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 IgGconcentrations
  • 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
  • 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
  • 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 IgAconcentrations
    • 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
    • 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

Diagnosis

• Indications for testing
  • Patient presents with recurrent sinopulmonary infections or chronic diarrhea
• Laboratory testing
  • Initial screen - quantitative serum immunoglobulins
    • If test is positive for deficiency or excess, order specific testing
  • Deficiency testing
    • IgG deficiency suspected with normal IgG level - do subclass testing; frequently associated with IgA deficiency
  • Suspected hyperglobulinemia
    • IgG, IgM - monoclonal increases in plasma cell dyscrasias require further testing
  • IgE - increased in allergic disease
  • 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 greater than or equal to 0.77 indicates increased synthesis, found in about 90% of MS cases. A ratio of greater than or equal to 0.27 is found in about 70% of MS cases.)