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 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 viruses [HIV, TB and HHV6], 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, 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 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 jirovecii, 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 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm