Defects of Cellular Immunity and Combined Immunodeficiency in Pediatric Age

Introduction to Primary Defects of Cellular Immunity in Children

Primary defects of cellular immunity in children encompass a group of inherited disorders characterized by impaired T-cell function, often accompanied by defects in other immune cell types. These conditions result in severe immunodeficiency, leaving affected children vulnerable to a wide range of infections, autoimmune disorders, and malignancies.

Key points:

  • Cellular immunity is primarily mediated by T lymphocytes and is crucial for defense against intracellular pathogens, viruses, and tumor cells.
  • Primary defects are genetic in origin, distinguishing them from secondary immunodeficiencies caused by external factors.
  • Early diagnosis is critical, as many of these conditions are life-threatening without prompt intervention.
  • Treatment often involves hematopoietic stem cell transplantation (HSCT) or gene therapy, alongside supportive care and infection prevention.

Severe Combined Immunodeficiency (SCID)

SCID represents the most severe form of primary immunodeficiency, characterized by profound defects in T-cell development and function, often accompanied by B-cell and NK-cell abnormalities.

Etiology:

  • Multiple genetic mutations can cause SCID, including defects in:
    • IL-2 receptor γ chain (X-linked SCID)
    • Adenosine deaminase (ADA-SCID)
    • JAK3, RAG1/2, IL-7Rα, and others

Clinical Presentation:

  • Recurrent severe infections starting in early infancy
  • Failure to thrive
  • Chronic diarrhea
  • Opportunistic infections (e.g., Pneumocystis jirovecii pneumonia)

Diagnosis:

  • Lymphopenia (especially T-cell lymphopenia)
  • Absent or very low T-cell function in mitogen stimulation assays
  • Genetic testing to identify specific mutations

Treatment:

  • Hematopoietic stem cell transplantation (HSCT) is curative
  • Gene therapy for specific forms (e.g., ADA-SCID)
  • Supportive care: antimicrobial prophylaxis, IVIG replacement

DiGeorge Syndrome (22q11.2 Deletion Syndrome)

DiGeorge syndrome is a complex disorder caused by a deletion in chromosome 22q11.2, affecting multiple organ systems including the immune system, heart, and parathyroid glands.

Immunological Features:

  • Thymic hypoplasia or aplasia leading to T-cell deficiency
  • Variable severity of T-cell defects, ranging from mild to complete absence (complete DiGeorge syndrome)

Clinical Presentation:

  • Recurrent infections
  • Congenital heart defects (e.g., truncus arteriosus, tetralogy of Fallot)
  • Hypoparathyroidism and resulting hypocalcemia
  • Characteristic facial features
  • Developmental delays and learning difficulties

Diagnosis:

  • FISH or microarray to detect 22q11.2 deletion
  • Immunological assessment: T-cell counts and function
  • Cardiac evaluation
  • Serum calcium and parathyroid hormone levels

Treatment:

  • Thymus transplantation for complete DiGeorge syndrome
  • Cardiac surgery for associated heart defects
  • Calcium and vitamin D supplementation for hypocalcemia
  • Speech therapy and developmental support
  • IVIG for patients with significant infections

Ataxia-Telangiectasia

Ataxia-telangiectasia (A-T) is a complex disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, and increased cancer susceptibility.

Etiology:

  • Mutations in the ATM gene, which is involved in DNA repair and cell cycle control

Immunological Features:

  • Variable T-cell deficiency
  • Low or absent IgA, IgG2, and IgG4
  • Impaired antibody responses to polysaccharide antigens

Clinical Presentation:

  • Progressive cerebellar ataxia, typically apparent by age 2-3 years
  • Oculocutaneous telangiectasias (usually apparent by age 5-8 years)
  • Recurrent sinopulmonary infections
  • Increased risk of malignancies, especially lymphomas and leukemias

Diagnosis:

  • Elevated serum alpha-fetoprotein (AFP) levels
  • Genetic testing for ATM mutations
  • Immunological assessment: lymphocyte subsets, immunoglobulin levels
  • Chromosomal breakage studies showing increased radiosensitivity

Treatment:

  • No cure; management focuses on supportive care
  • IVIG replacement for patients with recurrent infections
  • Physical and occupational therapy for ataxia
  • Avoidance of unnecessary radiation exposure
  • Regular cancer screening

Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS) is an X-linked recessive disorder characterized by the triad of eczema, thrombocytopenia with small platelets, and recurrent infections due to immunodeficiency.

Etiology:

  • Mutations in the WAS gene, which encodes the WAS protein (WASP)
  • WASP is crucial for actin cytoskeleton reorganization in hematopoietic cells

Immunological Features:

  • Progressive T-cell deficiency
  • Impaired antibody responses, especially to polysaccharide antigens
  • Decreased NK cell function

Clinical Presentation:

  • Eczema, often severe and treatment-resistant
  • Thrombocytopenia with small platelets, leading to easy bruising and bleeding
  • Recurrent infections, particularly otitis media, pneumonia, and skin infections
  • Increased risk of autoimmune disorders and malignancies

Diagnosis:

  • Genetic testing for WAS mutations
  • Flow cytometry to assess WASP expression in lymphocytes
  • Complete blood count showing thrombocytopenia with small platelets
  • Immunological assessment: lymphocyte subsets, immunoglobulin levels, antibody responses

Treatment:

  • Hematopoietic stem cell transplantation (HSCT) is curative
  • Gene therapy is emerging as a promising treatment option
  • IVIG replacement
  • Prophylactic antibiotics
  • Platelet transfusions for severe thrombocytopenia or active bleeding
  • Management of eczema with topical treatments and systemic immunosuppression if severe

Diagnosis and Screening of Primary Cellular Immunodeficiencies

Newborn Screening:

  • T-cell receptor excision circles (TRECs) assay on dried blood spots
    • Low TRECs indicate impaired T-cell development
    • Highly effective in identifying SCID and other T-cell deficiencies

Initial Evaluation:

  • Complete blood count with differential
  • Lymphocyte subset analysis (T, B, and NK cells)
  • Serum immunoglobulin levels

Functional Assays:

  • Lymphocyte proliferation assays (response to mitogens and antigens)
  • NK cell cytotoxicity assays
  • Specific antibody responses to vaccines

Advanced Diagnostics:

  • Flow cytometry for specific protein expression (e.g., WASP)
  • Genetic testing
    • Targeted gene sequencing for suspected disorders
    • Whole exome or genome sequencing for undiagnosed cases
  • Radiosensitivity testing (for A-T)

Imaging Studies:

  • Chest X-ray or CT to evaluate thymic shadow and lung pathology
  • Echocardiogram for suspected DiGeorge syndrome

Treatment Approaches for Primary Cellular Immunodeficiencies

Definitive Therapies:

  • Hematopoietic Stem Cell Transplantation (HSCT)
    • Curative for many cellular immunodeficiencies
    • Optimal outcomes when performed early, especially for SCID
    • Donor selection crucial: matched sibling > matched unrelated donor > haploidentical parent
  • Gene Therapy
    • Emerging option for specific disorders (e.g., ADA-SCID, X-linked SCID)
    • Involves ex vivo modification of autologous hematopoietic stem cells
  • Thymus Transplantation
    • Option for complete DiGeorge syndrome

Supportive Therapies:

  • Immunoglobulin Replacement
    • Intravenous (IVIG) or subcutaneous (SCIG) administration
    • Dose and frequency tailored to maintain adequate IgG levels
  • Antimicrobial Prophylaxis
    • Trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia
    • Antifungal prophylaxis in severe T-cell deficiencies
  • Management of Complications
    • Aggressive treatment of infections
    • Nutritional support
    • Treatment of associated conditions (e.g., eczema in WAS)

Monitoring and Follow-up:

  • Regular assessment of immune function
  • Growth and development monitoring
  • Screening for associated complications and malignancies
  • Genetic counseling for families

Introduction to Immunodeficiencies Affecting Multiple Cell Types

Immunodeficiencies affecting multiple cell types are a group of disorders characterized by defects in various components of the immune system, including T cells, B cells, and often other immune cells such as neutrophils or natural killer (NK) cells. These conditions result in complex immunological deficits, leading to a wide range of clinical manifestations.

Key points:

  • These disorders often have a genetic basis, although some may be acquired.
  • The involvement of multiple cell types leads to a broader spectrum of immunological defects compared to single-lineage deficiencies.
  • Clinical presentations can be highly variable, even within the same disorder.
  • Diagnosis often requires comprehensive immunological testing and genetic analysis.
  • Treatment strategies are typically multifaceted, addressing various aspects of immune dysfunction.

Common Variable Immunodeficiency (CVID)

CVID is the most common symptomatic primary immunodeficiency, characterized by hypogammaglobulinemia and impaired antibody production, often with associated T-cell abnormalities.

Etiology:

  • Genetic heterogeneity with mutations identified in several genes (e.g., TNFRSF13B, ICOS, CD19, TNFRSF13C)
  • Many cases remain genetically undefined

Immunological Features:

  • Low serum IgG, often with low IgA and/or IgM
  • Poor antibody responses to vaccines
  • Reduced switched memory B cells
  • Variable T-cell abnormalities (e.g., reduced T-cell proliferation, altered T-cell subsets)

Clinical Presentation:

  • Recurrent sinopulmonary infections
  • Gastrointestinal disorders (e.g., chronic diarrhea, malabsorption)
  • Autoimmune manifestations (e.g., cytopenias, thyroiditis)
  • Increased risk of lymphoma and other malignancies
  • Granulomatous disease in some patients

Diagnosis:

  • Serum immunoglobulin levels
  • Specific antibody responses to vaccines
  • Lymphocyte subset analysis
  • B-cell phenotyping (including memory B cells)
  • Genetic testing in some cases

Treatment:

  • Immunoglobulin replacement therapy (IVIg or SCIg)
  • Antibiotic prophylaxis in some cases
  • Management of complications (e.g., autoimmune disorders, enteropathy)
  • Regular monitoring for malignancies

Hyper-IgM Syndrome

Hyper-IgM syndrome is a group of disorders characterized by normal or elevated IgM levels with low IgG, IgA, and IgE due to defects in immunoglobulin class-switch recombination and somatic hypermutation.

Etiology:

  • X-linked: CD40 ligand deficiency (most common)
  • Autosomal recessive: CD40 deficiency, AID deficiency, UNG deficiency
  • Autosomal dominant: gain-of-function mutations in PIK3CD or PIK3R1

Immunological Features:

  • Normal or elevated IgM levels
  • Low IgG, IgA, and IgE levels
  • Impaired antibody responses to protein antigens
  • Defective B-cell class switching and somatic hypermutation
  • T-cell abnormalities in CD40L and CD40 deficiency

Clinical Presentation:

  • Recurrent sinopulmonary infections
  • Opportunistic infections (especially in CD40L and CD40 deficiency)
  • Neutropenia (in CD40L deficiency)
  • Chronic diarrhea and liver disease
  • Increased risk of lymphoid hyperplasia and malignancy

Diagnosis:

  • Serum immunoglobulin levels
  • Flow cytometry for CD40L expression on activated T cells
  • Genetic testing for specific mutations
  • B-cell phenotyping and in vitro class-switch recombination assays

Treatment:

  • Immunoglobulin replacement therapy
  • Prophylactic antibiotics (including against Pneumocystis jirovecii in CD40L/CD40 deficiency)
  • Hematopoietic stem cell transplantation for severe forms (especially CD40L and CD40 deficiency)
  • Management of complications (e.g., liver disease, malignancies)

Chronic Granulomatous Disease (CGD)

CGD is a primary immunodeficiency characterized by defects in the phagocyte NADPH oxidase complex, leading to impaired killing of certain bacteria and fungi.

Etiology:

  • X-linked: mutations in CYBB gene (about 70% of cases)
  • Autosomal recessive: mutations in CYBA, NCF1, NCF2, or NCF4 genes

Immunological Features:

  • Defective production of reactive oxygen species by phagocytes
  • Impaired killing of catalase-positive organisms
  • Excessive inflammation and granuloma formation
  • Variable T-cell abnormalities

Clinical Presentation:

  • Recurrent bacterial and fungal infections (e.g., S. aureus, Aspergillus, Burkholderia cepacia)
  • Granulomatous inflammation affecting various organs
  • Inflammatory bowel disease-like symptoms
  • Failure to thrive
  • Delayed wound healing

Diagnosis:

  • Dihydrorhodamine (DHR) flow cytometry test
  • Nitroblue tetrazolium (NBT) test (older method)
  • Genetic testing to confirm specific mutation
  • Assessment of NADPH oxidase component expression

Treatment:

  • Lifelong antibiotic prophylaxis (typically trimethoprim-sulfamethoxazole)
  • Antifungal prophylaxis (e.g., itraconazole)
  • Interferon-gamma therapy in some cases
  • Aggressive treatment of acute infections
  • Management of inflammatory complications
  • Hematopoietic stem cell transplantation in selected cases
  • Gene therapy (experimental)

DOCK8 Deficiency

DOCK8 deficiency is an autosomal recessive combined immunodeficiency characterized by recurrent viral infections, severe allergies, and increased risk of malignancy.

Etiology:

  • Biallelic mutations in the DOCK8 gene
  • DOCK8 protein is important for immune cell migration and function

Immunological Features:

  • T-cell lymphopenia with impaired T-cell function
  • Impaired antibody responses, especially to polysaccharide antigens
  • Reduced NK cell numbers and function
  • Elevated IgE levels
  • Eosinophilia

Clinical Presentation:

  • Recurrent viral infections (e.g., HPV, HSV, molluscum contagiosum)
  • Severe atopic dermatitis
  • Food and environmental allergies
  • Recurrent sinopulmonary infections
  • Increased risk of malignancies, especially squamous cell carcinomas
  • Vascular abnormalities (e.g., aneurysms)

Diagnosis:

  • Flow cytometry for DOCK8 protein expression
  • Genetic testing for DOCK8 mutations
  • Immunological assessment (lymphocyte subsets, immunoglobulins, vaccine responses)
  • Elevated serum IgE and eosinophil count

Treatment:

  • Hematopoietic stem cell transplantation (curative)
  • Management of atopic and allergic manifestations
  • Antimicrobial prophylaxis
  • Immunoglobulin replacement therapy
  • Aggressive treatment of infections
  • Regular skin examinations for early detection of malignancies

Diagnosis and Screening of Immunodeficiencies Affecting Multiple Cell Types

Initial Evaluation:

  • Detailed medical history and family history
  • Complete blood count with differential
  • Serum immunoglobulin levels (IgG, IgA, IgM, IgE)
  • Lymphocyte subset analysis (T, B, and NK cells)

Functional Assays:

  • Lymphocyte proliferation assays
  • Specific antibody responses to vaccines
  • NK cell cytotoxicity assays
  • Neutrophil function tests (e.g., DHR test for CGD)

Advanced Diagnostics:

  • Flow cytometry for specific protein expression (e.g., CD40L, DOCK8)
  • B-cell phenotyping (naive, memory, and switched memory B cells)
  • T-cell receptor excision circles (TRECs) analysis
  • Genetic testing
    • Targeted gene sequencing for suspected disorders
    • Next-generation sequencing panels for primary immunodeficiencies
    • Whole exome or genome sequencing for undiagnosed cases

Imaging Studies:

  • Chest X-ray or CT to evaluate for chronic lung disease or bronchiectasis
  • Abdominal imaging to assess for lymphoproliferation or inflammatory complications

Additional Investigations:

  • Endoscopy and tissue biopsy in cases of gastrointestinal symptoms
  • Bone marrow examination in cases of cytopenias or suspected malignancy

Treatment Approaches for Immunodeficiencies Affecting Multiple Cell Types

Immunoglobulin Replacement Therapy:

  • Intravenous (IVIG) or subcutaneous (SCIG) administration
  • Dosing typically 400-600 mg/kg every 3-4 weeks for IVIG, or equivalent for SCIG
  • Aim to maintain trough IgG levels above 7-8 g/L

Antimicrobial Prophylaxis:

  • Antibacterial (e.g., trimethoprim-sulfamethoxazole, azithromycin)
  • Antifungal (e.g., itraconazole for CGD)
  • Tailored to the specific immunodeficiency and individual patient needs

Hematopoietic Stem Cell Transplantation (HSCT):

  • Curative option for many severe combined immunodeficiencies
  • Increasingly considered for other disorders (e.g., CGD, DOCK8 deficiency)
  • Outcomes best when performed early before onset of significant complications

Gene Therapy:

  • Emerging option for some disorders (e.g., CGD)
  • Involves ex vivo modification of autologous hematopoietic stem cells
  • Still largely experimental for many conditions

Management of Complications:

  • Aggressive treatment of infections
  • Management of autoimmune manifestations (e.g., corticosteroids, immunosuppressants)
  • Treatment of allergic conditions (e.g., antihistamines, topical steroids, biologics)
  • Nutritional support and management of gastrointestinal complications
  • Regular screening and early intervention for malignancies

Targeted Therapies:

  • Interferon-gamma for CGD
  • G-CSF for neutropenia in some conditions
  • Monoclonal antibodies (e.g., rituximab) for specific complications
  • JAK inhibitors for some cases of STAT1 gain-of-function mutations

Supportive Care:

  • Pulmonary hygiene measures (e.g., chest physiotherapy, nebulized hypertonic saline)
  • Psychosocial support for patients and families
  • Educational support and vocational guidance
  • Genetic counseling for family planning

Lifestyle Management:

  • Avoidance of live vaccines
  • Proper hygiene practices
  • Dietary modifications as needed (e.g., in cases of inflammatory bowel disease)
  • Exercise and physical therapy to maintain overall health and manage complications

Emerging Therapies:

  • CAR-T cell therapy for EBV-associated lymphoproliferative disease
  • Enzyme replacement therapy for specific metabolic defects associated with immunodeficiency
  • CRISPR-based gene editing approaches (experimental)

Long-term Follow-up:

  • Regular monitoring of immune function and treatment efficacy
  • Surveillance for long-term complications (e.g., organ damage, malignancies)
  • Adjustment of treatment plans based on clinical course and new available therapies
  • Transition planning from pediatric to adult care


Defects of Cellular Immunity in Pediatric Age
  1. Q: What is the primary function of T cells in the immune system? A: To provide cell-mediated immunity and help regulate other immune cells
  2. Q: Which cytokine deficiency is associated with Mendelian Susceptibility to Mycobacterial Disease (MSMD)? A: Interferon-gamma (IFN-γ) or its receptor
  3. Q: What is the most severe form of cellular immunodeficiency? A: Severe Combined Immunodeficiency (SCID)
  4. Q: Which infections are particularly common in children with T cell deficiencies? A: Opportunistic infections, viral infections, and fungal infections
  5. Q: What is the role of the thymus in cellular immunity? A: It is the site of T cell development and maturation
  6. Q: Which genetic syndrome is associated with thymic aplasia or hypoplasia? A: DiGeorge syndrome (22q11.2 deletion syndrome)
  7. Q: What is the characteristic immunologic finding in Hyper-IgM syndrome type 1? A: Defective CD40 ligand expression on T cells
  8. Q: Which test is used to assess T cell receptor diversity? A: T cell receptor (TCR) spectratyping or next-generation sequencing
  9. Q: What is the primary mechanism of action for PD-1 inhibitors in cancer immunotherapy? A: They enhance T cell activation by blocking inhibitory signals
  10. Q: Which cytokine is deficient in patients with STAT3 deficiency (Hyper-IgE syndrome)? A: IL-17
  11. Q: What is the role of regulatory T cells (Tregs) in the immune system? A: To maintain self-tolerance and prevent autoimmune diseases
  12. Q: Which genetic defect is associated with IPEX syndrome (Immunodysregulation Polyendocrinopathy Enteropathy X-linked)? A: FOXP3 gene mutation
  13. Q: What is the primary cellular defect in Wiskott-Aldrich syndrome? A: Defective actin cytoskeleton reorganization in immune cells
  14. Q: Which test is used to assess T cell proliferation in response to stimuli? A: Lymphocyte proliferation assay
  15. Q: What is the role of CD8+ T cells in cellular immunity? A: To recognize and destroy virus-infected cells and tumor cells
  16. Q: Which cytokine is critical for T helper 1 (Th1) cell differentiation? A: IL-12
  17. Q: What is the primary cellular defect in Chronic Granulomatous Disease (CGD)? A: Defective oxidative burst in phagocytes
  18. Q: Which test is used to assess T cell function in response to specific antigens? A: Antigen-specific T cell proliferation assay
  19. Q: What is the role of Natural Killer T (NKT) cells in the immune system? A: To bridge innate and adaptive immunity and regulate immune responses
  20. Q: Which cytokine deficiency is associated with increased susceptibility to herpes simplex virus (HSV) encephalitis? A: Defects in the TLR3-IFN pathway
  21. Q: What is the primary cellular defect in Chediak-Higashi syndrome? A: Defective lysosomal trafficking and function in immune cells
  22. Q: Which test is used to assess T cell activation markers? A: Flow cytometry for CD25, CD69, and HLA-DR expression
  23. Q: What is the role of memory T cells in cellular immunity? A: To provide rapid and enhanced responses to previously encountered antigens
  24. Q: Which cytokine is critical for the development and function of Th17 cells? A: IL-23
  25. Q: What is the primary cellular defect in X-linked lymphoproliferative disease (XLP)? A: Defective control of Epstein-Barr virus (EBV) infection by T and NK cells
  26. Q: Which test is used to assess T cell receptor signaling? A: Calcium flux assay
  27. Q: What is the role of γδ T cells in cellular immunity? A: To provide rapid responses to stress antigens and maintain epithelial barrier integrity
  28. Q: Which genetic defect is associated with DOCK8 deficiency? A: Mutations in the DOCK8 gene, leading to combined immunodeficiency
  29. Q: What is the primary cellular defect in CARD11 deficiency? A: Impaired NF-κB activation in T and B cells
  30. Q: Which test is used to assess T cell exhaustion? A: Flow cytometry for PD-1, TIM-3, and LAG-3 expression
Combined Immunodeficiency in Pediatric Age
  1. Q: What is the definition of combined immunodeficiency? A: A group of disorders characterized by defects in both cellular and humoral immunity
  2. Q: Which is the most severe form of combined immunodeficiency? A: Severe Combined Immunodeficiency (SCID)
  3. Q: What is the typical age of onset for symptoms in SCID? A: Within the first few months of life
  4. Q: Which infections are particularly common in children with combined immunodeficiency? A: Opportunistic infections, including Pneumocystis jirovecii pneumonia, and severe viral infections
  5. Q: What is the gold standard treatment for SCID? A: Hematopoietic stem cell transplantation (HSCT)
  6. Q: Which genetic defect is associated with X-linked SCID? A: Mutations in the IL2RG gene encoding the common gamma chain
  7. Q: What is the characteristic immunologic finding in Omenn syndrome? A: Presence of oligoclonal, activated T cells with absence of B cells
  8. Q: Which test is used for newborn screening of SCID? A: T cell receptor excision circle (TREC) assay
  9. Q: What is the role of enzyme replacement therapy in Adenosine Deaminase (ADA) deficiency? A: To detoxify metabolites and improve immune function
  10. Q: Which clinical feature is often associated with Ataxia-Telangiectasia? A: Progressive cerebellar ataxia and oculocutaneous telangiectasias
  11. Q: What is the primary cellular defect in ZAP70 deficiency? A: Impaired T cell receptor signaling, particularly in CD8+ T cells
  12. Q: Which combined immunodeficiency is associated with short-limbed dwarfism? A: Cartilage-Hair Hypoplasia
  13. Q: What is the characteristic feature of MHC class II deficiency? A: Absence of HLA-DR, DP, and DQ expression on immune cells
  14. Q: Which test is used to assess T cell function in combined immunodeficiencies? A: Lymphocyte proliferation assay in response to mitogens and antigens
  15. Q: What is the role of gene therapy in treating certain forms of SCID? A: To introduce functional copies of the defective gene into hematopoietic stem cells
  16. Q: Which combined immunodeficiency is associated with DNA repair defects? A: Nijmegen breakage syndrome
  17. Q: What is the primary cellular defect in DOCK8 deficiency? A: Impaired T cell and NK cell cytoskeletal rearrangement and migration
  18. Q: Which clinical feature is often associated with DiGeorge syndrome? A: Cardiac defects, hypocalcemia, and characteristic facial features
  19. Q: What is the role of newborn SCID screening in managing combined immunodeficiencies? A: To enable early diagnosis and treatment before the onset of severe infections
  20. Q: Which combined immunodeficiency is associated with albinism? A: Chediak-Higashi syndrome
  21. Q: What is the primary cellular defect in ORAI1 deficiency? A: Impaired store-operated calcium entry in T cells
  22. Q: Which test is used to assess B cell function in combined immunodeficiencies? A: Measurement of serum immunoglobulins and specific antibody responses to vaccines
  23. Q: What is the role of prophylactic antibiotics in managing combined immunodeficiencies? A: To prevent opportunistic infections before definitive treatment
  24. Q: Which combined immunodeficiency is associated with autoimmune polyendocrinopathy? A: APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)
  25. Q: What is the primary cellular defect in RAG1/2 deficiency? A: Impaired V(D)J recombination, affecting both T and B cell development
  26. Q: Which test is used to assess NK cell function in combined immunodeficiencies? A: NK cell cytotoxicity assay
  27. Q: What is the role of intravenous immunoglobulin (IVIG) in managing combined immunodeficiencies? A: To provide passive immunity and prevent infections
  28. Q: Which combined immunodeficiency is associated with thrombocytopenia and eczema? A: Wiskott-Aldrich syndrome
  29. Q: What is the primary cellular defect in STAT3 deficiency (Hyper-IgE syndrome)? A: Impaired Th17 cell differentiation and function
  30. Q: Which test is used to assess thymic output in combined immunodeficiencies? A: Measurement of T cell receptor excision circles (TRECs)


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