Case 5

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1489 times

CASE 5

Bill was apparently well for most of his infant life, although he seemed to both his parents to have had an excess of upper respiratory tract infections and diarrhea (Giardia lamblia) compared with his friends. He had received all childhood immunizations without any notable negative side effects. At the age of 9 he developed an extremely severe case of sinusitis that responded well to antibiotics but caused even his family physician to wonder if there was something else going on. He was small for his age. There were no other siblings, but close attention to the family tree revealed that both an aunt and an uncle had also suffered from recurrent sinopulmonary infections and, in one case, a severe gastrointestinal infection. The aunt was still alive. Unfortunately the uncle had developed leukemia several years earlier and had died unexpectedly while receiving a blood transfusion at a small village hospital where he lived. A cousin had been diagnosed with common variable immunodeficiency (CVID) at age 30. Analysis of serum immunoglobulins using rate nephelometry, a technique that measures the amount of light scatter occurring as a beam of light encounters immune complexes in a dilute solution, showed IgG and IgM levels were normal but IgA levels were not detectable. IgG titers to childhood vaccines were in the normal range. A complete blood cell count with differential showed normal values.

QUESTIONS FOR GROUP DISCUSSION

1. This patient has had a number of infections in regions where mucous membranes play a protective role. What antibody isotype predominates at these sites?
2. The patient has received all childhood immunizations. How can this be used to assess B cell function?
3. Rate nephelometry is a technique used to quantitate serum immunoglobulin. What would you expect this test to reveal in this patient?
4. On the basis of the nephelometry results, the patient was diagnosed with selective IgA deficiency. Explain therefore the significance of a family history in which one relative died while receiving a blood transfusion while another was diagnosed with common variable immunodeficiency.
5. Explain in basic terms the principle underlying rate nephelometry.
6. Some patients with selective IgA deficiency have a normal total IgG level but yet have a deficiency of IgG2 or IgG4. Explain how this is possible.
7. Explain why intravenous administration of immunoglobulin (IVIG) is not an option for patients with selective IgA deficiency.
8. Explain why patients with selective IgA deficiency are at risk for an acute transfusion reaction if the serum contains some serum IgA.
9. How can transfusion reactions be avoided in patients with selective IgA deficiency?
10. ICOS (inducible co-stimulator) is found on activated, but not resting, T cells. On what cells is the counter molecule for ICOS expressed? What defects are noted in mice in whom the gene for ICOS or its counter molecule has been “knocked out”?

RECOMMENDED APPROACH

Implication/Analysis of Family History

Bill’s relatives have had similar clinical presentations, suggesting that Bill’s condition is the result of an inherited disorder. Because both males and females have presented with similar symptoms, Bill could have an autosomal recessive disorder.

Implication/Analysis of Clinical History

Consider first the types of infections that are reported: upper respiratory tract infections, sinusitis, and giardiasis. All of these infections are occurring in regions lined with mucous membranes where secretory IgA normally has a role in neutralizing pathogens that cause these infections (see Fig. 3-1). Already we should be considering that a defect in IgA is a possibility. This is further supported by the fact that an uncle had died during a blood transfusion (see later). As well, a cousin had been diagnosed with common variable immunodeficiency, a disorder that is more common among relatives of individuals with selective IgA deficiency than one would find in the general population.

Implication/Analysis of Laboratory Investigation

B cell function was normal, as determined by measuring antibody responses to vaccines (DPT: diphtheria, pertussis, tetanus toxoid) administered during childhood immunization. In major centers, quantitative measures of serum IgG, IgA, and IgM are determined using rate nephelometry, a technique that measures the amount of light scatter occurring as a beam of light encounters immune complexes in a dilute solution. This technique is a modification of the precipitin reaction (radial immunodiffusion) that was used for so many years to quantitate serum immunoglobulins. In rate nephelometry, the solution contains excess antibodies (anti-immunoglobulin for a particular isotype) and so when serum antibodies are added, immune complexes form readily. As the number of immune complexes increases, so does the amount of light scatter.

Additional Laboratory Tests

In some patients with IgA deficiency there is an accompanying defect in IgG antibody subclasses IgG2 or IgG4. Because some patients with a defect in IgG2 or IgG4 have elevated levels of IgG1 and IgG3, giving a normal total IgG level, rate nephelometry should be used to measure the subclass distribution. About 80% of total serum is IgG, with normal subclass distribution being IgG1, 67%; IgG2, 20% to 25%; IgG3, 5% to 10%; and IgG4, 5%.

Individuals with a deficiency in IgG2 do not produce antibodies in response to some encapsulated bacteria (e.g., Haemophilus influenzae type b), and so assessment of the antibody response to this vaccine would provide some insight into the patient’s IgG2 status. In this case, Bill’s clinical history did not include infections with encapsulated bacteria. His antibody response to childhood vaccines was normal, as was the distribution of IgG subclasses. Patients with serum levels below 7 mg/dL, in the presence of normal IgG and IgM, are considered to have IgA deficiency. Some patients have low levels of IgA, whereas others have a total absence of IgA.

DIAGNOSIS

Bill was diagnosed with selective IgA deficiency.

THERAPY

Secretory IgA is the predominant antibody at mucosal surfaces; therefore, patients present primarily with sinopulmonary and gastrointestinal infections (Fig. 5-1). In general, it is only necessary to treat the recurrent infections. Any other “heroic” measure to replace missing IgA is not warranted (cost/safety issues). Insufflation (intranasal) IgA preparations have been considered as therapy for upper respiratory tract sinus infections.

image

FIGURE 5-1 Synthesis and transportation of IgA to the lumen. IgA is synthesized in the lamina propria, binds to secretory component, and is transported to the lumen through epithelial cells. A portion of the secretory component remains attached to the IgA.

ETIOLOGY: SELECTIVE IgA DEFICIENCY

Selective IgA deficiency is the most common of the primary immunodeficiency disorders. This disorder has a genetic component in that family members and related individuals present with similar clinical symptoms. Although the cause of the defect is unknown, B cells are unable to switch isotypes to IgA production. Most patients are asymptomatic.

Anaphylaxis

Individuals who also have an IgG2 deficiency and present with recurring infections from encapsulated bacteria (e.g., Streptococcus pneumoniae) may benefit from gamma globulin prophylaxis. However, gamma globulin preparations carry minute amounts of IgA, so individuals who become sensitized to IgA and have anti-IgA antibodies are at risk for anaphylaxis on re-exposure to administered IgA.

Acute Transfusion Reaction

An acute transfusion reaction is also a risk for individuals with anti-IgA antibodies who receive a transfusion of blood containing some serum IgA. This is the most likely cause of Bill’s uncle’s death. Acute transfusion reactions occur within minutes of initiation of transfusion, reflecting effector molecules released from memory immune cells “armed” to detect the presence of molecules already recognized as being foreign. Patients typically become flushed and agitated and complain of a pain in the abdomen or chest. To avoid transfusion reactions or to avoid sensitizing IgA-deficient patients with IgA, it is recommended to transfuse red blood cells that have been washed to remove donor serum IgA

Associated Disorder

Common Variable Immunodeficiency

For individuals with IgA deficiency it is not uncommon to have a relative develop CVID as an adult. A diagnosis of CVID requires a deficiency in at least two antibody isotypes (e.g., IgG < 4 g/L; IgA < 0.5 g/dL; IgM decreased or absent). Although the cause of CVID is not known, studies of various patient populations have demonstrated different defects, including defects in B cell maturation, T cell abnormalities, and even defects in inducible co-stimulator (ICOS). ICOS is expressed on activated, but not resting, T cells. It binds to its counter molecule ICOS ligand (B7h) on B cells and provides important signals involved in ongoing B cell growth and differentiation.

About 10% of individuals diagnosed with CVID have a homozygous loss of ICOS on T cells, suggesting that ICOS-B7h interaction plays a role in class switching in activated B cells. Knockout mice for either ICOS or B7h have normal T and B cell subpopulations but defective germinal centers after antigen activation and decreased antibody production.

Related posts:

Default ThumbnailCase 7 Default ThumbnailCase 16 Case 46 Case 11 Default ThumbnailCase 21 Case 23