miRNA-Mediated Control of B Cell Responses in Immunity and SLE

Abstract

Loss of B cell tolerance is central to autoimmune diseases such as systemic lupus erythematosus (SLE). As such, the mechanisms involved in B cell development, maturation, activation, and function that are aberrantly regulated in SLE are of interest in the design of targeted therapeutics. While many factors are involved in the generation and regulation of B cell responses, miRNAs have emerged as critical regulators of these responses within the last decade. To date, miRNA involvement in B cell responses has largely been studied in non-autoimmune, immunization-based systems. However, miRNA profiles have also been strongly associated with SLE in human patients and these molecules have proven critical in both the promotion and regulation of disease in mouse models and in the formation of autoreactive B cell responses. Functionally, miRNAs are small non-coding RNAs that bind to complementary sequences located in target mRNA transcripts to mediate transcript degradation or translational repression, invoking a post-transcriptional level of genetic regulation. Due to their capacity to target a diverse range of transcripts and pathways in different immune cell types and throughout the various stages of development and response, targeting miRNAs is an interesting potential therapeutic avenue. Herein, we focus on what is currently known about miRNA function in both normal and SLE B cell responses, primarily highlighting miRNAs with confirmed functions in mouse models. We also discuss areas that should be addressed in future studies and whether the development of miRNA-centric therapeutics may be a viable alternative for the treatment of SLE.

Keywords: B cells; autoimmunity; germinal center; miRNA; systemic lupus erythematosus.

Figure 1

miRNA Processing and Activity. Transcription induced in the nucleus generates a pri-miRNA transcript. The pri-miRNA is cleaved by Drosha, with the aid of co-factor DGCR8, into the pre-miRNA while still in the nucleus. Subsequently, exportin 5 exports the pre-miRNA into the cytoplasm. Following delivery into the cytoplasm, Dicer cleaves the pre-miRNA into the mature miRNA duplex. The mature miRNA duplex (associated with Argonaute) is then dissociated into two strands, the guide strand and the passenger strand. The guide strand preferentially associates with Argonaute in the RNA-induced silencing complex (RISC) and the passenger strand is preferentially degraded. Following association of the miRNA and target transcript, the RISC drives the degradation of the mRNA or mediates translational repression to control gene expression.

Figure 2

B Cell Development and Sites of B Cell Tolerance. B cell development begins in the bone marrow through a series of steps. Hematopoietic progenitor stem cells (HPSCs) undergo a series of differentiation steps leading to the generation of the common lymphocyte progenitor (CLP), from which B cell differentiation can proceed. Throughout the stages of B cell development in the bone marrow, a functional BCR is assembled and central tolerance is employed, whereby self-reactive B cells are directed to undergo receptor editing or cell death. B cells that pass this checkpoint migrate to the secondary lymphoid organs, including the spleen (depicted here) and lymph nodes. In the spleen, B cells continue to mature and peripheral B cell tolerance is enacted at several different stages of development. B cells enter the spleen at the T1 stage and strong BCR engagement can drive apoptosis at this stage. T1 B cells can progress on to the T2 stage, and from there can be induced to seed the marginal zone and follicle. In addition to regulation at the T1 stage, transitional B cells can be directed to undergo anergy and assume the T3 phenotype, whereby the BCR is downregulated to promote hyporesponsiveness. Marginal zone B cells generally become activated to provide a source of IgM. Alternatively, the follicular B cell subset directs the generation of IgG-secreting plasmablasts through both the follicular germinal center pathway and the extrafollicular pathway. Regulation is employed through both of these pathways. To summarize, well-documented regulatory stages are highlighted in red.

Figure 3

miRNAs that Impact B Cell Development in the Bone Marrow. Many miRNAs have been identified in the regulation of B cell development through each of the individual stages. This indicates a dynamic regulation of miRNA expression is required for proper developmental programs. miRNA regulation involved at these different stages is depicted. miRNAs that positively regulate these specific steps are depicted in blue. miRNAs that negatively regulate these specific steps are depicted in red. miRNAs are indicated at their confirmed or predicted stages of activity. HPSC, hematopoietic progenitor stem cell; MPP, multipotent progenitor; CLP, common lymphocyte progenitor.

Figure 4

miRNAs with Confirmed Functions in the Non-autoimmune GC Response. The germinal center (GC) response involves a number of processes that can be targeted by miRNA function. The focus herein pertains to direct modulation of GC B cell and Tfh responses during normal, non-autoimmune GC responses. Major processes involved in the GC response are underlined. miRNAs that positively regulate these specific GC processes are depicted in blue. miRNAs that negatively regulate these specific GC processes are depicted in red. miRNAs are indicated at their confirmed or predicted stages of activity.

Figure 5

miRNAs Involved in SLE Development in Mice. miRNAs involved in SLE development can be divided into multiple categories depending on their association with different stages of the B cell response (central tolerance, germinal center, extrafollicular response, other mechanisms), in addition to whether they promote or regulate disease manifestations. Those miRNAs that promote disease are shown in blue whereas those that regulate disease are shown in red. miRNAs with currently undefined mechanisms in SLE may later be identified during a specific stage of the B cell response or may have B cell independent mechanisms during SLE.

Figure 6

Exosomal Delivery of miRNA to Modulate Recipient Cell Response. Donor immune cells produce and process miRNAs (as depicted in detail in Figure 1 ). The formation of multivesicular bodies (MVBs) with intraluminal vesicles containing mature miRNAs in the donor cell leads to fusion of the MVBs with the plasma membrane, releasing exosomes containing these miRNAs. Recipient immune cells can receive exosomal cargo into the cytosol by direct fusion of the exosome with the plasma membrane or exosomes can be internalized and delivered to the endosomal compartment. Within the cytosol, these received miRNAs may compete with the internally generated miRNAs for incorporation in the RNA-induced silencing complex (RISC) to mediate gene expression in the recipient cell. miRNAs that are directed into the endosomal compartment may bind to TLR7/8 to initiate downstream signaling cascades, triggering the induction of cytokines, interferons, and other interferon stimulated genes.