We found that two genes that are critical for T-cell function, PSMB4 and TBX21, are associated with major depression. We found that together, 47.8% of the population risk could be attributable to the risk genotypes at rs2296840 in PSMB4 or rs17244587 in TBX21. The joint effect of the combined genotypes of rs2296840 (recessive model) and rs17244587 (dominant model) was 26% greater than that predicted by assuming additivity of effects. Our analyses revealed a significant combined allele dose-effect; therefore, individuals who had one, two and three risk alleles in PSMB4 and TBX21 were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We also found associations of several SNPs in genes relevant to HPA axis and immune function and antidepressant response and describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. These lines of evidence are indicative of a predominance of Th1 activity in MDD.
Genetic variations in PSMB4
may also be relevant to two immune disorders, psoriasis37
that are known to be comorbid with MDD. These two disorders are polygenic and reactive to psychosocial stressors. Susceptibility to psoriasis has been associated to the area of chromosome 1q21 (PSORS4) that encodes PSMB4
and susceptibility to asthma and nasal polyps (O(MIM) MIM 208550)14
has been associated with functional promoter SNPs in TBX21
(1993T/C), in chromosome 17q21.3.
The UTR variations in TBX21
that we found to be significantly associated with MDD are in UTRs but they may nevertheless impact on immune response in our patients. Several roles in gene expression have been attributed to UTRs, including mRNA stability, localization and translational efficiency. The 5′ UTR, also known as the leader sequence, is a particular section of the mRNA that usually contains a ribosome-binding site; it is a major site of translational regulation and may affect the stability or translation of mRNA and gene expression. Evidence implicating the 3′ UTR of mRNA in the regulation of gene expression has accumulated recently. The 3′ UTR may influence transcript cleavage, polyadenylation and nuclear export, which determine transcript stability, level of translation and mRNA targeting.39
It is therefore plausible that SNPs associated with treatment response may have contributed to the increased plasma levels of the IFNγ-inducible chemokine CXCL10 found in our patients.
CXCL10 is a potent angiostatic factor with anti-fibrotic properties40
and its elevation is congruent with elevated leukocyte counts in peripheral blood that have been shown to be dependent on severity and treatment outcome in MDD.41
Inflammatory immune mediators and specifically CXCL10 have also been implicated in arteriosclerosis, and they may be a link between the presence of depressive symptoms and stress, and increased risk of, morbidity and mortality in myocardial infarction.42
The increase of an IFNγ-inducible chemokine supports the presumption of a predominance of Th1 type activity during the symptomatic phase of MDD, as well as its role in the pathophysiology, therapeutic outcome of this disorder and immunoregulatory effects of antidepressants.43
We found that genetic variations affecting T-cell function and HPA axis regulation were associated with antidepressant treatment response. The following T-cell functions may be implicated in treatment response: T-cell development (CD3E
, T-cell antigen receptor-ε subunit of T3),44
antigen processing/degradation (PSMD9
: proteasome 26S subunit, non-ATPase,9,45
and intracellular signaling (STAT3
: signal transducer and activator of transcription 3).46
The association of a variation in the urocortin III or stresscopin gene (UCN3
suggests a possible role for the adaptive stress response that mediates endocrine, autonomic, cardiovascular and immune systems in treatment outcome. The association of a SNP in the CRHR2
in the treatment response to desipramine indicates that HPA axis modulation may be particularly important for tricyclic antidepressants. Notably, some of the SNPs associated with treatment response could lead to differences in immune response such as nonsynonymous variations in the PSMD9
genes, and 3′ UTR SNPs in CD3E
genes. Somatic variations in some of those genes have been implicated in immunodeficiencies (CD3E
polycystic liver disease (PRKCSH
, protein kinase C substrate, 80 kD, heavy chain,50-52
type 2 diabetes53
or autosomal dominant hyper-immunoglobulin E (IgE) syndrome, also called `Job Syndrome'.54-56
We found no clear Th1 or Th2 cytokine patterns in our patients. Our results of decreased IL-13 levels in MDD contrast with a recent report of increased levels of Th2 cytokines IL-13 and IL-4 and decreased levels of Th1 cytokines.16
Several factors could account for this discrepancy, from differences in gender and age composition to differences in environment/pathogens or differences in the phases of neuroendocrine, counterregulatory systems or severity and stage of the disorder. Moreover, cytokine profiling in Th1 and Th2 cytokine expression seem to be relative, not absolute as inconsistencies between cytokine profiles, antibody and total serum IgE have been reported.57
Therefore, chemokines (such as CXCL10), which are low molecular weight chemotactic molecules, are emerging as a major communication system in the brain58
as their serum and CSF levels may be correlated.59
Chemokines are key mediators of inflammation that have major effects on migration of cells to inflammation sites as well as activation of recruited and resident central nervous system (CNS) cells, which have been implicated in a number of human pathophysiological systemic and CNS conditions60
and their level or expression has been linked to the activity of CNS disease.
summarizes our results of genetic variations associated with the diagnosis of MDD. These implicate that specific UTR variations in TBX21
increase the risks for and characterize a T-cell dysfunction in MDD in Mexican Americans. These genetic variations may be involved in the immune system dysregulation described in this disorder and in known comorbidity disorders such as psoriases38
Our patients had increased peripheral levels of the chemokine CXCL10, which decreased with response to antidepressant treatment.
Figure 4 Schematic of sites where variations in TBX21 or PSMB4 could influence the T-cell arm of the adaptive immunity and contribute to susceptibility to major depressive disorder (MDD): Two crucial functions, specifically antigen processing and T cell-programmed (more ...)
These results lead to the presumption that an imbalance of Th1/Th2 activity toward a predominance of Th1 response is present in the symptomatic phase of mild to moderate forms of MDD. Replication of our findings in other ethnic groups is needed to validate the role of TBX21
in major depression here reported in Mexican Americans. Because genes involved in immune function are highly polymorphic in human populations,61
allele frequency may vary considerably in different ethnic populations, and variations of T-cell function may result from common variations in other genes/gene regions, which may cause a predominance of net Th1 activity. The allele frequency for rs17244587 (TBX21
) in our subjects was similar to European populations; however, rs2296840 and rs4603 (PSMB4
) were significantly less frequent (respectively 0 and 10%) in Europeans than in the Mexican Americans we studied (24% in Mexican-American controls and 34% in MDD). It is therefore unlikely that the PSMB4
variations described here are significant in the susceptibility to MDD in individuals of predominant European descendant. Consequently, characterization of neuroimmune profiles may vary depending on specific genes and SNPs involved in T-cell function variations in different populations. Moreover, given our n
and limited numbers of patients in the desipramine and fluoxetine treatment groups, these results need to be taken with caution, pending replication by other independent studies.
Because chemokine networks already represent potentials targets for new therapies in several CNS and systemic conditions,58
further studies are needed to fully clarify the extent of CNS immunedysregulation in the pathophysiology of MDD.
In spite of the limitations of this study, our data support the hypothesis that key T-cell functions leading to Th1 net activity are features of immune dysfunction in MDD and may also have a role in antidepressant treatment response. Different genes and polymorphisms might characterize MDD immune dysfunctions in distinct populations, as genes that influence immune functions are highly polymorphic and their allele frequency varies across human populations. We suggest that interferon-γ-inducible chemokines, such as CXCL-10, may provide viable biomarkers and might also be useful in predicting/following antidepressant response. Our findings provide a basis for conceptually innovative pharmacological approaches to MDD with a focus on T-cell function dysregulation and variations in T-cell programmed differentiation, antigen processing and cellular proteasome organelle function.