Autoimmune Diseases

TL;DR. Your immune system builds roughly a billion different receptor shapes at random, which guarantees that some of them fit you. The process that deletes or suppresses those self-reactive cells is called tolerance, and autoimmune disease is what happens when it fails. What follows depends only on which tissue is targeted: the insulin-producing cells (type 1 diabetes), joint linings (rheumatoid arthritis), the gut lining (coeliac disease and inflammatory bowel disease), the thyroid, the skin, or nearly everything at once (lupus). Roughly 80 percent of people with autoimmune disease are women. None of it is contagious, and almost all of it is now treatable with drugs that target specific immune signals rather than suppressing everything.

Key takeaways

• Autoimmune diseases collectively affect roughly 5 to 10 percent of people, and their incidence is rising in industrialised countries faster than genetics can explain.
• Around 80 percent of patients are women, one of the strongest and least explained patterns in medicine.
• Autoimmunity is a failure of tolerance, and the common triggers are genetic susceptibility (especially HLA genes) plus something environmental: infection, smoking, gut microbiome changes, or drugs.
• Coeliac disease is the one autoimmune condition with a fully identified trigger (gluten) and a treatment that works by removing it.
• Biologic drugs transformed this field. Anti-TNF agents, introduced in the late 1990s, turned rheumatoid arthritis from a crippling disease into one where remission is a realistic target.
• The price of every effective treatment is increased infection risk, and screening for latent tuberculosis and hepatitis before starting is standard for good reason.

What it is

In short: Immune tolerance failing for one target, and which target it is determines everything about the resulting disease.

Tolerance is built in two stages. Central tolerance: developing T cells in the thymus that bind self-proteins strongly are deleted, aided by a gene (AIRE) that makes thymic cells display proteins from all over the body so that self-reactive cells can be caught. Peripheral tolerance: cells that escape are held in check by regulatory T cells and by the requirement for a second "danger" signal before activation.

Autoimmune disease occurs when both layers fail for one target.

Why women

In short: Roughly four in five patients are women, and the leading explanations involve X chromosome gene dosage, sex hormones, and cells left behind by pregnancy.

The female-to-male ratio ranges from about 9 to 1 in lupus and Sjögren's, through 3 to 1 in rheumatoid arthritis and multiple sclerosis, to roughly 1 to 1 in type 1 diabetes and ankylosing spondylitis. Several explanations have evidence and none is complete:

• X chromosome dosage. Many immune genes sit on the X chromosome. Females silence one X in each cell (X inactivation), and that silencing is incomplete for some genes, so certain immune genes are expressed at higher dose. A 2024 study implicated the Xist RNA complex, which performs X inactivation, in generating autoantibodies, offering a specific mechanism.
• Sex hormones. Oestrogen generally enhances antibody responses; testosterone is immunosuppressive. Disease activity in lupus and rheumatoid arthritis often changes with pregnancy and menopause, in opposite directions for the two conditions, which complicates any simple story.
• Microchimerism. Fetal cells persist in the mother for decades after pregnancy and may contribute to some conditions.

The history

In short: Autoimmunity was considered impossible until the 1950s, and treatment has moved from steroids to targeting one cytokine at a time.

Paul Ehrlich coined horror autotoxicus around 1900, arguing the body had mechanisms to prevent immune attack on itself and implying such attack would be catastrophic. For fifty years autoimmunity was considered essentially impossible.

That changed in the 1950s: autoantibodies were demonstrated in Hashimoto's thyroiditis (Roitt and Doniach, 1956), the LE cell was identified in lupus, and the concept of self-reactivity became respectable. Burnet and Medawar's clonal selection and immunological tolerance work, which won the 1960 Nobel Prize, gave the theoretical framework: tolerance is learned, so it can fail.

Treatment progressed in three eras. Corticosteroids from 1949 (Hench, Kendall, and Reichstein, Nobel Prize 1950), whose effect on rheumatoid arthritis was so dramatic that patients who had been bedbound walked, and whose long-term harms became apparent within years. Conventional immunosuppressants from the 1950s to 1980s: methotrexate, azathioprine, ciclosporin. And biologics from 1998, when the first anti-TNF drugs demonstrated that blocking a single cytokine could control disease that had resisted everything else.

What actually goes wrong

In short: Immune genes set susceptibility and something environmental triggers it, and molecular mimicry explains how an ordinary infection produces lifelong autoimmunity.

Genetic susceptibility. The strongest associations across nearly all autoimmune disease are in the HLA genes, which encode the molecules that display protein fragments to T cells. Different HLA variants present different self-peptides, which is presumably why particular variants confer risk for particular diseases: HLA-DQ2 and DQ8 for coeliac disease, HLA-DR4 for rheumatoid arthritis, HLA-DR15 for multiple sclerosis, HLA-B27 for ankylosing spondylitis. Non-HLA genes (PTPN22, CTLA4, and many others) affect the thresholds for immune activation, which is why one person can develop several autoimmune diseases and why they cluster in families.

Environmental triggers, with the strength of evidence varying:

Molecular mimicry is the mechanism worth understanding, because it explains how an ordinary infection produces lifelong autoimmunity: a microbial protein resembles a human one closely enough that the antibodies and T cells raised against the microbe also attack the tissue. Rheumatic heart disease is the cleanest example, and it remains a major cause of valve disease in low-income countries, entirely preventable by treating strep throat with penicillin.

The damage mechanisms are the ordinary tools of immunity, misdirected: autoantibodies binding tissue and activating complement, immune complexes depositing in kidneys and vessels, and cytotoxic T cells killing target cells directly.

The major diseases, briefly

In short: Eight conditions attacking eight different targets, from joints to gut lining to thyroid, with coeliac disease the only one whose trigger is fully identified.

Rheumatoid arthritis

Symmetrical inflammation of the synovium, the joint lining, typically small joints of hands and feet first, with morning stiffness lasting over an hour. The inflamed synovium proliferates into a pannus that erodes cartilage and bone, producing the deformities of untreated disease. It is systemic: fatigue, lung disease, and a substantially increased cardiovascular risk driven by chronic inflammation.

Affects roughly 0.5 to 1 percent of adults, three times more women. Anti-CCP antibodies are highly specific and appear years before symptoms. Smoking is the strongest environmental risk factor.

Treatment has been transformed. The strategy is treat to target: start disease-modifying therapy within weeks of diagnosis, escalate until remission or low disease activity is reached, and keep measuring. Methotrexate remains the anchor drug. Biologics (anti-TNF, anti-IL-6, B-cell depletion, T-cell costimulation blockade) and JAK inhibitors are added when it is not enough. Erosive deformity, which defined the disease a generation ago, is now uncommon in patients treated early.

Systemic lupus erythematosus

The prototype systemic autoimmune disease: autoantibodies against nuclear components (DNA, histones), immune complexes depositing throughout the body. Features include a photosensitive facial rash across the cheeks and nose, joint pain, mouth ulcers, hair loss, pleurisy and pericarditis, blood cell destruction, and, most seriously, lupus nephritis, which affects up to half of patients and can cause kidney failure. Neuropsychiatric involvement ranges from headache and cognitive difficulty to seizures and psychosis.

Roughly 9 to 1 female, with onset usually between 15 and 45, and substantially higher incidence and severity in people of African, Hispanic, and Asian ancestry. It relapses and remits.

Treatment: hydroxychloroquine for essentially everyone (it reduces flares, organ damage, and mortality and is the single most important drug in lupus), corticosteroids for flares at the lowest dose that works, immunosuppressants (mycophenolate, azathioprine, cyclophosphamide for severe disease), and newer targeted agents (belimumab, anifrolumab, and voclosporin for nephritis). Survival has gone from roughly 50 percent at five years in the 1950s to over 90 percent at ten years.

Coeliac disease

An immune reaction to gluten in genetically susceptible people (HLA-DQ2 or DQ8, present in about 30 percent of the population, of whom only a small fraction develop the disease). Gluten peptides are modified by the enzyme tissue transglutaminase, presented by HLA-DQ2/8, and drive a T cell response that flattens the intestinal villi.

Consequences: diarrhoea and weight loss in classic cases, and, much more commonly, iron-deficiency anaemia, osteoporosis, fatigue, infertility, and raised liver enzymes with no gut symptoms at all. It affects roughly 1 percent of people and most are undiagnosed.

Diagnosis requires tissue transglutaminase antibodies while still eating gluten, usually confirmed by biopsy. Going gluten-free before testing makes the diagnosis impossible to confirm, which is a common and frustrating problem.

Treatment is a strict lifelong gluten-free diet, which allows the intestine to heal and reverses most consequences. Non-adherence, often through cross-contamination rather than deliberate eating, maintains the damage.

Non-coeliac gluten sensitivity is a separate, poorly defined entity, likely overlapping with irritable bowel syndrome and possibly reacting to fermentable carbohydrates rather than gluten itself. It is not coeliac disease and carries none of the same complications.

Inflammatory bowel disease

Two conditions, distinguished by pattern:

Both cause diarrhoea (bloody in colitis), abdominal pain, weight loss, fatigue, and extraintestinal features affecting joints, eyes, skin, and liver. Incidence has risen sharply in newly industrialised countries, following the same pattern as other immune-mediated diseases.

Treatment: aminosalicylates (colitis), corticosteroids for flares only, immunomodulators (azathioprine, methotrexate), biologics (anti-TNF, anti-integrin vedolizumab which acts on gut homing specifically, anti-IL-12/23 ustekinumab), JAK inhibitors, and surgery, which is curative for ulcerative colitis (removing the colon) and not for Crohn's, where disease recurs at the anastomosis.

Thyroid autoimmunity

Hashimoto's thyroiditis: antibodies against thyroid peroxidase gradually destroy the gland, producing hypothyroidism. The commonest autoimmune disease and the commonest cause of hypothyroidism where iodine is sufficient. Treated with levothyroxine replacement (Chapter 51).

Graves' disease: antibodies that stimulate the TSH receptor, producing hyperthyroidism plus, in some patients, eye disease. A rare and instructive case of an autoantibody that activates rather than destroys.

Psoriasis and psoriatic arthritis

Immune-driven skin inflammation with accelerated keratinocyte turnover, producing well-demarcated scaly plaques. Around 20 to 30 percent develop psoriatic arthritis. Both are strongly linked to the IL-23/IL-17 axis, and the drugs targeting that pathway have produced clearance rates that were inconceivable a decade ago. Psoriasis is also associated with metabolic syndrome and cardiovascular disease, so it is treated as a systemic inflammatory disease rather than a skin complaint.

Others worth naming

Sjögren's syndrome (dry eyes and mouth from destruction of tear and salivary glands, plus fatigue and joint pain), systemic sclerosis (fibrosis of skin and internal organs, with Raynaud's phenomenon), vasculitis (inflammation of blood vessels, ranging from skin-limited to rapidly fatal renal and pulmonary disease), myasthenia gravis (antibodies against the acetylcholine receptor at the neuromuscular junction, causing fatigable weakness), and autoimmune hepatitis.

Is it deadly?

Varies enormously. Coeliac disease and treated thyroid disease are compatible with a normal lifespan. Severe lupus with kidney or nervous system involvement, systemic sclerosis with lung fibrosis or pulmonary hypertension, and severe vasculitis carry substantial mortality. Rheumatoid arthritis shortens life primarily through cardiovascular disease driven by chronic inflammation, and controlling the inflammation reduces that risk.

Across the group, mortality has fallen substantially with modern treatment, and the leading causes of death are now cardiovascular disease, infection related to immunosuppression, and, in some conditions, malignancy.

Is it contagious?

No. Autoimmune diseases cannot be transmitted between people.

Two connections regularly cause confusion. Some are triggered by infections that are contagious: rheumatic fever follows streptococcal throat infection, reactive arthritis follows certain gut and genital infections, and multiple sclerosis appears to require Epstein-Barr virus. Catching the trigger is possible; catching the autoimmune disease is not, and the vast majority of people who catch the trigger never develop it.

And autoimmune diseases cluster in families, through shared genes and, likely, shared environments. A person with one autoimmune disease has an elevated risk of another, and their relatives have elevated risk too.

Who gets it

• Roughly 5 to 10 percent of people in industrialised countries, and rising. A UK study of 22 million people found autoimmune diseases affecting about 10 percent of the population, with incidence rising over the study period for several conditions.
• Women, overwhelmingly, as above.
• Age: most present between 15 and 50, though type 1 diabetes and juvenile arthritis start in childhood, and giant cell arteritis and polymyalgia rheumatica are diseases of people over 50.
• Ancestry: lupus is more common and more severe in people of African, Hispanic, and Asian descent; multiple sclerosis is more common in northern European populations; Behçet's disease follows the historic Silk Road.
• The rising incidence in industrialised and industrialising countries points at environment: candidate explanations include microbiome changes, diet, obesity (adipose tissue is pro-inflammatory), smoking, vitamin D, pollution, and reduced early-life microbial exposure. None is proven.

Treatment, and how it works

In short: The strategy moved from suppressing everything to blocking one signal, which is why treatment now names a cytokine rather than a disease.

The strategy has moved from broad suppression toward targeted interference with specific signals.

What treatment costs

In short: Infection is the common price, and the specific risk tracks the mechanism, which is why latent tuberculosis is screened for before certain drugs.

Infection is the common price. Every effective immunosuppressant increases infection risk, and the specific risks track the mechanism:

• Anti-TNF drugs substantially increase the risk of reactivating latent tuberculosis, because TNF holds granulomas together (Chapter 29). Screening for latent TB and hepatitis B before starting is mandatory.
• Rituximab reduces antibody responses, including to vaccines, and causes prolonged hypogammaglobulinaemia in some patients.
• Natalizumab carries a risk of progressive multifocal leukoencephalopathy in JC virus-positive patients.
• Corticosteroids, long term: weight gain, diabetes, osteoporosis, cataract, thin skin, hypertension, adrenal suppression, mood disturbance, and infection. Almost every advance in this field is measured partly by how much it reduces steroid exposure.
• Methotrexate: mouth ulcers, nausea, liver enzyme rise, marrow suppression, and it is a potent teratogen requiring contraception. Folic acid supplementation reduces the common side effects. It is dosed weekly, and accidental daily dosing has caused deaths, which is why prescriptions carry specific warnings.
• JAK inhibitors: shingles reactivation, and increased cardiovascular events and clots in older patients with risk factors, per a large post-marketing safety trial.
• Live vaccines are contraindicated on most of these drugs, so vaccination should be planned before starting.

What the person can do

In short: Get diagnosed early, stop smoking, vaccinate before starting immunosuppression, attend monitoring bloods, and plan pregnancy in advance.

• Get diagnosed properly and early. Time to treatment predicts joint damage in rheumatoid arthritis and organ damage in lupus. Diagnostic delay is common, particularly for women whose fatigue and pain get attributed to stress.
• Stop smoking. It causes rheumatoid arthritis, worsens lupus and Crohn's, and reduces the effectiveness of several treatments.
• Get vaccinated before starting immunosuppression, including influenza, pneumococcal, COVID-19, shingles, and HPV where relevant. Live vaccines must be given before, not during.
• Have latent TB and hepatitis screening before biologics, and know the symptoms to report.
• Take sun protection seriously in lupus, where ultraviolet light reliably triggers flares.
• Attend monitoring blood tests. They are the mechanism by which serious drug toxicity is caught before it causes harm.
• In coeliac disease, be strict, including about cross-contamination, and get tested before removing gluten, not after.
• Look after cardiovascular risk. Chronic inflammation is itself a cardiovascular risk factor, and it is under-addressed in these patients.
• Exercise, which improves fatigue, pain, and function in inflammatory arthritis and does not damage joints when the disease is controlled.
• Be sceptical of elimination diets and unproven "autoimmune protocols." Except in coeliac disease, no diet has been shown to control autoimmune disease, and restrictive diets carry nutritional and social costs.

Living with it

These diseases are chronic, fluctuating, and frequently invisible, which produces a specific social difficulty: on a good day the person looks well, and on a bad day they cancel. Fatigue is consistently rated by patients as the most disabling symptom and is consistently under-addressed by clinicians, who tend to focus on the measurable inflammatory markers.

Because they predominantly affect women in their twenties to forties, they collide with careers, pregnancy planning, and childcare. Pregnancy needs planning: several drugs are teratogenic and must be stopped in advance, others are safe and should be continued because uncontrolled disease is worse for the pregnancy than the medication, and getting that balance right requires specialist advice rather than stopping everything on discovering a pregnancy.

What's next

• CAR-T cell therapy for autoimmune disease. Engineered T cells that deplete B cells completely have produced drug-free remission in small series of patients with severe refractory lupus, systemic sclerosis, and myositis. If it holds up in larger trials, it is the most significant development in the field in twenty-five years.
• Antigen-specific tolerance induction: re-teaching the immune system to ignore one target rather than suppressing it globally. The long-standing goal, and still experimental.
• Prediction and prevention: autoantibodies appear years before symptoms in rheumatoid arthritis and type 1 diabetes, and trials are testing whether treating at that stage prevents disease. Teplizumab in pre-symptomatic type 1 diabetes (Chapter 18) is the first success.
• Microbiome-directed therapy, currently more promising than proven outside C. difficile.
• Understanding the sex difference, where the X inactivation findings offer the first mechanistic handle in decades.

Sources and notes

Population prevalence: Conrad et al., The Lancet, 2023, a study of 22 million people in the UK finding autoimmune diseases in about 10 percent of the population. Female predominance figures are disease-specific aggregates from epidemiological literature. Xist and autoimmunity: Dubey et al., Cell, 2024. Horror autotoxicus: Ehrlich, circa 1900. Hashimoto autoantibodies: Roitt and Doniach, The Lancet, 1956. Corticosteroids in rheumatoid arthritis: Hench et al., 1949 (Nobel Prize 1950). Anti-TNF development: Feldmann and Maini, from 1992. Treat-to-target: Smolen et al., international recommendations. Hydroxychloroquine in lupus: Canadian Hydroxychloroquine Study Group, NEJM, 1991, and subsequent cohort data. Coeliac prevalence and diagnosis: Singh et al., meta-analysis, 2018. JAK inhibitor safety: ORAL Surveillance trial, NEJM, 2022. CAR-T in autoimmune disease: Müller et al., NEJM, 2024, and earlier case series from Erlangen.

Open questions. Why tolerance fails in any individual is unknown for every disease here. The cause of the rising incidence is not established. Whether antigen-specific tolerance can be induced in established disease remains unproven.

Next: diseases written into the genes before birth. 👉