Histamine in Autoimmune Diseases: An Integrative and Clinical Perspective

Did you know that histamine is not only related to allergies but also to autoimmune diseases such as Hashimoto’s hypothyroidism, lupus, multiple sclerosis, or rheumatoid arthritis?

In this article, I’ll explain step-by-step how histamine and certain cells called mast cells may influence the development and progression of these conditions. Most importantly, how understanding this connection can help you care for your health in a more personalized way.

Histamine and Autoimmune Hypothyroidism: What’s the Connection?

Autoimmune hypothyroidism, also known as Hashimoto’s thyroiditis, happens when the immune system mistakenly attacks the thyroid gland, affecting its function.

Several studies have shown that many people with Hashimoto’s also experience symptoms related to histamine: hives, migraines, digestive sensitivity, or fatigue.

One striking fact: people with chronic spontaneous urticaria (a condition closely linked to mast cells) are five to seven times more likely to have thyroid antibodies (anti-TPO).

Moreover, experimental studies show that hypothyroidism increases both the number of mast cells and the levels of histamine in tissues. In other words, the lack of thyroid hormone may make the body more sensitive to histamine, increasing inflammatory symptoms and worsening overall well-being.

It has also been suggested that histamine intolerance may be more common in people with Hashimoto’s due to associated gut microbiota imbalances or reduced activity of the DAO enzyme, which metabolizes histamine in the intestine. Altogether, the autoimmune inflammatory state could promote histamine release, and the excess histamine could further aggravate thyroid inflammation — creating a vicious cycle.

Controlling histamine levels is often part of integrative approaches to improve symptoms in these individuals, although the core focus remains on managing thyroid autoimmunity.

Histamine and Lupus: Amplified Inflammation

Systemic lupus erythematosus (SLE) is a complex autoimmune condition affecting various organs: skin, kidneys, joints, heart…

Damaged tissues in lupus have been found to contain more activated mast cells than healthy ones. These mast cells release not only histamine but also tissue-damaging enzymes like metalloproteinases (MMPs).

There is also evidence that the histamine pathway may be involved in lupus susceptibility. One genetic study found that certain copy number variations of the histamine H4 receptor gene were linked to a higher risk of SLE. The H4 receptor is expressed on immune cells (including T cells and dendritic cells) and is involved in chemotaxis and modulation of Th1/Th17 responses. Changes in this pathway could predispose to stronger autoimmune reactions.

Clinically, some lupus patients present allergic-like symptoms (such as hives or angioedema) during flare-ups, suggesting that histamine release and autoimmune activation may occur in parallel. While standard lupus treatment relies on targeted immunosuppressants (like corticosteroids or biologics), managing allergic symptoms with antihistamines can be helpful as supportive therapy.

This suggests that in people with lupus, histamine may act as an amplifier of the immune response, worsening flares and contributing to tissue damage.

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which the immune system attacks the myelin (the protective sheath around nerves) in the brain and spinal cord.

Mast cells are present in the nervous system and, when activated, increase the permeability of the blood-brain barrier by releasing histamine, TNF-α, IL-1β, and proteases. This allows inflammatory cells to enter the CNS, facilitating the development of the characteristic demyelinating lesions of MS.

In fact, during MS relapses, there is increased mast cell degranulation in the brain, which is associated with the infiltration of neutrophils and lymphocytes into the nervous tissue.

Histamine may also influence immune balance in MS. While it can promote Th2 responses in some cases, in MS (which is predominantly Th1/Th17), it seems to play a more pro-inflammatory role by recruiting cells to the CNS and activating encephalitogenic lymphocytes.

Interestingly, histamine levels in the cerebrospinal fluid of MS patients are higher than in healthy individuals, supporting the idea of mast cell/neuroimmune activation.

Furthermore, some animal studies have found that using antihistamines or mast cell stabilizers can reduce disease severity.

This opens the door to complementary approaches in MS. Alongside specific immunomodulators, histamine blockers or mast cell stabilizers could help reduce neurogenic inflammation.

While no standard MS therapy currently targets histamine directly, the evidence suggests that elevated histamine levels may worsen neuroinflammation, and managing them could have a modulatory benefit.

Rheumatoid Arthritis: Pain, Histamine, and Joint Damage

Rheumatoid arthritis is a chronic autoimmune disease that mainly affects synovial joints, causing inflammation, pain, and destruction of cartilage and bone.

In the inflamed joints of people with rheumatoid arthritis, high numbers of active mast cells have been found in the synovial tissue. As a result, mediators like histamine, tryptase, and chymase are elevated both in the synovial fluid and in peripheral blood.

This persistent release of histamine contributes to vasodilation and increased vascular permeability, leading to swelling and immune cell infiltration.

Histamine also acts on H1 receptors in nerve endings, causing pain and heightened sensitivity in the affected joints. Additionally, it can activate osteoclasts — the cells responsible for bone degradation.

In animal models, blocking the H4 receptor significantly reduced arthritis symptoms, suggesting this pathway could be a future therapeutic target.

Mast Cells and Low-Grade Chronic Inflammation

Mast cells are sentinel cells of the innate immune system. When activated, they release a wide range of inflammatory mediators like histamine, heparin, tryptase, chymase, pro-inflammatory cytokines, prostaglandins, and leukotrienes.

One of the most relevant aspects of the connection between histamine and autoimmunity is low-grade inflammation. This is not acute inflammation but rather a persistent, silent state that keeps the body inflamed over time.

Mast cells that are continuously activated may release small amounts of histamine — enough to maintain this low-level inflammation without initially noticeable symptoms. This persistent activation acts like a smoldering fire that never goes out, fueling autoimmunity.

An interesting aspect is the possible connection between environmental or dietary factors and mast cell activation in autoimmunity. For instance, certain gut bacteria or histamine-rich foods may raise systemic histamine tone, adding fuel to the inflammatory fire.

Additionally, mast cell activation syndrome (MCAS) is being reported more frequently in patients with autoimmune diseases, including thyroid autoimmunity and connective tissue disorders.

All of this suggests that in some individuals, autoimmunity and mast cell hyperreactivity may coexist — and both should be addressed.

What Can We Do?

While more studies are needed, some approaches from psychoneuroimmunology may help regulate this interaction:

• Follow an anti-inflammatory and, in some cases, low-histamine diet.
• Treat gut dysbiosis and strengthen the intestinal barrier.
• Consume foods rich in mast cell-stabilizing compounds: quercetin, luteolin, omega-3, turmeric…
• Avoid alcohol, ultra-processed foods, or those known to trigger histamine release.
• Use NaturDAO supplements in appropriate contexts, as well as mast cell stabilizers.
• Regulate stress and chronic activation of the sympathetic nervous system.

In summary, understanding how mast cells, histamine, and the immune system interact opens the door to more personalized and integrative approaches to managing autoimmune diseases like Hashimoto’s, lupus, multiple sclerosis, or rheumatoid arthritis.