6 promoter region in lupus patients, while interferon (IFN)-α, the signature cytokine for lupus, also increases AIM2 levels, albeit to a lesser degree. These results imply that multiple pathways promote T FH dysregulation in SLE.
AIM2, a family member of the pyrin and HIN domaincontaining proteins, is a sensor for cytosolic DNA, which plays a crucial role in the regulation of the inflammasome and innate immune response. 5 The inflammasomeindependent function of AIM2 is emerging, as it has been investigated in cells belonging to the adaptive immunity, such as B cells, regulatory T (Treg) cells and also T FH cells reported by Wu et al. 6,7 The mechanisms of action vary among these cell types, ranging from immune metabolism alterations to transcriptional regulation. The distribution of AIM2 within the cell may dictate its function, as AIM2 mainly resides in the nucleus of CD4 + T cells, which may aid in its regulation of the c-MAF-dependent transcriptional program to promote T FH cell differentiation.
AIM2 is expressed at the highest levels in T FH cells compared to other T H cells. Further analysis of mice with a T-cell-specific deletion of Aim2 may allow us to precisely determine whether Aim2 regulates the differentiation of other T H cells, particularly T H 17 cells, as IL-21 and c-Maf also regulate T H 17 development. 8 Since controlling the AIM2 expression level is the key to T FH cell fate determination, it is also important to understand why AIM2 levels decline gradually during in vitro T FH cell differentiation. Elucidating factors that modulate AIM2 expression in T FH cells may guide the strategies to target T FH cells in SLE and other autoimmune disorders.
Besides T H cells, Treg cells express Aim2, and Aim2 is important for the maintenance of stable suppressive Treg cells in a murine experimental autoimmune encephalomyelitis model. 7 Follicular regulatory T (T FR ) cells, a subset of Treg cells, share many features with T FH cells but play an important role in restraining T FH and GC B-cell responses to prevent autoantibody production. 2,9 Targeting T FH cells to treat lupus or other autoimmune disorders needs to consider keeping T FR cells intact. In this regard, understanding whether AIM2 regulates the differentiation and function of T FR cells differently from T FH cells will be important.
The same research team also recently revealed higher AIM2 expression in memory B cells and plasma cells from the circulation and skin lesions of lupus patients. 6 IL-10 has a greater capacity than IL-21 to upregulate AIM2 in B cells by reducing the DNA methylation level of AIM2. 6 Importantly, conditional knockout of Aim2 in B cells attenuates lupus symptoms and reduces T FH , GC B cells and plasma cells in the pristane-induced lupus model. 6 It is quite fascinating that both T FH cells and B cells adapt to the lupus environment by employing epigenetic regulation via upregulating AIM2, despite their responses to different triggers. Given the specific impact of autoantibody isotype, specificity or affinity to self-antigens on SLE pathogenesis, 1 it is imperative to evaluate whether AIM2 expression in T FH cells or B cells regulates the antibody class switching and/or affinity maturation.
Currently, there is no cure for lupus. Therapies targeting B cells, the autoantibody producer, have shown some promise, 10 but targeting B cells may not be sufficient, given the far more complicated regulation of B cells, including the newly identified pathways emanating from T FH cells. The increased AIM2 in T FH cells of SLE patients but not in psoriasis or healthy people suggests its potential as a diagnostic marker for SLE. However, the involvement of AIM2 in the regulation of multiple cell types suggests that it may not be an ideal therapeutic target. Moreover, epigenetic modifiers that regulate AIM2 are influenced by environmental cues, including cytokines IL-21, IFNα and high salt, adding another layer of complexity. Considering targeting cell-type specific factors and combinatorial therapies would bring better hopes to patients with this serious disease.

A C K N O W L E D G E M E N T S
JWL is supported by DoD W81XWH-18-1-0315, NIH grant R01AI148711 and the University of Alabama at Birmingham faculty start-up funds.

C O N F L I C T O F I N T E R E S T
The author declares that there is no potential conflict of interest.