Three general domains of immune measures have been examined in studies of depressed subjects: enumerative measures, functional measures, and markers of immune activation. Each domain will be briefly described with a review of the respective immune findings in depressive disorder.
The enumerative measures provide a measure of the total number of circulating immune cells and quantify the absolute and relative numbers of the major immune cell classes such as neutrophils, lymphocytes, and monocytes. In addition, enumerative measures provide an assessment of the number and percentage of cells expressing cell surface markers related to B cells and T lymphocyte subset phenotypes.
One of the first immunological findings identified in the study of depressed subjects was change in the total number of white blood cells and numbers and percentages of neutrophils and lymphocytes (Sengar, Waters, Dunne, & Bover, 1982; Schleifer, Keller, Meyerson, Raskin, Davis, & Stein, 1984; Kronfol,Turner, Nasrallah, & Winokur, 1984; Albrecht, Helderman Schlesser, & Rush, 1985; Schleifer, Keller, Siris, Davis, & Stein, 1985; Irwin, Smith, & Gillin, 1987; Kronfol, & House, 1989; Schleifer, Keller, Bond, Cohen, & Stein, 1989; Irwin, Caldwell, Smith, Brown, Schuckit, & Gillin, 1990a; Irwin, Patterson, Smith, Caldwell, Brown, Gillin, & Grant, 1990b; Maes, Lambrechts, Bosmans, Jacobs, Suy, Vandervorst, Jonckheere, Minner, & Raus, 1992a). Along with an increase in the total number of white blood cells, increases in the number of neutrophils and decreases in the number of lymphocytes have been reliably demonstrated (Herbert & Cohen, 1993a; Zorrilla et al., 1998). In regards to numbers of monocytes, a relative increase in the number of monocytes has been found in many studies of depressed subjects (Maes et al., 1992a), whereas other depression samples have shown decreases or no differences in the absolute or relative numbers of monocytes (Irwin et al., 1987; Irwin et al., 1990a,b). The two existing meta-analyses have also yielded discrepant results regarding change of monocyte numbers in depression.
Cellular enumeration of lymphocyte subsets by the quantification of phenotypic specific cell surface markers has been widely used to evaluate alterations of the immune system in relation to diagnostic depression. Depression is reported to be negatively related to the number and percentages of lymphocytes that are B cells, T cells, T helper cells, and T suppressor/cytotoxic cells (Herbert & Cohen, 1993a). A decrease in circulating number of cells that express the NK phenotype has also been reported which in part is moderated by gender; a decline of NK cell numbers is found in male but not female depressed subjects as compared to gender matched controls (Evans, Folds, Petitto, Golden Pedersen, Corrigan, Gilmore, Silva, Quade, & Ozer, 1992). However, multiple discrepant findings have also been reported and, in one of the largest study samples of depressed subjects, no difference in the number of peripheral blood lymphocytes or T lymphocyte subsets was found between depressed patients and controls (Schleifer et al., 1989). Indeed, with accumulation of a larger sample of studies and subjects, it is increasingly apparent that heterogeneous results predominate and there appears to be no consistent change in the number of circulating B-, T-, or NK cells in depression (Zorrilla et al., 1998).
Function of the immune system has been typically evaluated in depressed subjects by assay of nonspecific mitogen-induced lymphocyte proliferation, mitogen-stimulated cytokine production, and NK cytotoxicity. Lymphocyte proliferation assays examine how well lymphocytes divide in response to a nonspecific mitogen. This assay along with the release of cytokines assumes that with more proliferation and more cytokine release, the lymphocytes are functioning more effectively. The purpose of the third functional assay, NK cell cytotoxicity, is to determine the ability of NK cells to lyse tumor cells in culture.
2.2.1. Mitogen-induced lymphocyte proliferation. A reliable association between depression and lower proliferative responses to the mitogens PHA, ConA, and poke-weed has been found in each of the two meta-analytic reviews (Herbert & Cohen, 1993a; Zorrilla et al., 1998). Some of the first observations evaluating depression and mitogen responses showed reduced proliferation in depressed subjects as compared to controls (Kronfol, Silva, Greden, Dembinski, Gardner, & Carroll, 1983; Schleifer et al., 1984; Kronfol & House, 1985). However, subsequent studies failed to replicate these observations, raising questions about the reliability of this immune alteration in depression (Schleifer et al., 1989). Nevertheless, with over a dozen studies now conducted on lymphocyte proliferation in depression (Albrecht et al., 1985; Syvalahti, Eskola, Ruuska-nen, & Laine, 1985; Schleifer et al., 1985; Kronfol, House, Silva, Greden, & Carroll, 1986; Calabrese, Shwerer, Barna, Gulledge, Valenzuela, Butkus, Subichin, & Krupp, 1986; Lowy, Reder, Gormley, & Meltzer, 1988; Maes, Bosman, Suy, Minner, & Raus, 1989; Altshuler, Plaeger-Marshall, Richeimer, Daniels, & Baxter, 1989; Darko, Gillin, Risch, Bulloch, Golshan,Tasevska, & Hamburger, 1989; Kronfol & House, 1989; Cosyns, Maes, Vandewoude, Stevens, DeClerck, & Schotte, 1989; Bartoloni, Guidi, Antico, Pili, Cursi, Carbonin, Gambassi, Rumi, Di Giovanni, & Menichella, 1990; McAdams and Leonard, 1993; Birmaher, Rabin, Garcia, Jain, Whiteside, Williamson, Al-Shabbout, Nelson, Dahl, & Ryan, 1994), it appears that an impairment in the response of lymphocytes to all three non-specific mitogens predominates in studies of depressed subjects.
2.2.2. Natural killer cytotoxicity. A reduction of NK activity is considered to be one of the most reliable and reproducible alterations of ex vivo immune function in depression (Stein, Miller, & Trestman, 1991). Irwin and colleagues first reported a decline of NK activity in depressed subjects patients as compared to age-, and gender matched comparison controls (Irwin et al., 1987), and ten subsequent independent samples have replicated this observation (Kronfol, Nair, Goodson, Goel, Haskett, & Schwartz, 1989; Nerozzi, Santoni, Bersani, Magnani, Bressan, Pasini, Antonozzi, & Frajese, 1989; Irwin et al., 1990a; Irwin et al., 1990b; Bartoloni et al., 1990; Caldwell, Irwin, & Lohr, 1991; Maes, Stevens, Peeters, DeClerck, Scharpe, Bridts, Schotte, & Cosyns, 1992c; Shain, Kronfol, Naylor, Goel, Evans, & Schaefer, 1991; Irwin, Lacher, & Caldwell, 1992a; Evans et al., 1992; Birmaher et al., 1994). Although there are some discrepant findings (Mohl, Huang, Bowden, Fischbach, Vogtsberger, & Talal, 1987; Schleifer et al., 1989), Herbert and Cohen found a fixed effect size of (-0.266 to -0.254), a result that was confirmed by Zorrilla et al. with an accumulation of over 660 subjects. The factors that might moderate and/or mediate the effects of depression on NK activity will be discussed below.
Most previous studies have suggested that depression results in reductions of nonspecific cellular and natural immunity. However, Maes has argued that major depression is associated with immune activation reminiscent of an acute phase response (Maes, Smith, & Scharpe, 1995). Evidence has been accumulated showing increases in levels of cells bearing activation markers such as HLA-DR+, CD25+ (interluekin-2 receptor) (Maes et al., 1992a), and increases in humoral factors or plasma proteins associated with the acute phase of the immune response (al-acid glycoprotein, al-antitrypsin, and haptoglobin) (Maes, Scharpe, Van Grootel, Uyttenbroeck, Cooreman, Cosyns, & Suy, 1992b). In addition, cytokines such IL-6 that are typically associated with an inflammatory process are reportedly elevated in depression and there are also reported increases in the circulating concentration of the soluble IL-2 receptor that is released with immune activation (Maes et al., 1995).
While these findings that an inflammatory process may occur in association with depression primarily emanate from one research group, there are additional preclinical data that suggest that macrophage activation might occur in depressed subjects and could be a key factor in the observed impairments of T cell proliferation (Maier, Watkins, & Fleshner, 1994). In a putative animal of depression (uncontrollable shock), concomitant monokine release occurs, and this macrophage activation produces an impairment in T cell mediated proliferation.
Replication of clinical data concerning immune activation in depression is clearly needed, but there have been few independent studies separate from the work of Maes. Indeed, in the meta-analytic review conducted by Zorrilla et al., there were only three to five independent study samples identified depending on the immune activation marker. An increase in the circulating concentration of haptoglobin was reliably associated with depression, but the random effects model did not indicate reliable associations between depression and other measures of immune activation including number and percentage of cells expressing HLA-DR or CD25 or circulating levels of al-acid glycoprotein or al-antitypsin (Zorrilla et al., 1998).
To further evaluate the relationship between depression and immune activation, we have recently completed a study of 25 pairs of depressed subjects and age- and gender matched comparison controls in which serum levels of haptoglobin, al-acid glycoprotein, al-antitypsin, interleukin 6, and soluble interleukin-2 receptor were measured. None of these measures of immune activation differed between the carefully matched groups. The lack of finding elevated levels of soluble interleukin-2
receptor in depression is consistent with prior observations from our laboratory (Rapaport & Irwin, 1996). In addition, none of these measures of immune activation correlated with severity of depressive symptoms as measured by HDRS scores. However, correlations were found between cigarette smoking and increases in haptoglobin, al-acid glycoprotein, and al-antitypsin, suggesting the importance of assessing tobacco consumption in future immunological studies of depressed- and other psychiatric populations, as will be discussed below.
The relationship between clinical depression and measures of immunological function shows considerable variability with a predominance of heterogeneous findings for many of the immune parameters. However, two separate meta-analyses have now shown reliable associations between depression and several immune measures. It appears that depressed patients are likely to show an increase in total white blood cell counts with a relative neutrophilia and a relative lymphopenia. In addition, depressed subjects are likely to show impairments in functional assays of mitogen-induced lymphocyte proliferation and NK cytotoxicity. However, with the exception of haptoglobin, heterogeneous findings predominate in the characterization of immune activation in depression and future research is needed to replicate these results.
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