Lipopolysaccharide-responsive beige-like anchor (LRBA), a novel regulator of human immune disorders

Research Article

Austin J Clin Immunol. 2014;1(1): 1004.

Lipopolysaccharide-responsive beige-like anchor (LRBA), a novel regulator of human immune disorders

Jia-Wang Wang1* and Richard F Lockey1,2

1Department of Internal Medicine, University of South Florida Morsani College of Medicine, USA

2Department of Internal Medicine, University of South Florida College of Medicine, James A. Haley Veterans’ Hospital, Tampa, USA

*Corresponding author: Jia-Wang Wang, Department of Internal Medicine, University of South Florida Morsani College of Medicine, USA.

Received: January 04, 2014; Accepted: January 29 , 2014; Published: February 03, 2014


Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) is a novel gene essential for the normal function of the immune system. It is the eighth common variable immunodeficiency (CVID) gene, mutation of which causes CVID and autoimmunity, and is associated with inflammation. LRBA is a unique CVID gene when compared to other CVID genes: it is a large, PKA anchor and vesicle trafficking regulator. Other seven CVID genes that are associated with CVID are cell receptors. However, the molecular mechanism by which LRBA regulates the immune system is unknown. LRBA protein contains Concanavalin A (ConA)-like lectin binding domain, Vacuolar protein sorting-27, hepatocyte growth factor-regulated tyrosine kinase substrate domain and signal transducing adaptor molecule (VHS) domain, two RII binding motifs, WD-like (WDL), and Beige and Chediak-Higashi (BEACH) domains and five WD40 repeats (WBW super domain). An LC3 interaction region (LIR), which is involved in autophagy, is also predicted in LRBA. The WBW super domain defined the WBW gene family, members of which appear to function as scaffolding proteins in vesicle trafficking and are important in human diseases. The cargo proteins regulated by LRBA through vesicle trafficking may include cytokines and antibodies for secretion, plasma membrane proteins for disposition on the membrane, and proteins trafficking between different membrane compartments, or proteins for degradation through lysosome/autophagy or proteasome degradation. Specifically, LRBA interacts with multiple important signal transduction pathways, including epidermal growth factor receptor (EGFR), Notch, PKA, Ras, E2F1, p53, and mitogen-activated protein kinases (MAPKs). These molecular interactions may help to understand why and how LRBA is involved in critical cellular processes such as cell proliferation, apoptosis and autophagy, and plays a fundamental role in the normal immune system.

The discovery of the LRBA gene

To discover genes responsible for B cell development, a short DNA sequence (143bp), 7a65, was obtained through a gene trapping method that requires the fusion of Escherichia coli lactose operon lacZgene and a cellular gene at both the transcriptional and translational levels, in order for the cell to express ß-galactosidase [1]. To obtain the full length sequence of the transcript, primers were designed from this sequence and PCR fragments were obtained from a mouse B lymphocyte cDNA library. The 5’ and 3’ rapid amplification of cDNA ends (RACE) techniques were further used to obtain the full length murine Lrba gene sequence from murine cell lines as well as from the liver and thymus of C57BL6/J mice [2]. A search of the GenBank found that the murine Lrba gene has a high degree of homology to a 7.3-kb human partial cDNA sequence called Beige- Like Protein (BGL) [3], which belongs to the human LRBA gene. The rest of the cDNA sequences of human LRBA were obtained from human lung, brain, and kidney cDNA libraries to complete the human LRBA sequence [2]. Human LRBA and murine Lrba proteins are 90% identical (2587/2859)with 94% positive(2690/2859) amino acid homology. Three murine Lrba isoforms with differences at the C-terminal were identified [2], while the human LRBA has two major isoforms [2,4]. LRBA has structural similarity to the lysosomal trafficking regulator (LYST) and is potentially an A-kinase anchoring protein (AKAP) for it has two regulatory subunit (RII) binding motifs to bind the RII subunit of cAMP-dependent protein kinase [2]. It belongs to the WDL-BEACH-WD40 (WBW) gene family [2] and is colocalized with the Golgi complex (GC), lysosomes, endoplasmic reticulum (ER), plasma membrane, and perinuclear ER as demonstrated by GFP fluorescence confocal and immunoelectronic microscopy. This is the first direct evidence that a WBW family protein can physically associate with various vesicular compartments in cells [2]. LRBA is also associated with motor proteins involved in vesicle trafficking [5,6]. LRBA-deficient B cells show abnormally high numbers of GCs [4]. It too is over expressed in several different cancers and its promoter activity is inhibited by p53 and increased by E2F1 [7]. Repression of LRBA expression by RNA interference, or a dominant-negative mutant, down-regulates the phosphorylation of epidermal growth factor receptor (EGFR) and significantly inhibitscancer cell growth [7]. Three papers published in 2012 demonstrate that deleterious mutations of LRBA cause CVID and autoimmunity, and are associated with inflammation. LRBA deficient patients have an early onset of more severe and potentially life-threatening CVID [4,8-10], demonstrating that LRBA plays a fundamental role in the normal immune system.

Clinical features of LRBA deficiency

CVID is the most common late onset primary immunodeficiency disease (PID) and is characterized by hypogammaglobulinemia and recurrent bacterial infections [11]. It is caused by defective B cell differentiation and impaired secretion of immunoglobulins [12,13]. CVID is a diagnosis of exclusion and is highly heterogeneous, genetically, immunologically and clinically [14-16]. About twothird of CVID subjects have an autoimmune problem [17], most commonly autoimmune hemolytic anemia (AHA), autoimmune thrombocytopenia, rheumatoid arthritis, and pernicious anemia [18]. The etiology of about 80% of CVID remains unknown [18], although over the past ten years, significant progress has been made in elucidating genetic mechanisms that result in a CVID phenotype. A small group of genes are found to be associated with or cause CVID [15]. These include the members of the B cell coreceptor complex (CD19 [19] , CD21 [20] and CD81 [21]), CD20 [22], transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) [23] and B cell-activating factor receptor (BAFFR) [24], and inducible costimulator (ICOS) [25]. The discoveries of CVID-causing mutations of these genes show that a monogenic defect may produce the whole spectrum of CVID, and that it is possible to unravel the genetic causes underlying most human diseases thought to be polygenic [26].

All of the above named receptors are involved in the stimulation, survival and development of B cells. CD20 is expressed on all stages of B cell development, except for early pro-B and plasma cells. CD21 facilitates internalization of immune complexes by B cells to enhance antigen presentation [27]. It forms a B cell membrane complex with CD19 and CD81 to augment the B-cell receptor response to antigen [27]. Both BAFFR and TACI play an important role in B-cell biology and development [28]. BAFFR is a critical B cell survival gene, disruption of which causes a dramatic drop in B cell numbers [29,30]. BAFF is a ligand for both BAFFR and TACI. Abnormally active BAFF signaling may play a role in autoimmunity. Likewise, excessive BAFF plays a role in promoting an autoimmune condition in mice which closely resembles systemic lupus erythematosus (SLE) in humans. TACI is a negative regulator of BAFF signaling in B-cell survival and responses [31], is important for switched memory B cells [32] and is associated with autoimmunity [23,33]. TACI deficient mice have increased immune globulin production and autoimmunity [34]. However, some CVID receptor mutations identified in CVIDs are present in healthy individuals; therefore, the same mutations may have a great variability in disease presentation, indicating that other underlying factors are also involved in this disease. The importance of these receptors is illustrated by the fact that they are therapeutic targets for human diseases. For example, anti-CD20 therapy is used extensively to treat B cell lymphoma and multiple sclerosis [35]. A therapeutic monoclonal antibody against BAFF is the first SLE medication approved by the FDA in over 40 years to treat this disease [36].

LRBA is significantly different from the other seven CVID genes (Table 1): First, it encodes a 319 kD large protein composed of multiple domains [1,2] and could serve as a scaffold to interact with multiple proteins. Other CVID proteins are relatively small, from 19 kD to 145 kD. Second, the seven CVID genes are B cell membrane receptors, except for ICOS which is on T cells, while LRBA is ubiquitously expressed as a vesicle trafficking regulator, required for homeostasis and activation of plasma membrane receptors [2,37]. Thus, LRBA may regulate other CVID genes, for example, CD19, CD20 and BAFFR, because their levels are low when LRBA is absent [4]. Third, LRBA deficiency causes both immunodeficiency and autoimmunity [4,8,38]. All 11 LRBA deficient CVID subjects identified thus far have autoimmune diseases (Table 4). TACI mutations also are associated with autoimmunity but to a lesser degree (36% vs. 23% of patients with wild-type TACI) [39]. Finally, LRBA is the only CVID protein that is a protein kinase A(PKA)anchor and thus can function as PKA to regulate protein activity by phosphorylation. In addition to these above unique features, LRBA also is unique in regulating autophagy, apoptosis, membrane dynamics and receptor signaling, all of which are important for inflammation [1,2].