Proteomics, Saliva, and Sjögren's Syndrome

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


February 20, 2008

Salivary Production in Normal and Sjögren's Syndrome Glands

The rate of salivary protein secretion is controlled mainly by noradrenalin, which is released from the sympathetic terminals and acts through the alpha-adrenergic receptors.[2] The rate of fluid and electrolyte secretion is controlled by acetylcholine, which is released from the parasympathetic terminals and acts through the muscarinic cholinergic receptors. Thus, the finding of a cholinergic stimulator as increasing the level of defensin protein is surprising. Some hypotheses have been suggested by Peluso and colleagues:[1] (1) that increased innervations of the gland by cholinergic nerves may be partially inhibited by cytokines that inhibit the stimulation of the muscarinic receptors, and (2) that the augmentation of cholinergic neurotransmitters may help restore secretory function.

This would be analogous to the small intestine where Paneth cells at the base of the crypts of Lieberkühn secrete alpha-defensins and additional antimicrobial proteins at high levels in response to cholinergic stimulation.[3]

This stimulation of Paneth cells to secrete defensins plays a critical role in inflammatory bowel disease since these molecules protect mitotically active crypt cells from colonization by potential pathogens and confers protection from enteric infection.[4] By analogy in SS, decrease in small antimicrobial proteins may alter the micro flora of the mouth and predispose to the oral complications of SS. In addition to this study of small molecules, several other recent studies on the salivary proteosome have been published.

Amado and colleagues[5] discussed the different techniques and methodologies applied to the separation and identification of salivary proteins. Nowadays, proteomic techniques are the state-of-the-art for the analysis of biologic materials and saliva is no exception. Two-dimensional (2D) gel electrophoresis and tryptic digest analysis by mass spectrometry are the typical methodology, but new approaches using "fast" 2D liquid chromatography/mass spectrometry methods are now being supplemented by bioinformatics technology to also examine posttranslational modification of proteins including glycosylation and phosphorylation as they relate to dental problems and even cancer diagnosis.[6,7,8] They demonstrated in SS patients a series of new proteins related to oxidative injury and well as proteins induced in response to pro-inflammatory cytokines.

Beklen and colleagues[9] demonstrated that changes in metalloproteinase and biofilm constituents play a role in periodontitis and dental caries. Of interest, salivary components are different in response to different taste challenges.[10]

Results of the study by Peluso and colleagues[1] dealt with only small proteins (defensins), while Ryu and colleagues[11] examined larger salivary protein biomarkers using surface-enhanced laser desorption/ionization time-of-flight-mass spectrometry (SELDI-TOF-MS).

Examining the proteins in the 10-200 kilodalton (kDa) size range, they found eight peaks with > 2-fold change in quantity/concentration between the SS group and non-SS. They demonstrated that:

  • Proteins with sizes 11.8, 12.0, 14.3, 80.6, and 83.7 kDa were increased; and,

  • Proteins with sizes 17.3-, 25.4-, and 35.4-kDa peaks were decreased in SS samples.

2D-gel electrophoresis identified significant increases of beta-2-microglobulin, lactoferrin, immunoglobulin (Ig) kappa light chain, polymeric Ig receptor, lysozyme C, and cystatin C in all stages of SS. Two presumed proline-rich proteins, amylase and carbonic anhydrase VI, were reduced in the patient group.

Laine and colleagues[12] demonstrated a decreased level of the androgen-regulated CRISP3 in saliva of SS patients. Serum and salivary levels of dehydroepiandrosterone sulfate levels were low, suggesting a relative androgen deficiency as the cause for the decreased CRISP3 levels.

Porola and colleagues[13] have also suggested that imbalance of secretory proteins in SS patient's saliva results in part from deficient androgen action at the level of the salivary glands.


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