Tripeptidyl-Peptidase II (TPP2) Deficiency

Tripeptidyl-Peptidase II (TPP2) deficiency is a rare, inherited condition where the TPP2 gene does not work properly. The TPP2 gene makes an enzyme (tripeptidyl-peptidase II) that helps cells finish breaking down proteins into small pieces and helps the immune system prepare tiny protein fragments for HLA class I (MHC I) presentation. When this enzyme is missing or weak, immune cells age too fast, become unbalanced, and cannot control inflammation well. As a result, people get repeated infections, autoimmune problems (the immune system attacks the body’s own cells), and sometimes neurological issues such as development delay or brain inflammation that can look similar to multiple sclerosis. Doctors sometimes call the overall picture “TRIANGLE disease,” which stands for TPPII-related Immunodeficiency, Autoimmunity, and Neurodevelopmental delay with impaired glycolysis and lysosomal expansion. In short: protein-breakdown maintenance is impaired, energy handling inside cells is stressed, and the immune system becomes both weak and overactive. orpha.net+4ScienceDirect+4PMC+4

Tripeptidyl-Peptidase II (TPP2) deficiency is a very rare, inherited immune system disorder. It happens when both copies of the TPP2 gene have harmful changes (mutations). The TPP2 enzyme normally sits in the cell fluid (cytosol) and trims peptides into tiny three-amino-acid pieces so cells can recycle amino acids for energy and for making new proteins. When TPP2 is missing or weak, cells struggle to clear peptide leftovers and to keep normal energy balance. In people, this shows up as combined problems of immune defense (recurrent infections), immune mis-firing (autoimmunity, such as Evans syndrome), and brain/learning issues (neurodevelopmental delay). Doctors sometimes call the overall picture TPP2-related immunodeficiency, autoimmunity, and neurodevelopmental delay—you may also see TRIAD or TRIANGLE disease used for closely related phenotypes. Frontiers+2PMC+2

Pathophysiology

TPP2 is part of the cell’s protein “clean-up and recycle” line—proteasomes chop big proteins into medium pieces, then TPP2 nibbles those pieces down to tripeptides. This process helps keep cell proteins balanced, supports energy and amino-acid supply, and can influence how fragments are prepared for MHC class I antigen presentation (the way cells show bits of proteins to the immune system). Without enough TPP2, immune cells can age too early (“premature immunosenescence”), mis-read signals, and attack the body’s own cells (autoimmunity). Some patients also show brain inflammation or developmental delay, which researchers think links to energy stress and abnormal immune signaling within the brain. DIVA Portal+2Nature+2

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Other names

• TRIANGLE disease (acronym that summarizes the major features). Wikipedia

• TPPII-related immunodeficiency, autoimmunity, and neurodevelopmental delay (Orphanet listing). orpha.net

• TPP2 deficiency or Tripeptidyl-peptidase II deficiency (gene-centric names used in research). SpringerLink+1

• Early-onset Evans syndrome with immunodeficiency due to TPP2 deficiency (early core description). PMC+1

The condition is autosomal recessive: a child must inherit a non-working copy of TPP2 from both parents. Disease-causing (pathogenic) variants can be loss-of-function (e.g., nonsense, frameshift) or hypomorphic missense variants that reduce enzyme activity. This disrupts peptide trimming after proteasomal degradation, affects HLA class I antigen processing, disturbs amino-acid recycling and glycolysis, and promotes premature immunosenescence (early aging) of T and B cells—together causing vulnerability to infection plus autoimmunity. ScienceDirect+4NCBI+4UniProt+4

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Types

There is no universally agreed “official” subtype list yet. The groupings below reflect how doctors and researchers commonly describe the range of illness. PubMed

1. Classic, early-onset immune-dysregulation type – infants/young children with recurrent infections plus Evans syndrome (autoimmune hemolytic anemia + thrombocytopenia), lymphoproliferation, and failure to thrive. PMC+1

2. Neuro-inflammatory predominant type – episodes of sterile (non-infectious) brain inflammation; MRI lesions can mimic multiple sclerosis; variable immune problems. PMC

3. Milder / hypomorphic variant type – later onset, fewer infections, but measurable immune abnormalities; reported in single cases/families. SpringerLink

4. Mixed phenotype – combinations of recurrent viral infections (e.g., EBV/CMV), autoimmunity, growth/development delay, and organomegaly. ScienceDirect

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Causes

In a genetic disorder, the root cause is the biallelic TPP2 variant. The list below breaks that root cause into mechanistic contributors and modifiers that explain the clinical picture and why symptoms vary.

1. Biallelic pathogenic variants in TPP2 (autosomal recessive). PubMed

2. Loss of tripeptidyl-peptidase II enzyme activity (reduced peptide trimming). ScienceDirect

3. Defective downstream proteasome peptide processing, leaving peptides too long for HLA I. ScienceDirect

4. Impaired HLA class I antigen presentation, altering antiviral CD8+ T-cell responses. NCBI+1

5. Amino-acid recycling stress and glycolysis impairment inside immune cells. ScienceDirect

6. Lysosomal expansion and cellular stress responses, reflecting overloaded protein-clearance pathways. ScienceDirect

7. Premature immunosenescence of T and B cells (early “aging” phenotype). PMC+1

8. Defective homeostatic proliferation of lymphocytes, reducing effective immunity. PMC

9. Breakdown of peripheral tolerance, predisposing to autoimmunity. ScienceDirect

10. Chronic low-grade inflammation due to misprocessed antigens/DAMPs. (Inference from pathway data; see mechanistic reviews.) ScienceDirect

11. Metabolic vulnerability during infections, when proteostasis demands spike. ScienceDirect

12. Increased apoptosis of immune cells under stress conditions. (Mechanistic review.) PMC

13. Skewed CD4/CD8 and naïve/memory T-cell balance. PMC

14. Defective control of EBV/CMV and other viruses, triggering hyper-immune flares. PMC

15. Autoimmune cytopenias (e.g., Evans syndrome) driven by dysregulated B-cell responses. PMC

16. Neuroinflammation triggers within the CNS in some variants. PMC

17. Hypomorphic alleles (partial function) producing milder yet definite disease. SpringerLink

18. Founder variants in specific populations (rare, family-clustered). PubMed

19. Consanguinity, increasing autosomal-recessive risk (general genetic risk principle; observed in some reports). PMC

20. Environmental/infectious stressors that unmask immune/metabolic fragility. ScienceDirect

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Symptoms and signs

1. Frequent infections (often viral; sometimes severe or unusual). PMC

2. Autoimmune cytopenias—especially Evans syndrome (red cell and platelet destruction). PMC

3. Fevers that come and go, sometimes without a clear source. PMC

4. Enlarged spleen and/or liver (hepatosplenomegaly). PMC

5. Swollen lymph nodes (lymphadenopathy). PMC

6. Poor weight gain / failure to thrive in infants and children. PMC

7. Fatigue and low stamina, aggravated during infections or autoimmune flares. ScienceDirect

8. Mouth ulcers or prolonged viral warts/cold sores (impaired viral control). PMC

9. Easy bruising or bleeding (from low platelets during autoimmune episodes). PMC

10. Pale skin or shortness of breath (from autoimmune anemia). PMC

11. Headache, weakness, or neurological episodes when brain inflammation occurs. PMC

12. Developmental delay or learning problems in some patients. ScienceDirect

13. Recurrent chest infections and cough; risk of bronchiectasis over time. (General PIDs with recurrent infections.) humandiseasegenes.nl

14. Autoimmune thyroid or other autoimmune features (less common but reported). Wiley Online Library

15. Variable severity—from severe early-onset to milder courses. SpringerLink

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Diagnostic tests

A) Physical examination

1. General growth check – height/weight curves reveal failure to thrive or poor growth caused by chronic illness. PMC

2. Lymph node and spleen exam – looks for lymphadenopathy and splenomegaly that suggest immune activation. PMC

3. Skin and mucosa check – warts, cold sores, mouth ulcers, bruises (platelet issues) give immune and hematology clues. PMC

4. Neurologic screening – strength, coordination, vision/sensation to detect neuroinflammation signs needing MRI. PMC

B) “Manual” bedside assessments (simple clinic maneuvers)

5. Fever diary + symptom timeline – patterns (e.g., frequent viral episodes) point to immune trouble. humandiseasegenes.nl

6. Fatigue/functional tests (e.g., timed walk, hand-grip) – track stamina during flares. (General PID care principle.) humandiseasegenes.nl

7. Bleeding/bruising evaluation – nosebleeds, gum bleeding, petechiae suggest platelet autoimmunity. PMC

8. Vision and eye-movement check – screens for CNS involvement prompting imaging. PMC

C) Laboratory and pathological tests

9. Complete blood count (CBC) with smear – detects anemia, thrombocytopenia, lymphocyte counts and morphology. PMC

10. Direct antiglobulin test (Coombs) – confirms autoimmune hemolysis in Evans syndrome. PMC

11. Reticulocyte count, bilirubin, LDH, haptoglobin – shows hemolysis activity. PMC

12. Immunoglobulin levels (IgG, IgA, IgM) – screens for humoral immune deficiency. humandiseasegenes.nl

13. Specific antibody titers to vaccines – function test for B-cell responses. humandiseasegenes.nl

14. Lymphocyte subset flow cytometry – naïve/memory T-cell distribution, B-cell numbers (look for immunosenescence signatures). PMC

15. Functional T-cell assays (proliferation to mitogens/antigens) – measures cellular immunity. humandiseasegenes.nl

16. Viral PCR/serology (EBV, CMV, others) – documents chronic or recurrent viral replication. PMC

17. Metabolic and amino-acid panels / lactate – look for energy-use stress that aligns with impaired glycolysis. ScienceDirect

18. Genetic testing (targeted TPP2 sequencing or exome) – confirms biallelic pathogenic variants. PubMed

D) Electrodiagnostic tests

19. EEG – if seizures or encephalopathy occur, EEG can show abnormal brain activity. PMC

20. Evoked potentials / nerve-conduction studies – when symptoms suggest demyelination or peripheral involvement. PMC

E) Imaging tests

21. Brain MRI with contrast – key test to detect sterile neuroinflammation or MS-like lesions in some patients. PMC

22. Chest CT (or high-resolution CT) – evaluates recurrent pneumonia and possible bronchiectasis. (General PID imaging rationale.) humandiseasegenes.nl

23. Abdominal ultrasound – documents spleen and liver size safely and repeatedly. PMC

24. PET-CT (selected cases) – helps characterize lymphoproliferation or inflammation when diagnosis is unclear. humandiseasegenes.nl

Non-pharmacological treatments

1. Comprehensive infection-prevention plan
   Description (≈150 words): Create a home and clinic routine that lowers germ exposure: handwashing; alcohol gel; mask use in crowded seasons; keep distance from sick contacts; clean high-touch surfaces; safe food handling; avoid raw/undercooked foods; and prompt dental care to reduce oral bacteria. Build a written “fever plan” so caregivers know when to call, what labs to get, and when to start pre-agreed antibiotics/antivirals. Schools and workplaces should understand the condition and allow flexible attendance during outbreaks. Family members should keep their own vaccines up to date to form a protective “cocoon.”
   Purpose: Reduce infection frequency and severity.
   Mechanism: Lowers exposure dose and breaks transmission paths; earlier recognition shortens time to treatment. Frontiers

2. Individualized vaccination strategy (specialist-guided)
   Description: Work with immunology to plan inactivated vaccines on schedule and to avoid or carefully time live vaccines if immune function is insufficient. Household contacts should receive all routine vaccines, including influenza and COVID-19.
   Purpose: Build safe protection without undue risk.
   Mechanism: Leverages vaccine benefits while respecting impaired cellular immunity; cocooning reduces incoming pathogens. Frontiers

3. Immunization response monitoring
   Description: After key shots (e.g., pneumococcal, hepatitis B), check antibody titers to see if protection “took.”
   Purpose: Identify who needs extra doses or passive antibody (IVIG).
   Mechanism: Objective measurement guides tailored protection. Frontiers

4. Nutrition therapy with registered dietitian
   Description: Ensure adequate calories, protein, iron, B12/folate, zinc, selenium, vitamin D, and omega-3 sources; consider enteral support if growth falters.
   Purpose: Support growth, immunity, and wound healing.
   Mechanism: Corrects micronutrient deficits that blunt immune cell function and antibody production. Frontiers

5. Developmental and educational therapies
   Description: Early referral to speech, occupational, and physical therapy, plus individualized education plans if learning or coordination lags.
   Purpose: Maximize cognitive and motor outcomes.
   Mechanism: Structured repetition promotes neuroplasticity despite disease-related delays. orpha.net

6. Neuro-inflammation surveillance
   Description: Neurology follow-up for headaches, vision changes, limb weakness, or sensory symptoms; MRI if new deficits appear.
   Purpose: Catch sterile brain inflammation early.
   Mechanism: Timely identification allows prompt immune modulation to prevent damage. PMC

7. Sunlight and vitamin D lifestyle plan
   Description: Safe sun exposure and diet/supplements to maintain vitamin D in the sufficient range under medical guidance.
   Purpose: Support innate and adaptive immunity.
   Mechanism: Vitamin D modulates antimicrobial peptides and T-cell regulation. (General immune modulation principle aligned with PID care). Frontiers

8. Oral/dental hygiene program
   Description: Soft-brush twice daily, floss, fluoride, and regular dental checks; treat caries promptly.
   Purpose: Reduce oral infection seeding.
   Mechanism: Lowers bacterial load and translocation risk to the bloodstream. Frontiers

9. Sleep, stress, and mental-health care
   Description: Regular sleep schedule; mindfulness/CBT; family counseling to reduce caregiver burnout.
   Purpose: Improve resilience and adherence to care.
   Mechanism: Stress hormones alter immune balance; better sleep supports immune regulation. Frontiers

10. Physiotherapy and graded activity
    Description: Gentle, regular movement; infection-recovery pacing; avoid over-exertion during flares.
    Purpose: Maintain muscle strength and cardiorespiratory fitness.
    Mechanism: Enhances circulation and reduces deconditioning without triggering excessive inflammation. Frontiers

11. Exposure action plan for outbreaks
    Description: During community RSV/flu/varicella/COVID waves, tighten precautions; consider temporary remote schooling.
    Purpose: Minimize high-risk exposures.
    Mechanism: Reduces encounter rate with contagious individuals. Frontiers

12. Allergy/autoimmunity trigger diary
    Description: Track symptoms, infections, medications, and stressors.
    Purpose: Spot patterns that precede flares.
    Mechanism: Behavior change and pre-emptive care before full flare develops. Frontiers

13. Household “sick-room” protocol
    Description: Isolate ill family members, use dedicated utensils/linens, improve ventilation.
    Purpose: Protect the patient during family illnesses.
    Mechanism: Cuts secondary attack rate at home. Frontiers

14. Travel safety checklist
    Description: Pre-travel vaccines/antibiotics if appropriate, medical letter, and destination clinic contacts.
    Purpose: Prevent and rapidly manage travel infections.
    Mechanism: Preparedness reduces delays to care. Frontiers

15. School/Work accommodations
    Description: Flexible attendance, mask allowances, option to stay home during outbreaks.
    Purpose: Maintain education/work while staying safe.
    Mechanism: Lowers exposure density/time. Frontiers

16. Regular immunology follow-up
    Description: Scheduled reviews, labs, and medication checks.
    Purpose: Adjust therapy early.
    Mechanism: Detects immune shifts before complications. Frontiers

17. Genetic counseling for family
    Description: Explain autosomal recessive inheritance; discuss carrier testing and future pregnancy options.
    Purpose: Informed family planning.
    Mechanism: Identifies at-risk relatives and options like prenatal or preimplantation testing. OmicsDI

18. Home thermometer and pulse oximeter use
    Description: Teach families how and when to check temperature and oxygen and when to act.
    Purpose: Speed triage for fever or breathing symptoms.
    Mechanism: Early detection of serious infection. Frontiers

19. Skin care routine
    Description: Moisturizers, gentle cleansers, quick treatment of cuts.
    Purpose: Maintain barrier function.
    Mechanism: Prevents bacterial entry through cracked skin. Frontiers

20. Vaccinated “cocoon” around the patient
    Description: Encourage all close contacts to stay current with influenza, COVID-19, and other routine vaccines.
    Purpose: Indirect protection.
    Mechanism: Fewer pathogens reaching the patient. Frontiers

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Drug treatments

Important safety note: Doses below are typical adult ranges used for similar immune problems; children require weight-based specialist dosing. Always follow your immunologist’s prescription.

1. Intravenous immunoglobulin (IVIG)
   Class: Passive antibody replacement. Dose/time: Commonly 0.4–0.8 g/kg every 3–4 weeks (individualized). Purpose: Reduce infections and sometimes help autoimmunity. Mechanism: Supplies pooled antibodies the body can’t make well; also modulates immune cells and complement. Side effects: Headache, infusion reactions, rare thrombosis or hemolysis. Frontiers

2. Corticosteroids (e.g., prednisolone)
   Class: Broad anti-inflammatory/immunosuppressant. Typical dose: Often 0.5–1 mg/kg/day for active autoimmune cytopenias; tapered. Purpose: Control autoimmune flares (e.g., Evans syndrome). Mechanism: Dampens many inflammatory genes; reduces autoantibody-mediated destruction. Side effects: Weight gain, high sugar, infection risk, bone loss; tapering needed. PMC

3. Rituximab
   Class: Anti-CD20 monoclonal antibody. Dose: Common regimens 375 mg/m² weekly ×4 or 1,000 mg day 1, day 15. Purpose: Refractory autoimmune cytopenias; steroid-sparing. Mechanism: Depletes B cells that make autoantibodies. Side effects: Infusion reactions, hypogammaglobulinemia, infection risk. PMC

4. Mycophenolate mofetil
   Class: Antimetabolite immunosuppressant. Dose: Adults often 1–3 g/day divided. Purpose: Maintain remission of autoimmunity; steroid-sparing. Mechanism: Blocks inosine monophosphate dehydrogenase, suppressing lymphocyte proliferation. Side effects: GI upset, leukopenia, infection risk. Frontiers

5. Azathioprine
   Class: Purine analog immunosuppressant. Dose: Often 1–2.5 mg/kg/day with TPMT activity checked. Purpose: Autoimmune cytopenias maintenance. Mechanism: Inhibits DNA synthesis in lymphocytes. Side effects: Myelosuppression, liver toxicity, infection risk. Frontiers

6. Sirolimus (rapamycin)
   Class: mTOR inhibitor. Dose: Guided to trough levels; adults commonly 1–4 mg/day adjusted. Purpose: Control lymphoproliferation/autoimmunity in immune dysregulation. Mechanism: Inhibits T-cell proliferation downstream of IL-2. Side effects: Mouth ulcers, high lipids, delayed wound healing, infection. Frontiers

7. Tacrolimus
   Class: Calcineurin inhibitor. Dose: Individualized to trough targets. Purpose: Steroid-sparing for difficult autoimmunity. Mechanism: Blocks IL-2 transcription; reduces T-cell activation. Side effects: Kidney toxicity, tremor, hypertension, infection. Frontiers

8. Cyclosporine
   Class: Calcineurin inhibitor. Dose: Trough-guided; typical 2.5–5 mg/kg/day divided. Purpose: Refractory autoimmune cytopenias. Mechanism: Decreases T-cell activation and cytokines. Side effects: Gingival hyperplasia, hirsutism, nephrotoxicity, hypertension. Frontiers

9. Abatacept (CTLA-4-Ig)
   Class: T-cell co-stimulation blocker. Dose: Weight-based IV monthly or weekly SC per labeling. Purpose: Off-label immune-dysregulation states when B/T over-activation drives autoimmunity. Mechanism: Competes with CD28 for CD80/86, reducing T-cell activation. Side effects: Infections; screen for TB; headache. (Used in related immune-dysregulation disorders; consider only with specialists.) Frontiers

10. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis
    Class: Antibacterial/anti-Pneumocystis. Dose: Typical adult prophylaxis 160/800 mg once daily or thrice weekly. Purpose: Prevents Pneumocystis jirovecii and some bacterial infections during immunosuppression. Mechanism: Folate pathway inhibition in microbes. Side effects: Rash, cytopenias, hyperkalemia. Frontiers

11. Acyclovir/Valacyclovir
    Class: Antiviral. Dose: Suppressive dosing varies (e.g., valacyclovir 500 mg–1 g once/twice daily). Purpose: Prevent/treat HSV/VZV reactivations seen in reported TPP2 cases. Mechanism: Viral DNA polymerase inhibition after phosphorylation. Side effects: Headache, kidney issues (acyclovir crystals if dehydrated). Frontiers

12. Fluconazole (selective use)
    Class: Antifungal. Dose: 100–400 mg daily if indicated for prophylaxis per risk. Purpose: Prevent mucosal/systemic candidiasis during heavy immunosuppression. Mechanism: Inhibits ergosterol synthesis. Side effects: Liver enzyme elevation, drug interactions. Frontiers

13. G-CSF (filgrastim)
    Class: Hematopoietic growth factor. Dose: 5 µg/kg/day SC when neutropenic (specialist-guided). Purpose: Raise neutrophils if low. Mechanism: Stimulates marrow neutrophil production. Side effects: Bone pain, leukocytosis, rare splenic issues. Frontiers

14. Eltrombopag
    Class: Thrombopoietin-receptor agonist. Dose: Adults often 50 mg daily (adjust per platelets and liver tests). Purpose: Immune thrombocytopenia component of Evans syndrome. Mechanism: Stimulates megakaryocyte/platelet production. Side effects: Liver toxicity, thrombosis risk. PMC

15. Romiplostim
    Class: TPO-receptor agonist (peptibody). Dose: Weekly SC; titrate to platelet goal. Purpose: ITP in Evans syndrome unresponsive to first-line. Mechanism: Drives platelet production via MPL receptor. Side effects: Headache, thrombotic risk, marrow reticulin changes. PMC

16. Methotrexate (low-dose immunomodulation)
    Class: Antimetabolite. Dose: 7.5–25 mg weekly with folic acid. Purpose: Steroid-sparing for some autoimmune features. Mechanism: AICAR/TNF modulation; antiproliferative on lymphocytes. Side effects: Liver toxicity, cytopenias, mucositis; avoid in pregnancy. Frontiers

17. Hydroxychloroquine
    Class: Antimalarial immunomodulator. Dose: 200–400 mg/day (≤5 mg/kg real body weight). Purpose: Mucocutaneous or joint autoimmunity features. Mechanism: TLR signaling dampening, antigen presentation effects. Side effects: Retinal toxicity (dose-dependent), GI upset. Frontiers

18. Plasmapheresis (therapeutic plasma exchange; adjunct “drugs” category)
    Class: Procedure using albumin/FFP. Schedule: Daily or every other day in acute hemolysis crisis (specialist setting). Purpose: Rapidly remove pathogenic autoantibodies. Mechanism: Physical antibody removal. Side effects: Hypotension, bleeding; central line risks. Frontiers

19. Antibiotic “fever-plan” starters
    Class: Broad-spectrum antibiotics chosen by local protocols. Use: Begun promptly per plan when high fever plus neutropenia/ill appearance occurs. Purpose: Prevent sepsis. Mechanism: Rapid bacterial kill before cultures finalize. Side effects: Drug-specific; stewardship needed. Frontiers

20. HSCT conditioning/aftercare meds (specialist-directed bundle)
    Class: Examples include fludarabine, busulfan, thiotepa, ATG; plus GVHD prophylaxis. Use: Only if HSCT is chosen by a transplant team for severe cases. Purpose: Enable donor marrow to engraft and correct immune defect. Mechanism: Myeloablation/immune reset; donor stem cells reconstitute immunity. Side effects: Infection, mucositis, GVHD; requires expert center. Frontiers

*Again: dosing must be tailored by your specialist, especially in children.

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Dietary molecular supplements

Safety first: Always clear supplements with your doctor—interactions and infection risks vary.

1. Vitamin D3
   Dose: Commonly 1,000–2,000 IU/day; adjust to keep 25-OH vitamin D in target range. Function: Immune modulation and bone health. Mechanism: Enhances antimicrobial peptides; shifts T-cell responses toward regulation. Frontiers

2. Omega-3 fatty acids (EPA/DHA)
   Dose: 1–2 g/day combined EPA+DHA. Function: Anti-inflammatory support. Mechanism: Resolvin production reduces excessive cytokine signaling. Frontiers

3. Zinc
   Dose: 10–25 mg elemental zinc/day short-term. Function: Innate and adaptive immunity cofactor. Mechanism: Supports thymic hormones and lymphocyte function. Frontiers

4. Selenium
   Dose: 50–100 µg/day. Function: Antioxidant defense in immune cells. Mechanism: Selenoproteins limit oxidative damage during immune responses. Frontiers

5. Probiotics (strain-specific, inactivated if neutropenic)
   Dose: As labeled; consider non-live options if severely immunosuppressed. Function: Gut barrier and immune tone. Mechanism: Microbiome signals can reduce mucosal infections and modulate T-cells. Frontiers

6. N-acetylcysteine (NAC)
   Dose: 600–1,200 mg/day. Function: Antioxidant support. Mechanism: Replenishes glutathione, limiting oxidative stress in immune cells. Frontiers

7. Folate + Vitamin B12
   Dose: Folate 400–800 µg; B12 1,000 µg (route individualized). Function: Red cell production and neurologic function. Mechanism: DNA synthesis and myelin support, particularly important if cytopenias occur. Frontiers

8. Iron (only if iron-deficient)
   Dose: Per labs; often 18–65 mg elemental iron/day. Function: Correct iron-deficiency anemia. Mechanism: Supports hemoglobin and oxygen delivery; avoid if not deficient. Frontiers

9. Glutamine
   Dose: 5–10 g/day as tolerated. Function: Fuel for rapidly dividing cells (gut, immune). Mechanism: Supports barrier integrity and lymphocyte function. Frontiers

10. Multivitamin (avoiding excess vitamin A/K interactions)
    Dose: As labeled. Function: Fill small gaps in intake. Mechanism: Ensures baseline micronutrient sufficiency for immune competence. Frontiers

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Immunity-booster / regenerative / stem-cell–related drugs

1. Filgrastim (G-CSF) — Dose: ~5 µg/kg/day SC when neutropenic (specialist-guided). Function: Raises neutrophils to reduce bacterial/fungal risk. Mechanism: Stimulates marrow granulopoiesis. Note: Watch for bone pain, rare splenic issues. Frontiers

2. Sargramostim (GM-CSF) — Dose: Specialist-guided. Function: Broader myeloid recovery. Mechanism: Stimulates granulocytes, monocytes, dendritic cells. Note: Fever, injection-site reactions possible. Frontiers

3. Eltrombopag — Dose: 25–75 mg/day adjusted. Function: Raises platelets in ITP component of Evans syndrome. Mechanism: Thrombopoietin receptor agonism. Note: Monitor LFTs, thrombosis risk. PMC

4. Romiplostim — Dose: Weekly SC titration. Function: Platelet production. Mechanism: MPL receptor stimulation. Note: Monitor counts; avoid overshoot. PMC

5. Thymosin-alpha 1 (specialist-only, selective) — Dose: Protocol-based. Function: Experimental immune modulation in some PIDs. Mechanism: T-cell maturation signals; evidence varies—use only in trials/specialist care. Frontiers

6. Allogeneic HSCT (curative intent therapy rather than a “drug”) — Dose: Conditioning per center (e.g., fludarabine, busulfan, thiotepa, ATG). Function: Rebuild a functional immune system from donor stem cells in severe cases. Mechanism: Donor hematopoiesis replaces defective host immunity. Note: Major risks (infections, GVHD); one reported TPP2 case had cure after HSCT. Frontiers

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Surgeries / procedures

1. Allogeneic HSCT — Infusion of donor stem cells after conditioning. Why: For severe, refractory disease—aims for lasting immune reconstitution. Frontiers

2. Splenectomy (select, refractory Evans syndrome only) — Surgical removal of spleen. Why: Reduce immune-mediated destruction of blood cells when medications fail; used cautiously due to infection risks in immunodeficiency. PMC

3. Central venous port placement — Device for IVIG/medications. Why: Reliable access when frequent infusions are needed. Frontiers

4. PEG feeding tube (if severe failure to thrive) — Tube to stomach. Why: Ensure adequate calories and medicines if oral intake is poor. Frontiers

5. Bone-marrow biopsy — Needle sampling of marrow. Why: Evaluate unexplained cytopenias, rule out other marrow disease before major therapy. Frontiers

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Prevention tips

1. Hand hygiene and alcohol gel everywhere you spend time.

2. Keep vaccines up to date (inactivated for patient; all routine for household).

3. Mask in crowded indoor spaces during respiratory virus season

4. Have a written fever plan and rescue meds.

5. Maintain adequate sleep and nutrition.

6. Routine dental and skin care.

7. Avoid raw eggs/shellfish/unpasteurized dairy.

8. Post-exposure antivirals promptly for significant HSV/VZV exposure if advised.

9. Avoid live vaccines unless your immunologist confirms safety. 10) Keep regular immunology and neurology follow-ups. Frontiers

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When to see a doctor urgently

Seek urgent care for fever ≥38.0 °C, shortness of breath, severe headache or neck stiffness, new weakness, vision changes, or numbness, signs of severe bleeding or anemia (pale, dizzy, chest pain, fast heartbeat), painful mouth ulcers with fever, shingles-like rashes, or any rapidly worsening illness. Have a low threshold to call your immunology team; many patients need same-day antibiotics/antivirals during febrile episodes. Frontiers

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What to eat and what to avoid

Eat more: well-cooked lean proteins; legumes; yogurt or pasteurized fermented dairy; whole grains; colorful fruits/vegetables; nuts/seeds; healthy oils; adequate fluids; vitamin-D rich foods (fortified milk, cooked fish); iron- and B-12-containing foods if deficient.
Avoid/limit: raw or undercooked meats/eggs; unpasteurized juices/dairy; raw sprouts; buffet foods held warm too long; high-sugar ultra-processed snacks; excessive alcohol. Discuss any restrictive diets with your team to avoid deficiencies. Frontiers

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Frequently asked questions

1. Is TPP2 deficiency inherited?
   Yes—autosomal recessive. Both parents are usually healthy carriers. OmicsDI

2. What symptoms are most common?
   Recurrent infections, autoimmune blood problems (Evans syndrome), poor growth, and developmental delay. Some families also had brain inflammation. PMC+1

3. How is it confirmed?
   By genetic testing that finds two harmful TPP2 variants; sometimes activity tests support the diagnosis. OmicsDI

4. Does it affect how the immune system “sees” germs?
   Possibly—TPP2 helps process peptides and may influence MHC class I presentation, which can alter immune signaling. Nature+1

5. Why autoimmunity and infections together?
   Immune cells can become prematurely aged and mis-regulated—too weak against germs, yet prone to attack self tissues. Frontiers

6. Are there disease-specific medicines?
   There is no single “TPP2 pill”. Treatment targets infections and autoimmunity using standard immune therapies tailored by specialists. Frontiers

7. Can IVIG help?
   Yes. It replaces missing antibodies and can calm autoimmunity in some people. Frontiers

8. What about rituximab?
   Used for autoimmune cytopenias when steroids/IVIG aren’t enough. PMC

9. Is HSCT a cure?
   In one reported case, HSCT cured symptoms, but evidence is limited; risks are significant, so it’s considered only in severe, carefully selected cases. Frontiers

10. Could it look like multiple sclerosis?
    A TPP2 mutation caused sterile brain inflammation that mimicked MS in one family; this is rare but important to recognize. PMC

11. Are live vaccines safe?
    Only if your immunologist confirms immune function is sufficient; often avoided. Household contacts should get routine vaccines. Frontiers

12. Do diet and vitamins matter?
    They don’t cure TPP2 deficiency, but good nutrition and vitamin D sufficiency support the immune system and recovery. Frontiers

13. Can adults be diagnosed later?
    Yes—especially if earlier symptoms were mild. Genetic testing can still clarify the cause. OmicsDI

14. What specialists should be involved?
    Clinical immunology, hematology, neurology, infectious diseases, nutrition, and genetics. Team-based care works best. Frontiers

15. Where can I read more scientific details?
    Key resources include a transplant/immune-dysregulation review that summarizes the first HSCT case, the original Evans syndrome–TPP2 report, and reviews on TPP2 biology and brain involvement. PMC+3Frontiers+3PMC+3

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

Last Updated: September 29, 2025.

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