Mark Ballow, MD

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Mark Ballow, MD
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IgG subclass and Selective Antibody Deficiency
Disorders

• Mark Ballow, MD
• Division of Allergy. Immunology and Pediatric
  Rheumatology
• Women and Childrens Hospital of Buffalo
• SUNY Buffalo
• School of Medicine and Biomedical Sciences

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Relative Distribution of the Primary
Immunodeficiencies
Complement Deficiency
Phagocytic
Cellular Deficiency
Antibody Deficiencies
Combined Immunodeficiency
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Antibody Deficiency Disorders

• Agammaglobulinemia with absent B-cells
• Infantile x-linked (Brutons disease)
• Tyrosine kinase deficiency
• Defects of pre-B-cell receptor
• Defects of B-cell signaling pathway
• Transient hypogammaglobulinemia of infancy
• Isolated immunoglobulin deficiency
• IgA deficiency
• IgM deficiency
• X-linked and autosomal recessive forms of Hyper
  IgM Syndrome
• Common variable immunodeficiency
• ICOS deficiency
• Diminished switched memory B-cells
• TACI defects
• IgG subclass deficiency
• Selective antibody deficiency with normal
  immunoglobulins

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What are the serum immunoglobulins and IgG
subclasses
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Figure 4-18
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The IgG subclass with the shortest half-life is

• A. IgG1
• B. IgG2
• C. IgG3
• D. IgG4

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Figure 4-17 part 1 of 2
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Which of the following IgG subclasses activates
complement the best?

• A. IgG1
• B. IgG2
• C. IgG3
• D. IgG4

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Figure 4-17 part 2 of 2
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Figure 11-11
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Serum Immunoglobulin Levels

• Age related differences are significant and must
  be considered for each evaluation
• Normal range 95 confidence interval
• Geometric mean 2 SD
• Total immunoglobulin level is the net of
  production, consumption, and loss

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Specific Antibody Response
Evaluate specific antibody response to protein
and carbohydrate by obtaining pre- and 4 week
post-immunization serum to evaluate antibody
response to the immunization
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IgG Subclass Levels

• Normal range varies
• Varies with age-
• IgG2 and IgG4 mature later than other IgG
  subclasses
• Deficiency described statistically by normal
  distribution in the general population
• 2 S.D. below the mean (average)
• Antibodies to polysaccharide antigens are largely
  in the IgG2 subclass
• These antibodies are not readily made until after
  age 2 unless given a conjugate vaccine, e.g.
  Prevnar, Hib

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Evaluation of Possible Immunodeficiency

• MUST BE BASED ON
• Medical history of recurrent infections including
  frequency, site(s), therapy required
• Family history of recurrent infections
• Many PI are x-linked
• Physical examination
• Appropriate laboratory evaluation

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Specific Antibody Responses

• The standard in the evaluation of the B-cell
  immunity (humoral) is the capacity to mount a
  specific antibody response
• Natural antibody screen
• testing for isohemagglutinins (lt1yr unreliable)
• Provocative testing immunization with protein
  and carbohydrate (polysaccharide) vaccines-
• Tetanus toxoid
• Pneumococcal polysaccharides
• Pneumovax
• Prevnar
• neo-antigen FX - 174 antigen

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Antibodies to pneumococcal polysaccharides fall
into which of the following IgG subclasses

• A. IgG1
• B. IgG2
• C. IgG3
• D. IgG4

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The Biology of IgG Subclasses
Approximately 10 of individuals have absent IgG4
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IgG Subclass Deficiency and Primary Immune
Deficiency
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IgG2 and IgG4 deficiency is associated with which
of the following immune deficiencies

• A. Wiskott-Aldrich disease
• B. Severe Combined Immunodeficiency
• C. Hyper IgM syndrome
• D. IgA deficiency

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IgG Subclass Deficiency in Immunodeficiency
Patients

• IgG2 and IgG4 deficiency
• IgA deficiency
• Cartilage hair hypoplasia
• Ataxia telangectasia
• IgG3 deficiency
• Wiskott-Aldrich Syndrome
• Variable subclass deficiency
• Common variable hypogammaglobulinemia

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IgG Subclass Deficiency - Clinical Presentations
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IgG Subclass deficiency and IgA Deficiency

• Oxelius et al studied 37 IgA deficient patients
• Seven of 37 had IgG2 deficiency
• Patients with combined IgA-IgG2 deficiency had
  more severe and frequent lower respiratory tract
  infections
• IgA deficiency is mostly partial
• 15-18 IgG subclass deficiency
• IgG2 deficiency often occurred with IgG4
  deficiency (6 of 7)

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Recurrent sinopulmonary infections with selective
IgG2 subclass deficiency

• Normal total serum IgG (20 patients)
• IgG2/IgG3 subclass deficiency
• 3/20 had IgA deficiency
• Impaired antibody responses to bacterial capsular
  polysaccharide antigens
• Hemophilus influenzae type b (Hib)

Umetsu et al N Eng J Med 1985
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IgG subclass deficiency - the bigger picture

• Shackelford et al (1990) screened normal blood
  donors and found individuals with IgG2 deficiency
  who were healthy
• Subclass deficiency is a statistically derived
  value
• By definition subclass deficiency 2 std
  deviations from the mean
• Statistically - 2.5 of the general population
  will have low (2std) IgG subclass serum levels
• Individuals with deletion of their heavy chain
  genes for the IgG subclasses without infection
• Many of the children have a developmental lag
  in the maturation of their immune system

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IgG subclass deficiency - the bigger picture

• Controversy among clinical immunologists over
  measuring IgG subclasses
• Real issue is to evaluate the ability to make
  specific antibodies
• Protein antigens
• Polysaccharide antigens

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3 year old boy with a history of recurrent
sinusitis and pneumonias since age 18 months

• History-
• multiple ear infections until PE tubes placed at
  12 months of age
• At 18 months of age started to have recurrent
  sinusitis
• Several episodes of pneumonia
• Family and social history
• No allergies in family
• No other children
• No day care
• No smoking

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Screening of Immune Function

• Screening Tests
• Quantitative serum immunoglobulin (IgG, IgA, IgM)
  levels
• IgG subclasses
• Specific antibody responses
• Protein antigens - tetanus
• carbohydrate (polysaccharide) antigens

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Immune testing results-

• Normal serum immunoglobulins
• Normal IgG subclasses
• Good antibody production to tetanus, viral
  pathogens like RSV, influenza, and mycoplasma
• Poor antibody production to pneumococcal
  polysaccharides despite immunizations with
  Pneumovax
• Given one dose of Prevnar (conjugated
  pneumococcal vaccine) - still poor response

Diagnosis- Selective antibody deficiency
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Recurrent infections and normal serum IgG
subclass levels with selective antibody responses
to polysaccharide antigens

• Ambrosino et al
• J Allergy Clin Immunol 1988

Specific antibody deficiency can be seen in 5-10
of children referred for the evaluation of
recurrent infections
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Selective antibody deficiency

• Antibody response to protein antigens such as
  tetanus usually normal
• Potent antigen
• Memory B-cells
• Antibody responses to polysaccharide antigens
  poor
• Less T-cell dependent
• Antigen processing different

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Figure 11-1 part 1 of 3
Significant pathogen for airway
infections 20-40 of otitis media 30-40 of
sinusitis 10-25 of pneumonia More than 50 of
S. pneumoniae isolates in the US have reduced
sensitivity to penicillin
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Method for Evaluating a Specific Antibody
Response

• Serum pre and 4 weeks following immunization
• Testing the response to protein antigens (e.g.
  tetanus toxoid) is well established
• Testing for carbohydrate (polysaccharide)
  antigens
• Normal standards recently established
• Age has a significant impact on response
• New CDC assay standards improved testing

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Pneumococcal vaccines

• 23-valent polysaccharide vaccine
• After age 24 months
• Heptavalent conjugate vaccine
• Immunogenic in infants
• 4 doses
• 2-5 yrs of age - one dose
• Levels of protection
• Invasive disease (hematogenous) - 0.15 µg/ml
• Pneumonia - 1.3 µg/ml (200-300 ng Ab N/ml)

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In a 30 month old child an adequate response to
Pneumovax should be

• A. 25 of the 12 serotypes tested
• B. 35 of the 12 serotypes tested
• C. 50 of the 12 serotypes tested
• D. 75 of the 12 serotypes tested

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Percentage of patients in each age group and
their response to pneumococcal vaccine
9 serotypes tested of 23 valent vaccine
Sorensen et al JACI 98
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Pneumococcal vaccines

• Variables in response
• Age - increase in response to greater number of
  serotypes
• Age 2-5 - gt50 of serotypes
• gt 5 yrs of age - 70-80 of serotypes
• Vaccine/doses
• Ethnicity
• Persistence of antibody responses - immunologic
  amnesia

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Treatment of IgG Subclass Deficiency and
Selective Antibody Deficiency
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Treatment IgG Subclass Deficiency and Selective
Antibody Deficiencies

• Prophylactic antibiotics
• Sept. to May
• Many of the children are atopic
• Nasal steroids/decongestants
• Environmental controls
• ? IVIG therapy
• 9 months of IVIG therapy
• Re-vaccinate - 3-5 months off IVIG
• If responds often sinusitis decreases

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Therapy of IgG Subclass Deficiency with IVIG

• Bjorkander et al (1985) - 4 patients with
  combined IgA and IgG2/4 deficiency
• Geha et al (1987) - 12 patients with IgG2
  deficiency and recurrent sinopulmonary infections
• 300-400 mg/kg IVIG every 3-4 weeks
• Sinusitis decreased from 8.7 episodes / yr. to
  2.2 episodes per year
• Pneumonia markedly decreased
• Asthma - steroid sparing effect

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Summary

• Patients with a selective antibody deficiency
  to native polysaccharide antigens (pneumococcus)
  exist
• Look for contributory factors
• Allergy, smoking, day care, older sibs
• Treatment-
• Environmental intervention if atopic
• Prophylactic antibiotics (Sept to May)
• IGIV treatment - short term, e.g. 9 months
• Outcomes
• Many children outgrow this immune deficiency
• A developmental lag in immune maturation
• Adults may require long term IGIV therapy