Lupus
Posted October 10, 2023
Alexander J. Szalai, Ph.D., University of Alabama at Birmingham
Alexander J. Szalai, Ph.D., University of Alabama at Birmingham (Photo Provided)
People with Systemic Lupus Erythematosus (SLE) present with heterogeneous symptoms that can be traced back to the underlying immune cell hyperactivity seen in these patients. For example, in healthy individuals, immune cells called B-cells recognize foreign molecules (antigens) and produce antibodies that coordinate their removal. However, in individuals with SLE, B-cell hyperactivity causes them to mistakenly recognize a person’s own cells as a potential threat, and so they produce autoantibodies (immune components that recognize “self”).
The propensity for B-cells to make autoantibodies is partly related to genetics, and this may explain why SLE runs in families. One example of this genetic effect is inheritance of a mutation in a gene called ITGAM that encodes a protein called CD11b (a subunit of the receptor Mac-1). Mac-1 is known to be expressed in the cell membrane of B-cells and is known to play an important role in the regulation of normal immune system function. Thus, if the ITGAM gene is overexpressed or the Mac-1 protein is ‘faulty,’ the abundance or function of Mac-1, respectively, might change, and this could contribute to the common symptoms of SLE. Understanding how changes in ITGAM/Mac-1 can potentially affect B-cells’ ability to interact with other cells is important to fully understand SLE onset and its progression.
To better understand the contribution of ITGAM/CD11b to SLE, Dr. Alexander J. Szalai and his team studied two specific changes in the genetic code, called single-nucleotide polymorphisms (SNPs), that are known to frequently occur in the ITGAM gene of patients with SLE. Dr. Szalai reasoned that these SNPs potentially can change Mac-1’s structure/function and thereby alter the function of B-cells in a way that contributes to SLE symptoms. With a fiscal year 2017 Lupus Research Program Impact Award, Dr. Szalai and his team tested this hypothesis.
The Szalai team first assessed the abundance of extracellular CD11b on B-cells from donors with different ITGAM SNP genotypes, comparing the results obtained from healthy people versus SLE patients. One particular ITGAM SNP (called rs1143678) became of special interest, as it was found that B-cells from people with this SNP had increased expression of CD11b/Mac-1. They also discovered that rs1143678-affected B-cells express more CD24, a protein known to affect the ability of B-cells to engage other immune receptors and thereby energize the cell-signaling process. Other findings suggested that in people carrying SNP rs1143678, B-cell activation was altered in a way that impeded the normal breakdown of CD11b, leading to prolonged CD11b surface expression and Mac-1 receptor activity. These results provide the first causal link between ITGAM SNPs, overexpression of CD11b, Mac-1 hyperactivity, and the progression of SLE.
The team also found intriguing evidence that in SLE patients carrying the ITGAM SNP, B-cells are more able to present antigens and to activate the immune system, which is predicted to increase autoantibody production. For example, by combining the results of computer simulations and in vitro experiments, Dr. Szalai and his team showed that the ITGAM SNPs allowed for B-cells to make more interferon-γ (IFN-γ), a molecular messenger that is important for immune cell activation. Also, the overproduction of IFN-γ was the result of increased “JAK/STAT” signaling, which might promote enhanced antigen presentation by B-cells. Increased IFN-γ production and antigen presentation together should lead to increased autoantibody production, thereby promoting the progression of SLE symptoms in patients with the ITGAM SNP.
Dr. Szalai and his team have provided a new understanding of SLE at a cellular level and, in particular, the impact of ITGAM SNPs on CD11b expression, antigen presentation, and B-cell function. The work done in this project enables a deeper understanding of the potential genetic causes of SLE, and how those genetic changes affect immune system function. Dr. Szalai and his team hope their findings will facilitate the exploration of Mac-1 as a potential target for the treatment of SLE. Furthermore, since similar B-cell dysfunction is apparent in many other autoimmune diseases, these new findings could provide insights beyond just SLE.
Last updated Tuesday, October 10, 2023