Combined Immunodeficiency Due to Lipopolysaccharide-Responsive Beige-Like Anchor (LRBA) Protein Deficiency

Combined immunodeficiency due to lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency is a rare, inherited immune system disease where both antibody-producing cells (B cells) and T cells do not work properly, and the immune system also becomes overactive in a harmful way. Children and adults can have repeated lung, ear, and sinus infections, chronic diarrhea, poor growth, enlarged lymph nodes and spleen, and many autoimmune problems such as low blood counts or gut inflammation. [LRBA] is a gene important for recycling a key immune “brake” called CTLA-4 on T cells; when LRBA is missing, CTLA-4 cannot work well, so the immune system attacks the body and at the same time cannot fully fight germs.

Combined immunodeficiency due to lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency is a rare inborn problem of the immune system. It happens when both copies of the LRBA gene are changed (mutated), so the body cannot make enough working LRBA protein. This leads to weak defense against infections and loss of normal control of the immune system, causing both infections and autoimmune diseases in the same person. [] The LRBA protein normally helps immune cells, especially T cells and B cells, to talk to each other and to switch off immune reactions at the right time. It is closely linked to a control protein called CTLA-4, which acts like a “brake” on the immune system. When LRBA is missing, CTLA-4 cannot be recycled properly, so the immune system becomes overactive and attacks the body’s own tissues, while at the same time failing to fight infections well. []

Because this condition affects many organs, treatment is usually guided by a specialist in clinical immunology or hematology and often needs a combination of infection control, immune-modulating drugs, nutritional support, and sometimes curative bone marrow (stem cell) transplantation. Current evidence from large patient series shows that targeted biologic therapy such as abatacept and, in severe disease, allogeneic hematopoietic stem cell transplantation (HSCT) can significantly improve survival and quality of life, but they carry risks and must be managed in expert centers.

Because of this mix of weak defense and loss of control, LRBA deficiency is often described as both a primary immunodeficiency (a built-in immune weakness) and an immune-dysregulation syndrome. People may have repeated chest and sinus infections, chronic diarrhea, enlarged spleen and liver, and autoimmune problems like low blood cells or bowel inflammation. []

Other names

Doctors and scientists use several other names for this condition. One common name is “LRBA deficiency,” which simply means that the LRBA protein is missing or not working. Another formal name is “common variable immunodeficiency-8 with autoimmunity (CVID8),” because many patients look similar to people with common variable immunodeficiency but also have strong autoimmune features. []

The disease is also called “combined immunodeficiency due to LRBA mutation” or “immune dysregulation syndrome due to LRBA deficiency.” These names remind us that both the antibody-producing B cells and the regulating T cells are affected, so the problem is not limited to one branch of the immune system. []

Some papers describe an “IPEX-like syndrome due to LRBA deficiency,” because the clinical picture with severe autoimmunity, bowel disease, and endocrine problems can look like IPEX (a different genetic disease affecting immune regulation). This highlights how LRBA deficiency can mimic several other immune disorders and may be hard to recognize without specific tests. []

Types

Doctors do not have one official “type” classification for LRBA deficiency, but they notice repeating patterns. These patterns can be grouped into clinical types based on the features that stand out the most in each patient. []

1. Infection-predominant type – In this type, repeated bacterial and viral infections are the main problem. Children may have many pneumonias, ear infections, and sinus infections every year, often starting early in life. Autoimmunity may be mild or appear later. []

2. Autoimmunity-predominant type – Here, autoimmune diseases are the leading signs. Patients may first show low platelets, low red cells, or low white cells caused by the immune system attacking blood cells, sometimes called Evans syndrome. They may get diagnosed after long evaluation for autoimmunity rather than for infections. []

3. Inflammatory bowel disease–predominant type – Some patients mainly have chronic diarrhea, weight loss, and gut pain, similar to Crohn’s disease or ulcerative colitis. Endoscopy may show severe colitis in early childhood, and only later do doctors discover the underlying LRBA defect. []

4. Lymphoproliferative-predominant type – In this pattern, the body makes too many lymphocytes that collect in lymph nodes, liver, and spleen. This causes large lymph nodes, big spleen (splenomegaly), and big liver (hepatomegaly), sometimes mimicking autoimmune lymphoproliferative syndrome. []

5. Mild or late-onset CVID-like type – A few people present later, even in adolescence or adulthood, with mainly low antibodies, sinus and lung infections, and mild autoimmunity. They may be first labeled as having common variable immunodeficiency until gene testing finds LRBA variants. []

Causes

The main cause of this disease is inherited genetic change in both copies of the LRBA gene. Other “causes” below are better understood as mechanisms or risk factors that help explain how the gene defect leads to disease or why some patients get sicker than others. The primary driver is always the LRBA mutation. []

1. Biallelic LRBA gene mutations – LRBA deficiency is autosomal recessive, meaning a child must receive one faulty LRBA gene from each parent. These two faulty copies stop the body from making normal LRBA protein, which leads directly to the immunodeficiency and immune dysregulation. []

2. Missense mutations – Some patients have missense mutations, where a single DNA “letter” change makes the LRBA protein built with the wrong amino acid. The protein is present but does not work properly, which can cause a milder or more variable disease, sometimes called functional LRBA deficiency. []

3. Nonsense and frameshift mutations – Other patients have mutations that cause early stop signals or shifts in the reading frame of the gene. These changes usually destroy LRBA protein production almost completely, often leading to more severe disease and earlier symptoms. []

4. Large deletions or insertions – Rarely, bigger pieces of the LRBA gene are missing or moved. This also prevents normal protein formation and is another genetic route to full LRBA deficiency. The clinical picture is similar to other damaging mutations. []

5. Consanguinity (parents related by blood) – In some families, parents are cousins or otherwise related. This increases the chance that both carry the same rare LRBA mutation, so their children have a higher risk of inheriting two faulty copies and developing LRBA deficiency. []

6. Founder mutations in certain populations – In some regions, a specific LRBA mutation has been passed down through generations, called a founder mutation. People from those regions may share the same genetic change and similar disease features. []

7. Defective CTLA-4 recycling – LRBA helps move CTLA-4 in and out of the cell surface. When LRBA is missing, CTLA-4 cannot be recycled well, so the “brake” on T cells is lost. This is a key mechanistic cause of immune over-activity and autoimmunity in LRBA deficiency. []

8. Regulatory T-cell dysfunction – LRBA deficiency makes regulatory T cells (Tregs), which normally calm the immune system, less effective and more likely to die. Without good Treg control, immune cells attack the body’s own tissues, leading to autoimmune cytopenias and gut disease. []

9. B-cell differentiation defects – LRBA mutations disturb normal B-cell maturation, so patients have fewer switched memory B cells and poor antibody responses. This is a direct cause of low antibodies (hypogammaglobulinemia) and repeated infections. []

10. Abnormal T-follicular helper cells – T-follicular helper (Tfh) cells support antibody production in lymph nodes. In LRBA deficiency, Tfh numbers and function are often abnormal, further harming the body’s ability to make strong, high-quality antibodies. []

11. Immune activation and chronic inflammation – Because control pathways are broken, LRBA-deficient immune cells stay over-activated. This long-lasting activation causes chronic inflammation in the gut, lungs, joints, and other organs, contributing to symptoms like diarrhea and arthritis. []

12. Genetic background (other immune genes) – Other genes involved in immune regulation may change how severe LRBA deficiency becomes. Variants in these genes can partly explain why some patients are very sick while relatives with the same LRBA mutation are milder. []

13. Early childhood infections as triggers – Common infections do not cause LRBA deficiency, but they can reveal it earlier. When a child with LRBA mutations catches common germs, they may develop unusually severe or frequent infections, bringing the hidden disease to medical attention. []

14. Vaccination response stress – Routine vaccines are safe and important, but in LRBA deficiency the body may fail to make normal antibody responses. This poor vaccine response is not the cause of the disease, but it is a sign that the underlying LRBA defect is present. []

15. Environmental infection pressure – Living in places with high exposure to respiratory or gut infections may make symptoms appear more often or more severely. The LRBA mutation is still the main cause, but the environment shapes how often problems occur. []

16. Delayed diagnosis and lack of treatment – When the condition is not recognized, repeated infections and uncontrolled autoimmunity can damage organs like lungs and gut. While this does not cause LRBA deficiency itself, it causes more disease complications and worse overall health. []

17. Hormonal and growth factors – Growth and puberty affect the immune system. In LRBA deficiency, these changes may influence when symptoms peak, for example worsening autoimmunity during adolescence, though the basic genetic problem is unchanged. []

18. Co-existing autoimmune conditions – Some patients also carry risk genes for other autoimmune diseases. These extra risks can intensify autoimmunity driven by LRBA deficiency, leading to severe bowel disease, arthritis, or endocrine problems. []

19. Possible infection–immune cross-talk – Certain infections may provoke strong immune reactions that, in the absence of proper regulation, accidentally target the body’s own cells. In LRBA deficiency this mis-direction may be more likely because CTLA-4 control is lost. []

20. Limited access to specialist care – In many regions, lack of access to immunology centers and genetic testing delays diagnosis. This does not create the disease but contributes to worse infections, organ damage, and malnutrition, making the genetically caused condition much more serious. []

Symptoms

1. Recurrent respiratory infections – Many patients have repeated coughs, pneumonias, sinus infections, or ear infections from early childhood. These infections may need frequent antibiotics and can leave long-term damage such as bronchiectasis (permanent widening of airways). []

2. Chronic diarrhea and gut pain – Inflammation in the bowel is common, so patients may have long-lasting diarrhea, belly pain, and sometimes blood in the stool. The picture often looks like inflammatory bowel disease, and children can lose weight or stop growing well. []

3. Poor weight gain and growth failure – Many affected children struggle to gain weight and height. Frequent infections and chronic gut disease mean they do not absorb nutrients properly, and long-term inflammation also slows growth. []

4. Enlarged spleen and liver – The spleen and liver often become enlarged because immune cells and blood cells build up in these organs. Doctors may feel a big spleen or liver on exam, and scans confirm this lymphoproliferation, which is a key sign of LRBA deficiency. []

5. Enlarged lymph nodes – Lymph nodes in the neck, underarms, or groin may remain big for a long time without clear infection. This reflects ongoing immune activation and is part of the autoimmune lymphoproliferative–like pattern linked to LRBA deficiency. []

6. Autoimmune low blood cells (cytopenias) – The immune system may attack platelets (causing bruising and bleeding), red cells (causing anemia, pale skin, and tiredness), or white cells. When both red cells and platelets are affected, doctors may call it Evans syndrome. []

7. Chronic fatigue – Many patients feel very tired because of repeated infections, anemia, poor sleep from cough or pain, and general inflammation. This fatigue can limit school, work, and daily activities even between major infections. []

8. Joint pain and arthritis – Some people develop chronic joint pain and swelling, sometimes similar to juvenile idiopathic arthritis. This is thought to be autoimmune inflammation of the joints related to the LRBA defect. []

9. Skin rashes and autoimmune skin disease – Eczema-like rashes, urticaria (hives), or other inflammatory skin problems may appear. These may reflect allergies, autoimmunity, or general immune imbalance, all of which are more common in LRBA deficiency. []

10. Mouth ulcers and oral infections – Recurrent painful ulcers in the mouth, thrush, or gum infections may occur. They are caused both by weak local defense and by ongoing systemic inflammation and autoimmunity. []

11. Frequent fevers – Children and adults often have repeated or long fevers. Sometimes the fever is from infection; other times it is from inflammation or autoimmunity with no obvious infection source. []

12. Endocrine autoimmunity – Some patients develop autoimmune thyroid disease, type 1 diabetes, or other hormone gland problems. The immune system wrongly attacks glands like the thyroid or pancreas, further showing the broad immune dysregulation. []

13. Lung damage (bronchiectasis) – Over time, repeated lung infections can scar and widen the airways. This bronchiectasis leads to chronic cough, sputum production, and increased risk of further infections, creating a harmful cycle. []

14. Risk of lymphoma or other malignancy – A small number of patients may develop lymphomas or other cancers, likely because of long-term immune activation and disturbed control of lymphocyte growth. This risk is recognized but not present in every patient. []

15. Psychosocial and school difficulties – Chronic illness, hospital stays, and fatigue can affect mood, learning, and social life. While not a direct immune symptom, this is an important part of the lived experience of LRBA deficiency. []

Diagnostic tests

Because LRBA deficiency is complex, doctors use many tests together. They look at the person’s history, examine the body, and then do blood tests, imaging, and sometimes genetic studies. No single simple test is enough; a full picture is needed. []

Physical examination tests

1. General physical examination – The doctor looks at height, weight, growth charts, and overall appearance. They check for signs of malnutrition, pallor (pale skin), bruises, and any visible distress. This helps show whether infections and gut problems have already affected growth and general health. []

2. Skin and mucous membrane check – The doctor examines the skin for rashes, bruising, and infections, and checks the mouth and eyes. Findings like eczema, thrush, or unusual bruises may point toward immunodeficiency and autoimmune cytopenias. []

3. Lymph node examination – All major lymph node areas are gently felt for enlargement, tenderness, or abnormal texture. Persistent big lymph nodes without clear infection can suggest chronic immune activation, as seen in LRBA deficiency. []

4. Abdominal palpation for spleen and liver – The doctor feels the abdomen to detect enlarged spleen or liver. This is a key physical sign; splenomegaly and hepatomegaly often occur in LRBA deficiency and hint at lymphoproliferation or ongoing immune over-activity. []

Manual / bedside clinical tests

5. Respiratory system examination – Using a stethoscope, the doctor listens to the lungs for wheezes, crackles, or reduced breath sounds and checks breathing rate and effort. Abnormal sounds can show repeated infections or chronic lung damage like bronchiectasis. []

6. Joint examination – The doctor gently moves the joints to assess pain, swelling, warmth, and range of motion. Signs of arthritis in a child with immune problems may point toward autoimmune joint disease linked to LRBA deficiency. []

7. Neurological bedside examination – Basic checks of strength, reflexes, walking, and coordination may be done. Though not specific for LRBA deficiency, these tests help rule out nervous system complications from infections, autoimmunity, or treatment effects. []

8. Growth and pubertal staging – Doctors compare height, weight, and pubertal development with age-matched charts. Delayed puberty or growth failure may reflect long-term illness from chronic infections and gut disease in LRBA deficiency. []

Laboratory and pathological tests

9. Complete blood count (CBC) – A CBC measures red cells, white cells, and platelets. In LRBA deficiency it may show anemia, low platelets, or low white cells from autoimmunity, or high lymphocytes from lymphoproliferation. It is a simple but very important first test. []

10. Serum immunoglobulin levels – Levels of IgG, IgA, and IgM are measured. Many patients with LRBA deficiency have low IgG and sometimes low IgA or IgM, reflecting poor antibody production similar to CVID. []

11. Specific antibody responses to vaccines – Doctors may check antibody levels to previous vaccines (such as tetanus or pneumococcus). Poor responses indicate that B cells are not making effective antibodies, supporting the diagnosis of an antibody deficiency. []

12. Lymphocyte subset analysis by flow cytometry – This test counts different types of lymphocytes (T, B, and NK cells) and their sub-groups. In LRBA deficiency, there may be reduced switched memory B cells and abnormal T-cell subsets, which supports a diagnosis of combined immunodeficiency. []

13. LRBA protein expression by flow cytometry – Specialized labs can stain cells for LRBA protein and measure it by flow cytometry. Low or absent LRBA protein strongly suggests LRBA deficiency, especially when combined with typical clinical signs. []

14. Genetic testing for LRBA mutations – Sequencing the LRBA gene is the definitive test. Finding two disease-causing mutations confirms the diagnosis and allows family testing and genetic counseling. This is now the gold standard for final diagnosis. []

Electrodiagnostic tests

15. Electrocardiogram (ECG) – An ECG records the heart’s electrical activity. It is not specific for LRBA deficiency but may be used when there is concern about heart involvement from infections, inflammation, or certain medicines used in treatment. []

16. Electroencephalogram (EEG) – If a patient has seizures or altered consciousness, an EEG may be done to record brain electrical activity. This helps doctors see whether symptoms are due to seizures or brain inflammation, which can be rare complications of immune disorders. []

17. Nerve conduction studies and EMG – In patients with suspected nerve or muscle problems, doctors may perform nerve conduction studies or electromyography (EMG). These tests check how well nerves and muscles transmit electrical signals and help detect any secondary neuropathies. []

Imaging tests

18. Chest X-ray – A simple chest X-ray can show pneumonia, lung scarring, or enlarged heart and mediastinal lymph nodes. It is often the first imaging test when a patient with LRBA deficiency has cough, fever, or breathing problems. []

19. High-resolution CT scan of the chest – CT scans give detailed images of the lungs and airways. They can show bronchiectasis, nodules, or interstitial changes that result from repeated infections and chronic inflammation. This helps in deciding long-term management. []

20. Abdominal ultrasound or CT – Ultrasound of the abdomen can measure spleen and liver size and look for enlarged abdominal lymph nodes. CT or MRI may be added if there is concern about masses, lymphoma, or other organ damage. These images support the diagnosis of lymphoproliferation in LRBA deficiency. []

Non-pharmacological treatments (therapies and other supports)

1. Individual infection-prevention plan
People with LRBA deficiency need a personalized infection-prevention plan, including hand-washing, mask use in crowded places, early use of medical care for fever, and sometimes home isolation during outbreaks. These steps reduce exposure to bacteria and viruses that the weakened immune system cannot clear easily, lowering the risk of pneumonia, sepsis, and chronic lung damage. The plan is usually written by an immunologist and updated over time based on infection history and living conditions (school, work, travel).

2. Structured vaccination strategy (by specialists)
Vaccines can be helpful but also tricky in combined immunodeficiency. Inactivated vaccines (like killed influenza or pneumococcal vaccines) are often recommended to reduce severe infections, while live vaccines may be avoided or used only after specialist review. The purpose is to give as much safe protection as possible without causing disease from live vaccine strains. Decisions are based on immune tests, treatment (such as biologics or HSCT), and current guidelines for inborn errors of immunity.

3. Pulmonary rehabilitation and chest physiotherapy
Chronic lung infections and inflammation in LRBA deficiency can cause bronchiectasis and long-term breathing problems. Pulmonary rehab uses breathing exercises, airway-clearance techniques (like chest percussion and positive expiratory pressure devices), and supervised fitness training to improve lung function. The mechanism is mechanical: helping mucus move out of the airways so bacteria are cleared more easily, which lowers exacerbations and protects lung tissue.

4. Nutritional counseling and growth support
Chronic diarrhea, malabsorption, and increased energy needs can lead to poor growth and nutrient deficits. A dietitian plans energy-dense, protein-rich meals, special formulas, or tube feeding when needed. Adequate calories, protein, and micronutrients support immune cell production, wound healing, and recovery from infections. In some patients, avoiding trigger foods can also reduce gut inflammation and improve symptoms.

5. Psychological and family support
Living with a chronic, rare immune disease can cause anxiety, depression, and school or work stress. Counseling, support groups, and family education help patients cope emotionally and practically. Psychological support works by reducing chronic stress, which may also indirectly support immune function, and by improving adherence to complex treatment regimens (infusions, hospital visits, and transplant preparation).

6. Regular dental and oral care
People with immunodeficiency are at higher risk of gum disease, mouth ulcers, and dental infections, which can spread to the bloodstream. Regular dental check-ups, good brushing and flossing, and treatment of cavities early help keep the mouth as a low-bacteria environment. This simple mechanical and hygienic approach lowers the number of bacteria that can trigger serious infections and bacteremia.

7. Skin care and wound protection
Dry, inflamed, or infected skin is common due to autoimmune issues and recurrent infections. Gentle cleansing, moisturizing, quick treatment of cuts, and avoiding harsh chemicals or scratching help maintain the skin barrier. The skin is the first defense wall; when intact, it prevents germs from entering, so basic skincare reduces cellulitis, abscesses, and hospital stays.

8. Infection-control training at home and school
Families and teachers are taught how to reduce infection risk: avoiding sick contacts, good ventilation, cleaning shared surfaces, and safe food handling. This environmental control strategy reduces the “dose” of germs that the patient encounters. In households with many children or in school settings, consistent hygiene rules greatly lower respiratory and gastrointestinal infection rates.

9. Physiotherapy and musculoskeletal rehabilitation
Long hospital stays, steroids, and chronic illness can weaken muscles and bones. Physiotherapy uses stretching, balance work, and strength exercises to maintain mobility, prevent contractures, and reduce pain. By improving physical fitness, it helps patients better tolerate infections, intensive treatments like HSCT, and daily activities, increasing independence and quality of life.

10. Gut-directed lifestyle measures
For patients with autoimmune enteropathy, small but frequent meals, adequate hydration, and avoidance of irritating foods (e.g., very spicy, high-fat, or contaminated food) help reduce diarrhea and abdominal pain. These steps work mechanically by limiting triggers that worsen inflammation. They are usually combined with medical therapy but can significantly improve daily comfort and nutritional status.

11. Structured school and work planning
Personalized education or work plans (home schooling options, flexible hours, remote learning or working) help patients maintain education and employment while attending frequent medical visits. Reducing physical exposure to crowded settings during high-risk periods can lower infection rates and stress, while still supporting social and cognitive development.

12. Sleep hygiene programs
Good sleep is vital for immune regulation. Setting regular bedtimes, reducing screen use before sleep, and optimizing bedroom comfort can improve sleep quality. Restorative sleep supports T-cell function and lowers inflammation, which may help the body cope better with infections and autoimmune activity associated with LRBA deficiency.

13. Stress-management and relaxation techniques
Chronic illness often causes ongoing stress, which can suppress parts of the immune system and worsen symptoms. Techniques such as mindfulness, breathing exercises, and guided relaxation are safe, non-drug methods that may reduce stress hormones, improve mood, and support better adherence to medical care.

14. Sun protection and skin-cancer vigilance
Some immunosuppressive drugs and chronic immune activation may increase skin-cancer risk. Using sunscreen, protective clothing, and avoiding intense midday sun are simple physical measures that reduce UV damage to skin cells. Regular dermatology checks allow early detection and treatment of suspicious lesions.

15. Infection-focused travel planning
Travel plans should include vaccination checks, carrying medical summaries, avoiding high-risk food and water, and knowing where expert medical care is available. This preventive planning reduces the chance of severe infections in areas with unfamiliar pathogens and limited healthcare access. It also ensures quick treatment if fever or diarrhea develops.

16. Early physiologic oxygen and respiratory support when needed
For serious lung infections or chronic lung damage, timely use of oxygen, non-invasive ventilation, or high-flow nasal cannula in hospital can prevent exhaustion and respiratory failure. These supportive technologies do not treat the immune defect but buy time while antibiotics or other drugs work, protecting vital organs like the brain and heart.

17. Infection source control (e.g., drainage of abscesses)
When localized infections such as abscesses or empyema occur, imaging-guided drainage or surgical removal of infected tissue is crucial. Physically removing pus decreases bacterial load and helps antibiotics work better, preventing sepsis and chronic complications.

18. Rehabilitation after HSCT
Patients undergoing HSCT for LRBA deficiency need intensive physical, nutritional, and psychological rehabilitation afterward. Rehab supports engraftment recovery, reduces muscle loss, and helps manage graft-versus-host disease–related disability. Structured rehabilitation improves the chance of returning to school, work, and normal daily life after this demanding treatment.

19. Genetic counseling for family members
As LRBA deficiency is usually autosomal recessive, genetic counseling helps families understand carrier status, recurrence risk, and options for prenatal or preimplantation diagnosis. While it does not treat the patient directly, counseling guides informed reproductive choices and helps identify other affected relatives earlier, allowing prompt treatment.

20. Multidisciplinary case conferences
Regular meetings between immunologists, hematologists, gastroenterologists, pulmonologists, dietitians, and psychologists allow a unified care plan. This coordination prevents conflicting treatments, improves monitoring of side effects, and ensures that non-drug supports are properly combined with medications and HSCT strategies.

Drug treatments

Important: All medicines below must be prescribed and monitored by specialists. Doses and timing are individualized; never start, stop, or change these drugs without medical supervision.

1. Intravenous or subcutaneous immunoglobulin (IVIG/SCIG)
Immunoglobulin replacement provides pooled antibodies from healthy donors to compensate for low or dysfunctional antibodies in LRBA deficiency. It reduces serious bacterial infections, especially in the lungs and sinuses, and may help control autoimmune symptoms in some patients. IVIG/SCIG is typically given every 3–4 weeks (IV) or weekly/biweekly (SC), with dose adjusted by body weight, infection history, and IgG levels. Common side effects include infusion reactions and headache.

2. Systemic glucocorticoids (e.g., prednisone, methylprednisolone)
Steroids are broad anti-inflammatory and immunosuppressive drugs used to control autoimmune cytopenias, enteropathy, and organ inflammation. They work by blocking many inflammatory pathways and reducing immune cell activity. While often effective in the short term, long-term use can cause weight gain, high blood pressure, diabetes, osteoporosis, infection risk, and mood changes, so physicians try to taper to the lowest effective dose or replace with targeted agents.

3. Abatacept (CTLA-4-Ig)
Abatacept is a fusion protein that copies the CTLA-4 “brake” missing in LRBA deficiency, blocking excessive T-cell activation by binding CD80/CD86 on antigen-presenting cells. Long-term studies show that abatacept can control autoimmunity, lymphoproliferation, and gut disease in many LRBA-deficient patients and is often used as long-term targeted therapy or as a bridge to HSCT. According to FDA labeling, it is given as weight-based IV infusions or subcutaneous injections for diseases like rheumatoid arthritis and juvenile idiopathic arthritis, with infusion-related reactions and infection risk as key side effects.

4. Sirolimus (rapamycin)
Sirolimus is an mTOR inhibitor that reduces T-cell activation and proliferation. In LRBA deficiency, it has been used for autoimmune enteropathy, lymphoproliferation, and cytopenias, sometimes reducing steroid needs. It is taken orally, with dosing guided by blood drug levels and kidney function. Side effects include mouth ulcers, high cholesterol, delayed wound healing, and infection risk. Evidence shows sirolimus can significantly lower disease activity scores in LRBA deficiency when carefully monitored.

5. Rituximab
Rituximab is a monoclonal antibody that targets CD20 on B cells, leading to their depletion. In LRBA deficiency it is used to treat autoimmune cytopenias and some autoimmune manifestations by removing autoreactive B cells. FDA labels for indications such as lymphoma and rheumatoid arthritis describe IV infusions given in courses every 1–2 weeks initially, with infrequent maintenance dosing; main side effects include infusion reactions, low immunoglobulin levels, and rare severe infections such as PML.

6. Azathioprine
Azathioprine is a classic steroid-sparing immunosuppressant that interferes with DNA synthesis in rapidly dividing immune cells. It may be used in LRBA deficiency to control autoimmune cytopenias or gut disease when steroids alone are not enough. Dosing is weight-based and adjusted to blood counts and liver function, with risks of bone-marrow suppression, infections, liver toxicity, and rare malignancies. Because patients already have immune problems, careful monitoring is essential.

7. Mycophenolate mofetil (MMF)
MMF blocks purine synthesis in lymphocytes and is widely used in autoimmune diseases and after transplantation. In LRBA deficiency it can help control autoimmune cytopenias, enteropathy, and other immune-mediated organ damage. It is taken orally in divided doses, with common side effects including diarrhea, low white-cell counts, and increased risk of infections; pregnancy avoidance is important because of teratogenicity.

8. Calcineurin inhibitors (cyclosporine, tacrolimus)
These drugs inhibit calcineurin, a key enzyme for T-cell activation. They may be used in selected LRBA-deficient patients with severe autoimmunity or after HSCT to prevent graft-versus-host disease. Doses are guided by drug level monitoring to avoid kidney toxicity, high blood pressure, and neurologic side effects. They provide strong immunosuppression but must be balanced against infection risks.

9. Anti-TNF agents (e.g., infliximab)
Anti-TNF biologics block tumor necrosis factor-alpha, a major inflammatory cytokine. Some LRBA-deficient patients with severe autoimmune enteropathy or arthritis have been treated with infliximab or similar agents when other drugs failed. These agents are IV or subcutaneous and carry risks of serious infections, reactivation of tuberculosis, and rare demyelinating disease. Use requires pre-screening for latent infections and careful follow-up in a specialized center.

10. Prophylactic antibacterial antibiotics (e.g., trimethoprim-sulfamethoxazole)
Low-dose daily or intermittent prophylactic antibiotics can reduce bacterial infections like pneumonia and Pneumocystis jirovecii pneumonia. They work by keeping bacterial numbers low so the impaired immune system is not overwhelmed. Side effects depend on the drug and may include rash, bone-marrow suppression, or kidney issues, so regular blood tests are needed.

11. Antifungal prophylaxis
In patients with severe T-cell defects, long-term steroid use, or HSCT, antifungal drugs such as azoles may be given to prevent invasive fungal infections of the lungs or bloodstream. They inhibit fungal cell-membrane synthesis. However, they can interact with many other drugs and may cause liver enzyme elevation, so they are reserved for those at highest risk.

12. Antiviral prophylaxis (e.g., acyclovir)
Herpes family viruses can cause severe disease in immunocompromised patients, especially after HSCT. Low-dose antivirals like acyclovir may be used preventively in high-risk periods. These medicines block viral DNA replication, reducing outbreaks and systemic infection; kidney function and hydration are monitored to minimize toxicity.

13. Granulocyte colony-stimulating factor (G-CSF)
Where LRBA deficiency is associated with neutropenia or prolonged infection, G-CSF (e.g., filgrastim) may be used to stimulate bone marrow production of neutrophils. This biologic drug binds to the G-CSF receptor on precursors, speeding neutrophil maturation and release. It is given by injection, with bone pain and high white-cell counts as common side effects.

14. Proton-pump inhibitors or gut-protective drugs
To protect the stomach and intestines during high-dose steroids or NSAID use, proton-pump inhibitors may be prescribed. They reduce stomach acid, lowering the risk of ulcers or bleeding. Because long-term use may alter microbiota and nutrient absorption, doctors aim for the shortest effective duration.

15. Antidiarrheal agents (with caution)
In cases of autoimmune enteropathy, selected antidiarrheal medications may be used, always together with evaluation for infection. They slow bowel movement to reduce fluid loss and improve comfort, but if infection is present they may worsen disease, so medical supervision and stool tests are essential.

16. Biologic GVHD prophylaxis/treatment after HSCT
For LRBA patients undergoing HSCT, additional biologics (such as abatacept or other targeted drugs) may be used to prevent or treat graft-versus-host disease. These reduce abnormal donor T-cell reactions against tissues. Benefits must be weighed against higher infection risk, and therapy is always individualized.

17. Broad-spectrum IV antibiotics for severe infections
When sepsis or severe pneumonia occurs, prompt IV broad-spectrum antibiotics are life-saving. They rapidly decrease bacterial load while doctors refine treatment based on cultures. In LRBA deficiency, threshold to start IV antibiotics should be low, because infections can progress quickly. Side effects include allergic reactions, kidney injury, and microbiome disruption.

18. Immunoglobulin during HSCT (supportive)
During and after HSCT, IVIG is often continued or temporarily intensified to protect against infections while new donor immune cells engraft. This supportive use follows the same mechanism as standard IVIG but in a higher-risk period, aiming to bridge the gap until immune recovery.

19. Thromboprophylaxis (anticoagulants) when indicated
Some LRBA patients may be at risk of blood clots due to inflammation, immobilization, or central lines. Low-dose anticoagulants can prevent clots in high-risk settings like HSCT or prolonged hospitalization. As they thin the blood, bleeding risk must be closely monitored, and they are used only when clear benefit is expected.

20. Pain-control and symptom-relief medicines
Analgesics, anti-nausea drugs, and other supportive medications are important to keep patients comfortable enough to eat, sleep, and participate in rehabilitation. Symptom control does not treat the immune defect directly but improves overall function and adherence to complex treatment plans. Doses are chosen to minimize side effects, especially on kidneys, liver, and bone marrow.

Dietary molecular supplements (adjuncts, not cures)

Supplements should only be used after discussion with the treating team, especially because some interact with immunosuppressive drugs.

1. Vitamin D
Vitamin D supports bone health and modulates immune responses by acting on T and B cells and antimicrobial peptides. Many patients with chronic illness are deficient. Correcting low vitamin D, usually with daily or weekly oral doses chosen by blood levels, may reduce infection risk and bone fragility from steroids. Excessive doses can cause high calcium and kidney problems, so regular monitoring is needed.

2. Omega-3 fatty acids (fish oil)
Omega-3 fatty acids from fish oil have anti-inflammatory effects by changing cell-membrane lipid composition and reducing production of pro-inflammatory eicosanoids. In LRBA deficiency, they may modestly help joint pain, gut inflammation, and cardiovascular risk, especially in long-term steroid users. Typical regimens use divided daily doses with food; side effects include fishy aftertaste and, at high doses, increased bleeding tendency.

3. Zinc
Zinc is crucial for normal T-cell and neutrophil function. Deficiency, common in chronic diarrhea and malnutrition, can worsen infection susceptibility. Carefully dosed zinc supplements can restore levels and support immune responses, but excessive zinc may cause copper deficiency and anemia. Short- to medium-term supplementation is usually guided by blood tests.

4. Selenium
Selenium is a trace element involved in antioxidant enzymes such as glutathione peroxidase. Adequate selenium helps limit oxidative stress during inflammation and infection. In patients with poor nutrition, cautious supplementation may support immune function; however, high doses can be toxic (hair loss, nail changes, neuropathy), so dosing must remain within safe ranges.

5. Probiotics (with immunologist approval)
Selected probiotic strains may help restore a healthier gut microbiome, which can indirectly regulate immune responses and improve barrier function. In LRBA deficiency with autoimmune enteropathy, probiotics are considered carefully because of a theoretical risk of bloodstream infection from live organisms in severely immunocompromised patients. Decisions are individualized, often favoring well-studied strains and close monitoring.

6. Folate and vitamin B12
Folate and B12 are needed for DNA synthesis and red blood cell production. Chronic inflammation, malabsorption, and certain drugs (like azathioprine) can lower levels, worsening anemia and fatigue. Replacing documented deficiencies by oral or injectable forms supports bone marrow and reduces some side effects of immunosuppressants. Over-replacement without need is usually avoided.

7. Iron (only if iron-deficiency anemia is proven)
Iron supplements are used when blood tests show iron-deficiency anemia, which may occur from chronic gut blood loss or malnutrition. Iron restores hemoglobin, improving oxygen delivery and energy. However, unnecessary iron can feed some bacteria and cause digestive upset, so physicians confirm the cause of anemia first and monitor ferritin and transferrin saturation.

8. Antioxidant vitamins (C and E in moderate doses)
Vitamins C and E help neutralize free radicals produced during chronic inflammation and infection. Moderate supplementation through diet or small doses may support tissue repair and immune cell function, but very high doses could interfere with some chemotherapy or transplantation regimens, so timing and dose must be discussed with the care team.

9. Glutamine
Glutamine is an amino acid used as fuel by intestinal cells and some immune cells. Supplemental glutamine may help maintain gut barrier integrity and reduce muscle breakdown during serious illness or after HSCT, although evidence is mixed. If used, dosing is tailored to nutritional status and kidney function.

10. Multinutrient medical nutrition formulas
Some patients need special oral or tube-feeding formulas enriched with protein, calories, vitamins, and trace elements. These products provide balanced nutrition when normal eating is not enough due to diarrhea, swallowing problems, or fatigue. Adequate nutrition is a foundation for all other therapies, supporting wound healing, immune cell production, and recovery after HSCT.

Immunity-boosting / regenerative / stem-cell–related treatments

1. Allogeneic hematopoietic stem cell transplantation (HSCT)
HSCT replaces the patient’s defective immune system with donor blood-forming stem cells from bone marrow, peripheral blood, or cord blood. It is currently the only treatment with curative potential for severe LRBA deficiency, leading to long-term remission of infections and autoimmunity in many patients, although transplant-related mortality and graft-versus-host disease remain important risks. Conditioning chemotherapy prepares the marrow for engraftment. HSCT should be done only at experienced centers with careful patient selection.

2. Abatacept as long-term targeted immune “reset”
Although listed above as a drug, abatacept deserves mention here because it functionally replaces the missing CTLA-4 “brake,” restoring a more balanced immune state. Longitudinal studies show abatacept can dramatically improve disease scores and sometimes delay or avoid HSCT in selected patients. It does not fix the gene but partially normalizes immune signaling, acting as a physiologic immune modulator rather than broad suppression.

3. Post-HSCT immune reconstitution protocols
After HSCT, careful tapering of immunosuppression, scheduled vaccinations, and close monitoring of T-cell and B-cell recovery help build a new, functional immune system. This “guided re-education” of immunity supports long-term cure and reduces relapse of autoimmunity or infections. The exact protocol depends on donor type, conditioning regimen, and complications such as graft-versus-host disease.

4. Research-stage gene-therapy approaches (future direction)
For some inborn errors of immunity, gene therapy using viral vectors or gene editing in autologous stem cells is already in clinical use. For LRBA deficiency, gene-therapy strategies are still experimental, but the basic principle is to correct the faulty LRBA gene in the patient’s own stem cells, then re-infuse them to create a self-tolerant, functional immune system without graft-versus-host disease. Any such therapy must be done in controlled clinical trials.

5. G-CSF-driven marrow support
G-CSF does not correct LRBA deficiency but can temporarily increase neutrophil counts, helping the body fight bacterial infections or recover from chemotherapy used in HSCT conditioning. This growth factor acts directly on stem-cell progenitors in the bone marrow, promoting differentiation into mature neutrophils. It is used intermittently under hematology supervision.

6. Supportive therapies promoting tissue repair (e.g., nutritional and rehab “regeneration”)
Nutritional rehabilitation, physical therapy, and organ-specific supportive care after severe infections or HSCT create a “regenerative environment” where muscles, bones, lungs, and gut can recover. While not stem-cell drugs in the narrow sense, they are essential for full functional regeneration after disease control or curative therapy.

Surgeries and procedures

1. Hematopoietic stem cell transplantation procedure
HSCT itself is a major procedure involving central line placement, conditioning chemotherapy, stem cell infusion, and prolonged hospital stay. It is performed to cure or markedly improve severe LRBA deficiency with uncontrolled infections or autoimmunity. The goal is long-term immune reconstitution, accepting short-term risks such as infections, organ toxicity, and graft-versus-host disease.

2. Central venous catheter or port insertion
Because patients often require repeated IVIG, biologics, chemotherapy, or HSCT infusions, a central venous catheter or implantable port is frequently placed surgically. This allows safe, repeated access to the bloodstream with less pain and fewer needle sticks, but carries infection and clotting risks, so meticulous care is essential.

3. Splenectomy (in selected severe autoimmune cytopenias)
In LRBA deficiency with life-threatening autoimmune destruction of blood cells not responding to medicine, removal of the spleen may be considered. Splenectomy can reduce blood cell destruction and transfusion needs, but it further increases susceptibility to encapsulated bacteria, so lifelong vaccines and antibiotic precautions are needed. It is used very selectively, usually in older patients or those with high surgical tolerance.

4. Surgical management of bowel complications
Severe autoimmune enteropathy or long-standing inflammation can rarely cause strictures, perforation, or bleeding that require surgery. Operations may remove the damaged section of bowel or control bleeding. Surgery does not cure the immune disease, so medical therapy continues afterward to prevent new lesions.

5. Surgical treatment of localized lung disease (e.g., resection of destroyed lobe)
In extreme cases of localized, destroyed lung segments with recurrent infection and bleeding, lung surgery such as lobectomy may be needed. Removing the non-functional, infected tissue can reduce infection burden and improve overall respiratory function, but it is a last-resort measure and requires careful pre-operative assessment and postoperative pulmonary rehab.

Key prevention strategies

1. Early diagnosis and genetic testing for at-risk families
Prompt recognition of LRBA deficiency and confirmation by genetic testing prevent years of uncontrolled infections and autoimmunity, allowing early protective measures and timely consideration of abatacept or HSCT.

2. Personalized infection-prevention and vaccination plans
As described above, tailored hygiene and vaccine strategies reduce exposure and severity of infections, which are major causes of damage and hospitalization.

3. Avoidance of live vaccines without immunology approval
Live vaccines like oral polio or certain measles vaccines can cause disease in people with combined immunodeficiency, so they are avoided unless an immunologist confirms safety after immune recovery, such as post-HSCT.

4. Rapid treatment of any fever or infection signs
Families are taught to seek medical care quickly for fever, cough, breathing difficulty, or new pain. Early antibiotics and supportive care can prevent sepsis, organ failure, and long-term damage.

5. Smoking avoidance and clean air
Avoiding active and passive smoke and improving home ventilation help protect lungs from chronic damage and make infections less severe.

6. Safe food and water practices
Proper cooking, avoiding raw meat or eggs, washing fruits and vegetables, and using safe drinking water reduce gut infections that can be dangerous in LRBA deficiency.

7. Regular follow-up in an immunology center
Scheduled visits, blood tests, and imaging allow early detection of new autoimmune problems, lung damage, or treatment side effects, so therapy can be adjusted before severe complications appear.

8. Pre-HSCT optimization (nutrition, infection control)
For those heading to HSCT, improving nutritional status, controlling existing infections, and stabilizing organ function reduce transplant-related mortality and improve engraftment success.

9. Family carrier testing and counseling
Testing siblings and parents for LRBA mutations helps identify affected family members early and prevents unexpected severe disease in relatives. It also helps families plan future pregnancies using informed choices.

10. Education about drug adherence and side-effect reporting
Teaching patients and caregivers to take medicines as prescribed and report side effects quickly prevents both disease flares and drug-related harm, making long-term treatment safer and more effective.

When to see a doctor (or go to emergency care)

People with LRBA deficiency should contact a doctor urgently or go to emergency care for fever above local emergency thresholds, difficulty breathing, rapid breathing, chest pain, severe abdominal pain, blood in stool or vomit, seizures, confusion, very low energy, or signs of sepsis such as cold extremities or fast heart rate. They should also seek prompt review if bruising, nosebleeds, or paleness suggest anemia or low platelets, or if diarrhea, weight loss, or joint swelling worsen. Regular planned follow-ups with an immunologist and hematologist are essential even when feeling well, to adjust IVIG, abatacept, or other therapies and to discuss HSCT timing.

Simple diet eat and avoid tips

1. Eat: well-cooked lean proteins (fish, chicken, eggs) to support immune-cell and muscle repair.

2. Eat: a variety of fruits and vegetables that are thoroughly washed and, when needed, peeled or cooked to provide vitamins, minerals, and fiber for gut and immune health.

3. Eat: whole grains and complex carbohydrates for steady energy during chronic illness and recovery.

4. Eat: probiotic-containing foods (like yogurt with live cultures) only if approved by the medical team, especially in patients on heavy immunosuppression or early after HSCT.

5. Eat: small, frequent meals and plenty of fluids to fight diarrhea and prevent dehydration in enteropathy.

6. Avoid: raw or undercooked meat, fish, eggs, and unpasteurized dairy to lower risk of bacterial and parasitic gut infections.

7. Avoid: street food or doubtful water sources when hygiene cannot be guaranteed, especially during travel or neutropenia.

8. Avoid: very high-sugar, highly processed foods that add calories but few nutrients and may worsen weight gain from steroids.

9. Avoid: large amounts of herbal supplements or “immune boosters” sold online without discussing them with doctors, because some interact with immunosuppressive drugs or may stimulate autoimmunity.

10. Avoid: alcohol and smoking in older patients, as these damage liver, lungs, and bone marrow, which are already stressed by disease and treatment.

Frequently asked questions (FAQs)

1. Is LRBA deficiency always life-threatening?
LRBA deficiency is serious, but the course varies. Some patients have milder disease controlled with IVIG and abatacept, while others develop severe infections and autoimmunity needing HSCT. Early diagnosis, careful monitoring, and timely targeted therapy can greatly improve outlook and reduce life-threatening complications.

2. Can LRBA deficiency be cured?
At present, the only treatment with curative potential is allogeneic HSCT, which can replace the defective immune system with healthy donor cells. Many transplanted patients achieve long-term remission, but HSCT carries risks and is not needed or suitable for everyone. Other therapies like abatacept are disease-controlling but not curative.

3. How is LRBA deficiency different from CVID or CTLA-4 haploinsufficiency?
LRBA deficiency often looks like a common variable immunodeficiency (CVID) with added autoimmunity and lymphoproliferation, but the genetic cause is biallelic LRBA mutations leading to defective CTLA-4 recycling. CTLA-4 haploinsufficiency involves a different gene with overlapping but distinct features. Genetic testing is needed to distinguish them and select therapies like abatacept or HSCT.

4. Why is abatacept so important in LRBA deficiency?
Because LRBA normally helps protect CTLA-4 inside cells, its absence means CTLA-4 is lost too quickly, and T cells stay overactive. Abatacept is a CTLA-4-Ig fusion that restores the missing inhibitory signal, calming the immune system more precisely than broad steroids. Many studies show significant improvement in disease activity and quality of life with long-term abatacept.

5. Will I always need IVIG?
Many patients require long-term IVIG or SCIG because their B-cell function and antibody production remain impaired. Some who undergo successful HSCT may eventually stop IVIG when donor-derived immunity is strong and stable. Decisions are based on infection history, IgG levels, and vaccine responses.

6. Can children with LRBA deficiency attend school?
With careful infection-prevention planning, many children can attend school, at least part-time. Some may need home schooling during very high-risk periods (severe neutropenia, early post-HSCT). Collaboration between families, doctors, and schools helps balance safety with normal development and social life.

7. Is pregnancy possible in LRBA deficiency?
Some women with primary immunodeficiencies have successful pregnancies, but LRBA deficiency plus immunosuppressive drugs or HSCT history makes planning more complex. Pregnancy should be managed in a high-risk obstetric and immunology setting, with pre-pregnancy counseling about medication safety and genetic risks for the child.

8. Do siblings need testing if one child has LRBA deficiency?
Yes, because LRBA deficiency is usually autosomal recessive, siblings may be affected or carriers even if they appear healthy. Genetic testing allows early diagnosis, closer monitoring, and informed family planning.

9. Can lifestyle changes alone control LRBA deficiency?
No. Healthy food, hygiene, exercise, and stress management are very helpful but cannot correct the genetic immune defect. Medical treatment such as IVIG, abatacept, or HSCT is usually necessary to prevent organ damage and life-threatening infections.

10. How often are check-ups needed?
Frequency depends on disease severity and treatments. Many patients are reviewed every 1–3 months, more often after starting a new biologic or around HSCT. Stable patients may later be seen twice a year, but urgent visits are needed any time new serious symptoms appear.

11. What are the main risks of HSCT in LRBA deficiency?
Risks include transplant-related mortality from infections, organ toxicity, graft-versus-host disease, and graft failure. However, expert centers report good survival and often complete remission in patients with high disease burden, especially when performed before severe organ damage.

12. Can LRBA deficiency affect hearing or other organs beyond the immune system?
LRBA is expressed in many tissues; the main known effects are immune-related, but chronic inflammation, infections, and autoimmunity can indirectly damage lungs, gut, liver, joints, and sometimes the nervous system. Regular multi-organ screening helps detect these complications early.

13. Are all LRBA mutations equally severe?
No. Some mutations cause complete loss of LRBA protein, while others allow partial function. Clinical severity can still vary even with similar mutations, likely due to modifying genes and environmental factors. This is why treatment plans are highly individualized rather than based only on genetic results.

14. Why do some patients still receive steroids if biologics exist?
Steroids act quickly and are widely available, so they are often used to control acute flares or while waiting for targeted drugs or HSCT. The goal is to switch to safer long-term agents like abatacept, sirolimus, or other steroid-sparing drugs as soon as possible to minimize long-term side effects.

15. What should families remember most?
The key messages are: LRBA deficiency is serious but increasingly treatable; early diagnosis and specialist care matter; targeted therapy like abatacept and, when needed, HSCT can change the course of disease; and day-to-day measures—good nutrition, infection prevention, and mental health support—are vital parts of care. Families should maintain close partnership with their immunology team and seek help quickly for any worrying symptoms.

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: February 13, 2025.