Proteomics, Saliva, and Sjögren's Syndrome

Robert I. Fox, MD; Carla M. Fox, RN


February 20, 2008

Relevance to Rheumatologists

Proteomics is important to rheumatologists for several reasons. We have all seen numerous reports of genetic markers associated with particular autoimmune disorders, yet few new therapeutic leads have derived from this exhaustive gene hunt. Therefore, the search for new therapies now has moved to "gene expression" and "posttranslational modification" as a method to understand the interplay of genetic and environmental factors. This new area of research is termed "proteomics" and is actively being applied to other fields of endocrine and oncologic diseases.

More recently, these methods have been applied to autoimmune diseases that involve a complex array of different cell types. As an initial dip into the proteomic pool, investigators have begun by studying the relatively simple system of saliva and have taken advantage of the safety of obtaining biopsy specimens from the salivary glands.

In addition to briefly reviewing the molecular gymnastics of the proteomics technology, the recent reports described below have also revealed some surprising results that may help clarify pathogenesis or provide new leads to therapy.

Peluso and colleagues[1] recently applied the methods of proteomic analysis to compare changes in saliva in patients with Sjögren's syndrome (SS) and those of normal patients. The researchers then evaluated changes in the salivary profile of low-molecular-weight proteins following a specific therapy using a cholinergic agonist. The investigators then decreased the levels of defensins in the salivary gland of patients with SS saliva compared to the normal patients. This decrease in saliva production was unexpected, since the defensins are made in situ both by the inflamed ductal glands and by the lymphocytes that surround these glands. However, the defensins are not being transported/secreted into the SS patient's saliva. This observation was not predicted by "genomics" (i.e., the gene sequences are normal) but reveals the "microenvironment" of the gland revealed by "proteomics."

The second observation by Peluso and colleagues[1] was that a neurotransmitter (pilocarpine) increased the level of defensin in the saliva. The investigators studied small peptides including proline-rich peptide, defensins, and other small molecules involved in mucosal defense such as statherin, cystatin, and histatins.

It has been shown that in SS patients, 60% of the small salivary proteins in samples from primary SS patients were at significantly lower levels than those in healthy controls. However, 30-60 minutes following pilocarpine treatment, many of the less represented proteins returned to the level in non-SS controls.

Although there is relatively limited interest in mucosal immunity in general (or salivary defensins in specific) among rheumatologists, there is increasing recognition of the importance of the interaction of cytokines, neurokines, and the endocrine systems in autoimmune disease. For example, our traditional pathogenetic models do not provide much insight into chronic fatigue -- one of our most common and difficult to treat problems in patients with systemic lupus erythematosus or SS.

Perhaps an understanding of the interactions of the neuro-endocrine-immune axis that operates in an easily measured system such as tear or saliva flow may provide insight in poorly understood conditions such as chronic fatigue syndrome. The role of gender (androgen/estrogen) has been unclear in SS and systemic lupus erythematosus, and proteomic studies have recently demonstrated a role for androgen that is required for post-translational modification of the salivary protein cysteine-rich secretory protein 3 (CRISP3, discussed below).

If past decade was the era of understanding/treating imbalance of the acquired/innate immune system with tumor necrosis factor inhibitors or B-cell depleters, perhaps the next decade need to focus on the complex interactions leading to fatigue and interaction of the immune system with the neural system.

These studies on a process as simple as salivation help us expand the studies conducted a hundred years ago by Pavlov, who showed the interaction of cortical function and salivation as he taught dogs to salivate as a conditioned response to ringing a bell.

Most rheumatologists suspect that fibromyalgia will ultimately be more like a conditioned response to stress that involves the hypothalamic-adrenal axis, literally an extension of the Hans Selwyn famous experiments on the role of the adrenergic/cholinergic responses to stress, and we must now reinterpret the "stress axis" in the newer knowledge of the important influence of cytokines and neurokines.

The article by Peluso and colleagues[1] emphasizes several general points about mucosal immunity, an area of research that is not generally considered by rheumatologists. We have come to accept the parallel and overlapping existence of "acquired" (adaptive, human leukocyte antigen [HLA]-DR linked lymphocyte responses) and "innate" (HLA-DR independent responses mediated by Toll receptors) immune systems. However, the full breadth of the innate immune system (ie, immediate response to particular environmental antigen motifs) also includes mucosal defense mechanisms. This has been emphasized in current research in inflammatory bowel disease (ie, the NOD/card system), but has received less attention in rheumatology journals. Small molecules such as defensins represent an important link between the environment and the "innate" immune system.


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