Michelle M. Klinek, M.D.
March 23, 1995
IMMUNOGLOBULIN A DEFICIENCY
I. EPIDEMIOLOGY
* Defined as serum IgA < 5mg/dl, which is < 1-3% of normal age adjusted levels.
* Recently a subgroup has been identified with Partial Deficiency.
5mg/dl < serum IgA > 2 SD
Believed to be a separate disease than complete IgA deficiency
50% of these patients show reversal of their IgA deficiency
all have normal T cell proliferation
Cause ascribed to environmental factors in some cases
1. Drugs - phenytoin, sulfasalazine, penicillamine
2. Viral induced ie. Rubella, EBV
* Prevalence in Caucasians is approximately 1:660, Japanese 1:18,500 and among blacks is undefined.
II. CLINICAL FEATURES
A. Primary role of IgA is in defense of the Mucosal Immune System which includes GALT or Gut associated lymphoid tissue and BALT bronchus associated lymphoid tissue.
1. IgA can be actively and efficiently secreted through epithelial cells to mucosal sites
- a 70kg adult secretes about 3gm/day accounting for 60-70% of total antibody output
- in humans IgA is encoded by 2 genes Figure 1
1 IgA1 which is primary constituent of circulating IgA
2 IgA2 which is a constituent of secretory IgA
Figure 2
2. IgA has the ability to join J chains which are produced by B cells which confers the ability to polymerize and then be connected to the secretory component produced by epithelial cells. This protects the IgA from proteolytic digestion and mediates transport of IgA into muscosal lumens. (GI tract, salivary glands, bronchial mucosa, lactating mammary glands and uterine mucosa) Figure 3
B. IgA in the mucosal system prevents entry of potential harmful antigens while also interacting with mucosal pathogens without potentiating damage because it doesn't bind complement.
- Immune Exclusion is the process whereby IgA binds to ag at the mucosal surface and thus lead to their entrapment in the mucous layer and their degradation by proteases before they become bound to and taken up by epithelial cells. Patients as will be discussed later with IgA deficiency have increased absorption of macromolecules and high levels of circulating immune complexes following ingestion of ag. This may be the cause of the increase in infection, autoimmunity and food allergy seen in IgA deficiency.
C. Infections in IgA Deficiency
1. Recurrent infections of the respiratory and GI tracts are the most common reasons IgA is identified. ie. Pneumonias, Bronchiectasis, Meningitis, GI infections from salmonella and giardia
2. Complete IgA deficiency is associated with more frequent and more severe infections than partial IgA
3. Infections are similar in type to CVID being more extracellular than opportunistic
4. Some patients have associated IgG subclass deficiency resulting in more severe and recurrent infection. Oxelius et. al. observed a higher frequency of IgG2 and IgG4 deficiency with IgA deficiency which suggests a more global immunologic defect. This can be explained by the occurrence of a large defect on Chrm 14 involving 1 and 2 and 3 and 4. Figure 4
D. Autoimmunity
1. Tendency of IgA deficient patients to develop inappropriate immune response resulting in food allergy and autoimmune diseases such as JRA, SLE and Type I Diabetes. Two theories for these phenomena are the following;
a:Excessive absorption of mucosal ag that leads to an inappropriate response to usually excluded ag that cross react with self and benign ag. Cunningham -Rundles notes that IgA deficient patients have circulating antibodies against food proteins. Her group has also noted a rough correlation between antimilk antibodies and the presence of autoantibodies. This hypothesis, however, doesn't explain why only certain patients with IgA deficiency develop autoimmune disease.
b: Disease may be determined by a unifying genetic mechanism. This hypothesis is supported by the observation that IgA deficiency occurs in a familial pattern. The frequency among first degree relatives is 7.5% which is 38x greater than in patients without a relative of IgA deficiency. There are also kindreds with IgA deficiency with autoimmune diseases suggesting a genetic association.
2. Disease determined by MHC-associated gene/genes.
Several studies have shown that a particular combination of MHC alleles rather than individual HLA alleles or supratypes are associated with IgA deficiency and also to autoimmune diseases. Figure 5 and 6
- These supratypes involve MHC class III with rare C2 alleles, C4 deletions and defects in 21 hydroxylase. Figure 7 These central MHC products code for macrophage-derived products that regulate B cells and antibody production. For example, IgA deficiency may have impaired lymphocyte proliferation which may be caused by decreased IL-1 which is influenced by TNF. IL-1 may function as a priming factor allowing IL-5 to be effective in the later stages of B-cell differentiation.
- CVID and IgA Deficiency
These are heritable disorders that can occur within the same family. both are characterized by arrests in B cell differentiation. As above susceptibility appears to be determined by genes within or near the MHC class III genes
III. Mechanisms Leading to Impairment of IgA Switch Differentiation
Figure 8
A. Studies have shown that IgA deficient patients have B cells with surface IgA implying that early B cell differentiation is intact. The problems seems to involve the terminal differentiation of IgA bearing cells into plasma cells. This involves T cell derived factors IL-5, IL-6 and IFN. Results of these studies have shown that IgA deficiency is a heterogeneous defect.
Studies have involved different combinations of T and B cells from patients with IgA deficiency and those from a control group.
Group 1: Intrinsic B cell defect - Majority of Ig A deficient patients
: The addition of control T cells to patient B cells did not result in the production of IgA
Group 2: Suppresser T cell involvement
The addition of control B cells with patient T cells results in a decrease of IgA production
Group 3: T cell defect
The addition of control T cells to patient B cells resulted in increase IgA production
IV: THERAPY
A. History
- frequency and types of infections
- diet history
- autoimmune phenomena
- familial occurrence of Ig A deficiency, CVID and autoimmune disease
B. Physical Exam
- dysmorphisms as seen in different conditions associated with IgA deficiency
ie. Ataxia-Telangiectasia, Chromosome 18 Deletion
C. Laboratory Tests
- Serial IgA with age matched controls
- Quantitative Immunoglobulins
- Immunoglobulin subclasses
- Functional antibodies
- Autoimmune workup as indicated
- Anti-IgA antibodies
D. Decision for IVIG
Usually reserved for those with associated IgG subclasses and recurrent infections and/or abnormal functional antibodies.
Complicated by the risk of developing anti IgA antibodies causing anaphylaxis
Sensitization from IgA that occurs during transfusion or from cross sensitization to animal IgA in food.
It may be prudent to use IVIG with low IgA concentration and monitor anti IgA titers.
E. Blood Transfusions
Rare anaphylactic reactions, but family needs to be aware of the risk.
Consider checking for anti IgA antibodies and if positive wash blood products with saline.
V. LABORATORY EVALUATION
Methods of Measuring IgA are classified into 2 major categories:
1. Measurements of physical properties of immune complexes between antigen and antisera. ie. turbidimetry, light scattering, precipitation in gel
2. Measurement of amount of labeled antibody bound to antigen ie. labels with enzymes, fluorescent compounds or radioisotopes.
figure 9
The trends are for increased use of Nephelometry followed by Radial Immunodiffusion (RID).
A. Nephelometry
Soluble immune complexes formed by the reaction of antibody with antigen in a dilute solution will scatter light of the appropriate wavelength. If the concentration of the antibody is held constant the amount of complex formed depends on antigen concentration. The degree of light scatter is measured in a photoelectric cell as the optical density. The addition of polyethylene glycol enhances the formation of immune complexes. Antigen concentration is then calculated from a dose-response curve generated from reference sera. This process rests on the principle of zone of excess. Figure 10 and Figure 11
Disadvantages: 1. high cost of clear, potent antisera of uniform specification
2. high background from sera with lipids and hemoglobin
3. Need for dilutions with high antigen concentrations
B. Radial Immunodiffusion (RID)
Often used in smaller laboratories.
Purpose of all immunodiffusion techniques is to detect the reaction of antigen+anitbody by precipitation. The most important determinants of the reaction are the concentrations of the antibody and antigen. Immunodiffusion reactions may be single or double. Single implies either the antigen or the antibody is fixed and the other is allowed to move and complex with the fixed component. Double implies both reactants are free to move. The movement may be linear or radial.
Radial Diffusion is based on the principle that a quantitative relationship exists between the amount of antigen placed in a well cut in the agar-antibody plate and the resulting ring of precipitation. Figure 12 The size of the diameter of the ring is proportional to the concentration . Sensitivity 1-3ug/ml.
C. Passive Hemagglutination (PHA)
Used by various blood banks such as the American Red Cross to detect Anti-IgA .RBC are coated with IgA1 and IgA2. Sera to be tested is then added. Agglutination of the RBC implies the presence of Anti-IgA in the sera.