Immunoglobulin Disorders

Diagnosis

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 testing at an accredited cystic fibrosis center
    • If only recurrent sinopulmonary disease, consider pneumococcal antibody IgG titers pre- and postvaccine (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 multiple sclerosis (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

Clinical Background

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 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 of the 3 major immunoglobulin classes (IgG, IgA and IgM) to mono- and polyclonal increases in one or more immunoglobulins
    • Polyclonal increases occur in chronic inflammation
    • Monoclonal increases occur in plasma cell dyscrasias and monoclonal gammopathies of undetermined significance

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 75-85% of total serum immunoglobulins
        • IgG1 – 60-70%
        • IgG2 – 14-20%
        • IgG3 – 4-8%
        • IgG4 – 2-6%
    • Increased IgG concentrations
    • IgG deficiency
      • Protein losses (protein-losing enteropathy, nephropathy)
      • Inherited defect in synthesis
      • Acquired defects in production
      • Immunosuppressive drugs or toxins
      • Associated with primary immunodeficiencies
      • 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
        • Clinical presentation
          • Often asymptomatic
          • Associated with autoimmune disease (eg, CD, SLE, rheumatoid arthritis [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
      • Hyper-IgM with X-linked immunodeficiency
    • IgM deficiency
      • Primary
        • Inherited defects
        • Toxins
        • Clinical presentation
          • May be asymptomatic
          • May present with severe bacterial infections
      • Secondary
    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
        • Significantly 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 Laboratory Testing

  • 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
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

General health screen for immunodeficiency

Normal test result does not rule out disease

 
Comprehensive Metabolic Panel 0020408
Method: Quantitative Ion-Selective Electrode/Quantitative Enzymatic/Quantitative Spectrophotometry

General health screen for immunodeficiency

Normal test result does not rule out disease

 
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Confirm hypogammaglobulinemia in patient with recurrent sinopulmonary infections or chronic diarrhea

   
Monoclonal Protein Detection Quantitation and Characterization, SPEP, IFE, IgA, IgG, IgM, Serum 0050615
Method: Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Quantitative Nephelometry

Rule out monoclonal proteins

   
Kappa and Lambda Free Light Chains (Bence Jones Protein), Quantitative, Urine 0050618
Method: Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Rule out renal loss

   
Alpha-1-Antitrypsin, Feces 0099991
Method: Quantitative Radial Immunodiffusion

Rule out protein-losing enteropathy

   
Immunoglobulin G Subclasses (1, 2, 3, 4) 0050577
Method: Quantitative 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

   
Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Initial screen for immunoglobulin disorders

   
Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862
Method: Quantitative Flow Cytometry

Useful for assessing primary T-cell immunodeficiency disorders

Measures percentage and absolute numbers of CD4  (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (suppressor T cells), CD4: CD8 ratio, CD3 (total T cells), CD19 (B cells), NK cells

   
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

Determine presence of T-cell deficiency

Measures percentage and absolute numbers of CD2, CD4  (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (suppressor T cells), CD4: CD8 ratio, CD3 (total T cells), CD19 (B cells), NK cells

   
Streptococcus pneumoniae Antibodies, IgG (14 Serotypes) 0050725
Method: Quantitative Multiplex Bead Assay

Secondary evaluation in immunodeficiency

   
Diphtheria, Tetanus, and H. Influenzae b Antibodies, IgG 0050779
Method: Quantitative Multiplex Bead Assay

Secondary evaluation in immunodeficiency

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Immunoglobulin A, Saliva 0050525
Method: Quantitative Nephelometry

Quantify salivary IgA in patients with recurrent upper respiratory infections

Immunoglobulin G 0050350
Method: Quantitative Nephelometry

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

Immunoglobulin M 0050355
Method: Quantitative Nephelometry

Determine if patient has elevated IgM or primary deficiency

Immunoglobulin D, Serum 0099200
Method: Quantitative Nephelometry

Used for research purposes primarily

Detect immune deficiencies in patients with clinical symptoms

Immunoglobulin E 0050345
Method: Quantitative ImmunoCAP® Fluorescent Enzyme 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: Quantitative Nephelometry
Immunoglobulin G Subclass 2 0050572
Method: Quantitative Nephelometry
Immunoglobulin G Subclass 3 0050573
Method: Quantitative Nephelometry
Immunoglobulin G Subclass 4 0050576
Method: Quantitative Nephelometry
Immunoglobulin G4 by Immunohistochemistry 2005844
Method: Immunohistochemistry
Immunoglobulins, CSF Quantitative 0050631
Method: Quantitative Nephelometry
Immunoglobulin A, CSF 0050341
Method: Quantitative Nephelometry
Immunoglobulin G, CSF 0050670
Method: Quantitative Nephelometry
Immunoglobulin G/Albumin Ratio, CSF 0050680
Method: Nephelometry
Immunoglobulin G, CSF Index 0050676
Method: Quantitative Nephelometry
Immunoglobulin M, CSF 0050356
Method: Quantitative Nephelometry
Humoral Immunity Panel I 0050980
Method: Quantitative Nephelometry/Semi-Quantitative Multiplex Bead Assay
Immunoglobulin A Subclasses (1&2) 0093149
Method: Quantitative Nephelometry
Humoral Immunity Panel II 0050981
Method: Semi-Quantitative Multiplex Bead Assay
Anti-IgA Antibody 2003126
Method: Quantitative Enzyme-Linked Immunosorbent Assay

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