T Helper Dominance

Advances in the role of helper T cells in autoimmune diseases

TH-1 Dominance

• Cell mediated immune response – Natural killer and cytotoxic T-cell activity
• Delayed-type hypersensitivity, intracellular pathogens defense
• Patient that “seldom gets sick”
• Tends to go with rheumatoid arthritis, multiple sclerosis, type 1 diabetes, Hashimoto’s and psoriasis.
• Stimulated by IL-12, Tbet transcription factor
• Produces IL-2, TNF-alpha, Interferon-gamma

TH-2 Dominance

• Humoral immune response – B-cell activity
• IgE production, extracellular pathogens, eosinophilic inflammation and the protection for helminthic parasite infection.
• Patient that “is always sick” or has allergies
• Tends to go with systemic Sclerosis, ulcerative colitis, asthma, eczema and lupus
• Stimulated by IL-4, GATA3 transcription factor
• Produces IL-4, IL-5, IL-13, IL-25

TH-17 Dominance

• Respond to fungi, extracellular and gram negative pathogens
• Involved in autoimmune inflammatory disorders
• Require the combination of IL-6 and TGF-β and the transcription factors, RORC2/RORgt (mice) and STAT3 for differentiation
• Stimulated by TGF-beta, IL-6 and Roryt transcription factor
• Produces IL-17, IL-21, TNF-alpha, IL-22, IL-17F, and CCL20

T-Regulatory

• Responsible for maintaining peripheral tolerance, regulates immune balance, prevents autoimmunity
• Stimulated by TGF-beta, IL-2 and Foxp3 transciption factor
• Produces TGF-beta, IL-10

TH-9

• Antitumor and prevents autoimmunity
• Stimulated by TGF-beta, IL-4 and Stat6 transcription factor
• Produces IL-9

TH-22

• Plays roles in various immune responses and inflammatory conditions, particularly in skin-related diseases
• Stimulated by IL-6, TGF-beta, TNF-alpha, and AhR transcription factor
• Produces IL-22

TH-fh (follicular helper)

• Prevents autoimmunity
• Play a crucial role in regulating B cell responses within the germinal centers of lymphoid tissues, particularly in the context of antibody production and affinity maturation.
• Stimulated by IL-6, IL-21, Bcl6 transcription factor
• Produces IL-6, IL-21, TGF-beta

NKT (Natural Killer T cells)

• Unique subset of T lymphocytes that share characteristics with both conventional T cells and natural killer (NK) cells
• Plays roles in immune regulation, host defense against infections, tumor surveillance, and autoimmune diseases
• Bridge innate and adaptive immunity by rapidly responding to lipid antigens and influencing the activation and function of other immune cells, including dendritic cells, B cells, and conventional T cells.
• Produce IFN-gamma, IL-4

Here’s a quick, practical cheat-sheet listing cytokines.  Many cytokines are context-dependent; below are their typical roles.

Pro-inflammatory (promote activation, fever, leukocyte recruitment)

• IL-1α/IL-1β – fever, endothelial activation
• TNF-α – vascular leak, shock at high levels
• IL-6 – acute-phase response, fever
• IFN-γ – macrophage activation (Th1)
• IL-12 – drives Th1 differentiation
• IL-17A/F – neutrophil recruitment (Th17)
• IL-23 – maintains Th17 cells
• GM-CSF – myeloid activation/recruitment
• IL-18 – boosts IFN-γ; inflammasome-linked
• Type I interferons (IFN-α/β) – antiviral, can amplify inflammation
• IL-33, IL-25, TSLP – “alarmins” that drive type-2 inflammation (allergy/asthma)
• IL-8/CXCL8 – neutrophil chemotaxis (chemokine; often grouped with pro-inflammatory)

Anti-inflammatory / Immunoregulatory (limit or resolve inflammation)

• IL-10 – broad suppression of macrophages/T cells; key tolerogenic cytokine
• TGF-β – immune regulation, Treg and tissue repair (fibrosis risk if excessive)
• IL-1Ra – natural IL-1 receptor antagonist
• IL-4, IL-13 – dampen Th1/Th17 responses (though pro-allergic/type-2)
• IL-27 – restrains Th17/Th1; promotes IL-10
• IL-35 – Treg-derived suppressive cytokine
• IL-37, IL-38 – IL-1 family members with anti-inflammatory effects

Notes to interpret panels

• Th1-leaning: ↑IFN-γ, IL-12
• Type-2 (allergic): ↑IL-4, IL-5, IL-13, IL-33/TSLP
• Th17-leaning: ↑IL-17A/F, IL-23, GM-CSF
• Regulatory tone: ↑IL-10, TGF-β (and sometimes IL-27/IL-35)

Compounds that stimulate TH-1 (downregulate TH-2)

• Astragalus
• Echinacea
• Berberine
• Andrographis
• Sambucus nigra (black elderberry)
• Mushrooms (beta-glucan, maitake)
• Glycyrrhiza
• Melissa officinali
• Lemon balm
• Mushroom
• Sulforaphane
• Ginger
• Ginseng
• Zinc
• Glutathione
• Vitamin C
• Resveratrol (modulates)

Compounds that stimulate TH-2 (downregulate TH-1)

• Caffeine
• Green tea extract
• Pycnogenol
• White willow bark
• Grape seed extract
• Resveratrol
• Lycopene
• Pine bark extract
• Antioxidants in berries
• Caffeine
• Pycnogenol
• Genistein
• Curcumin (modulates)
• Quercetin (modulates)
• Resveratrol (modulates)

Compounds that downregulate TH17 Dominance

• Probiotics: L. salivarius , L. plantarum
• Curcumin
• Berberine
• EGCG
• Ursolic acid
• Andrographolide
• Black Cumin Seed Oil
• Olive leaf extract [81, 82]
• Fisetin [83] (inhibits IL-17)
• Chinese Skullcap/Baicalin [84, 85] (Number of Th17 and IL-17)
• NAG [86]
• Red Yeast Rice/statins [20] – synergizes with corticosteroids
• Grape Seed Extract [87, 88] (STAT3-)
• Boswellia [89]
• R-Lipoic Acid [90]
• Epimedium/Icariin [91]
• Apigenin [92]
• Honokiol
• CBD [94]
• Galantamine [95, 96, 97]
• Huperzine A [95]
• Butyrate [98] – but increases it in response to an infection [99]
• Cinnamon/NaB [100] (increases IL-17)
• Artemisinin [101]
• Beta-Caryophyllene [102]
• Resveratrol* [103, 104] (conflicting)
• Probiotics: Enterococcus faecalis [105], (Mice)
• Parthenolide [106] – IL-17A [107]
• Ancient Wheat [82]
• Licorice/Lico A [108] (uncertain) [109]
• Ginger extract [110]