Immunoglobulin Disorders

Antibody deficiencies are the most common primary immunodeficiency.

Epidemiology

• Incidence – primary immunodeficiency: 1/2,000 live births

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 chains
    • 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 secretions
    • 10-15% of immunoglobulins
  • IgM
    • First antibody to appear in immune response
    • 5-10% of body’s immunoglobulins
  • 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

Specific Immunoglobulins

• IgG
  • Characteristics
    • IgG antibodies produced in response to antigens of most bacteria and viruses and to small soluble protein antigens
    • IgG is the only class of immunoglobulins that pass the placenta in humans
      • Responsible for protection of newborns during the first 4-6 months of life
    • IgG also capable of fixing complement
      • Subclasses fix complement in the following order of descending efficiency – IgG3, IgG1, IgG2, IgG4 and neutrophils
  • 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 cause)
      • Multiple myeloma
      • Chronic lymphocytic leukemia
      • Monoclonal gammopathy of undetermined significance (MGUS)
    • Increased intra-blood-brain-barrier (IBBB) synthesis of IgG is found in a wide variety of infectious, inflammatory and neoplastic conditions of the 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
      • 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
    • Treatment
      • May require life-saving immunoglobulin administration
• 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
    • IgA 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, CNS, systemic lupus erythematosus (SLE)
    • In portal cirrhosis and other forms of liver disease, IgA and sometimes IgG are increased
  • IgA deficiency
    • Primary
      • Epidemiology
        • 1/700 of European descent
        • Uncommon in Asian and African populations
      • Etiologies
        • Familial
        • TORCH syndrome
        • Drugs
          • Penicillamine
          • Phenytoin
        • Primary immunodeficiencies associated with IgA
          • CVID
          • IgG subclass deficiency
          • Hyper IgM syndrome
          • Ataxia telangiectasia
          • Chronic mucocutaneous candidiasis
          • Cartilage hair hyperplasia
      • Clinical Presentation
        • Often asymptomatic
        • Associated with autoimmune disease – celiac, systemic erythematosus, rheumatoid arthritis
        • Many patients have increased respiratory and gastrointestinal tract infections (Giardia lamblia is most common)
        • IgA-deficient individuals may have circulating anti-IgA, which can mediate fatal anaphylactoid reactions if IgA infused; eg, in blood component therapy, plasma or intravenous immunoglobulin (IVIG)
      • 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 1 year
  • Increased IgM concentrations
    • Polyclonal increase occurs in
      • Infections
      • Autoimmune disease (eg, rheumatoid arthritis)
      • Primary biliary cirrhosis
      • Fetus, if intrauterine infection present
        • At birth, cord blood may have specific IgM to offending pathogen
    • Monoclonal increase occurs in Waldenström's macroglobulinemia and monoclonal cryoglobulinemias
    • Increased intra-blood-brain-barrier (IBBB) synthesis of IgM characteristically abnormal in
      • Infectious meningoencephalitis (bacterial and viral meningitis – examples include Borrelia burgdorferi [CNS infection], Japanese encephalitis virus, neurosyphilis)
      • Neurosyphilis treatment may be followed by measuring IgG, IgA and IgM indices
    • Hyper-IgM with X-linked immunodeficiency
      • Clinical Presentation
        • May present with recurrent bacterial infections and P. carinii, CMV, aspergillus and cryptosporidium, leading to severe liver disease
      • 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 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 features
      • 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 decrease 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

Diagnosis

• Indications for testing
  • Patient presenting with recurrent sinopulmonary infections or chronic diarrhea
• Laboratory testing
  • Initial screen – CBC with differential; comprehensive metabolic profile; quantitative serum immunoglobulins (IgA, IgG, IgM,) (and consider lymphocyte subset analyses, 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 SPE; sweat chloride; and if only recurrent sinopulmonary disease, pneumococcal antibody IgG titers pre and post vaccine (1 month)
    • Clinical presentation may require multiple immune systems investigations (see Immunodeficiency Evaluation algorithms for specific evaluations)
    • If test is 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 – do 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
      • IgM typically elevated
      • T-cell responses are compromised
    • Hyper IgE syndromes
      • Job syndrome
        • Very elevated IgE levels
        • Defective neutrophil chemotaxis
        • Mutations in STAT3 gene
      • IPEX
        • Normal IgA, IgG, IgM initially but decrease due to protein losses from enteropathy
    • IgE – increased in allergic disease
  • Other testing
    • IgA – CSF immunoglobulins
      • Serum indexed against CSF may be diagnostic in multiple sclerosis
    • IgG – CSF immunoglobulins
      • Majority (93-99%) of patients with clinically definite multiple sclerosis will have CSF abnormalities, including oligoclonal immunoglobulins and increased synthesis of IgG
      • CSF index and serum albumin ratio may indicate multiple sclerosis
        • 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

Indications for Ordering

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.
Test Name and Number	Comments
Immunoglobulin A, Saliva 0050525 Method: Nephelometry	Quantify salivary IgA in patients with recurrent upper respiratory infections
Immunoglobulin G, Serum 0050350 Method: Nephelometry	Order for patients with recurrent infections and a positive serum immunoglobulins quantitative test
Immunoglobulin M, Serum 0050355 Method: Nephelometry	Determine if patient has elevated IgM or primary deficiency
Immunoglobulin D, Serum 0099200 Method: Nephelometry	Used for research purposes primarily Detect immune deficiencies in patients with clinical symptoms
Immunoglobulin E 0050345 Method: Electrochemiluminescent Immunoassay	Useful in assessment of atopic diseases - allergic rhinitis, extrinsic asthma, urticaria and atopic eczema Useful in raising possibility of parasitic infection
Immunoglobulin G Subclass 1 0050571 Method: Nephelometry
Immunoglobulin G Subclass 2 0050572 Method: Nephelometry
Immunoglobulin G Subclass 3 0050573 Method: Nephelometry
Immunoglobulin G Subclass 4 0050576 Method: Nephelometry
Immunoglobulins, CSF Quantitative 0050631 Method: Nephelometry
Immunoglobulin A, CSF 0050341 Method: Nephelometry
Immunoglobulin G, CSF 0050670 Method: Nephelometry
Immunoglobulin G/Albumin Ratio, CSF 0050680 Method: Nephelometry
Immunoglobulin G, CSF Index 0050676 Method: Nephelometry
Immunoglobulin M, CSF 0050356 Method: Nephelometry
Humoral Immunity Panel I 0050980 Method: Nephelometry/Multi-Analyte Fluorescent Detection
Immunoglobulin A Subclasses (1&2) 0093149 Method: Nephelometry
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899 Method: Flow Cytometry
Humoral Immunity Panel II 0050981 Method: Multi-Analyte Fluorescent Detection

General References