Immunoglobulin Disorders

Antibody deficiencies are the most common primary immunodeficiency.

Epidemiology

Incidence – 1/2,000 live births (primary immunodeficiency)

Pathophysiology

Immunoglobulins are B-cell products that mediate the humoral arm of immune response
Functions
- Bind to antigens and activate complement
- Inactivate or remove offending toxins, foreign substances, opsonized bacterial pathogens
- Neutralize viruses
Structure
- 2 heavy and 2 light chains; isotype (G, M, A, D or E) determined by type of heavy chain
Subclasses
- IgG and IgA subdivided based on antigenic determinants on heavy chain
  - IgG – subclasses 1, 2, 3, 4
  - IgA – subclasses 1, 2
Isotypes
- IgG
  - IgG1 highest concentration
  - 75-85% of body's immunoglobulin
- IgA
  - Main immunoglobulins in respiratory and gastrointestinal (GI) secretions
  - 10-15% of immunoglobulins
- IgM
  - First antibody to appear in immune response
  - 5-10% of body’s immunoglobulins; circulates mainly in the bloodstream
- IgE
  - Binds to mast cells and basophils
  - Basophils involved in immediate hypersensitivity response and parasitic immunity
- IgD
  - Found in small quantities with IgM as major receptor for antigen on B-cell surfaces
Abnormal concentrations of serum immunoglobulins range from virtual absence of 1 or more of the 3 major immunoglobulin classes (IgG, IgA and IgM) to mono- and polyclonal increases in 1 or more immunoglobulins
- Polyclonal increases occur in chronic inflammation
- Monoclonal increases occur in plasma cell dyscrasias and monoclonal gammopathies of undetermined significance (MGUS)

Specific Immunoglobulins

IgG
- Characteristics
  - Antibodies produced in response to antigens of most bacteria and viruses and to small soluble protein antigens
  - Only class of immunoglobulins that pass the placenta in humans
    - Responsible for protection of newborns during the first 4-6 months of life
  - Capable of fixing complement
    - Subclasses fix complement in the following order of descending efficiency – IgG3, IgG1, IgG2, IgG4
- Subclasses and concentrations
  - In normal adults, IgG constitutes approximately 75% of total serum immunoglobulins
    - IgG1 – 60-70%
    - IgG2 – 14-20%
    - IgG3 – 4-8%
    - IgG4 – 2-6%
- Increased IgG concentrations
  - Lymphoid malignancy (secondary)
    - Multiple myeloma
    - Chronic lymphocytic leukemia (CLL)
    - MGUS
  - Increased intra-blood-brain-barrier (IBBB) synthesis of IgG is found in a wide variety of infectious, inflammatory (eg, multiple sclerosis [MS]) and neoplastic conditions of the central nervous system (CNS)
- IgG deficiency
  - Protein losses (protein-losing enteropathy, nephropathy)
  - Inherited defect in synthesis
  - Acquired defects in production
  - Immunosuppressive drugs or toxins
  - Associated with primary immunodeficiencies
    - Hypogammaglobulinemia of infancy
    - X-linked agammaglobulinemia – Bruton type
    - X-linked immunodeficiency with hyper-IgM
    - Common variable immunodeficiency (CVID)
  - Subclass deficiency may go undetected because total IgG level may be normal
    - Subclass deficiencies may be associated with recurrent infections
  - Clinical presentation
    - Patients with severe deficiency associated with recurrent invasive infection and chronic diarrhea
  - Treatment
    - May require life-saving immunoglobulin administration as well as routine therapy in follow-up
IgA
- Characteristics
  - Predominant class of immunoglobulins in secretions
  - Secretory IgA found in tears, sweat, saliva, milk and colostrum as well as gastrointestinal and bronchial secretions
    - Synthesized mainly by plasma cells in gut and bronchi and ductules of lactating breast
    - Secretory IgA is more resistant to enzymes and able to protect mucosa from bacteria and viruses
  - Affects development of allergic (IgE) reactions to various ingested antigens
    - Binds antigens and prevents IgE responses (immune exclusion)
- Subclasses
  - IgA1 – predominant in serum
  - IgA2 – predominant in secretions
- Increased serum IgA concentrations
  - Common in skin, gut, respiratory and renal infections and in AIDS-related complex (ARC), AIDS and CNS involvement in systemic lupus erythematosus (SLE)
  - In portal cirrhosis and other forms of liver disease, IgA and sometimes IgG are increased
- IgA deficiency
  - Primary
    - Epidemiology
      - European descent – 1/700
      - Asian and African populations – uncommon
    - Etiologies
      - Familial
      - TORCH syndrome (Toxoplasmosis, Other-HIV, TB and HHV-6, Rubella, Cytomegalovirus, Herpes simplex virus)
      - Drugs
        Penicillamine
        Phenytoin
      - Primary immunodeficiencies associated with IgA
        CVID
        IgG subclass deficiency
        Hyper-IgM syndrome
        Ataxia telangiectasia
        Chronic mucocutaneous candidiasis
        Cartilage hair hyperplasia
        Celiac disease (CD)
    - Clinical presentation
      - Often asymptomatic
      - Associated with autoimmune disease (eg, CD, SLE, RA)
      - Many patients have increased number of respiratory and GI tract infections (Giardia duodenalis most common)
      - IgA-deficient individuals may have circulating anti-IgA, which can mediate fatal anaphylactoid reactions if IgA is infused (eg, in blood component therapy, plasma or intravenous immunoglobulin)
    - Treatment is symptomatic for infections
IgM
- Characteristics
  - Primary immune response antibody
  - IgM tends to predominate in primary viral and blood stream infections for first 2-3 months and may persist for 1 year
- Increased IgM concentrations
  - Polyclonal increase occurs in the following
    - Infections
    - Autoimmune disease (eg, RA)
    - Primary biliary cirrhosis (PBC)
    - Fetus, if intrauterine infection present
      - At birth, cord blood may have specific IgM to offending pathogen
  - Monoclonal increase occurs in Waldenström macroglobulinemia and monoclonal cryoglobulinemias
  - Increased IBBB synthesis of IgM characteristically abnormal in the following
    - Infectious meningitis/encephalitis (bacterial and viral meningitis such as Borrelia burgdorferi [CNS infection], Japanese encephalitis virus, neurosyphilis)
    - Neurosyphilis treatment may be monitored by measuring IgG, IgA and IgM indices
  - Hyper-IgM with X-linked immunodeficiency
    - Pathophysiology – defect in class switch recombination
    - Clinical presentation
      - May present with recurrent bacterial infections and Pneumocystis jiroveci, cytomegalovirus (CMV), aspergillus and cryptosporidium, which can lead to severe liver disease
      - May also manifest with autoimmune diseases
    - Treatment may be indicated
- IgM deficiency
  - Primary
    - Inherited defects
    - Toxins
    - Clinical presentation
      - May be asymptomatic
      - May present with severe bacterial infections
  - Secondary
    - Lymphoid malignancies
    - Autoimmune disease
    - Protein-losing enteropathies
    - AIDS
IgE
- Characteristics
  - Important in parasitic immunity
  - Binds to mast cells and basophils
  - Causes allergic or anaphylactic reactions
  - Involved in immediate hypersensitivity and atopic disease
  - Strong correlation between total serum plasma IgE levels and allergic disease
    - Increased cord blood and infant IgE is predictive of early-onset allergic disease
    - Levels vary due to variety of factors (eg, genetic)
- Increased IgE concentrations
  - Allergic disease
    - Allergic rhinitis
    - Extrinsic asthma
    - Urticaria
    - Atopic eczema
  - Pulmonary aspergillosis
  - Allergic drug reactions
  - Job syndrome – hyperimmunoglobulinemia E associated with recurrent infections and abscesses, early-onset eczema, sinopulmonary disease and classic facial abnormalities
    - Very elevated IgE levels
    - Defective neutrophil chemotaxis
    - Mutations in STAT3 gene
  - Immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance syndrome (IPEX)
    - Normal IgA, IgG, IgM initially but decreases due to protein losses from enteropathy
- IgE deficiency
  - Does not indicate absence of allergic disease
  - Certain allergic individuals have low total IgE but high concentration of allergen-specific IgE and may even suffer anaphylaxis with low to undetectable concentrations of IgE or allergen-specific IgE antibodies
IgD
- Characteristics
  - Probably an early B-cell antigen receptor
  - Found in small quantities in serum (with IgM) as major receptor for antigen on B-cell surface
  - May help regulate B-cell function
- Increased IgD concentrations
  - Rare elevation in multiple myeloma
  - Part of hereditary group of disorders (familial Mediterranean fever)
  - Hyper-IgD and periodic syndrome
  - High-spiking fevers
  - Minor viral illnesses
  - Lymphadenopathy
  - Gastrointestinal – abdominal pain, diarrhea, emesis
  - Musculoskeletal – arthritis
  - Dermatologic – maculopapular rash, purpura, urticaria

Indications for Testing

Patient presenting with recurrent sinopulmonary infections or chronic diarrhea

Laboratory Testing

Initial screen
- CBC with differential (general health screen for immunodeficiency)
- Comprehensive metabolic profile (general health screen for immunodeficiency)
- Quantitative serum immunoglobulins (IgA, IgG, IgM); also consider lymphocyte subset analyses and vaccination responses
- HIV-1,2 combined antibodies with reflex to HIV-1 confirmation by Western blot
- Immunofixation electrophoresis monoclonal protein detection quantitation and characterization with SPEP, IFE, IgA, IgG, IgM
- Sweat chloride
- If only recurrent sinopulmonary disease, consider pneumococcal antibody IgG titers pre- and post-vaccine (1 month)
- Clinical presentation may require multiple immune system investigations (see Immunodeficiency Evaluation algorithms)
If positive for deficiency or excess, order specific testing
- Extensive secondary testing should be performed with consultation from immunologist
Immunoglobulin deficiency present
- IgA deficiency – confirmed by <0.07 g/dL of IgA for nephelometry; often concomitant with IgG2 and IgG4 deficiency
- IgG deficiency suspected with normal IgG level – perform subclass testing; frequently associated with IgA deficiency
Hyperglobulinemia present
- IgG, IgM – monoclonal increases in plasma cell dyscrasias require further testing
- Hyper IgM syndromes
  - IgG and IgA levels low or absent
  - IgM typically elevated
  - T-cell responses are compromised
- Hyper IgE syndromes
  - Job syndrome
    - Significantly elevated IgE levels
    - Impaired inflammatory responses
    - Mutations in STAT3 gene
  - IPEX
    - Normal IgA, IgG, IgM initially but decreases due to protein losses from enteropathy
- IgE – increased in allergic disease

Other Testing

IgA – CSF immunoglobulins
- Serum indexed against CSF may be diagnostic in MS
IgG – CSF immunoglobulins
- Majority (93-99%) of patients with clinically definite MS will have CSF abnormalities, including oligoclonal immunoglobulins and increased synthesis of IgG
- CSF index and serum albumin ratio may indicate MS
  - Index of ≥0.77 indicates increased synthesis, found in about 90% of MS cases
  - Ratio of ≥0.27 is found in about 70% of MS cases

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

General health screen for immunodeficiency

Limitations:

Normal test result does not rule out disease

Test name: Comprehensive Metabolic Panel

ARUP #: 0020408

Methodology: Refer to individual components

Use:

General health screen for immunodeficiency

Limitations:

Normal test result does not rule out disease

Test name: Immunoglobulins, Quantitative

ARUP #: 0050630

Methodology: Quantitative Nephelometry

Use:

Confirm hypogammaglobulinemia in patient with recurrent sinopulmonary infections or chronic diarrhea

Test name: Monoclonal Protein Detection Quantitation and Characterization, SPEP, IFE, IgA, IgG, IgM, Serum

ARUP #: 0050615

Methodology: Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Quantitative Nephelometry

Use:

Rule out monoclonal proteins

Test name: Bence Jones Protein, Quantitative Free Kappa & Lambda Light Chains, Urine

ARUP #: 0050618

Methodology: Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Use:

Rule out renal loss

Test name: Alpha-1-Antitrypsin, Feces

ARUP #: 0099991

Methodology: Quantitative Radial Immunodiffusion

Use:

Rule out protein-losing enteropathy

Test name: Immunoglobulin G Subclasses (1, 2, 3, 4)

ARUP #: 0050577

Methodology: Quantitative Nephelometry

Use:

Order for patients with recurrent infections and a positive serum immunoglobulins quantitative test

Order in lieu of individual immunoglobulin G subclass tests; more precise and less costly

Test name: Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies

ARUP #: 0095899

Methodology: Quantitative Flow Cytometry

Use:

Assess T-cell function

Test name: Streptococcus pneumoniae Antibodies, IgG (14 serotypes)

ARUP #: 0050725

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Secondary evaluation in immunodeficiency

Test name: Diphtheria, Tetanus, and H. Influenzae b Antibodies, IgG

ARUP #: 0050779

Methodology: Quantitative Multi-Analyte Fluorescent Detection

Use:

Secondary evaluation in immunodeficiency

Test name: Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies with Reflex to Human Immunodeficiency Virus Type 1 (HIV-1) Antibody Confirmation by Western Blot

ARUP #: 2005377

Methodology: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Use:

Initial screen for immunoglobulin disorders

Additional Tests Available

Test name: Immunoglobulin A, Saliva

ARUP #: 0050525

Methodology: Quantitative Nephelometry

Comments:

Quantify salivary IgA in patients with recurrent upper respiratory infections

Test name: Immunoglobulin G

ARUP #: 0050350

Methodology: Quantitative Nephelometry

Comments:

Order for patients with recurrent infections and a positive serum immunoglobulins quantitative test

Test name: Immunoglobulin M

ARUP #: 0050355

Methodology: Quantitative Nephelometry

Comments:

Determine if patient has elevated IgM or primary deficiency

Test name: Immunoglobulin D, Serum

ARUP #: 0099200

Methodology: Quantitative Nephelometry

Comments:

Used for research purposes primarily

Detect immune deficiencies in patients with clinical symptoms

Test name: Immunoglobulin E

ARUP #: 0050345

Methodology: Quantitative Electrochemiluminescent Immunoassay

Comments:

Useful in assessment of atopic diseases - allergic rhinitis, extrinsic asthma, urticaria and atopic eczema

Useful in raising possibility of parasitic infection

Test name: Immunoglobulin G Subclass 1

ARUP #: 0050571

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulin G Subclass 2

ARUP #: 0050572

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulin G Subclass 3

ARUP #: 0050573

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulin G Subclass 4

ARUP #: 0050576

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulins, CSF Quantitative

ARUP #: 0050631

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulin A, CSF

ARUP #: 0050341

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulin G, CSF

ARUP #: 0050670

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulin G/Albumin Ratio, CSF

ARUP #: 0050680

Methodology: Nephelometry

Comments:

Test name: Immunoglobulin G, CSF Index

ARUP #: 0050676

Methodology: Quantitative Nephelometry

Comments:

Test name: Immunoglobulin M, CSF

ARUP #: 0050356

Methodology: Quantitative Nephelometry

Comments:

Test name: Humoral Immunity Panel I

ARUP #: 0050980

Methodology: Quantitative Nephelometry/Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Test name: Immunoglobulin A Subclasses (1&2)

ARUP #: 0093149

Methodology: Quantitative Nephelometry

Comments:

Test name: Humoral Immunity Panel II

ARUP #: 0050981

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Test name: Anti-IgA Antibody

ARUP #: 2003126

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test for antibodies to IgA in patients with IgA deficiency and blood transfusion reaction

Guidelines

Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson RP Jr, Patel DD, Secord E, Sorensen RU, Wasserman RL, Cunningham-Rundles C. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006; 117 (4 Suppl) :S525-S553.PubMed

General

Comprehensive Review: January 2011
Last Update: January 2011

Bruton Agammaglobulinemia

Chronic Granulomatous Disease

Common Variable Immune Deficiency

Complement Deficiency

Immunodeficiency, Innate System

Leukocyte Adhesion Deficiency

Neutrophil Disorders

Plasma Cell Dyscrasias

Severe Combined Immunodeficiencies

T-Cell Deficiency Disorders, Inherited