Unmedicated, remitted patients with major depression have decreased serum immunoglobulin A
Highlights
► Patents with major depression have evidence of a proinflammatory state. ► Selective IgA deficiency is the most common form of immunoglobulin abnormality. ► We measured immunoglobulin A in medication-free major depressive in remission patients. ► Serum IgA was lower in remitted patients vs. controls measured on multiple occasions. ► This finding supports the proinflammatory state of major depression.
Introduction
Alterations in mood and affect in patients with major depression is only one component of a systemic syndrome associated with premature coronary disease [11], osteoporosis [20], and a doubling of mortality at any age, independent of suicide, smoking, hypertension, or other common risk factors for poor health. One common denominator of relevance to each of these components of major depression is a proinflammatory state comprised predominantly of mediators of the innate immune response [1], [9], [21], [23].
We have previously reported that the female medication-free patients with major depression in the remitted state (ruMDD) in the present study, have increased levels of two key acute phase proteins that are mainstays of innate immunity, C-reactive protein and serum amyloid A (SAA) [16]. The present study contains not only the female studies in this tryptophan depletion (TrpD) study, but the males as well. Since major depression is thought to represent a deficiency of serotonin neurotransmission, the Trp depletion strategy was designed to determine if reduction of central serotonin availability in the CNS for three days precipitated a return of depressive symptoms. There is no evidence linking serotonin function to levels of IgA. To determine if other components of the immune response are altered in these subjects, we examined the levels of the immunoglobulin (Ig) A in the overall group of subjects. Selective IgA deficiency is by far the most common abnormality of immunoglobulin secretion [8], [31], and is not associated with overt pathology in the majority of cases. However, 6–10% of patients with isolated complete or partial IgA deficiency suffer from atopic states or autoimmune disease. Moreover, 40% have abnormal serum antibodies to cells or tissues including antinuclear (ANAs) and anti-thyroglobulin antibodies [8], [14], [31].
The increased incidence of atopic phenomena and autoimmune disease in patients with selective IgA deficiency is compatible with emerging data that in addition to its significant role in mucosal immunity, IgA is also a mediator of the immune system that contributes to maintaining a balance between pro-and-anti-inflammatory states [14]. IgA exerts a multiplicity of anti-inflammatory effects that include interference with the complement system of the innate immune system, down-regulation of cell mediated responses of heterologous receptors such as monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α), and inhibition of processes that include IgG-mediated phagocytosis and proinflammatory cytokine release [12], [14], [25], [29].
Given the immune activation in patients with major depression and the anti-inflammatory effects of IgA, we postulated that patients with major depression were in a state of partial selective IgA deficiency. To determine the extent to which the putative IgA deficiency is selective, we also measured the levels of IgG and IgM.
Section snippets
Materials and methods
Patients with a history of major depressive disorder (MDD) who were off psychotropic medications and in clinical remission (ruMDD) for at least two months prior to the time of study and carefully matched control subjects (Ctrl) were studied, as previously described (Neumeister et al. 2004). Patients and controls were recruited from the greater Washington, DC metropolitan area through newspaper and radio advertisements; respondents passing a telephone screen for eligibility were evaluated in the
Serum IgA
The linear mixed model revealed a significant main effect of diagnosis on serum IgA levels (F = 4.68, d.f. = 1,53; p = 0.04). Mean serum IgA levels in the ruMDD patients were reduced by approximately 20% relative to controls (estimated marginal means, 1.73 ± (sem) 0.14 vs. 2.17 ± 0.15 g/L, respectively; d = 0.59) (Fig. 1).
A significant main effect of time on serum IgA was observed (F = 5.47, d.f. = 2,265; p = 0.005). Mean serum IgA levels were 3.6% higher at 24 h vs. baseline (1.99 ± 0.10 vs. 1.93 ± 0.10 g/L,
Discussion
Patients with major depression who were remitted and unmedicated for at least three months prior to study had significantly reduced mean plasma IgA levels taken over 24 h at midnight, 7AM and the following midnight on two occasions separated by 8 days. In contrast, plasma IgG and IgM levels were similar to those in controls.
Given the nature of this patient population, these findings are unlikely to be due to transient effects of depressive episodes or to effects of antidepressants. It is also
Conclusions
We do not know the significance of the fact that plasma IgA levels are significantly reduced in ruMDD patients. It is tempting to speculate that these findings and other proinflammatory phenomena in patients with major depression are trait markers. Thus, there may be discordance between demonstrable affective and cognitive symptoms and what are clear systemic manifestations of depressive illness. Alternatively, such findings may reflect the sequellae of somatic changes that occurred during the
Disclosure statement
All authors have contributed to the research and/or article preparation and they have approved the final article.
Dr. Philip W. Gold, Dr. Maria G. Pavlatou, Dr. Paul J. Carlson, Dr. David A. Luckenbaughc, Mr. Rene Costello, Dr. Omer Bonne, Dr. Gyorgy Csako, Dr. Alan Remaley, Dr. Alexander Neumeister, and Dr. Mitchel A. King have no conflicts to disclose. Dr. Wayne C. Drevets has reported that the research support for this project was provided entirely by the NIMH DIRP. Although Dr. Drevets has
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Contributed equally to the paper.