A Unified Theory of the Pathogenesis of Non-Infectious Disease

The holy grail of medicine is to develop a treatment for non-infectious diseases that’s as effective as antibiotics are for infectious diseases. The need to do so becomes more pressing every day, because if current trends continue, non-infectious diseases will account for 7 out of 10 deaths even in the developing world by 2020.1 Recent research has revealed that although there are several potential etiologies for any given instance of non-infectious disease, there is a single general pathogenesis that is applicable to many, perhaps all instances of non-infectious disease, including psychiatric disorders. In its simplest form, that pathogenesis is:

Immunological Insult →

Chronic Proinflammatory Cytokine Release ←→ Epigenetic Dysregulation →

Pathogenic Protein Synthesis and Cells →

Non-Infectious Disease Presentation.

Understanding this universally applicable pathogenesis should help invent novel cures for non-infectious diseases.

The True Root Causes of Non-Infectious Diseases

Before discussing the generalized pathogenesis of non-infectious disease, we should back up and talk about its most common root causes, or etiologies. In the general pathogenic formula, the etiology is simply described as “Immunological Insult.” The most obvious and overt kind of immunological insult is infection, and indeed people with infections are at a much higher risk of developing non-infectious diseases like cancer and depression.2 But puzzlingly, people seem to develop non-infectious diseases even in the absence of obvious and overt immunological insults like infection. Even more puzzlingly, in countries where people are exposed to a lesser diversity of pathogens (which tend to be relatively rich countries), there is a higher prevalence of non-infectious diseases like depression.3

Recent research has solved this conundrum with the “old friends” hypothesis. According to this hypothesis, chronic immunoreactivity is often caused by insufficient exposure to a group of micro- and macroorganisms in early life that are frequently referred to as humanity’s “old friends,” which coevolved with humans in a mutually dependent relationship. In human’s prehistoric past, the old friends taught the immune system to ignore harmless stimuli, rather than becoming chronically stimulated by them. Due to modern hygiene and antibiotics however, our exposure to the old friends is usually insufficient in our developing years.4 This leads to chronic and often subclinical activation of the immune system, which leads to chronic circulation of proinflammatory cytokines in the bloodstream, which leads to maladaptive epigenetic alterations to cellular genomes, which leads to the development of non-infectious disease.4

Without exposure to the old friends in early life to teach the immune system to ignore harmless stimuli, the immune system can become chronically activated by everyday psychosocial stressors, allergens, and even the body’s own cells in autoimmunity. Examples of macroorganismic old friends include the supposedly parasitic helminth worms, which have recently been used successfully to treat autoimmune diseases and immune disorders like Crohn’s disease.5

Harvill goes so far as to suggest in Cultivating Our “Frienemies”: Viewing Immunity as Microbiome Management (2013) that:

…our rapidly growing knowledge of immune interactions with our healthy microbiota, and the many benefits it confers, suggests there may be value to an alternative view: that mechanisms of defense against pathogens are one aspect of a complex system with the broader purpose of managing our healthy microbiome. From this perspective, adaptive immunity may be viewed as a flexible system for simultaneously recruiting and managing a near limitless number of potential symbionts.

Another common risk factor for triggering the pathogenesis of non-infectious disease is eating a typical western diet, which has too many Omega-6s and too few Omega-3s, too much LDL and too little HDL, too many short-acting carbohydrates like sugar, and poor nutritional value. Another is toxic exposure, such as to heavy metals, pesticides, and organic pollutants.6 7 8

What is the Pathogenesis of Non-Infectious Disease?

Immunological Insult →

Chronic Proinflammatory Cytokine Release ←→ Epigenetic Dysregulation →

Pathogenic Protein Synthesis and Cells →

Non-Infectious Disease Presentation.

Now that we’ve discussed the etiology of non-infectious disease, let’s move on to a deeper discussion of the above pathogenesis. There is ample evidence that chronic exposure to proinflammatory cytokines is associated with various non-infectious diseases, including cardiovascular disease, diabetes, metabolic syndrome, allergies, asthma, HIV, cancer, ALS, Chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, depression, Parkinson’s, chronic pain, Alzheimer’s, Hungtington’s, as well as virtually every non-infectious disease in existence.9 10 11 12 13 14 15 16 17 18 19 20 For instance, in a systematic review of cytokine patterns in cancer patients, the authors said:

Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types…. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4)…

The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12—interferon-γ—HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient’s prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer.21

In these scientists’ view, cytokine cascade is an integral part of the underlying paraneoplastic systemic disease in cancer patients. The immune system becomes activated, which releases proinflammatory cytokines, which somehow participate in the pathogenesis of non-infectious disease.

So how do cytokines cause non-infectious disease? Cytokines contribute to disease pathology by epigenetic means. A smoking gun linking proinflammatory cytokines to epigenetic induction of non-infectious disease pathogenesis is found in the study Epigenetics – the Key to Understand Immune Responses in Health and Disease (2011):The intracellular signaling pathways downstream of cytokine receptors induce the expression of cell lineage–specific transcription factors, with the ability to induce chromatin remodeling within their DNA-binding regions.” For instance, “Cell lineage decision in T-helper cells is influenced by the surrounding cytokine milieu at the site of antigen encounter.” In other words, cytokines induce epigenetic chromatin remodeling.

According to Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders (2008):

“Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition….”

This study correlates cytokines with the silencing methylation of anti-inflammatory genes, a form of epigenetic chromatin remodeling and modification the last study was talking about:

DNA methylation may mediate persistent changes in gene function following chronic stress….Methylation levels were examined for association with PTSD, child abuse history, and Total Life Stress (TLS)….Global methylation was increased in subjects with PTSD….Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and Total Life Stress. Together, these results suggest that psychosocial stress may alter global and gene-specific DNA methylation patterns potentially associated with peripheral immune dysregulation.

This is how some cytokines work their pathogenic effect; they methylate and silence anti-inflammatory genes. Other cytokines acetylate and promote the transcription of proinflammatory, cytokine-synthesizing genes.

Not only can cytokines induce epigenetic alterations, conversely epigenetic alterations can trigger the synthesis of cytokines. Cytokine production by gestational tissues has been shown to be regulated by epigenetic mechanisms.23 So the causal relationship between cytokines and epigenetic alterations to the genome is bidirectional, meaning that it seems to go both ways.

What causes the epigenetic changes in cases where the chain of causality is Epigenetic Changes → Proinflammatory Cytokine Synthesis? Often, the cause is simply other cytokines of a different type. “One cytokine often influences the synthesis of other cytokines. They can produce cascades, or enhance or suppress production of other cytokines.”24 This is called a positive feedback loop induced signal cascade, which basically means the effects of a cytokine signal are often self-amplifying because they change the expression of genes in such a way that more genes are expressed that code for cytokines, or less genes are expressed that inhibit the synthesis of cytokines.

And now, a special message about cytokines and the brain from the National Institute of Health:

“Despite the brain’s status as an immune privileged site, an extensive bi-directional communication takes place between the nervous and the immune system in both health and disease. Immune cells and neuroimmune molecules such as cytokines, chemokines, and growth factors modulate brain function through multiple signaling pathways throughout the lifespan. Immunological, physiological and psychological stressors engage cytokines and other immune molecules as mediators of interactions with neuroendocrine, neuropeptide, and neurotransmitter systems. For example, brain cytokine levels increase following stress exposure, while treatments designed to alleviate stress reverse this effect.

“Neuroinflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurological disorders such as stroke, Parkinson’s and Alzheimer’s disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines also modulate CNS function in the absence of overt immunological, physiological, or psychological challenges. For example, cytokines and cytokine receptor inhibitors affect cognitive and emotional processes. Recent evidence suggests that immune molecules modulate brain systems differently across the lifespan. Cytokines and chemokines regulate neurotrophins and other molecules critical to neurodevelopmental processes, and exposure to certain neuroimmune challenges early in life affects brain development. In adults, cytokines and chemokines affect synaptic plasticity and other ongoing neural processes, which may change in aging brains. Finally, interactions of immune molecules with the hypothalamic-pituitary-gonadal system indicate that sex differences are a significant factor determining the impact of neuroimmune influences on brain function and behavior.”

Vaccinations Against the Incurable

What can be done to prevent or treat cytokine-induced non-infectious disease? Vaccinations are possible. For instance, in the fascinating study Can we vaccinate against depression?, Rook et al. state: 

Major depression is common in the context of autoimmune and inflammatory diseases and is frequently associated with persistently raised levels of proinflammatory cytokines and other markers of inflammation, even in the absence of another diagnosable immune pathology to account for these findings. Therefore immunoregulation-inducing vaccines or manipulations of the gut microbiota might prevent or treat depression. These strategies are already undergoing clinical trials for chronic inflammatory disorders, such as allergies, autoimmunity and inflammatory bowel disease. In this article, we summarize data suggesting that this approach might be effective in depression and encourage the initiation of clinical vaccination trials in this disorder.

HDACi’s Part 2

But the most exciting future treatment for non-infectious disease is by far the histone deacetylase inhibitors, or HDACi’s, which I’ve written about previously. HDACi’s specific to HDAC2 and 3 promote activating acetylation of cytoprotective and anti-inflammatory genes in most tissues, an epigenetic change that that counters cytokines’ gene-silencing effects of pathogenic methylation and deacetylation, which silences the cytokine cascade and reduces the production of proinflammatory cytokines. In “Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer,” the authors report:

This issue of Molecular Medicine contains 14 original research reports and state-of-the-art reviews on histone deacetylase inhibitors (HDACi’s), which are being studied in models of a broad range of diseases not related to the proapoptotic properties used to treat cancer. The spectrum of these diseases responsive to HDACi’s is for the most part due to several antiinflammatory properties, often observed in vitro but importantly also in animal models. One unifying property is a reduction in cytokine production as well as inhibition of cytokine postreceptor signaling.

The only unifying property of effective HDACi’s the authors consider worth mentioning is that they all reduce the production of proinflammatory cytokines.

According to Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders (2008):

“Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington’s disease, Parkinson’s disease, anxiety and mood disorders, Rubinstein-Taybi syndrome and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological and psychiatric disorders.

Some HDACs are good for certain types of cells but not for others. An example of this is HDAC1, which is neuroprotective in the brain and if you inhibit it there it causes neurodegeneration, but in the pancreases HDAC1 inhibition restores insulin sensitivity in diabetics.

In addition, it’s important to remember that HDACs are just one type of epigenetic enzymes. Here is a table of all that are currently known:


Epigenetic medicine promises to be the biggest revolution in medical knowledge and practice since the invention of the antibiotic. The more people who are trying to figure out what each of the above enzymes and markers do the better. Generally speaking, HDACi’s and other epigenetic medicines are the future of neuropsychiatric medicine, and most probably of medicine in general. Just disrupt the following pathogenesis and the Nobel is yours:

Immunological Insult →

Chronic Proinflammatory Cytokine Release ←→ Epigenetic Dysregulation →

Pathogenic Protein Synthesis and Cells →

Non-Infectious Disease Presentation.



  1. Wikipedia: Non-communicable disease.
  2. Oral Cancer Risk in Relation to Sexual History and Evidence of Human Papillomavirus Infection
  3. US and France More Depressed Than Poor Countries
  4. A Darwinian View of the Hygiene or “Old Friends” Hypothesis
  5. An update on the use of helminths to treat Crohn’s and other autoimmunune diseases
  6. Association between Dietary Patterns and Depressive Symptoms Over Time: A 10-Year Follow-Up Study of the GAZEL Cohort (2008).
  7. Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial (2011).
  8. The importance of the ratio of omega-6/omega-3 essential fatty acids (2002).
  9. Chronic activation of the innate immune system may underlie the metabolic syndrome.
  10. Chronic immune activation, causes and pathogenic mechanisms in HIV infection
  11. Role of cytokines in inflammatory process in Parkinson’s disease.
  12. Peripheral cytokines profile in Parkinson’s disease.
  13. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer’s disease.
  14. Non-Motor Symptoms in Patients with Parkinson’s Disease – Correlations with Inflammatory Cytokines in Serum
  15. Huntington’s Disease Linked To Overactive Immune Response In The Brain
  16. ALS: cytokine profile in cerebrospinal fluid T-cell clones.
  17. Cytokines, allergy, and asthma.
  18. Cytokines, Inflammation and Pain
  19. Cytokines and major depression (2005).
  20. Inflammation, chronic obstructive pulmonary disease and aging
  21. Cytokines in the pathogenesis of rheumatoid arthritis
  22. Cytokine patterns in patients with cancer: a systematic review

23. Epigenetic regulation of cytokine production in human amnion and villous placenta.


Extra Reading:

  1. Inflammation and Depression: Cause or Effect (2012).
  2. Type 2 diabetes as an inflammatory disease (2011).
  3. Neuroinflammatory Cytokines—The Common Thread in Alzheimer’s Pathogenesis (2012).
  4. Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer’s disease-related pathology (2013).
  5. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: Transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling (2002).
  6. Inflammation, Sanitation, and Consternation Loss of Contact With Coevolved, Tolerogenic Microorganisms and the Pathophysiology and Treatment of Major Depression (2010).
  7. Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression (2009).
  8. Neuroimmune mechanisms of cytokine-induced depression: Current theories and novel treatment strategies (2011).