Primary Defects of Antibody Production in Children

Topic Introduction X-linked Agammaglobulinemia Common Variable Immunodeficiency Selective IgA Deficiency Hyper-IgM Syndromes Specific Antibody Deficiency Transient Hypogammaglobulinemia of Infancy Good Syndrome Diagnosis and Management Emerging Therapies

Introduction to Primary Defects of Humoral Immunity in Children

Primary defects of humoral immunity, also known as antibody deficiencies, constitute a heterogeneous group of inherited disorders characterized by impaired production of antibodies. These conditions result in an increased susceptibility to infections, particularly those caused by encapsulated bacteria, and can lead to significant morbidity if left undiagnosed or untreated.

Key Concepts:

• Humoral immunity is mediated by B lymphocytes and plasma cells, which produce antibodies (immunoglobulins).
• Antibodies play crucial roles in pathogen neutralization, opsonization, complement activation, and antibody-dependent cell-mediated cytotoxicity.
• Primary antibody deficiencies can affect different stages of B cell development, maturation, and function.
• These disorders are typically diagnosed in childhood but can sometimes present in adults.
• The spectrum of clinical manifestations ranges from asymptomatic to severe, recurrent infections.

Epidemiology:

Primary antibody deficiencies are the most common type of primary immunodeficiencies, accounting for approximately 50-60% of all cases. The prevalence varies among different populations and specific disorders, with some being relatively common (e.g., Selective IgA Deficiency) and others being extremely rare (e.g., X-linked Agammaglobulinemia).

Classification:

Primary humoral immunodeficiencies can be classified based on the stage of B cell development affected or the specific molecular defect involved. The International Union of Immunological Societies (IUIS) provides a comprehensive classification system that is updated regularly.

X-linked Agammaglobulinemia (XLA)

X-linked agammaglobulinemia, also known as Bruton's agammaglobulinemia, is a rare genetic disorder affecting male children. It is characterized by a severe deficiency or absence of mature B lymphocytes and all classes of immunoglobulins.

Pathophysiology:

• Caused by mutations in the BTK gene (Bruton's tyrosine kinase) on the X chromosome
• BTK is essential for B cell development and maturation
• Results in arrested B cell development at the pre-B cell stage in the bone marrow
• Leads to absence of mature B cells in peripheral blood and lymphoid tissues

Clinical Presentation:

• Typically presents in male infants after 6 months of age when maternal antibodies wane
• Recurrent bacterial infections:
  • Otitis media
  • Sinusitis
  • Pneumonia
  • Septicemia
• Increased susceptibility to enteroviruses (can cause chronic meningoencephalitis)
• Absence of tonsils and lymph nodes
• Growth retardation and failure to thrive
• Neutropenia in some cases

Laboratory Findings:

• Markedly decreased or absent serum immunoglobulins (IgG, IgA, IgM, IgE)
• Absence of B cells in peripheral blood (<1% CD19+ or CD20+ cells)
• Normal T cell numbers and function
• Absent isohemagglutinins
• Poor or absent antibody responses to vaccines

Genetics and Inheritance:

XLA is an X-linked recessive disorder. Affected males inherit the mutated BTK gene from their carrier mothers. Female carriers are generally asymptomatic but may have subtle immunological abnormalities.

Differential Diagnosis:

• Autosomal recessive agammaglobulinemia (mutations in μ heavy chain, λ5, Igα, Igβ, or BLNK)
• Common Variable Immunodeficiency (CVID)
• Hyper-IgM syndrome

Common Variable Immunodeficiency (CVID)

Common Variable Immunodeficiency is the most common symptomatic primary immunodeficiency. It is characterized by hypogammaglobulinemia and impaired antibody responses to antigens, with a heterogeneous clinical presentation.

Pathophysiology:

• Heterogeneous disorder with various genetic mutations identified:
  • ICOS (Inducible T-cell COStimulator)
  • CD19
  • CD20
  • CD81
  • TNFRSF13B (TACI)
  • TNFRSF13C (BAFF-R)
  • NFKB2
  • PIK3CD
• Defects in B cell differentiation and antibody production
• Some patients also have T cell abnormalities
• Impaired germinal center formation and somatic hypermutation

Clinical Presentation:

• Variable age of onset, often in late childhood or early adulthood
• Recurrent sinopulmonary infections:
  • Pneumonia
  • Bronchitis
  • Sinusitis
  • Otitis media
• Gastrointestinal manifestations:
  • Chronic diarrhea
  • Malabsorption
  • Inflammatory bowel disease-like symptoms
• Increased risk of autoimmune diseases:
  • Immune thrombocytopenia
  • Autoimmune hemolytic anemia
  • Rheumatoid arthritis
  • Vitiligo
• Higher incidence of malignancies, especially lymphomas
• Granulomatous disease in some patients (lungs, liver, spleen)
• Bronchiectasis as a long-term complication

Laboratory Findings:

• Low serum IgG, often with low IgA and/or IgM
• Poor antibody responses to vaccines (protein and polysaccharide antigens)
• Variable B cell numbers (can be normal, low, or elevated)
• Impaired B cell differentiation into memory and plasma cells
• Reduced switched memory B cells (CD27+IgD-)
• T cell abnormalities in some patients (reduced T cell proliferation, Treg dysfunction)

Diagnosis:

Diagnosis is based on clinical presentation, immunoglobulin levels, and exclusion of other causes of hypogammaglobulinemia. The European Society for Immunodeficiencies (ESID) and the Pan-American Group for Immunodeficiency (PAGID) have established diagnostic criteria for CVID.

Selective IgA Deficiency

Selective IgA Deficiency is the most common primary immunodeficiency, characterized by an isolated absence of IgA with normal levels of other immunoglobulin isotypes. Its prevalence varies among populations, ranging from 1:143 to 1:18,500.

Pathophysiology:

• Exact mechanism unknown, likely multifactorial
• Defect in B cell differentiation into IgA-producing plasma cells
• Associated with certain HLA haplotypes (HLA-A1, B8, DR3)
• Possible roles for TACI mutations and regulatory T cell dysfunction

Clinical Presentation:

• Many individuals are asymptomatic (50-70%)
• Increased susceptibility to infections:
  • Recurrent sinopulmonary infections
  • Gastrointestinal infections
• Higher incidence of autoimmune disorders:
  • Celiac disease
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Type 1 diabetes mellitus
• Allergic diseases more common:
  • Allergic rhinitis
  • Asthma
  • Food allergies
• Increased risk of anaphylaxis with blood products containing IgA

Laboratory Findings:

• Serum IgA <7 mg/dL in individuals >4 years of age
• Normal levels of IgG and IgM
• Normal B and T cell numbers
• Some patients may have anti-IgA antibodies
• Normal antibody responses to vaccines (except for some mucosal vaccines)

Diagnosis:

Diagnosis is based on serum IgA levels and exclusion of other causes of hypogammaglobulinemia. It's important to rule out transient hypogammaglobulinemia of infancy and to consider the possibility of progression to CVID.

Management:

• Most patients do not require specific treatment
• Prompt treatment of infections
• Prophylactic antibiotics in cases of recurrent infections
• Management of associated autoimmune or allergic conditions
• Avoidance of blood products containing IgA in patients with anti-IgA antibodies

Hyper-IgM Syndromes

Hyper-IgM syndromes are a group of rare primary immunodeficiencies characterized by normal or elevated serum IgM levels with markedly decreased IgG, IgA, and IgE due to defects in immunoglobulin class-switching and somatic hypermutation.

Types and Pathophysiology:

1. X-linked Hyper-IgM Syndrome (XHIGM, CD40 ligand deficiency):
   • Most common form (65-70% of cases)
   • Mutations in the CD40LG gene on the X chromosome
   • Impaired T cell-B cell interactions
2. Autosomal Recessive Hyper-IgM due to CD40 deficiency:
   • Mutations in the CD40 gene
   • Similar clinical features to XHIGM
3. Autosomal Recessive Hyper-IgM due to AID deficiency:
   • Mutations in the AICDA gene (Activation-Induced Cytidine Deaminase)
   • Defective class-switch recombination and somatic hypermutation
4. Autosomal Recessive Hyper-IgM due to UNG deficiency:
   • Mutations in the UNG gene (Uracil-DNA Glycosylase)
   • Impaired class-switch recombination
5. Autosomal Recessive Hyper-IgM due to PMS2 deficiency:
   • Mutations in the PMS2 gene
   • Defects in DNA mismatch repair and class-switch recombination

Clinical Presentation:

• Onset usually in infancy or early childhood
• Recurrent sinopulmonary infections
• Opportunistic infections:
  • Pneumocystis jirovecii pneumonia (especially in CD40L and CD40 deficiency)
  • Cryptosporidium (can cause sclerosing cholangitis)
• Neutropenia (in CD40L deficiency)
• Autoimmune disorders:
  • Autoimmune cytopenias (thrombocytopenia, hemolytic anemia)
  • Inflammatory bowel disease
  • Arthritis
  • Autoimmune hepatitis
• Increased risk of lymphoid hyperplasia and malignancies:
  • Lymphomas (particularly in CD40L and CD40 deficiency)
  • Carcinomas of the liver, pancreas, and biliary tract
• Growth retardation and failure to thrive
• Oral and rectal ulcers
• Chronic liver disease (especially in CD40L deficiency)

Laboratory Findings:

• Low serum IgG and IgA with normal or elevated IgM
• Impaired antibody responses to protein antigens
• Normal B cell numbers but defective memory B cells
• T cell abnormalities in CD40L and CD40 deficiency:
  • Reduced CD4+ T cell numbers
  • Impaired T cell proliferation to specific antigens
  • Neutropenia (in CD40L deficiency)
  • Elevated liver enzymes in cases with liver involvement

Diagnosis:

Diagnosis is based on clinical presentation, immunoglobulin profile, and specific genetic testing:

• Flow cytometry for CD40L expression on activated T cells (for XHIGM)
• Genetic sequencing for mutations in CD40LG, CD40, AICDA, UNG, or PMS2 genes
• In vitro B cell class-switching assays
• T cell proliferation assays

Management:

• Immunoglobulin replacement therapy (intravenous or subcutaneous)
• Prophylactic antibiotics (e.g., trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis)
• Prompt treatment of infections
• G-CSF for neutropenia in CD40L deficiency
• Management of autoimmune complications
• Regular screening for malignancies
• Hematopoietic stem cell transplantation (HSCT) for severe forms, especially CD40L and CD40 deficiency

Prognosis:

Prognosis varies depending on the specific genetic defect and the adequacy of treatment. HSCT can be curative for CD40L and CD40 deficiency but carries significant risks. With appropriate management, many patients can have improved quality of life and longevity, but long-term complications remain a concern.

Specific Antibody Deficiency (SAD)

Specific Antibody Deficiency is characterized by normal serum immunoglobulin levels but impaired antibody responses to specific antigens, particularly polysaccharide antigens.

Pathophysiology:

• Exact mechanism unknown
• Defect in B cell maturation or T cell help for antibody production
• May be associated with other immune dysregulations

Clinical Presentation:

• Recurrent respiratory tract infections:
  • Sinusitis
  • Otitis media
  • Pneumonia
• Increased susceptibility to infections with encapsulated bacteria
• Variable age of onset, can occur in children and adults

Laboratory Findings:

• Normal serum immunoglobulin levels (IgG, IgA, IgM)
• Poor antibody responses to polysaccharide vaccines (e.g., pneumococcal vaccine)
• Normal responses to protein antigens
• Normal B and T cell numbers

Diagnosis:

• Based on clinical history of recurrent infections
• Normal immunoglobulin levels
• Impaired response to pneumococcal vaccination:
  • <50% of serotypes reaching protective levels in children
  • <70% of serotypes reaching protective levels in adults

Management:

• Antibiotic prophylaxis for recurrent infections
• Prompt treatment of acute infections
• Immunoglobulin replacement therapy in severe cases
• Re-vaccination strategies

Transient Hypogammaglobulinemia of Infancy (THI)

Transient Hypogammaglobulinemia of Infancy is characterized by a prolonged physiological hypogammaglobulinemia beyond 6 months of age, which eventually resolves spontaneously.

Pathophysiology:

• Delayed maturation of the humoral immune system
• Possible role of maternal factors affecting fetal B cell development
• May be associated with certain HLA haplotypes

Clinical Presentation:

• Often asymptomatic
• Some infants may experience:
  • Recurrent upper respiratory tract infections
  • Otitis media
  • Gastroenteritis
• Symptoms typically resolve by 2-4 years of age

Laboratory Findings:

• Low serum IgG levels (<2 SD below mean for age)
• IgA and IgM may also be low
• Normal B and T cell numbers
• Variable responses to vaccines

Diagnosis:

Diagnosis is often retrospective, based on the resolution of hypogammaglobulinemia. It's important to exclude other causes of hypogammaglobulinemia and monitor for potential progression to other primary immunodeficiencies.

Management:

• Watchful waiting in asymptomatic cases
• Prompt treatment of infections
• Antibiotic prophylaxis in cases of recurrent infections
• Immunoglobulin replacement therapy rarely needed

Good Syndrome

Good Syndrome is a rare adult-onset immunodeficiency characterized by thymoma and hypogammaglobulinemia. While it typically affects adults, it's important for pediatricians to be aware of it for differential diagnosis.

Pathophysiology:

• Associated with thymoma (usually benign)
• Impaired T cell development and function
• B cell lymphopenia or absence
• Hypogammaglobulinemia affecting multiple immunoglobulin classes

Clinical Presentation:

• Recurrent sinopulmonary infections
• Opportunistic infections (e.g., CMV, Candida)
• Autoimmune manifestations (e.g., pure red cell aplasia, myasthenia gravis)
• Chronic diarrhea
• Symptoms related to thymoma (e.g., cough, chest pain)

Laboratory Findings:

• Hypogammaglobulinemia (low IgG, IgA, and often IgM)
• B cell lymphopenia or absence
• CD4+ T cell lymphopenia
• Inverted CD4:CD8 ratio
• Reduced T cell proliferation to mitogens

Diagnosis:

• Chest imaging (CT or MRI) to detect thymoma
• Immunoglobulin levels
• Lymphocyte subset analysis
• T cell function tests

Management:

• Surgical resection of thymoma
• Immunoglobulin replacement therapy
• Prophylactic antibiotics
• Management of autoimmune complications
• Monitoring for recurrence of thymoma

Diagnosis and Management of Primary Antibody Deficiencies

Diagnostic Approach:

1. Clinical History:
   • Pattern and frequency of infections
   • Age of onset
   • Family history of immunodeficiency
   • Presence of autoimmune or allergic manifestations
2. Physical Examination:
   • Assessment of growth and development
   • Evaluation of lymphoid tissues
   • Signs of chronic infections or complications
3. Laboratory Investigations:
   • Complete blood count with differential
   • Serum immunoglobulin levels (IgG, IgA, IgM, IgE)
   • Specific antibody responses to vaccines (protein and polysaccharide antigens)
   • Lymphocyte subsets analysis (B, T, and NK cells)
   • B cell subpopulations (naïve, memory, transitional B cells)
   • T cell function tests (proliferation assays)
   • Genetic testing for specific mutations
4. Imaging Studies:
   • Chest X-ray or CT scan to evaluate for bronchiectasis or other pulmonary complications
   • Sinus CT scan for chronic sinusitis

Management Strategies:

1. Immunoglobulin Replacement Therapy:
   • Intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG)
   • Typical starting dose: 400-600 mg/kg every 3-4 weeks for IVIG, or weekly/biweekly for SCIG
   • Goal: Maintain trough IgG levels >500-700 mg/dL
   • Adjust dose based on clinical response and trough levels
2. Antimicrobial Management:
   • Prompt and aggressive treatment of acute infections
   • Prophylactic antibiotics in selected cases (e.g., trimethoprim-sulfamethoxazole, azithromycin)
   • Antifungal prophylaxis in specific situations (e.g., fluconazole for chronic mucocutaneous candidiasis)
3. Management of Complications:
   • Pulmonary: Chest physiotherapy, bronchodilators, inhaled corticosteroids
   • Gastrointestinal: Nutritional support, management of malabsorption
   • Autoimmune: Immunosuppressive therapy as needed
4. Hematopoietic Stem Cell Transplantation (HSCT):
   • Considered for severe forms of immunodeficiency (e.g., XLA, some cases of HIGM)
   • Potential for cure but carries significant risks
   • Outcomes improving with advances in transplant techniques and supportive care
5. Supportive Care:
   • Vaccinations: Avoid live vaccines, optimize protection with inactivated vaccines
   • Nutritional support and vitamin supplementation
   • Psychosocial support for patients and families

Monitoring and Follow-up:

• Regular assessment of clinical status and infection frequency
• Periodic measurement of serum immunoglobulin levels
• Annual pulmonary function tests in patients with recurrent respiratory infections
• Screening for associated conditions (e.g., autoimmune diseases, malignancies)
• Growth and developmental monitoring in children

Emerging Therapies and Future Directions

Gene Therapy:

Gene therapy holds promise for several primary antibody deficiencies, particularly monogenic disorders like XLA.

• Lentiviral vector-mediated gene transfer:
  • Preclinical studies showing successful correction of BTK deficiency in XLA models
  • Ongoing clinical trials for XLA patients
• CRISPR/Cas9 gene editing:
  • Potential for precise genetic correction
  • Still in early stages of research for antibody deficiencies

Targeted Therapies:

• BTK inhibitors:
  • Paradoxical use in XLA to stabilize mutant BTK protein
  • Potential to enhance residual B cell function in some patients
• Recombinant CD40L:
  • Under investigation for CD40L deficiency
  • Aims to restore T cell-B cell interactions

Advanced Cellular Therapies:

• CAR-T cell therapy:
  • Potential application in EBV-associated lymphoproliferative disease in immunodeficient patients
  • Research ongoing for expanding its use in primary immunodeficiencies
• Regulatory T cell (Treg) therapy:
  • Investigational use for autoimmune complications in CVID
  • Aims to restore immune tolerance

Microbiome Modulation:

Emerging research suggests a role for the gut microbiome in immune system development and function.

• Probiotics and prebiotics:
  • Potential to enhance mucosal immunity
  • May reduce the risk of certain infections
• Fecal microbiota transplantation:
  • Under investigation for restoring gut microbiome diversity
  • Potential benefits in reducing inflammation and enhancing immunity

Improved Diagnostics:

• Next-generation sequencing panels:
  • Comprehensive genetic testing for known immunodeficiency genes
  • Potential for identifying novel genetic causes
• Functional genomics:
  • Integration of genetic data with functional immune assays
  • Improved understanding of genotype-phenotype correlations

Personalized Medicine Approaches:

• Tailored immunoglobulin replacement:
  • Optimization of dosing based on pharmacokinetics and clinical response
  • Development of subcutaneous formulations with recombinant hyaluronidase for improved absorption
• Precision antimicrobial prophylaxis:
  • Individualized approaches based on infection history and microbiome analysis
  • Development of novel antimicrobial agents with reduced resistance potential

Future Research Directions:

• Elucidation of epigenetic factors influencing antibody production
• Investigation of the role of innate lymphoid cells in humoral immunity
• Development of biomarkers for early detection and monitoring of primary antibody deficiencies
• Long-term studies on the natural history and outcomes of patients with antibody deficiencies in the era of modern therapies

X-linked Agammaglobulinemia

1. Q: What gene mutation causes X-linked Agammaglobulinemia (XLA)? A: Mutation in the Bruton tyrosine kinase (BTK) gene
2. Q: Which gender is primarily affected by XLA? A: Males
3. Q: What is the primary immunological defect in XLA? A: Failure of B-cell development, resulting in very low or absent B cells and immunoglobulins
4. Q: At what age do symptoms of XLA typically appear? A: Between 6 and 12 months of age, after maternal antibodies wane
5. Q: What types of infections are patients with XLA particularly susceptible to? A: Recurrent bacterial infections, especially of the respiratory tract
6. Q: Which laboratory finding is characteristic of XLA? A: Very low or absent serum immunoglobulins (IgG, IgA, and IgM)
7. Q: What is the standard treatment for XLA? A: Lifelong immunoglobulin replacement therapy
8. Q: How is immunoglobulin replacement typically administered in XLA patients? A: Intravenously (IVIG) or subcutaneously (SCIG)
9. Q: What complication can occur in XLA patients infected with enteroviruses? A: Chronic meningoencephalitis
10. Q: Why do XLA patients have small or absent tonsils and lymph nodes? A: Due to the lack of B cells in lymphoid tissues
11. Q: What is the life expectancy for well-managed XLA patients? A: Near normal with appropriate treatment
12. Q: Which vaccine types are contraindicated in XLA patients? A: Live attenuated vaccines
13. Q: What is the role of antibiotics in managing XLA patients? A: Prophylactic use to prevent infections and prompt treatment of acute infections
14. Q: How does XLA affect T-cell function? A: T-cell function is generally normal in XLA
15. Q: What percentage of male patients with agammaglobulinemia have XLA? A: Approximately 85%
16. Q: What is the risk of passing XLA to offspring for a female carrier? A: 50% chance of passing it to male offspring
17. Q: What imaging finding might be seen in the lungs of XLA patients? A: Bronchiectasis due to recurrent respiratory infections
18. Q: What is the typical B-cell count in the peripheral blood of XLA patients? A: Less than 2% of normal or often undetectable
19. Q: What autoimmune complication can occur in some XLA patients? A: Inflammatory bowel disease-like symptoms
20. Q: What is a potential curative treatment for XLA being researched? A: Gene therapy to correct the BTK gene mutation

Common Variable Immunodeficiency

1. Q: What is Common Variable Immunodeficiency (CVID)? A: A primary immunodeficiency characterized by hypogammaglobulinemia and impaired antibody production
2. Q: At what age is CVID typically diagnosed? A: Usually in adulthood, but can occur at any age
3. Q: What are the primary immunoglobulins affected in CVID? A: IgG, IgA, and often IgM
4. Q: What is the most common clinical presentation of CVID? A: Recurrent sinopulmonary infections
5. Q: What gastrointestinal complication is common in CVID patients? A: Chronic diarrhea and malabsorption
6. Q: What is the standard treatment for CVID? A: Immunoglobulin replacement therapy
7. Q: What is the risk of malignancy in CVID patients? A: Increased risk, especially lymphoma and gastric cancer
8. Q: What autoimmune conditions are commonly associated with CVID? A: Autoimmune cytopenias, such as immune thrombocytopenia and autoimmune hemolytic anemia
9. Q: What lung complication can develop in CVID patients? A: Bronchiectasis
10. Q: What is granulomatous-lymphocytic interstitial lung disease (GLILD) in CVID? A: A non-infectious lung complication characterized by granulomas and lymphocytic infiltration
11. Q: How does CVID differ from X-linked agammaglobulinemia in terms of B-cell numbers? A: CVID patients usually have normal or near-normal B-cell numbers, unlike XLA
12. Q: What percentage of CVID cases have an identified genetic cause? A: Approximately 10-20%
13. Q: What is the role of vaccinations in diagnosing CVID? A: Poor response to vaccinations is a diagnostic criterion for CVID
14. Q: What is the typical frequency of immunoglobulin replacement therapy in CVID? A: Every 3-4 weeks for IVIG, or weekly/biweekly for SCIG
15. Q: What is the goal IgG trough level for CVID patients on replacement therapy? A: Usually >700 mg/dL, but individualized based on clinical response
16. Q: What is the risk of developing CVID for first-degree relatives of affected individuals? A: Approximately 10-20%
17. Q: What is the role of prophylactic antibiotics in CVID management? A: May be used in patients with recurrent infections despite adequate Ig replacement
18. Q: What is the prognosis for CVID patients with appropriate treatment? A: Generally good, but can be affected by complications and delayed diagnosis
19. Q: What is the recommended screening for CVID patients to monitor for complications? A: Regular pulmonary function tests, chest imaging, and gastrointestinal cancer screening
20. Q: What is the role of rituximab in some CVID patients? A: Treatment of autoimmune complications and some forms of GLILD

Selective IgA Deficiency

1. Q: What is Selective IgA Deficiency? A: A primary immunodeficiency characterized by very low or absent serum IgA with normal IgG and IgM levels
2. Q: What is the prevalence of Selective IgA Deficiency in the general population? A: Approximately 1 in 600 individuals
3. Q: What is the typical serum IgA level in Selective IgA Deficiency? A: Less than 7 mg/dL (0.07 g/L) in individuals over 4 years of age
4. Q: What percentage of individuals with Selective IgA Deficiency are asymptomatic? A: Approximately 85-90%
5. Q: What types of infections are symptomatic individuals with Selective IgA Deficiency prone to? A: Recurrent sinopulmonary and gastrointestinal infections
6. Q: What autoimmune conditions are associated with Selective IgA Deficiency? A: Celiac disease, systemic lupus erythematosus, and thyroiditis
7. Q: What is the risk of anaphylaxis in IgA-deficient individuals receiving blood products? A: Increased risk due to potential development of anti-IgA antibodies
8. Q: How is Selective IgA Deficiency inherited? A: Variable inheritance pattern, often autosomal dominant with incomplete penetrance
9. Q: What is the relationship between Selective IgA Deficiency and Common Variable Immunodeficiency (CVID)? A: Some individuals with Selective IgA Deficiency may progress to CVID
10. Q: What is the standard treatment for symptomatic Selective IgA Deficiency? A: Prompt treatment of infections; immunoglobulin replacement is not typically used
11. Q: Why is immunoglobulin replacement therapy not routinely used in Selective IgA Deficiency? A: IgG levels are normal, and most preparations lack IgA
12. Q: What precaution should be taken for IgA-deficient individuals during blood transfusions? A: Use of IgA-depleted blood products when possible
13. Q: What is the role of secretory IgA in mucosal immunity? A: It provides first-line defense against pathogens at mucosal surfaces
14. Q: Can individuals with Selective IgA Deficiency produce IgA in saliva or breast milk? A: Generally no, both serum and secretory IgA are affected
15. Q: What is the recommended approach to vaccinations in Selective IgA Deficiency? A: Follow routine vaccination schedules, including live vaccines if otherwise healthy
16. Q: What is the risk of malignancy in Selective IgA Deficiency? A: Slightly increased risk, particularly for gastrointestinal and lymphoid malignancies
17. Q: How does Selective IgA Deficiency affect pregnancy? A: Generally no significant impact, but may increase risk of some pregnancy-related complications
18. Q: What is the prognosis for individuals with Selective IgA Deficiency? A: Generally good, especially for asymptomatic individuals
19. Q: What is the recommended monitoring for individuals with Selective IgA Deficiency? A: Regular check-ups and screening for associated conditions, especially autoimmune disorders
20. Q: Can Selective IgA Deficiency resolve spontaneously? A: Rarely, some children may develop normal IgA levels over time

Hyper-IgM Syndromes

1. Q: What are Hyper-IgM Syndromes? A: A group of primary immunodeficiencies characterized by normal or elevated IgM levels with low IgG, IgA, and IgE
2. Q: What is the most common genetic cause of Hyper-IgM Syndrome? A: Mutations in the CD40 ligand (CD40L) gene, causing X-linked Hyper-IgM Syndrome
3. Q: What cellular interaction is impaired in CD40L deficiency? A: T cell-B cell interaction necessary for class-switch recombination and somatic hypermutation
4. Q: What are other genetic causes of Hyper-IgM Syndromes? A: Mutations in CD40, AID (activation-induced cytidine deaminase), UNG (uracil DNA glycosylase), and INO80
5. Q: What is the inheritance pattern of CD40L deficiency? A: X-linked recessive
6. Q: What types of infections are patients with Hyper-IgM Syndromes susceptible to? A: Recurrent sinopulmonary infections, opportunistic infections (e.g., Pneumocystis jirovecii pneumonia)
7. Q: What opportunistic infection is particularly common in CD40L deficiency? A: Pneumocystis jirovecii pneumonia
8. Q: What gastrointestinal complication is common in Hyper-IgM Syndromes? A: Chronic diarrhea, often due to Cryptosporidium infection
9. Q: What liver complication can occur in patients with CD40L deficiency? A: Sclerosing cholangitis, often associated with Cryptosporidium infection
10. Q: What is the standard treatment for Hyper-IgM Syndromes? A: Immunoglobulin replacement therapy and prophylactic antibiotics
11. Q: Why is Pneumocystis jirovecii prophylaxis important in Hyper-IgM Syndromes? A: Due to impaired T cell function, especially in CD40L deficiency
12. Q: What is the role of hematopoietic stem cell transplantation (HSCT) in Hyper-IgM Syndromes? A: Potentially curative treatment, especially for CD40L and CD40 deficiencies
13. Q: How does Hyper-IgM Syndrome affect neutrophil function? A: Neutrophil function is generally normal, except in rare variants
14. Q: What malignancies are patients with Hyper-IgM Syndromes at increased risk for? A: Lymphomas and carcinomas, especially of the liver and biliary tract
15. Q: How does CD40L deficiency affect CD8+ T cell function? A: CD8+ T cell function is generally preserved
16. Q: What is the life expectancy for untreated patients with CD40L deficiency? A: Often less than 25 years without treatment
17. Q: How does AID deficiency differ clinically from CD40L deficiency? A: AID deficiency typically has a milder clinical course and does not affect T cell function
18. Q: What autoimmune complications can occur in Hyper-IgM Syndromes? A: Autoimmune cytopenias, inflammatory bowel disease, and arthritis
19. Q: How is the diagnosis of Hyper-IgM Syndrome confirmed? A: Genetic testing for known mutations and functional assays of class-switch recombination
20. Q: What is the role of gene therapy in treating Hyper-IgM Syndromes? A: Experimental approach being researched, particularly for CD40L deficiency

Specific Antibody Deficiency

1. Q: What is Specific Antibody Deficiency (SAD)? A: An immune deficiency characterized by normal immunoglobulin levels but impaired antibody responses to specific antigens, particularly polysaccharides
2. Q: What type of antigens do patients with SAD have difficulty responding to? A: Polysaccharide antigens, particularly those found in encapsulated bacteria
3. Q: What are the typical immunoglobulin levels in SAD? A: Normal levels of IgG, IgA, IgM, and IgE
4. Q: What is the most common clinical presentation of SAD? A: Recurrent respiratory tract infections, particularly sinusitis and pneumonia
5. Q: Which encapsulated bacteria are SAD patients particularly susceptible to? A: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis
6. Q: How is SAD diagnosed? A: By measuring antibody responses to pneumococcal polysaccharide vaccine (PPV23)
7. Q: What is considered an adequate response to PPV23 in adults? A: A 2-fold increase in antibody titers to at least 70% of serotypes tested
8. Q: What is the first-line treatment for patients with mild SAD? A: Prophylactic antibiotics and aggressive treatment of infections
9. Q: When is immunoglobulin replacement therapy considered in SAD? A: For patients with severe or frequent infections despite antibiotic prophylaxis
10. Q: What is the role of protein-conjugate vaccines in managing SAD? A: They can help improve antibody responses to polysaccharide antigens
11. Q: Can SAD occur in children? A: Yes, but diagnosis can be challenging due to immature immune responses in young children
12. Q: What is the relationship between SAD and Common Variable Immunodeficiency (CVID)? A: Some patients with SAD may progress to CVID over time
13. Q: What lung complication can develop in patients with untreated SAD? A: Bronchiectasis
14. Q: Is SAD considered a primary or secondary immunodeficiency? A: It can be either primary or secondary to other conditions
15. Q: What secondary causes can lead to SAD? A: Conditions such as asplenia, chronic lung disease, and immunosuppressive treatments
16. Q: How does SAD differ from selective IgA deficiency? A: In SAD, IgA levels are normal, but specific antibody production is impaired
17. Q: What is the prognosis for patients with SAD? A: Generally good with appropriate management, but varies depending on severity and complications
18. Q: Can SAD resolve spontaneously? A: In some cases, especially in children, SAD can improve over time
19. Q: What is the recommended follow-up for patients with SAD? A: Regular monitoring of infection frequency, lung function, and periodic reassessment of vaccine responses

Transient Hypogammaglobulinemia of Infancy

1. Q: What is Transient Hypogammaglobulinemia of Infancy (THI)? A: A temporary condition in infants characterized by low immunoglobulin levels that eventually normalize
2. Q: At what age is THI typically diagnosed? A: Between 3 and 6 months of age
3. Q: What is the primary immunoglobulin affected in THI? A: IgG
4. Q: What causes the initial low IgG levels in THI? A: Delayed onset of the infant's own IgG production after maternal antibodies have decreased
5. Q: By what age do most cases of THI resolve? A: By 2 to 4 years of age
6. Q: What is the most common clinical presentation of THI? A: Recurrent respiratory tract infections
7. Q: How is THI diagnosed? A: Low serum IgG levels for age with normal or near-normal B and T cell numbers
8. Q: What other immunoglobulins may be affected in some cases of THI? A: IgA and sometimes IgM
9. Q: What is the standard treatment approach for THI? A: Watchful waiting with prompt treatment of infections
10. Q: When is immunoglobulin replacement therapy considered in THI? A: In severe cases with recurrent or serious infections
11. Q: What is the role of prophylactic antibiotics in THI management? A: May be used in cases of recurrent infections, but not routinely recommended
12. Q: How does THI differ from severe combined immunodeficiency (SCID)? A: THI has normal T cell function and numbers, unlike SCID
13. Q: What is the prognosis for children with THI? A: Excellent, with most cases resolving spontaneously
14. Q: Can THI progress to other immunodeficiencies? A: Rarely, some cases may progress to common variable immunodeficiency (CVID)
15. Q: What vaccinations are recommended for children with THI? A: All routine vaccinations, including live vaccines if T cell function is normal
16. Q: How often should immunoglobulin levels be monitored in THI? A: Every 3-6 months until normalization
17. Q: What is the role of genetic testing in THI? A: Generally not indicated unless there's suspicion of another underlying immunodeficiency
18. Q: Can THI affect antibody responses to vaccines? A: Responses may be reduced but usually improve as IgG levels normalize
19. Q: What factors may predispose to THI? A: Premature birth and familial predisposition have been suggested
20. Q: How does breastfeeding affect the course of THI? A: Breastfeeding may provide additional passive immunity and potentially mitigate symptoms

Good Syndrome

1. Q: What is Good Syndrome? A: A rare adult-onset immunodeficiency associated with thymoma and hypogammaglobulinemia
2. Q: At what age is Good Syndrome typically diagnosed? A: Usually in the 4th or 5th decade of life
3. Q: What are the three main components of Good Syndrome? A: Thymoma, hypogammaglobulinemia, and reduced or absent B cells
4. Q: How does Good Syndrome affect T cell populations? A: It can cause reduced CD4+ T cells and inverted CD4:CD8 ratio
5. Q: What types of infections are patients with Good Syndrome susceptible to? A: Recurrent sinopulmonary infections, opportunistic infections, and chronic mucocutaneous candidiasis
6. Q: What opportunistic infection is particularly common in Good Syndrome? A: Cytomegalovirus (CMV) infection
7. Q: What autoimmune conditions are associated with Good Syndrome? A: Myasthenia gravis, pure red cell aplasia, and pernicious anemia
8. Q: How is Good Syndrome diagnosed? A: Presence of thymoma with hypogammaglobulinemia and reduced or absent B cells
9. Q: What is the standard treatment for the thymoma component of Good Syndrome? A: Surgical resection of the thymoma
10. Q: Does thymoma removal usually reverse the immunodeficiency in Good Syndrome? A: No, the immunodeficiency typically persists after thymoma removal
11. Q: What is the primary treatment for the immunodeficiency in Good Syndrome? A: Immunoglobulin replacement therapy
12. Q: Why is CMV prophylaxis important in Good Syndrome? A: Due to high susceptibility to severe CMV infections
13. Q: What is the prognosis for patients with Good Syndrome? A: Generally poor, with increased mortality compared to other adult-onset immunodeficiencies
14. Q: How does Good Syndrome differ from Common Variable Immunodeficiency (CVID)? A: Good Syndrome is associated with thymoma and has more severe T cell defects
15. Q: What gastrointestinal complications are common in Good Syndrome? A: Chronic diarrhea, malabsorption, and inflammatory bowel disease-like symptoms
16. Q: Can Good Syndrome occur in children? A: No, it is exclusively an adult-onset condition
17. Q: What is the role of immunosuppression in managing Good Syndrome? A: May be used to treat associated autoimmune complications
18. Q: How does Good Syndrome affect vaccine responses? A: Patients typically have poor responses to both protein and polysaccharide vaccines
19. Q: What monitoring is recommended for patients with Good Syndrome? A: Regular checks for infections, autoimmune complications, and thymoma recurrence
20. Q: Is there a genetic predisposition to Good Syndrome? A: No clear genetic basis has been identified; it is considered an acquired immunodeficiency