The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)

Raison, C L; Miller, A H

Currently, only two candidate single-nucleotide polymorphisms (SNPs; rs12520799 in DCNP1 (dendritic cell nuclear protein-1) and rs16139 in NPY (neuropeptide Y)) and one candidate gene for MDD (TNF-a), smallest P-value for rs76917) have been confirmed by GWASs. 35 It is striking that each of these genes plays an important role in processes central to host defense, including proinflammatory cytokine signaling (TNF), antigen presentation (DCNP1) and T helper type 1 cell differentiation and function (NPY). Of these SNPs, functionality has only been established for rs16139 in NPY. Although NPY has numerous and contrasting effects on innate and adaptive immune functioning, its primary actions appear to be anti-inflammatory in both the brain and periphery. [36] [37] [38] Given this, the PATHOS-D theory predicts that MDD should be characterized by reduced NPY activity and that the depression risk T allele at rs16139 should be associated with reduced NPY production. Significant data support both predictions. [39] [40] [41] [42] [43] Unlike NPY, the functionality of rs76917 in TNF is currently unknown. A clear prediction of PATHOS-D theory is that this SNP should be associated with increased TNF-a production, given that TNF-a is increased in MDD and appears to be especially relevant to enhanced survival from infection in the types of pathogen-dense environments that were normative during human evolution. A separate SNP (À308G/A) in the promoter region for TNF is worthy of comment in this regard. Although not found to be significant by GWASs, 35 several studies have associated the high-production A allele at À308 (ref. 44) Figure 1 The integrated suite of immunological and behavioral responses to infection and wounding that comprise pathogen host defense. Upon encountering a pathogen or cellular debris from tissue damage or destruction, the body reacts with an orchestrated local and systemic response that recruits both immunological and nervous system elements. The response is initiated by interaction of pathogens and/or cellular debris with pattern recognition receptors such as Toll-like receptors on relevant immune cells including macrophages that in turn are linked to inflammatory signaling pathways such as nuclear factor-kB (NF-kB), a lynchpin transcription factor in the host defense cascade. Release of cytokines (including tumor necrosis factor-a (TNF-a), interleukin (IL)-1, IL-6 and interferon-a (IFN-a)) and chemokines as well as the induction of adhesion molecules attracts and activates cells such as T cells at the site of infection/wounding, leading to the cardinal signs of inflammation (redness, heat, swelling and pain) and ultimately promoting local pathogen elimination and wound healing. Cytokines and cells in the peripheral circulation mediate the systemic host response that engages neurocircuits in the brain that mediate hypervigilance (dorsal anterior cingulate cortex (dACC)) to avoid further wounding and pathogen exposure and conservation/withdrawal (basal ganglia), which promotes the shunting of energy resources to pathogen elimination and wound healing.