Cytokines are separate from depression and allergies because the latter are diseases while cytokines are part of normal physiology.
- However, since cytokines are involved in both health and disease, their dysregulation could be a feature in both depression and allergies.
- For example, studies do show cytokine dysregulation in both depression and allergies but question remains about the extent to which such dysregulation is causative as opposed to merely consequence.
- Cytokine dysregulation also needs to be understood within the broader framework of immunopathology, i.e., inflammation that is either not well-controlled or lasts longer than necessary or both.
- Within this broader framework, cytokines are just one set of players, the others being hormones and neuropeptides, i.e., the (HPA).
- Into this already confusing mix, we now also need to add local tissue microbiota and their myriad ways of influencing both local and systemic physiology.
Having thus clarified the premise, we are left with two possibilities. One, does depression predispose to allergies? Two, do allergies predispose to depression?
Diagnosis of depression and allergies
Answers to these questions are more than a little difficult because diagnosis of depression and allergies aren’t equivalent.
- While diagnostic tests for allergies are more or less objective laboratory-based measures, a depression diagnosis is largely based on self-reporting of symptoms that range from vague and nebulous to crippling, lists of which vary over time and across countries.
- Thus, even today depression remains a syndrome, not a disease, and that too one whose definition is problematic.
- With a syndrome, people suffering from altogether different diseases get unwittingly grouped together under a common diagnosis, be it clinical depression or major depressive disorder (MDD).
- In the meantime, cultural differences prioritize assertion of affective symptoms in Western societies while elsewhere patients tend to emphasize somatic symptoms (1), relative differences in stigma associated with mental illness being the key reason for such differences.
- Thus, in the words of Tom Insel, the director of the US NIH National Institute of Mental Health (NIMH) ‘Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM* diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure‘ (2).
- Difference in diagnostic certitude is thus a major caveat to keep front and center while exploring depression-allergy connections.
*DSM (Diagnostic and Statistical Manual) published by the American Psychiatric Association to diagnose mental illnesses.
Epidemiological studies of depression-allergy association
While many studies have explored an association between depression and allergies, is a useful approach to assess what, if any, concordance there is between different studies.
- A recent such meta-analysis of 6 peer-reviewed prospective studies on the relationship between depression and asthma concluded that depression was associated with a 43% increased risk for developing adult-onset asthma (3). Advantage of prospective studies? Diagnoses untainted by recall bias.
- However, there just weren’t enough prospective studies that had asked if asthma predisposed to depression so authors couldn’t conclude likewise the other way around.
- This is a gap in research that needs to be plugged.
Are there other kinds of studies that assessed if allergy predisposed to depression?
- A different kind of study (4) called a population-based study assessed the relation between atopy and depression.
- Atopy typically includes asthma, eczema and hay fever, i.e., allergies with the hallmark feature of high plasma IgE levels.
- They concluded that such atopy was associated with a 59% increased likelihood of depression (4).
Cytokines and Depression
- Evidence of differences in expression of many important cytokines such as IL-1alpha, -2, -3, -5, -8, -9, -10, -12A, -13, -15, -18 and IFN-gamma in the (BA10) (5), a region of the brain associated with reward processing (6).
- Patients diagnosed with major depression showed elevated transmembrance TNF-aplha in (BA46) (7), a region of the brain associated with emotion regulation (8).
Do cytokines link depression and allergies?
- A meta-analysis of several studies found that circulating IL-1,-4, -6 and TNF-alpha levels tended to be elevated in depressed individuals.
- At the same time, their analysis also concluded that diagnosis of depression was associated with a 3.17 times higher likelihood of asthma (9).
- Even with the caveat that linking circulating cytokine levels to local effects in the CNS (Central Nervous System) is neither easy nor straightforward, ample epidemiological studies such as this example suggest association between depression, allergies and their attendant cytokine dysregulations.
How to connect the dots between depression, allergies and cytokines?
- Allergies mainly afflict sites of microbial colonization, namely, skin and mucosa (respiratory tissue, GI tract).
- Obvious question is whether local microbiota perturbations accompany allergies.
- Indeed, alteration in composition of normal microbiota (dysbiosis) is a well-established risk factor for allergies (10).
- For example, C-sections are associated with altered microbiota since such infants acquire their microbes from their birth environment rather than from their mother’s vaginal tract, and this difference correlates with higher rates of allergies in later life **.
- At the same time, CNS (Central Nervous System) involvement is also self-evident since it quickly perceives local distress at these sites through hormones, cytokines and neuropeptides since it has specific receptors for all of these chemical messengers, all of which can be synthesized locally at the site of distress (see figure below from 11 for details on who and what in the case of skin, an example of a site that harbors microbes and is also subject to a variety of allergies such as atopic dermatitis, eczema, psoriasis, etc.).
- Link between allergies and microbiota perturbation is thus well-established. Has a link for depression and microbiota perturbation been established?
- The ‘leaky gut‘ hypothesis links perturbations not in gut microbiota but rather in gut epithelium with depression (12).
- According to this idea, a perturbed gut epithelium allows entry of gut microbes that are normally restricted to the gut lumen (13, 14).
- Supporting data is sparse, restricted to rat and mouse models, or to comparisons of circulating blood immune cell responses to bacterial components between non-depressed and depressed individuals. If depression diagnosis is far from satisfactory in humans, stands to reason it’s likely non-existent for animal models so value of such studies is dubious to say the least.
- Another open question. What causes the gut to become ‘leaky‘ in the first place? Possibilities include dysbiosis, which could be from birth or due to antibiotics.
- For example, studies are beginning to show that clinical depression is associated with altered gut microbiota, assessed as alterations in fecal microbiota (15, 16).
- A meta-analysis of 28 studies assessed the link between microbes and depression (17). Borna disease virus (BDV), herpes simplex virus-1, varicella zoster virus, and Epstein-Barr virus were significantly associated with depression.
- These studies have plenty of caveats.
- For one, the molecular methods used have inherent biases in relative sensitivities of the microbes they detect.
- They’re still largely restricted to bacteria, not viruses, fungi and eukaryotes.
- Cause and effect aren’t readily decipherable from such studies.
- Nevertheless, they suggest a link between altered microbiota and depression.
- Are there common features of microbiota alterations between depression and certain allergies? Obvious as-yet unanswered question.
Finally and most nebulous of all is the attribute that links all three, depression, allergies and their attendant cytokine dysregulations, namely, stress.
- Problem with stress is multiple definitions and most importantly, the role of individual agency.
- After all, definition of stress cannot be separated from our individual perception of it.
- As Gailen D. Marshall explains, ‘Stress is a term often used to connote an adverse situation. Yet our use of the term stress derives from an engineering term that is used to reflect the impact of a situation (often called a stressor) on host homeostasis. It is best thought of as a psychophysiological process that is a product of both the appraisal of a given situation (either acutely or chronically over time) and the ability to cope with that situation. If the situation threatens harm, loss, or danger and/or the host-coping ability is deemed inadequate, the stress is termed distress. Most common uses of the term stress actually mean distress‘ (18).
- Thus, individual perception of distress and attendant responses are key determining attributes for both depression and allergies. How to accurately assess and quantify a nebulous concept like stress or more accurately distress, let alone individual differences in their perception? We haven’t even begun to do so.
- Portable, wireless sensors that could measure and record various brain activities and physiological responses (pulse, blood pressure, perspiration, temperature) in real-time would be a way to have tangible measurements that could be later correlated with self-reported stress/distress levels. This could be a way to at least start quantifying the hitherto unquantified individual perceptions of stress. Only with such a database in hand could we build a complete picture of the way in which depression, allergies, cytokines, microbiota and stress intersect.
- Canli, Turhan. “Reconceptualizing major depressive disorder as an infectious disease.” Biology of mood & anxiety disorders 4.1 (2014): 10.
- Gao, Yong-hua, et al. “The Relationship between Depression and Asthma: A Meta-Analysis of Prospective Studies.” PloS one 10.7 (2015): e0132424.
- Sanna, Livia, et al. “Atopic disorders and depression: findings from a large, population-based study.” Journal of affective disorders 155 (2014): 261-265.
- Shelton, R. C., et al. “Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression.” Molecular psychiatry 16.7 (2011): 751-762.
- Rogers, Robert D., et al. “Choosing between small, likely rewards and large, unlikely rewards activates inferior and orbital prefrontal cortex.” The Journal of Neuroscience 19.20 (1999): 9029-9038.
- Dean, Brian, et al. “Regionally-specific changes in levels of tumour necrosis factor in the dorsolateral prefrontal cortex obtained postmortem from subjects with major depressive disorder.” Journal of affective disorders 120.1 (2010): 245-248.
- Kohn, N., et al. “Neural network of cognitive emotion regulation—an ALE meta-analysis and MACM analysis.” Neuroimage 87 (2014): 345-355.
- Jiang, Mingdi, Ping Qin, and Xu Yang. “Comorbidity between depression and asthma via immune-inflammatory pathways: a meta-analysis.” Journal of affective disorders 166 (2014): 22-29.
- Marsland, Benjamin J., and Olawale Salami. “Microbiome influences on allergy in mice and humans.” Current opinion in immunology 36 (2015): 94-100.
- Chen, Ying, and John Lyga. “Brain-Skin Connection: Stress, Inflammation and Skin Aging.” Inflammation & allergy drug targets 13.3 (2014): 177.
- Smythies, Lesley E., and John R. Smythies. “Microbiota, the immune system, black moods and the brain—melancholia updated.” Frontiers in human neuroscience 8 (2014). ).
- Berk, Michael, et al. “So depression is an inflammatory disease, but where does the inflammation come from?.” BMC medicine 11.1 (2013): 200.
- Mass, Michael, Marta Kubera, and Jean-Claude Leunis. “The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression.” Neuroendocrinology Letters 29.1 (2008): 117-124.
- Naseribafrouei, A., et al. “Correlation between the human fecal microbiota and depression.” Neurogastroenterology & Motility 26.8 (2014): 1155-1162.
- Jiang, Haiyin, et al. “Altered fecal microbiota composition in patients with major depressive disorder.” Brain, behavior, and immunity (2015).
- Wang, Xiao, et al. “Meta-analysis of infectious agents and depression.” Scientific reports 4 (2014).
- Marshall, Gailen D. “Neuroendocrine mechanisms of immune dysregulation: applications to allergy and asthma.” Annals of Allergy, Asthma & Immunology 93.2 (2004): S11-S17.