SLAM Associated Protein (SAP) may Provide a Critical Role for Autoimmune Collagen Induced Arthritis through T Cell Development

             The formation of immune cells which attack one's own body (known collectively as autoimmune diseases) is still a widely studied topic which has yet to be fully understood. In normal immune function adaptive immune cells such as B cells and T cells are screened during development so that they do not recognize an antigen which is present in the body and therefore only attack invading pathogens; however when this process is disrupted these B and T cells will recognize cells of the body and attack them as if they were a pathogen. These diseases can be focused on the attack of specific organs or the body as a whole leading to devastating and often lethal consequences.   Recent studies have implicated a small protein (SAP) which is encoded by the SH2D1A gene in the manifestation of autoimmune diseases such as Systematic Lupus Erythematosus, Rheumatoid Arthritus, and Myasthenia Gravis.  This intracellular protein contains a single SH2 domain which binds to a family of receptors (known as the SLAM receptors) and is  implicated in a number of immune system functions including the differentiation and production of T cell subsets.  This protein acts in two ways: 1. It has the capacity to bind and activate the protein Fyn which is critical for the signaling pathways involved in cell growth and differentiation  2. It prevents the binding of inhibitory proteins SHIP1 and SHP1 which act to impede cell growth and differentiation.  Therefore the presence of the SAP protein presents a two fold mechanism for cell growth and differentiation which helps explain why it is a key regulator of immunce cell functions.

A recent paper published in the November 1st addition of the Journal of Biochemistry examined the role of SAP in the regulation of the autoimmune disease Collagen-induced Arthritus (CIA).  This study induced murine CIA (similar to Rheumatoid Arthritis in humans) and altered the expression of SH2D1A in order to elucidate the role SAP plays in disease progression.  The authors of the paper found that when the SH2D1A gene was eliminated in the mice using a Cre-Lox system the mice did not develop CIA while the genetically normal mice did.  The implication of this initial test demonstrated that SAP must be playing  some kind of role in the progression of this autoimmune disease.  To further this investigation, researchers then used the same Cre-Lox system to eliminate the SH2D1A gene (and thus the formation of SAP) but utilized different promoter regions which were specific to B cell or T cells.  This meant that half of the mice had the gene deleted in their B cells only and the other half had the gene deleted in their T cells only.  The results of this demonstrated that when the gene was deleted from B cells there was no change in the disease course but when the gene was deleted in T cells the mice did not develop CIA.  So essentially SAP plays role in the development of T cells likely through its binding of SLAM receptors and concurrent phosphorylation and activation of the Fyn protein.  To test this idea, a final line of mice were induced with CIA but this time the mice expressed a different allele in which the SAP protein could bind to the SLAM receptors but not Fyn.  When the disease induction was given in a high dose the inability of SAP to bind and activate Fyn made no difference in the disease incidence and only a slight decrease in disease progression.  In contrast, when the disease was induced with a low dose of the antigen only half the mice developed CIA and the disease progression was even more reduced.  This would indicate that the binding of SAP to Fyn IS (in fact) necessary for the course of the disease.


Given that the autoimmune diseases in which SAP function is critical (SLE, RA etc.) are antibody mediated, and that B cells and B cell progenitors are the source of antibodies one would expect that SAP function in B cells must be essential for these auto-antibodies.  However, this most recent study showed that T cells are the where SAP is critical for autoimmune development, therefore it is likely that the interaction between T cells and B cells which produces the auto-antibodies characteristic of these diseases.  Thus, future studies may want to investigate the intergration between B cells and T cells and how SAP mediates this process.  A few studies have generally shown that SAP elimination affects the follicle T cells and their interaction with germinal centers but this research is in its preliminary stages.

I think that this look into the role of the SH2D1A gene is really important for the study of autoimmune diseases.  We know that many of these diseases have similar features and that the process of creating auto reactive lymphocytes must be generally similar.  Who is to say that one or two genes couldn't be the cause of the disruption of he process and which specific autoimmune disease occurs is just the result of which specific antigen these cells encounter?  I think its even more interesting that a lot of these disease have a female bias and the SH2D1A gene is in fact on the X chromosome.  If I would you the reader, I would keep an eye out because I think we will be seeing a lot more from this gene in the future. 


Sources:
The Adaptor Molecule Signaling Lymphocytic Activation Molecule (SLAM)-associated Protein (SAP) Is Essential in Mechanisms Involving the Fyn Tyrosine Kinase for Induction and Progression of Collagen-induced Arthritis

SLAM receptors and SAP influence lymphocyte interactions, development and function