Topic Name

A	B	C	D	E	F	G	H	I
J	K	L	M	N	O	P	Q	R
S	T	U	V	W	X	Y	Z	#

Disease Categories > Infectious Disease > Chronic

Font

Immunoglobulin Disorders

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
- IgD
  - Found in small quantities with IgM as major receptor for antigen on B-cell surfaces

Pathophysiology

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, immunoglobulin G (IgG) constitutes approximately 75% of total serum immunoglobulins
  - IgG1 – 60-70%
  - IgG2 – 14-20%
  - IgG3 – 4-8%
  - IgG4 – 2-6%
  - IgG deficiency
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
  - 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. A ratio of ≥ 0.27 is found in about 70% of MS cases.)
IgG deficiency
- Protein losses (protein-losing enteropathy, nephropathy)
- Inherited defect in synthesis
- Acquired defects in production
- Immunosuppressive drugs or toxins
- 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
  - If deficiency is suspected with normal IgG, do subclass testing
  - Subclass deficiencies may be associated with recurrent infections
- Patients with severe deficiency associated with recurrent invasive infection require life-saving immunoglobulin administration
IgA
- Characteristics
  - Predominant class of immunoglobulins in secretions
  - Secretory IgA found in tears, sweat, saliva, milk, 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 ARC/AIDS, CNS, 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
    - Often concomitant with IgG2 and IgG4 deficiency
    - IgA-deficient individuals may have circulating anti-IgA, which can mediate fatal anaphylactoid reactions if sources of immunoglobulin infused; e.g., in blood component therapy, plasma or intravenous immunoglobulin (IVIG)
  - Absence of IgA
    - Found in ataxia telangiectasia
  - Laboratory testing
    - Measurement of IgA in CSF and serum used to determine IgA index
      - May be useful in multiple sclerosis
      - Intra-blood-brain-barrier synthesis of IgA elevated in approximately 18% of patients with multiple sclerosis
    - IgA CSF may be abnormal in patients with viral meningitis and CNS lupus erythematosus
  - Treatment is symptomatic
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 is typical in infections
  - Autoimmune disease (e.g., 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 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
    - IgG and IgA levels low
    - IgM typically elevated
    - T-cell responses are compromised
    - May present with recurrent bacterial infections and P. carinii, CMV, aspergillus and cryptosporidium, leading to severe liver disease
- IgM deficiency
  - Primary
    - Inherited defects
    - Toxins
  - Secondary
    - Lymphoid malignancies
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, e.g., 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

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

Test Name and Number	Recommended Use	Limitations	Follow Up
Immunoglobulins, Serum Quantitative 0050630 Method: Nephelometry	Confirm hypogammaglobulinemia in patient with recurrent sinopulmonary infections or chronic diarrhea		To rule out: Monoclonal proteins – order immunofixation electrophoresis testing for all adults Renal loss – order Bence Jones protein in urine Protein losing enteropathy – order alpha-1 antitrypsin in stool
Immunoglobulin A, Saliva 0050525 Method: Nephelometry	Quantify salivary IgA in patients with recurrent upper respiratory infections		To rule out: Monoclonal proteins, order immunofixation electrophoresis testing for all adults Renal loss, order Bence Jones protein in urine Protein losing enteropathy, order alpha-1 antitrypsin in stool
Immunoglobulin G, Serum 0050350 Method: Nephelometry	Order for patients with recurrent infections and a positive serum immunoglobulins quantitative test	Normal level of total IgG in serum does not rule out a clinically important deficiency of 1 or more IgG subclasses Compensatory increases can occur in serum levels of other IgG subclasses	To rule out: Monoclonal proteins, order immunofixation electrophoresis testing for all adults Renal loss, order Bence Jones protein in urine Protein losing enteropathy, order alpha-1 antitrypsin in stool
Immunoglobulin G Subclasses (1, 2, 3, 4) 0050577 Method: Nephelometry	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
Immunoglobulin M, Serum 0050355 Method: Nephelometry	Determine if patient has elevated IgM or primary deficiency		To rule out: Monoclonal proteins, order immunofixation electrophoresis testing for all adults Renal loss, order Bence Jones protein in urine Protein losing enteropathy, order alpha-1 antitrypsin in stool
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	Low levels of IgE do not indicate absence of allergic disease; individuals may have low total IgE levels but a high concentration of clinically significant allergen-specific IgE	Consider specific allergen testing if lgE levels are elevated

Additional Tests Available

Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Comments
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
IgA Subclasses 0093149 Method: Nephelometry
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899 Method: Flow Cytometry

General References

Durandy A, Wahn V, Petteway S, Gelfand EW. Immunoglobulin replacement therapy in primary antibody deficiency diseases--maximizing success. Int Arch Allergy Immunol. 2005;136(3):217-229. (Link to PubMed)

Goldstein MF, Goldstein AL, Dunsky EH, Dvorin DJ, Belecanech GA, Shamir K. Selective IgM immunodeficiency: retrospective analysis of 36 adult patients with review of the literature. Ann Allergy Asthma Immunol. 2006;97(6):717-730. (Link to PubMed)

Hernandez M, Bastian JF. Immunodeficiency in childhood. Curr Allergy Asthma Rep. 2006;6(6):468-474. (Link to PubMed)

Immune Deficiency Foundation (Accessed 30 May 2008) (Linked to Resource)

Latiff AH, Kerr MA. The clinical significance of immunoglobulin A deficiency. Ann Clin Biochem. 2007;44(Pt 2):131-139. (Link to PubMed)

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. (Link to PubMed)

Stiehm RE. The four most common pediatric immunodeficiencies. Adv Exp Med Biol. 2007;601:15-26. (Link to PubMed)

Toubi E, Etzioni A. Intravenous immunoglobulin in immunodeficiency states: state of the art. Clin Rev Allergy Immunol. 2005;29(3):167-172. (Link to PubMed)

Wiertsema SP, Veenhoven RH, Sanders EA, Rijkers GT. Immunologic screening of children with recurrent otitis media. Curr Allergy Asthma Rep. 2005;5(4):302-307. (Link to PubMed)

Woof JM, Kerr MA. The function of immunoglobulin A in immunity. J Pathol. 2006;208(2):270-282. (Link to PubMed)

Reviewed by

Hill, Harry R., M.D. Group Medical Director, Laboratory of Immunology, ARUP Laboratories, and Executive Director of the ARUP Institute for Clinical and Experimental Pathology; Professor and Division Head, Clinical Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Roberts, William L. , M.D., Ph.D. Medical Director, Automated Core Laboratory at ARUP Laboratories; Professor, Pathology, University of Utah

Comprehensive Review: January 2008
Last Update: March 2008