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TO THE EDITOR:

Professor of Oral Biology University of Manitoba Winnipeg, MB, Canada

The recent paper by Chaushu et al. ("Severe impairment of secretory Ig production in parotid saliva of Down syndrome individuals", J Dent Res 81:308-312, 2002) raises the interesting question of the relative importance of the concentration of a substance secreted into saliva as opposed to the total amount of that substance secreted per unit time. Chaushu et al. found no difference between normal controls and Down syndrome individuals in the parotid salivary concentrations of IgA and IgG, but the latter group had much lower flow rates, and thus the amounts of immunoglobulins secreted per minute were significantly less. However, the authors could equally well have claimed "severe impairment" of the amounts of water, calcium, sodium, chloride, etc., secreted per minute by the Down syndrome individuals (assuming, as with the immunoglobulins, that the electrolyte concentrations were similar to those in the saliva of the control subjects).

If an individual has the normal residual volume of saliva of about 0.8 mL, the total amount of a salivary component secreted by a gland per minute might be important only if the component is used up by some reaction in the mouth such that its concentration in whole saliva is greatly reduced. A possible example of this is salivary urea, which can diffuse into plaque and be converted by certain micro-organisms to ammonia and carbon dioxide, thereby raising plaque pH. However, only a very small fraction of salivary urea is normally metabolized in this way, so that the urea concentration in whole saliva is little different from that in the individual gland secretions.

The amounts of immunoglobulins secreted per minute, as opposed to the concentration in the saliva, may be important only if it could be shown for Down syndrome individuals, but not for normal control subjects, that the concentration of free immunoglobulin (i.e., that not bound to micro-organisms) in whole saliva is very low, compared with the levels in the individual gland secretions. Such a result would imply that Down syndrome individuals might secrete insufficient salivary immunoglobulins to react fully with the normal oral flora. The fluid assayed for immunoglobulins by Chaushu et al., though, was not whole saliva but parotid saliva, and since this is essentially sterile, the IgA would not have had a chance to be bound to the oral flora.

THE AUTHORS REPLY:

We are grateful to Professor Dawes for having taken the trouble to relate to our article. His letter gives us the unique opportunity to address some classic issues, which were, and probably will continue to be, in debate.

First, those engaged in the research of saliva have been faced with the dilemma as to the best quantitative way to express amounts of salivary constituents. It is well-established that changes in salivary flow rate may influence the concentrations of the various salivary constituents (Mandel, 1980). Therefore, to evaluate salivary composition in abnormal states, one must be aware of the specific relationship of the concentration to the flow rate. Such a relationship is not necessarily constant and can be time- and flow-rate-dependent. For example, sodium and chloride are directly related to flow rate, potassium is independent of flow rate in stimulated saliva, while calcium is flow-dependent only at the highest flow rates (Mandel, 1980). This being so, it follows that the statement "the authors could equally have claimed ‘severe impairment’ of the amounts of water, calcium, sodium, chloride, etc." does not take into consideration the specific relationship of the concentrations of each mentioned constituent to the flow rate. To justify this position, one would need to demonstrate severe impairment for each constituent separately.

As to salivary immunoglobulins, the concentration-to-flow-rate relationship is even more complicated than it is for salivary electrolytes. Mandel and Khurana (1969) demonstrated more than 30 years ago an inverse relation between IgA and flow rate as opposed to intrinsic salivary proteins (amylase, glycoproteins, etc.), which were either independent or directly related to flow rate. Gustatory stimulation also affects the specific relationship of the concentration to the flow rate (Brandtzaeg, 1971; Ben-Aryeh et al., 1986). It is for these reasons that researchers working on salivary immunoglobulins, unlike those involved with salivary electrolytes, have considered secretion rate (amount of immunoglobulins secreted per minute) as the more accurate parameter of mucosal function, because it accounts for individual variations due to rate of salivary flow (Brandtzaeg et al., 1970; Chandler et al., 1974; Ørstavik and Brandtzaeg, 1975; Challacombe et al., 1995).

There is a second dilemma: Which saliva should be studied? The use of whole saliva in immunological diagnosis is very limited, since it is an admixture of all salivary glands’ secretions inextricably mixed with food debris, bacteria, shed cells, etc. (Mandel, 1980). Gingival inflammation has an effect on the composition of the crevicular fluid, which comes to be included. By contrast and as Professor Dawes correctly points out, parotid saliva is "sterile", which means that the fluid investigated is the pure, uncontaminated secretion (Chandler et al., 1974). Moreover, one investigator may be concerned with saliva and its effects on the oral cavity, while another might be additionally interested in its composition, as a representative of the entire common mucosal immune system (CMIS). This may facilitate an insight into additional mucosal systems (e.g., respiratory). It is well-known that the prevalence of periodontal disease in Down syndrome (DS) individuals is high (Reuland-Bosma and van Dijk, 1986); therefore, the presence of periodontal disease among the sample subjects may be expected to yield misleading results, had whole saliva been the fluid of choice in the present study. Furthermore, in a recently published study, we concluded that parotid salivary Ig might serve as a predictor of the susceptibility of DS individuals to recurrent respiratory tract infections (Chaushu et al., 2002).

In the present study, which was designed to be an initial study, our aims were deliberately restricted to discovering alterations of the composition of salivary Ig in DS individuals. It is our intention to continue our work on saliva and to direct our attention to the study of specific antibodies, at which point Professor Dawes’ idea becomes very relevant. Subsequently, our research will be directed at correlating specific antibodies secreted in parotid saliva with specific free antibodies in whole saliva. As always in research, our aim has been, first, to understand the pathogenesis and only afterward to continue to study its implications.

REFERENCES

Ben-Aryeh H, Naon H, Szargel R, Horowitz G, Gutman D (1986). The concentration of salivary IgA in whole and parotid saliva and the effect of stimulation. Int J Oral Maxillofac Surg 15:81–84.[Medline]

Brandtzaeg P (1971). Human secretory immunoglobulins. VII. Concentrations of parotid IgA and other secretory proteins in relation to the rate of flow and duration of secretory stimulus. Arch Oral Biol 16:1295–1310.[Medline]

Brandtzaeg P, Fjellanger I, Gjeruldsen ST (1970). Human secretory immunoglobulins. I. Salivary secretions from individuals with normal or low levels of serum immunoglobulins. Scand J Haematol 12(Suppl):3–83.

Challacombe SJ, Percival RS, Marsh PD (1995). Age-related changes in immunoglobulin isotypes in whole and parotid saliva and serum in healthy individuals. Oral Microbiol Immunol 10:202–207.[Medline]

Chandler DC, Silverman MS, Lundblad RL, McFall WT (1974). Human parotid IgA and periodontal disease. Arch Oral Biol 19:733–735.[Medline]

Chaushu S, Yefe-Nof E, Becker A, Shapira J, Chaushu G (2002). A link between parotid salivary Ig level and recurrent respiratory infections in young Down’s syndrome patients. Oral Microbiol Immunol 17:172–176.[Medline]

Mandel ID (1980). Sialochemistry in diseases and clinical situations affecting salivary glands. Crit Rev Clin Lab Sci 12:321–366.[Medline]

Mandel ID, Khurana HS (1969) The relation of human salivary ãA globulin and albumin to flow rate. Arch Oral Biol 14:1433–1435.[Medline]

Ørstavik D, Brandtzaeg P (1975). Secretion of parotid IgA in relation to gingival inflammation and dental caries experience in man. Arch Oral Biol 20:701–704.[Medline]

Reuland-Bosma W, van Dijk J (1986). Periodontal disease in Down’s syndrome: a review. J Clin Periodontol 13:64–73.[Medline]

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