Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression

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Abstract

The first findings that depression is characterized by cell-mediated immune activation and inflammation were published between 1990–1993 (Maes et al.). Recently, it was reported that – based on meta-analysis results – depression is an inflammatory disorder because the plasma levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2 and interferon-(IFN)γ levels are not altered in depression, suggesting that there is no T cell activation in that illness. The present paper reviews the body of evidence that depression is accompanied by cell-mediated immune activation. The findings include: increased serum levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule; increased numbers and percentages of T cells bearing T cell activation markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels; induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of plasma tryptophan and increased levels of tryptophan catabolites along the IDO pathway (TRYCATs); and glucocorticoid resistance in immune cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and IFNα-induced activation of T cells, IDO activity and TRYCAT formation are related to the development of IFNα-induced depressive symptoms. Animal models of depression show that a cell-mediated immune response is related to the development of depression-like behavior. Antidepressants and mood stabilizers suppress different aspects of cell-mediated immunity and rather specifically target IFNγ production. This review shows that inflammation and cell-mediated immune activation are key factors in depression.

Introduction

In 1990–1993 the first original papers were published that depression is an illness characterized by inflammation and monocytic and T cell activation (Maes et al., 1990–1991, Maes et al., 1991a, Maes et al., 1991b, Maes et al., 1992a, Maes et al., 1992b, Maes et al., 1993a). These findings in clinical depression laid the foundation for a novel hypothesis that inflammation and cell-mediated immune activation are key factors in depression (Maes et al., 1990–1991, Maes et al., 1991b, Maes et al., 1992a, Maes et al., 1992b, Maes, 1993). Since 1990–1991, we have published the first reports that major depression is characterized by: a) an inflammatory response as shown by monocytic activation with increased production of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNFα) (Maes et al., 1990–1991, Maes et al., 1991b, Maes et al., 1993a, Mikova et al., 2001); and an acute phase response (Maes et al., 1992b, Maes et al., 1993d, Maes et al., 1993e); b) cell-mediated immune activation, with T and T helper (Th)-1-like cell activation, as demonstrated by – for example – increased serum soluble IL-2 receptor (sIL-2R) levels and interferon-γ (IFNγ) production (Maes et al., 1990–1991, Maes et al., 1991b, Maes et al., 1992a, Maes et al., 1993d, Maes et al., 1994c); and c) significant interrelationships between the acute phase or inflammatory response and cell-mediated immune activation (Maes et al., 1993e).

We were the first to show that a) activation of the inflammatory response system (IRS) in depression is related to indices of hypothalamic-pituitary-adrenal-axis (HPA) hyperactivity, suggesting that HPA-hyperactivity in depression is induced by pro-inflammatory cytokines (Maes et al., 1993a, Maes et al., 1993d). b) The serotonergic disturbances in depression are the consequence of cell-mediated immune activation. Thus, the lowered availability of plasma L-tryptophan to the brain in depression is a marker of immune activation indicating that lowered plasma L-tryptophan, and hence serotonin, are induced through activation of indoleamine 2,3-dioxygenase (IDO) (Maes et al., 1993b, Maes et al., 1994c). c) The “psychosomatic” or “vegetative” symptoms occurring in depression are manifestations of cell-mediated immune activation in depression and resemble the sickness behavioral symptom complex in the rodent (Maes, 1993, Maes et al., 1993c).

The first review papers showing that depression is accompanied by cell-mediated immune activation were based on the abovementioned results, new results emerging from other European laboratories and results of papers published before 1990 that were not interpreted to indicate immune activation in depression (Maes, 1993, Maes, 1995, Maes et al., 1995f). The latter review was co-authored by R. Smith who some years earlier coined the macrophage hypothesis of depression based on a literature search (Smith, 1991). His research consisted of big boxes with many research papers, which were offered to me by his wife when he passed away too early. As of 1992 until his death we collaborated and examined further the monocyte-T lymphocyte hypothesis of depression, e.g. the effects of psychological stress on Th-1 versus Th-2-like cytokines; the associations between polyunsaturated fatty acids and inflammatory markers, etc. (Maes et al., 1996a, Maes et al., 1998). He agreed that based on the research findings all evidence indicated that macrophages are activated by T lymphocytes and thus that depression is characterized by cell-mediated immune activation (Maes et al., 1995f).

Somewhat later we changed the label “monocyte-T lymphocyte theory of depression” into “the IRS activation” theory, because it appeared that many more aspects of the inflammatory system and cell-mediated immunity were disturbed during major depression (Song et al., 1998, van West and Maes, 1999, Schiepers et al., 2005). Later, we changed this label again and called the theory “induction of inflammatory, and oxidative and nitrosative stress (IO&NS) pathways”, because the body of evidence showed not only signs of IRS activation, but also induction of oxidative and nitrosative stress (O&NS) pathways (Maes, 2008, Maes et al., 2010). Very recently, we called this theory “the inflammatory and (neuro)degenerative (I&ND)” hypothesis of depression (Maes et al., 2009, Maes et al., 2010). That theory brings together the inflammatory and O&NS (IO&NS) theories with recent findings that depression is accompanied by neurodegeneration and decreased neurogenesis (Maes et al., 2009). The theory entails that the neuroprogression in depression is caused by multiple IO&NS pathways. In this special issue many papers focus on different aspects of the I&ND hypothesis of depression (Maes et al., 2010, Szewczyk et al., 2010, Kubera et al., 2010, Song and Wang, 2010, Zunszain et al., 2010, Gardner and Boles, 2010).

Recently, the results of a meta-analysis of cytokine levels in major depression were published (Dowlati et al., 2010). This meta-analysis shows that two cytokines are consistently increased in depression, i.e. serum IL-6 and TNFα (Dowlati et al., 2010). At the same time the authors mention that their analysis could not detect significant differences in Th-1 like cytokines, such as plasma IL-2 and IFNγ, or Th-2-like cytokines, such as IL-10 (Dowlati et al., 2010). Consequently, the results that plasma IL-6 and TNFα are increased are interpreted to indicate that depression is an inflammatory disease (Dubovsky, 2010). The reader is left with the impression that only two cytokines are increased in depression and that this is enough to indicate that depression is an inflammatory disorder; and that no cell-mediated immune response is present during depression. In addition, since this meta-analysis (Dowlati et al., 2010) does not cite the earlier landmark findings and reviews reporting cell-mediated immune activation in depression the big picture that depression is an inflammatory disorder with monocytic and T cell activation is not addressed.

The aim of the present paper is to review that activation of cell-mediated immunity is a key factor in major depression. Towards this end we will review the body of evidence showing a) cell-mediated immune and T (Th-1-like) cell activation in clinical and animal models of depression and in depression following cytokine-based immunotherapy; and b) the suppressive effects of antidepressants on the monocytic and lymphocytic arms of cell-mediated immunity.

Section snippets

Cell-mediated immune activation

Cell-mediated immunity is that part of the immune system not involving antibodies and that involves cellular interactions between T lymphocytes and monocytes. Fig. 1 shows key effector mechanisms in cell-mediated immune activation and the interactions between T lymphocytes and monocytes through different cytokines. The basic mechanisms of cell-mediated immunity entail the cellular immune response to antigen with the involvement of T lymphocytes, like Th (CD4+) and T suppressor/cytotoxic (CD8+)

Measurements of cell-mediated immune activation

One adequate method to measure T cell cytokines, such as IFNγ and IL-2, and Th-2-like cytokines, like IL-4 and IL-10, consists of stimulating whole blood with polyclonal activators and assaying the abovementioned cytokines in culture supernatant (Zangerle et al., 1992, Maes et al., 1999a). It is a common practice to compute the IFNγ/IL-10 or the IFNγ/IL-4 production ratios, as the latter reflects the Th-1/Th-2 ratio and thus indicates a shift towards a Th1-like cell-mediated immune or

Misinterpretations in the literature concerning cell-mediated immune activation in depression

The meta-analysis described above (Dowlati et al., 2010) strongly focused on plasma measurements of selected T lymphocytic markers, i.e plasma levels of IL-2 and IFNγ. However, neither plasma IL-2 nor plasma IFNγ are sensitive markers for T cell activation and are frequently not even measurable in the peripheral blood. The methods employed in most studies included in the abovementioned meta-analysis did therefore not allow to adequately elucidate the production of the above cytokines. Dowlati

Increased serum IL-2 receptor levels in depression

There is now evidence that serum sIL-2R concentrations are significantly higher in depressed patients than in normal controls. The first paper showing increased sIL-2R values was published by Maes et al. (1990–1991). Not only serum sIL-2R levels were increased in depression, but also the mitogen-stimulated sIL-2R production by PBMCs (Maes et al., 1990-1991). In another study, the increased levels of serum sIL-2Rs were significantly correlated to antinuclear- and anticardiolipin antibodies (Maes

Antidepressants

There is evidence that antidepressants exert specific effects on inflammatory responses and on the monocytic and T lymphocytic arms of cell-mediated immunity. Seidel et al. (1995) reported that a 6-week treatment with antidepressants significantly decreased the initially elevated plasma concentrations of a number of APPs, such as C-reactive protein, haptoglobin and alpha 2-macroglobulin. Antidepressants may suppress the increased plasma levels of various APPs in depression, e.g. haptoglobin,

Conclusions

Table 1 summarizes the body of evidence that depression is accompanied not only by inflammation but also by cell-mediated immune activation and T cell and Th-1-like activations. This evidence includes findings in clinical depression on increased sIL-2R; sCD8; T cell activation markers, like CD25+ and HLA-DR+; increased IFNγ, neopterin, sTNFR-1 or sTNFR-2, IDO activity and TRYCAT levels and lowered plasma tryptophan availability to the brain; and glucocorticoid resistance in immune cells, which

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