Combined Immunodeficiency Due to LRBA Deficiency

Combined immunodeficiency due to LRBA deficiency is a rare inherited disease where a mistake in a single gene (the LRBA gene) makes the immune system weak and badly controlled at the same time. In this condition, the body cannot make a normal, balanced immune response, so people get many infections and also develop autoimmune problems, where the immune system attacks the body’s own organs. Doctors call this a “primary immunodeficiency” and also an “immune dysregulation” disorder, because both infection risk and autoimmunity are common.

In LRBA deficiency, the main problem is that the LRBA protein is missing or works very poorly. This protein helps immune cells control “checkpoints” that stop them from staying switched on for too long. When LRBA is missing, important brake molecules, especially CTLA-4 on T cells, are not kept safely inside the cell and cannot move correctly to the cell surface. As a result, immune cells stay overactive, causing chronic inflammation and autoimmune disease, even while the person is also prone to infections.

People with this disease often show problems early in life, such as repeated chest infections, chronic diarrhea, poor weight gain, and autoimmune problems like low blood counts or bowel inflammation. However, some people are diagnosed only in teenage years or adulthood, which shows that the same gene problem can cause mild or severe illness in different families or even in different members of the same family.

Other names

Doctors and researchers have used several names for this same condition. One common name is “combined immunodeficiency due to LRBA deficiency,” which highlights that both T cells and B cells do not work properly. Another name is “common variable immunodeficiency type 8 (CVID-8) with autoimmunity,” because many patients look like they have common variable immune deficiency plus strong autoimmune features.

The disease is also called “LRBA deficiency,” “LPS-responsive beige-like anchor (LRBA) deficiency,” or “syndromic autoimmune enteropathy due to LRBA deficiency,” especially when severe bowel inflammation (enteropathy) is one of the main problems. All these names describe the same core issue: loss-of-function changes (mutations) in the LRBA gene that disturb immune balance and cause a mixture of infections, autoimmunity, and chronic inflammation.

In summary, this condition is an autosomal recessive, monogenic primary immunodeficiency. Most patients have mutations in both copies of the LRBA gene (one from each parent), leading to reduced immunoglobulins, abnormal T-cell and B-cell function, enlarged lymph nodes or spleen, and a variety of autoimmune complications.

Types

Although there is no strict official “type” classification, patients with LRBA deficiency can be grouped into several clinical patterns. These patterns help doctors recognize the disease, because different people may show different main problems even with the same gene defect.

1. Infection-predominant type – In some patients, repeated bacterial and viral infections are the main issue. They often have pneumonia, sinus infections, ear infections, and sometimes serious bloodstream infections. Autoimmune problems may be mild or appear later.

2. Autoimmunity-predominant type – Other patients mainly show autoimmune diseases, such as autoimmune low platelets, autoimmune low red cells, autoimmune thyroid disease, or type 1 diabetes, sometimes before many infections are seen. Doctors may first think of autoimmune illness rather than immunodeficiency in these patients.

3. Enteropathy-predominant type – Many people with LRBA deficiency have severe, long-lasting diarrhea, weight loss, and poor nutrition due to autoimmune inflammation of the gut. These patients resemble those with inflammatory bowel disease or autoimmune enteropathy, and the gut symptoms are often the most disabling part.

4. Lymphoproliferative or ALPS-like type – Some patients mainly show enlarged lymph nodes, enlarged spleen, and signs of too many lymphocytes, similar to autoimmune lymphoproliferative syndrome (ALPS). They may have chronic fevers, night sweats, and cytopenias due to spleen overactivity and immune overgrowth.

5. IPEX-like immune dysregulation type – A subgroup resembles IPEX syndrome, with early-onset enteropathy, eczema, endocrinopathies, and severe autoimmunity, because LRBA deficiency disrupts regulatory T cells and CTLA-4 function in a similar way.

6. Cancer-associated type – A few reported patients with LRBA deficiency have developed cancers such as gastric adenocarcinoma, likely due to long-standing inflammation and chronic immune disturbance, which increase malignancy risk over time.

7. Early-onset severe type – Some children present in infancy or early childhood with very severe infections, uncontrollable diarrhea, and life-threatening autoimmunity, needing strong treatments such as hematopoietic stem cell transplantation.

8. Late-onset milder type – Other patients are not diagnosed until adolescence or adulthood, with milder infections but chronic autoimmune features such as cytopenias or inflammatory bowel disease, showing that disease severity can vary widely even within LRBA deficiency.

Causes

The root cause of combined immunodeficiency due to LRBA deficiency is genetic, but many linked mechanisms and factors explain why the immune system becomes both weak and overactive. Each point below describes one aspect that “causes” or drives the disease manifestations.

1. Biallelic LRBA loss-of-function mutations – Most patients have harmful changes in both copies of the LRBA gene, leading to little or no working LRBA protein. Without this protein, key control pathways in immune cells fail, causing immune deficiency and dysregulation.

2. Autosomal recessive inheritance – The disease is usually passed in an autosomal recessive way, meaning each parent carries one faulty LRBA gene but is healthy, while the child inherits both faulty copies and becomes sick. This inheritance pattern explains why the disease often appears in families with more than one affected child.

3. Consanguinity (related parents) – Many reported families have consanguineous parents (for example, cousins), which increases the chance that both parents carry the same rare LRBA mutation. This social and genetic factor makes the disease more common in some regions.

4. Defective CTLA-4 trafficking and recycling – LRBA helps protect CTLA-4, an important “brake” receptor on T cells, from being destroyed inside the cell. When LRBA is missing, CTLA-4 is broken down faster, so the brake does not work, and T cells stay too active, driving autoimmunity.

5. Impaired regulatory T-cell survival – Regulatory T cells (Tregs) normally keep other T cells under control. In LRBA deficiency, Tregs have abnormal metabolism and increased cell death, so they are fewer and weaker. This loss of Treg function causes immune dysregulation and organ-specific autoimmune disease.

6. Abnormal B-cell signaling and NF-κB control – LRBA participates in signaling pathways inside B cells, including NF-κB activation. When LRBA is defective, B cells may not respond normally to stimulation and cannot build a proper antibody response, worsening the immunodeficiency.

7. Reduced immunoglobulin production (CVID-like) – Many patients have low levels of IgG, IgA, and sometimes IgM, and poor response to vaccines. This antibody deficiency makes infections more frequent and severe, similar to common variable immune deficiency.

8. T-cell lymphopenia or functional defect – Some individuals have reduced numbers of T cells, or T cells that do not proliferate or signal normally. This weakens cellular immunity, allowing viral, fungal, and opportunistic infections.

9. B-cell lymphopenia and low memory B cells – Patients often have reduced memory B cells that normally remember past infections and vaccines. Without them, the body cannot mount a fast secondary response, and infections may relapse or become chronic.

10. Chronic immune activation and lymphoproliferation – Loss of CTLA-4 control and Treg function leads to ongoing immune activation and overgrowth of lymphocytes. This chronic activation damages tissues, enlarges lymph nodes and spleen, and contributes to cytopenias and cancer risk.

11. Autoantibody formation – Because the tolerance system is weak, the immune system can create antibodies that attack red cells, platelets, endocrine glands, and other tissues. These autoantibodies cause many autoimmune complications seen in LRBA deficiency.

12. Gut barrier breakdown and microbiome changes – Chronic gut inflammation and infections in these patients disturb the intestinal barrier and gut bacteria balance. This allows more triggers to enter the body and fuels a vicious cycle of inflammation and autoimmunity.

13. Environmental infections as triggers – Viral and bacterial infections can further disturb the fragile immune balance in LRBA deficiency. Each infection may trigger flares of autoimmunity or lymphoproliferation on top of the underlying genetic defect.

14. Delayed diagnosis and treatment – If the condition is not recognized early, repeated infections and ongoing inflammation can cause permanent lung damage, chronic diarrhea with malnutrition, and organ damage, which then become part of the disease picture.

15. Coexisting variants in other immune genes – In some patients, variants in additional immune-related genes may modify the disease, making symptoms more severe, milder, or different from typical LRBA deficiency. This genetic background can act as a co-cause of the final clinical picture.

16. Epigenetic and regulatory effects on LRBA expression – Even with the same mutation, factors that change how much LRBA mRNA or protein is made can influence disease severity. Lower residual expression worsens immune deregulation, while partial expression may lead to milder disease.

17. Malnutrition and micronutrient deficiency – Long-standing diarrhea and poor intake can lead to malnutrition, which further weakens immune function. Although this does not cause LRBA deficiency itself, it becomes an important co-factor in the severity of infections and recovery.

18. Chronic tissue inflammation and organ damage – Ongoing immune attacks on gut, liver, lungs, and endocrine organs cause scarring and functional loss. Once organs are damaged, they cannot work normally, and this damage then becomes a cause of many clinical symptoms.

19. Increased cancer risk from long-term immune disturbance – Constant inflammation, DNA damage from reactive molecules, and poor immune surveillance (reduced ability to kill cancer cells) together increase the risk of malignancies such as gastric cancer in a subset of patients.

20. Family-specific founder mutations – In some communities, a particular LRBA mutation is shared by many related families. This founder effect means the same genetic cause leads to multiple affected individuals and a higher apparent local disease rate.

Symptoms

Symptoms vary a lot, but most patients show a combination of repeated infections, autoimmune disease, and problems in several organs.

1. Recurrent respiratory infections – Many patients have frequent pneumonia, bronchitis, sinus infections, and ear infections. These infections may take longer than usual to clear, and repeated episodes can leave permanent lung damage such as bronchiectasis.

2. Chronic diarrhea and gut inflammation – Persistent loose stools, abdominal pain, and blood or mucus in the stool are common. The gut lining becomes inflamed in a way similar to inflammatory bowel disease, and children may fail to gain weight or grow normally because they cannot absorb nutrients well.

3. Failure to thrive and poor growth – Because of infections and gut disease, many children do not grow as expected. Their height and weight fall below normal curves, and puberty may be delayed. This is often one of the early signs that makes doctors suspect an underlying immune problem.

4. Autoimmune cytopenias – The immune system may attack blood cells, leading to autoimmune hemolytic anemia (low red blood cells), immune thrombocytopenia (low platelets), or neutropenia (low neutrophils). These problems cause tiredness, pale skin, easy bruising, or frequent infections.

5. Enlarged lymph nodes and spleen – Many patients have big lymph nodes in the neck, armpits, or groin, and an enlarged spleen. This lymphoproliferation reflects chronic immune activation and sometimes contributes to low blood counts due to spleen overactivity.

6. Asthma-like symptoms and chronic cough – Wheezing, breathlessness, and chronic cough can occur, partly from repeated infections and partly from airway inflammation or asthma-like disease. Over time, lung function may slowly decline.

7. Autoimmune endocrine disease – Some patients develop type 1 diabetes, autoimmune thyroid disease, or other hormone problems. These appear because the misdirected immune system attacks hormone-producing organs like the pancreas or thyroid.

8. Skin rashes and dermatitis – Eczema-like rashes, urticaria, or other chronic skin changes are common. They may be due to allergy, autoimmunity, infection, or a mixture of these factors in the disturbed immune system.

9. Joint pain and arthritis – Autoimmune joint inflammation can cause pain, swelling, and stiffness, especially in the knees, ankles, or small joints of the hands. This may resemble juvenile idiopathic arthritis or other rheumatic diseases.

10. Chronic fatigue and weakness – Ongoing infections, anemia, poor sleep, and chronic inflammation all make patients feel very tired. Fatigue can strongly affect school, work, and daily life even when other symptoms are partly controlled.

11. Hepatomegaly and liver dysfunction – Some patients have enlarged liver and abnormal liver tests, due to autoimmune hepatitis, chronic inflammation, or infections involving the liver. Over time, scarring (fibrosis) may develop if inflammation is not controlled.

12. Splenomegaly-related discomfort – A very large spleen may cause pain or a feeling of fullness in the left upper abdomen, and may increase the risk of spleen rupture after trauma, so contact sports may be risky in some patients.

13. Increased risk of malignancy – A small number of patients have developed cancers, especially gastric adenocarcinoma. Signs can include weight loss, stomach pain, vomiting, or bleeding. This cancer risk reflects the long-term combination of immune deficiency, immune activation, and chronic inflammation.

14. Frequent hospitalizations and need for strong treatments – Because infections and autoimmune flares are severe, patients may need many hospital stays, intravenous antibiotics, blood transfusions, steroids, or biologic drugs. This treatment burden itself becomes a major part of the illness experience.

15. Psychosocial stress and reduced quality of life – Chronic illness, growth problems, and repeated procedures can cause anxiety, sadness, and school or work difficulties. Both patients and families often experience emotional and social stress that needs active support.

Diagnostic tests

Diagnosing combined immunodeficiency due to LRBA deficiency requires careful clinical evaluation plus specific laboratory and genetic tests. The following 20 tests are commonly used, grouped into physical exam, manual/bedside tests, lab and pathological tests, electrodiagnostic tests, and imaging tests.

1. Comprehensive physical examination – The doctor carefully checks height, weight, body proportions, vital signs, breathing pattern, abdominal organs, skin, and joints. They look for signs like small size, enlarged lymph nodes, enlarged liver or spleen, skin rashes, or clubbing of fingers, which suggest chronic immune and organ problems.

2. Growth and puberty assessment – Measuring and plotting height, weight, and body mass index on growth charts helps show if the child is failing to thrive. Checking puberty stage gives extra information about long-term disease impact on growth and hormone development.

3. Respiratory system examination – Listening to the lungs with a stethoscope can detect crackles, wheezes, or reduced breath sounds, which may suggest pneumonia, bronchiectasis, or airway obstruction from repeated infections.

4. Abdominal examination for organ enlargement – Palpating the abdomen allows the doctor to feel for enlarged liver and spleen. Organ enlargement points toward chronic inflammation, lymphoproliferation, or portal hypertension and is very common in LRBA deficiency.

5. Skin and mucosal examination – Inspecting the skin, mouth, and eyes can reveal eczema, chronic rashes, mouth ulcers, or signs of infection. These findings support the presence of immune dysfunction and ongoing inflammation.

6. Manual infection history and diary – Asking the family to keep a simple written record of infections, fevers, antibiotics, and hospital stays helps show that infections are unusually frequent or severe, supporting suspicion of a primary immunodeficiency.

7. Growth chart plotting over time – Manually drawing growth points on standardized charts over months or years gives a visual pattern of growth failure, which often points to chronic disease such as LRBA-related enteropathy and immunodeficiency.

8. Symptom and quality-of-life questionnaires – Structured questionnaires about fatigue, pain, gut symptoms, and daily function help quantify how much the disease affects life and can be repeated to monitor response to treatment over time.

9. Complete blood count with differential (CBC) – This basic blood test measures red cells, white cells, and platelets. It can show anemia, low platelets, low neutrophils, or lymphopenia, which are common in LRBA deficiency because of autoimmunity and bone marrow involvement.

10. Serum immunoglobulin levels (IgG, IgA, IgM, IgE) – Measuring antibody levels shows if there is hypogammaglobulinemia, a hallmark of the CVID-like pattern seen in many patients. Low IgG and IgA, with or without low IgM, strongly support a combined immunodeficiency.

11. Lymphocyte subset analysis by flow cytometry – This test counts different types of lymphocytes (T cells, B cells, NK cells, and their subtypes). Many patients have reduced B cells, reduced memory B cells, and abnormalities in T-cell subpopulations, which help distinguish LRBA deficiency from other immune diseases.

12. Assessment of vaccine antibody responses – Measuring specific antibodies after standard vaccines (like tetanus or pneumococcal vaccines) shows how well the immune system responds. Poor responses despite vaccination suggest a defect in antibody production typical of CVID-like immunodeficiency.

13. Autoantibody screening – Blood tests for autoantibodies (such as Coombs test for red cells, anti-platelet antibodies, anti-thyroid antibodies, or other tissue-specific antibodies) help document autoimmune cytopenias and endocrine disease that often accompany LRBA deficiency.

14. Inflammatory markers (ESR, CRP, fecal calprotectin) – Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) show systemic inflammation in blood. Fecal calprotectin measures gut inflammation and is especially helpful in monitoring LRBA-related enteropathy and inflammatory bowel disease-like symptoms.

15. Endoscopy and intestinal biopsy – Upper endoscopy and colonoscopy with biopsies are used to examine the gut mucosa directly. Biopsies may show lymphocytic infiltration, villous atrophy, and chronic inflammation, supporting autoimmune enteropathy or inflammatory bowel disease in the context of LRBA deficiency.

16. LRBA protein expression by flow cytometry or Western blot – In specialized laboratories, LRBA protein levels can be measured in immune cells. Very low or absent LRBA expression strongly suggests LRBA deficiency and directs the clinician toward genetic confirmation.

17. Genetic testing of the LRBA gene – Sequencing the LRBA gene, either alone or as part of an immunodeficiency gene panel or exome test, is the gold-standard diagnostic test. Finding two disease-causing mutations (biallelic variants) confirms the diagnosis of LRBA deficiency.

18. Electrocardiogram (ECG) – An ECG records the heart’s electrical activity and is sometimes used to monitor heart rhythm in patients receiving certain immunosuppressive drugs or who may have myocarditis or electrolyte disturbances related to severe illness. It does not diagnose LRBA deficiency itself but helps manage complications safely.

19. Electroencephalogram (EEG) when neurological symptoms occur – If seizures, unexplained loss of consciousness, or suspected central nervous system involvement appear, an EEG can detect abnormal brain electrical activity and guide further neurological evaluation in these complex patients.

20. Chest imaging (X-ray and high-resolution CT) and abdominal ultrasound – Chest X-ray and high-resolution CT scan show lung changes such as pneumonia, bronchiectasis, or interstitial disease from repeated infections and inflammation. Abdominal ultrasound images the liver, spleen, and lymph nodes, helping document organ enlargement and structural damage due to chronic immune dysregulation.

Non-pharmacological treatments

These supportive and lifestyle-based measures are essential in combined immunodeficiency due to LRBA deficiency. They should always be planned with the treating specialist. [1][2]

1. Strict infection-prevention hygiene
   Regular hand-washing with soap, alcohol hand rubs, careful coughing etiquette, and safe food and water handling lower the chance of bacteria and viruses entering the body. For LRBA deficiency, this daily hygiene routine is a simple but powerful “first shield” against recurrent infections and hospitalizations. [1][2]

2. Avoidance of crowded and high-risk environments
   During outbreaks of influenza, COVID-19, or other infections, avoiding crowded buses, markets, and poorly ventilated rooms can reduce exposure. Masks and physical distancing may further protect patients whose immune systems cannot clear germs efficiently. [1][3]

3. Safe vaccination planning (mainly inactivated vaccines)
   Inactivated vaccines (such as inactivated influenza, pneumococcal, and COVID-19 vaccines) are often recommended, while live vaccines may be avoided or delayed. Household members should be fully vaccinated so they do not bring serious infections home. Vaccine schedules must be customized by an immunologist. [1][2]

4. Early infection action plan
   Families receive written instructions on what to do if fever, cough, or diarrhea starts: when to call the doctor, when to go to the hospital, and which “rescue” antibiotics might be needed. This helps avoid delays that can turn a mild infection into sepsis. [2][3]

5. Nutrition and growth support
   Many patients have chronic diarrhea, malabsorption, and poor weight gain. Individual nutrition plans with high-energy, high-protein meals, oral supplements, or tube feeding can support growth, wound healing, and immune cell production, especially in children. [1][4]

6. Specialist gastroenterology care for enteropathy
   Autoimmune enteropathy related to LRBA deficiency can cause severe diarrhea and weight loss. Gastroenterologists can adjust diet (low-residue or lactose-free diets), monitor intestinal inflammation, and coordinate biopsies or endoscopy when needed. [2][4]

7. Pulmonary rehabilitation and chest physiotherapy
   Recurrent lung infections may lead to bronchiectasis and chronic cough. Regular chest physiotherapy, breathing exercises, and airway-clearance techniques (e.g., oscillating devices, postural drainage) help clear mucus and protect lung function. [2][3]

8. Dental and oral care
   Frequent mouth ulcers and dental infections can be an extra infection source. Routine dental checks, gentle brushing, fluoride use, and early treatment of cavities reduce bacterial load and lower the risk of bloodstream infections from the mouth. [1][2]

9. Psychological support and counseling
   Living with a rare chronic disease, repeated hospital visits, and transplant decisions can cause anxiety, depression, or school problems. Counseling and psychosocial support help patients and families cope, stick to treatment, and maintain quality of life. [1][3]

10. Physiotherapy and regular gentle exercise
    Chronic illness and steroid use can weaken muscles and bones. Supervised physiotherapy and low-impact exercise (walking, swimming when safe) maintain mobility, bone strength, and lung capacity without overwhelming the patient. [2][4]

11. Sun protection and skin care
    Autoimmune skin disease and steroid therapy may make skin fragile and photosensitive. Sunscreen, protective clothing, and gentle moisturizing routines help prevent damage, infections in skin breaks, and worsening of autoimmune rashes. [1][3]

12. Home environment optimization (clean air and surfaces)
    Regular cleaning, avoiding indoor mold, using HEPA air filters where possible, and minimizing exposure to cigarette smoke or biomass fumes can reduce respiratory triggers and infections in vulnerable lungs. [1][2]

13. Genetic counseling for families
    Because LRBA deficiency is inherited, parents and siblings may wish to understand carrier status, recurrence risk, and options for future pregnancies. Genetic counseling provides clear explanations and supports informed family planning. [1][4]

14. Educational and workplace accommodations
    Schools and employers may need to adjust schedules, allow mask use, and support remote learning or work during high-risk times. This helps patients continue education and employment while reducing infection exposure and fatigue. [2][3]

15. Multidisciplinary clinic follow-up
    Regular visits with a team (immunology, gastroenterology, hematology, pulmonology, psychology, dietetics) allow early detection of new autoimmune problems, infections, or drug side effects, improving long-term outcomes. [2][4]

16. Home-based infusion services where available
    For stable patients on long-term IVIG or biologics, supervised home infusions can reduce hospital exposure, save travel time, and improve quality of life while maintaining close nursing support and emergency plans. [1][5]

17. Patient and caregiver education programs
    Teaching families to recognize early signs of sepsis, cytopenias, or autoimmune flare (new bruises, severe fatigue, bloody stools) empowers them to act quickly and communicate effectively with doctors. [1][2]

18. Support groups and patient organizations
    Connecting with primary immunodeficiency groups provides emotional support, practical tips, and access to educational materials on LRBA deficiency, treatments, and transition to adult care. [2][5]

19. Careful pregnancy and fertility planning (adults)
    For adult patients, pre-pregnancy counseling and close monitoring during pregnancy are crucial because some drugs (for example, mycophenolate) are teratogenic and immune changes can worsen disease activity. [3][4]

20. Advance care and transplant planning
    In severe cases, early discussion about HSCT, its risks, possible benefits, and timing helps families decide before irreversible organ damage occurs. Clear written plans reduce uncertainty and crises. [2][4]

Drug treatments

Drug choices must always be individualized and supervised by specialists. Typical dosing ranges below are examples only; doctors adjust based on age, weight, organ function, drug levels, and other medicines. [2][4]

1. Abatacept (CTLA-4-Ig biologic)
   Abatacept mimics the CTLA-4 molecule and calms T-cell over-activation, directly targeting the pathway disturbed in LRBA deficiency. It is usually given IV or subcutaneously every 1–4 weeks, with dose based on weight. Main risks are infections, infusion reactions, and rarely malignancy. [1][2]

2. Intravenous immunoglobulin (IVIG)
   Pooled IgG from thousands of donors replaces missing antibodies, reduces serious bacterial infections, and may also modulate autoimmunity. IVIG is usually given every 3–4 weeks (around 400–600 mg/kg), with side effects such as headache, fever, and rarely thrombosis or kidney injury. [1][3]

3. Subcutaneous immunoglobulin (SCIG)
   SCIG delivers the same antibodies slowly under the skin once or several times per week. It keeps more stable IgG levels and can be done at home after training. Local site reactions, itching, or swelling are more common but usually mild. [2][3]

4. Prednisone (oral corticosteroid)
   Prednisone quickly suppresses autoimmune cytopenias, colitis, and lymphoproliferation. Doses vary widely (for example, 0.5–2 mg/kg/day short-term). Long-term use causes weight gain, diabetes, hypertension, bone loss, mood changes, and infection risk, so doctors try to taper when possible. [2][4]

5. Methylprednisolone (IV pulse steroid)
   High-dose IV methylprednisolone pulses (e.g., 10–30 mg/kg/day for a few days) may be used for severe flares such as life-threatening autoimmune hemolytic anemia or severe colitis. It brings fast control but carries similar side effects to oral steroids, including high blood sugar and infection risk. [2][4]

6. Sirolimus (mTOR inhibitor)
   Sirolimus blocks mTOR signaling in T and B cells, reducing lymphoproliferation and autoimmune enteropathy. Typical daily doses are adjusted to reach target blood levels. Side effects include high cholesterol, mouth ulcers, delayed wound healing, and increased infection risk. [1][3]

7. Mycophenolate mofetil (MMF)
   MMF reduces DNA synthesis in proliferating lymphocytes, helping control autoimmunity like colitis or cytopenias. It is given orally in split daily doses. Common side effects are gastrointestinal upset, low blood counts, and higher infection risk, so blood tests are needed regularly. [2][4]

8. Azathioprine
   Azathioprine is another antimetabolite that suppresses over-active T and B cells. Doctors usually start at low doses and increase slowly while monitoring liver enzymes and blood counts. Side effects include bone-marrow suppression, liver toxicity, and higher risk of infections and rare malignancies. [2][4]

9. Tacrolimus (calcineurin inhibitor)
   Tacrolimus inhibits calcineurin, blocking T-cell activation and cytokine release. It can be used in steroid-dependent or refractory autoimmunity, especially gut or liver involvement. Side effects include kidney dysfunction, tremor, high blood pressure, and neurotoxicity; drug levels must be monitored. [3][4]

10. Cyclosporine
    Cyclosporine acts similarly to tacrolimus by inhibiting calcineurin, helping control severe autoimmune complications and graft-versus-host disease after HSCT. It carries risks of kidney damage, gum overgrowth, high blood pressure, tremor, and increased infection risk, so careful monitoring is essential. [3][4]

11. Rituximab (anti-CD20 monoclonal antibody)
    Rituximab depletes B cells, which can improve autoimmune cytopenias and some antibody-mediated diseases. It is usually given as IV infusions every 1–2 weeks for several doses. Side effects include infusion reactions, progressive multifocal leukoencephalopathy (rare), and increased risk of serious viral and bacterial infections. [1][2]

12. Infliximab (anti-TNF monoclonal antibody)
    Infliximab targets TNF-alpha and can treat severe inflammatory bowel disease not controlled by steroids or MMF. Dosing is weight-based at weeks 0, 2, 6, then every 8 weeks. Risks include serious infections, reactivation of TB or hepatitis B, and infusion reactions. [2][3]

13. Vedolizumab (gut-selective integrin blocker)
    Vedolizumab blocks α4β7 integrin and mainly works in the gut, making it attractive for LRBA-related colitis with fewer systemic immune effects. It is given IV at weeks 0, 2, 6, then every 8 weeks. Side effects include infections, headache, and infusion reactions. [2][3]

14. Ustekinumab (IL-12/23 inhibitor)
    Ustekinumab dampens Th1 and Th17 pathways, and may help LRBA patients with Crohn-like disease. It starts with a weight-based IV dose, followed by subcutaneous injections. Side effects include upper respiratory infections, skin cancer risk, and rare serious infections. [2][3]

15. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis
    Low-dose TMP-SMX is often used to prevent Pneumocystis jirovecii pneumonia and some bacterial infections. Side effects include allergic rashes, bone-marrow suppression, kidney issues, and, rarely, severe skin reactions, so patients need monitoring and clear instructions. [1][2]

16. Acyclovir or valacyclovir
    These antiviral medicines help prevent or treat herpes simplex and varicella-zoster infections in immunocompromised patients. Dosing varies with kidney function. Side effects are usually mild (nausea, headache) but high doses can cause kidney toxicity if patients are not well hydrated. [1][3]

17. Fluconazole or other antifungals
    Triazole antifungals can prevent or treat fungal infections, especially in patients on high-dose steroids or post-transplant. They are usually given orally once daily. Side effects include liver enzyme elevations, drug interactions, and gastrointestinal upset. [2][3]

18. Broad-spectrum IV antibiotics for sepsis
    When a patient with LRBA deficiency has high fever, low blood pressure, or suspected sepsis, early hospital IV antibiotics (for example, piperacillin-tazobactam or meropenem) are lifesaving. Doses are weight-based and adjusted to cultures, with risks like allergic reactions, kidney injury, and C. difficile colitis. [2][4]

19. Filgrastim (G-CSF)
    In patients with neutropenia, filgrastim stimulates bone-marrow production of neutrophils, lowering the risk and length of infections. It is given as daily or intermittent injections. Side effects include bone pain, splenomegaly, and rare splenic rupture, so spleen size should be monitored. [2][4]

20. Eltrombopag or romiplostim (platelet growth factors)
    These thrombopoietin-receptor agonists are used for severe immune-mediated thrombocytopenia. They increase platelet production to reduce bleeding risk. Side effects include liver enzyme elevation, thrombosis risk, and, rarely, bone-marrow fibrosis, so they require careful specialist monitoring. [2][3]

Dietary molecular supplements

Supplements must never replace medical therapy; they should only be taken with a doctor’s approval, especially in immunodeficiency. [1][2]

1. Vitamin D
   Vitamin D supports bone health, immune balance, and muscle strength. Many LRBA patients on steroids or with gut disease are deficient, so replacement based on blood levels can be helpful. Excessive doses can cause high calcium and kidney problems, so monitoring is essential. [1][3]

2. Omega-3 fatty acids (EPA/DHA)
   Omega-3s from fish oil may reduce gut and joint inflammation and support heart health. They can be useful in inflammatory bowel disease and autoimmune arthritis, but very high doses increase bleeding risk and may cause fishy aftertaste or stomach upset. [2][4]

3. Zinc
   Zinc is important for normal function of many enzymes and immune cells. Correcting mild deficiency may improve wound healing and resistance to infections, but high doses over time can cause copper deficiency, nausea, and changes in taste. [1][3]

4. Selenium
   Selenium is a key antioxidant cofactor and supports thyroid and immune function. In low-selenium areas or in patients with malabsorption, careful supplementation may help, but excess selenium can cause hair loss, nail changes, and nerve symptoms. [2][4]

5. Vitamin A
   Vitamin A helps maintain healthy mucosal barriers in the gut, lungs, and eyes. Deficiency can worsen infection risk, but high doses are toxic to the liver and harmful in pregnancy, so supplementation must be closely supervised. [1][2]

6. Vitamin C
   Vitamin C has antioxidant properties and supports collagen formation and immune function. Normal dietary intake usually suffices; modest supplements may be used, but very high doses can cause kidney stones and diarrhea. [1][3]

7. Folate and vitamin B12
   These vitamins are needed for DNA synthesis and red blood-cell production. In patients with chronic diarrhea or autoimmune gastritis, replacement can correct anemia and support bone-marrow function, but high doses should be guided by blood tests. [2][4]

8. Probiotics (with caution)
   Selected probiotic strains may improve gut barrier function and reduce diarrhea, but in severe immunodeficiency or central line use they may rarely cause bloodstream infections, so clinicians must decide case-by-case and choose well-studied products. [2][3]

9. Glutamine
   Glutamine is a fuel for intestinal cells and may help repair the gut lining in chronic enteropathy. It is usually given as oral powder blended into drinks, but evidence is limited, and high doses can cause abdominal discomfort. [2][4]

10. Curcumin (turmeric extract)
    Curcumin has anti-inflammatory properties in laboratory and early clinical studies. It may be an adjunct in gut inflammation, but absorption is low and quality of products varies widely, so it should only be used after discussion with specialists. [2][3]

Immunity-booster, regenerative, and stem-cell related drugs

1. Filgrastim (G-CSF)
   Filgrastim stimulates bone-marrow stem cells to produce more neutrophils, reducing bacterial infection risk during neutropenia. It is also used in stem-cell mobilization before HSCT. Side effects include bone pain and enlarged spleen, so careful dosing and monitoring are required. [2][4]

2. Sargramostim (GM-CSF)
   Sargramostim promotes production of neutrophils, monocytes, and other myeloid cells, sometimes used in prolonged neutropenia or after chemotherapy. It can cause fever, bone pain, fluid retention, and capillary leak, so it is typically used in hospital settings. [2][3]

3. Eltrombopag
   Eltrombopag stimulates megakaryocytes to produce more platelets, supporting bone-marrow recovery and reducing bleeding in immune thrombocytopenia or marrow failure. It is given orally but requires monitoring for liver toxicity and thrombosis risk. [2][4]

4. Romiplostim
   Romiplostim is an injectable thrombopoietin mimetic that also increases platelet production. It is used weekly with dose adjustments based on platelet counts, and may support recovery after HSCT in selected cases, but can increase risk of clots and marrow fibrosis. [2][3]

5. Plerixafor
   Plerixafor blocks CXCR4 and mobilizes hematopoietic stem cells from bone marrow to blood, allowing their collection for transplantation. It is generally used together with G-CSF. Side effects include gastrointestinal upset and injection-site reactions. [2][4]

6. Intravenous immunoglobulin as immune replacement
   IVIG not only replaces missing antibodies but also modulates immune responses, sometimes improving autoimmune complications and supporting immune recovery after HSCT. Regular infusions are part of long-term “immune support” for many LRBA patients. [1][2]

Surgical and procedural treatments

1. Allogeneic hematopoietic stem cell transplantation (HSCT)
   HSCT replaces the diseased immune system with healthy donor stem cells and is currently the only curative option for severe LRBA deficiency. Modern conditioning regimens (e.g., fludarabine-based) have achieved good remission rates but carry significant risks of infection, graft-versus-host disease, and treatment-related mortality. [1][2]

2. Central venous catheter or port insertion
   Many patients need long-term IV access for IVIG, biologics, or HSCT. A surgically placed tunneled catheter or implanted port reduces repeated needle sticks but increases risk of bloodstream infection and thrombosis, so strict line care protocols are needed. [2][3]

3. Intestinal surgery (e.g., segmental resection)
   In rare cases of life-threatening bleeding, perforation, or strictures from LRBA-related enteropathy, limited bowel resection or colectomy may be necessary. Surgery can relieve acute complications but does not cure the underlying immune disease, so medical therapy must continue. [2][4]

4. Splenectomy
   Splenectomy may be considered for severe autoimmune cytopenias that do not respond to drugs. It can raise blood counts but permanently increases infection risk, so extra vaccines and lifelong antibiotic precautions are required. [2][3]

5. Diagnostic biopsies (lymph node, liver, lung, gut)
   Surgical or endoscopic biopsies help confirm diagnoses like lymphoproliferation, IBD, or interstitial lung disease, guiding treatment. These procedures carry bleeding and infection risks, especially with low blood counts, so they are carefully timed and supported with transfusions if needed. [1][3]

Preventions and lifestyle precautions

1. Keep vaccinations (inactivated) up to date for the patient and all family members, under immunology guidance. [1][2]

2. Follow a written fever and infection plan with clear thresholds for contacting the doctor or going to hospital. [2][3]

3. Avoid smoking and second-hand smoke, and minimize exposure to indoor pollution and mold. [2][4]

4. Attend regular follow-up in a specialist primary immunodeficiency clinic for lab tests and imaging. [2][4]

5. Carry a medical alert card or bracelet listing diagnosis, main drugs, and emergency contact. [1][3]

6. Avoid raw or undercooked animal products and unsafe water to reduce food-borne infections. [1][2]

7. Use sun protection to prevent skin damage, especially when on immunosuppressants or steroids. [2][3]

8. Adhere strictly to all medicines and prophylactic antibiotics as prescribed; do not stop abruptly. [2][4]

9. Plan travel carefully, including vaccines, prophylactic medicines, and access to medical facilities. [2][3]

10. Seek early treatment for dental, skin, or urinary infections to prevent spread to blood or organs. [1][2]

When to see doctors urgently

A person with combined immunodeficiency due to LRBA deficiency should seek urgent medical help for high fever, breathing difficulty, chest pain, confusion, extreme weakness, severe abdominal pain, or blood in stools or urine. New large bruises, nosebleeds, or very pale skin may signal dangerous cytopenias that need emergency treatment. [1][2]

You should contact your immunologist promptly if infections become more frequent, diarrhea or weight loss worsens, cough persists, or if new autoimmune symptoms appear, even without fever. Sudden changes after starting a new medicine (allergy, rash, swelling, jaundice, major mood change) also require quick medical review. [2][3]

What to eat and what to avoid

1. Prefer well-cooked lean protein (fish, eggs, poultry, legumes) to support muscle and immune cell repair; avoid raw or undercooked meats, eggs, or seafood. [1][2]

2. Choose cooked vegetables and peeled fruits rather than raw salads from restaurants to lower bacterial load and support vitamins and fiber. [1][2]

3. Use safe, treated drinking water and avoid ice or drinks from unsafe sources, especially during travel. [2][3]

4. Include complex carbohydrates (rice, oats, whole grains if tolerated) for steady energy and weight maintenance. [1][3]

5. Add healthy fats (olive oil, nuts if safe, avocado) in moderation to increase calories for underweight patients. [2][3]

6. Limit highly processed foods, deep-fried snacks, and sugary drinks, which can worsen obesity, diabetes risk, and non-alcoholic fatty liver disease, especially with steroid use. [2][4]

7. Avoid unpasteurized milk, cheese, and juices because they may carry harmful bacteria for immunocompromised people. [1][2]

8. Be cautious with buffet or street foods where temperature control and hygiene may be uncertain. [1][3]

9. If lactose or gluten worsen symptoms, discuss possible intolerance with a dietitian rather than self-removing many foods without guidance. [2][3]

10. For very low appetite or weight, use prescribed oral nutrition supplements rather than random high-sugar drinks, and always check supplement ingredients with the care team. [2][4]

FAQs

1. Is combined immunodeficiency due to LRBA deficiency the same as common variable immunodeficiency (CVID)?
   No. LRBA deficiency is a specific genetic cause of immune dysregulation and combined immunodeficiency that can sometimes look like CVID, but it has a distinct molecular defect and often more severe autoimmunity and enteropathy. [1][2]

2. How is LRBA deficiency diagnosed?
   Doctors suspect LRBA deficiency based on clinical features and immunology tests, then confirm it with LRBA gene sequencing and/or flow-cytometry measurement of LRBA protein expression in immune cells. [1][3]

3. Is LRBA deficiency inherited?
   Yes. It is usually autosomal recessive, meaning both parents carry one altered LRBA gene but are healthy. Each child then has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of having two normal copies. [1][4]

4. Can a person with LRBA deficiency live a normal life?
   Many patients, especially those diagnosed early and treated with modern care (IVIG, targeted biologics, HSCT where needed), can attend school and work and enjoy family life, though they usually need lifelong follow-up and some lifestyle adjustments. [2][3]

5. Is HSCT a cure for LRBA deficiency?
   HSCT can cure the underlying immune defect in many patients, especially when done before severe organ damage, but it carries significant risks and is not suitable for everyone. Long-term outcome studies show improved disease control in successful transplants. [2][4]

6. What is the role of abatacept in LRBA deficiency?
   Abatacept targets the CTLA-4 pathway disrupted in LRBA deficiency and has shown good control of autoimmunity and lymphoproliferation in many patients, sometimes allowing steroid reduction. However, it is not curative and long-term safety and access differ by country. [1][3]

7. Why are sirolimus and other immunosuppressants used?
   Sirolimus, steroids, and other agents such as MMF or azathioprine reduce harmful immune activation and inflammation, especially in gut and blood disorders, but they must be balanced against infection risk and long-term toxicity. [2][4]

8. Will all patients eventually need HSCT?
   No. Some patients remain stable for many years on immunoglobulin replacement and targeted drugs like abatacept or sirolimus. HSCT is usually reserved for those with very severe, multi-organ disease or poor response to medical therapy. [2][3]

9. Can live vaccines be given in LRBA deficiency?
   Many experts avoid live vaccines in significant combined immunodeficiency, but decisions depend on individual immune tests and treatment (for example, after HSCT). This must always be decided by an immunologist, not at home. [1][2]

10. Are there gene therapies for LRBA deficiency yet?
    As of now, there is no widely available clinical gene therapy for LRBA deficiency, although research in gene-based treatments for primary immunodeficiencies is rapidly progressing. HSCT remains the curative option in routine practice. [2][3]

11. How often are follow-up visits needed?
    Frequency depends on disease severity and treatment stage. During active disease or after HSCT, visits may be monthly or more; in stable patients on long-term IVIG or abatacept, follow-up every 3–6 months is common. [2][4]

12. Can children with LRBA deficiency attend school?
    Yes, many can attend school with infection-prevention measures, flexible attendance, and coordination between parents, doctors, and school staff. Plans may include allowing masks, avoiding sick classmates, and home learning during outbreaks. [1][3]

13. What long-term complications should be monitored?
    Doctors watch for chronic lung disease, liver involvement, bone-marrow failure, malignancy risk, and medication toxicities using blood tests, imaging, and sometimes biopsies, so problems can be caught and treated early. [2][4]

14. Can adults be newly diagnosed with LRBA deficiency?
    Yes. Some people present later in life with autoimmune disease, cytopenias, or unexplained inflammatory bowel disease and are only then found to have LRBA mutations. Adult diagnosis is becoming more common as genetic testing spreads. [1][3]

15. Where can families find reliable information and support?
    Families can connect with national and international primary immunodeficiency organizations, patient handbooks, and specialized centers that publish guidelines and patient-friendly materials on LRBA deficiency and its treatments. [1][2]

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.