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Clinical Chemistry 46: 1157-1161, 2000;
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(Clinical Chemistry. 2000;46:1157-1161.)
© 2000 American Association for Clinical Chemistry, Inc.

Articles

An IgM {lambda} Antibody to Escherichia coli Produces False-Positive Results in Multiple Immunometric Assays

Michael Covinsky1,2, Omar Laterza1, John D. Pfeifer2, Tunde Farkas-Szallasi1,2 and Mitchell G. Scott1,a

Divisions of
1 Laboratory Medicine and
2 Surgical Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
a Author for correspondence. Fax 314-362-1461; e-mail mscott{at}labmed.wustl.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Interferences in immunometric assays as a result of human anti-immunoglobulin antibodies frequently have been described in the literature. The etiology of these interfering antibodies is usually not known but has been associated with rheumatoid factors in some assays. It is known that microorganisms in experimental settings can induce anti-immunoglobulin antibodies.

Methods: Following Escherichia coli septicemia, a 56-year-old male patient had increased immunoassay results for cardiac troponin I, thyrotropin, human chorionic gonadotropin, {alpha}-fetoprotein, and CA-125 that were consistent with myocardial infarction, hyperthyroidism, and pregnancy, and suggestive of an occult neoplasm such as hepatic or ovarian cancer. None of these diagnoses were consistent with the rest of his medical exam. In addition, the patient had a restricted IgM {lambda} paraprotein by immunofixation. Plasma from the patient was incubated with Sepharose-conjugated protein A, irrelevant murine monoclonal antibodies, and formalin-killed E. coli organisms from his infection to determine whether these immunoassay values were falsely increased.

Results: Incubation of the patient’s plasma with irrelevant murine monoclonal antibodies or the E. coli organism produced normal immunoassay values and removed the IgM {lambda} paraprotein.

Conclusions: The patient produced a very restricted IgM {lambda} antibody response to the E. coli infection that had anti-immunoglobulin activity and caused falsely increased values in numerous immunometric assays. Microorganism-induced anti-immunoglobulin antibodies are discussed in the context of this patient.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Human anti-animal immunoglobulin antibodies are known to interfere in immunological assays used for in vitro diagnostic purposes. A recent review extensively discussed the species specificities of various human anti-animal antibodies, their effects in different immunoassay formats, and the etiology of some interfering anti-animal antibodies (1). Because murine monoclonal antibodies are used in most commercial in vitro diagnostic immunoassays, the anti-animal antibodies of most concern are human anti-mouse antibodies (HAMAs)1 (1)(2)(3). The literature is replete with descriptions of circulating HAMAs that cause positive interferences in two-site "sandwich" immunometric assays by cross-linking the solid-phase antibody to the soluble antibody in the absence of antigen (3)(4)(5)(6). The use of murine monoclonal antibody (mAb)-derived products for therapeutic purposes or as diagnostic imaging tools is an easily understood cause of HAMAs (7). Beyond this, however, the etiology of many interfering antibodies is poorly understood and based mainly on speculation of exposure to animal proteins in foods or from farm and food-handling areas (1).

The incidence of HAMAs in the general population has been estimated to be as low as 0.7% (8) and as high as 10% (9). Nevertheless, even the lowest estimate is too high to be accounted for by individuals receiving parenteral administration of murine mAb products. One possibility to account for the relatively high incidence of interfering antibodies is heterophilic antibodies. Heterophilic antibodies are antibodies that bind multiple antigens as represented by the IgM antibody against the Paul-Bunnell antigen on sheep, horse, and bovine erythrocytes that frequently develop in immune responses to the Epstein-Barr virus. Among antibodies that bind multiple antigens are those that are the product of germ-line VH and VL genes that react with self-immunoglobulin and play an important role in the development of the mature immune system (10)(11). Related to these are rheumatoid factors, which are IgM anti-immunoglobulin antibodies and often present in serum at detectable concentrations in patients with autoimmune diseases (12). Recently, rheumatoid factor antibodies were clearly demonstrated to interfere in a cardiac troponin I (cTnI) sandwich immunoassay from Abbott (13)(14). Because such antibodies are relatively common in the elderly and in patients with autoimmune disease, it is possible that heterophilic antibodies may account for many instances of interference in immunometric assays. Finally, similar heterophilic antibodies that react with immunoglobulin may also result from antibodies raised against microbial antigens (15).

The awareness of HAMA interference has led manufacturers to indicate the possibility of HAMA interference in their package inserts and to add blocking reagents to immunometric assays along with the use of Fab fragments (16). These reagents contain irrelevant antibodies of the same species used in the assay configuration. Nevertheless, occasional patients will exhibit an interference that is difficult to explain. For example, serum from the rheumatoid factor patients studied by Dasgupta et al. (13) did not interfere in an assay for creatine kinase MB isoenzyme (CK-MB) on the same instrument as the cTnI assay. Presumably this is attributable to different blocking reagents in different assay configurations or possibly to an idiotype specificity of the interfering antibodies (17). Alternatively, the amount of blocking reagent may not always be sufficient to prevent cross-linking, or the heterophilic antibody may react with other, non-immunoglobulin, components of the assay. Here we describe the cause of an interfering antibody that affected numerous immunometric assays from a patient never exposed to murine antibodies but who was diagnosed as having an Escherichia coli septicemia.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical assays
Immunometric assays for CK-MB, myoglobin, and cTnI were performed on the Dade Dimension RxL and the Dade Stratus II. Assays for carcinoembryonic antigen, {alpha}-fetoprotein, thyrotropin, human chorionic gonadotropin, CA-125, luteinizing hormone, ferritin, and follicle-stimulating hormone were performed on the Abbott AxSYM. The assay for prostate-specific antigen was performed on the Beckman/Hybritech ERA, and the assay for parathyroid hormone was performed on the DPC IMMULITE. Serum protein electrophoresis and immunofixation were performed using the Beckman Paragon system. All assays were performed according to the manufacturers’ recommended procedures.

Immunologic reagents
Protein A-Sepharose was purchased from Pharmacia. Mouse IgG1 monoclonal antibodies to the parathyroid hormone receptor (mAbs 3D1.1 and 5G3.1) were prepared by one of us (M.G.S.), and the mouse IgG1 mAb to cTnI was kindly provided by Dr. Jack Ladenson, Washington University, St. Louis, MO (18). The mAbs were coupled to CNBr-activated Sepharose 4B (Pharmacia) and washed extensively with phosphate-buffered saline (PBS), pH 7.4, containing 10 g/L bovine serum albumin before use.

Bacterial cultures
E. coli isolated from the patient in question, from an isolate of another patient, and from the ATCC strain 25952 was cultured in tryptic soy broth for 16–18 h. The organisms were then centrifuged, washed in PBS, and then formalin killed and fixed as described previously (19). The fixed organisms were washed in PBS and then resuspended in PBS containing 10 g/L bovine serum albumin at ~5 x 109 organisms/mL.

Patient serum and plasma
All dilutions of the patient plasma samples were prepared using a 10 g/L solution of bovine serum albumin in PBS. Plasma or serum from the patient was incubated with protein A-conjugated Sepharose 4B, murine mAb-conjugated Sepharose, or unconjugated Sepharose. Briefly, 600 µL of undiluted sample or 600 µL of sample prediluted 1:5 was added to a 400-µL pellet of conjugated or unconjugated Sepharose and incubated with rotation at room temperature for 16–18 h. A 500-µL undiluted serum or plasma sample was also mixed with a 200-µL pellet (~109 organisms) of each of the E. coli isolates as described previously (19) and incubated as above.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Case
The patient was a 56-year-old white male who presented with a history of benign prostatic hypertrophy and a urinary tract infection presumably attributable to urethral obstruction. After intravenous ampicillin/sulfbactam and cefipime therapy, the patient did not improve and was admitted to the hospital several days later. E. coli was isolated from blood cultures collected on the day of admission and found to be ampicillin/sulfbactam resistant. The patient was placed on intravenous cefipime and oral ciprofloxacin antibiotic therapy. On the third day of hospitalization, the patient complained of jaw pain, fever, and chills. A cTnI was ordered because of the jaw pain, and the result was 8.7 µg/L from the Dade Dimension RxL. Six hours later, the cTnI was 12.7 µg/L, and the patient was admitted to the coronary care unit. Over the next 5 days, the cTnI value nearly doubled every day until it reached a value of 220 µg/L on day 7. Despite the increased cTnI values, there was no evidence of cardiac damage or arterial obstruction by angiography, echocardiogram, or electrocardiography. By day 5 of hospitalization, the patient was ambulatory, eating well, and requesting discharge despite the fact his cTnI value was 52 µg/L. The laboratory medicine resident was contacted, and the following experiments were carried out to help assess the patient’s status.

Values from other immunometric assays
To investigate the possibility of an interference in the RxL cTnI assay, CK-MB and myoglobin assays were performed on the Dade Dimension RxL and on the Dade Stratus analyzers. Interestingly, all values (including cTnI) from the Stratus, as well as the CK-MB and myoglobin assays on the Dimension RxL, were below the limit of assay detection. These results were immediately transmitted to the patient’s physician with our suspicion that the cTnI values were falsely increased. Because of our suspicion of interference in some immunometric assays, we examined every immunometric assay in our laboratory to see how general the interference might be. Most striking were the markedly increased values obtained for human chorionic gonadotropin, CA-125, thyrotropin, and {alpha}-fetoprotein on the Abbott AxSYM system (Table 1 ). Values for carcinoembryonic antigen, luteinizing hormone, follicle-stimulating hormone, ferritin, prostate-specific antigen, and parathyroid hormone were within the reference ranges and unlikely to represent falsely increased values (data not shown).


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  		Table 1. Effect of different immunoadsorptions on immunoassay values.1

Adsorption studies
To further elucidate the cause of the apparent interference in these immunometric assays, the patient’s sample was incubated with protein A-Sepharose, murine mAb-conjugated Sepharose, or unconjugated Sepharose. Incubation with protein A-Sepharose had no effect on the interference exhibited in the cTnI assay (Table 1Up ). In contrast, incubation with any of three murine mAbs conjugated to Sepharose produced marked diminution or elimination of the interference, suggesting that the interference was caused by HAMAs. The lack of effect from protein A adsorption suggested that the HAMA activity was attributable to an IgM antibody, and because of the patient’s recent E. coli septicemia, we speculated that the IgM HAMA activity may have been induced by the organism. Therefore, the patient’s sample was incubated with formalin-killed E. coli from three sources. All of the interferences were either eliminated or markedly diminished after adsorption to the E. coli isolate from the patient but not after adsorption to an E. coli isolate from another patient or ATCC strain 25952 (Table 1Up ). Taken together, the antibodies this patient raised to E. coli clearly had HAMA activity and were causing the interference in these immunometric assays. In a follow-up visit 30 days after his hospitalization, the interference had markedly waned such that the falsely increased "cTnI" value from the RxL analyzer was 22 µg/L, which is consistent with the half-life of IgM.

Serum protein electrophoresis
Because antibodies to bacterial capsular carbohydrates (CHOs) often are very restricted in their V-region heterogeneity (19)(20)(21)(22) and because of the apparent magnitude of this response, we performed serum protein electrophoresis. Serum protein electrophoresis demonstrated an abnormal restricted peak in the {gamma} region (not shown). Immunofixation revealed that the restricted peak was IgM {lambda} (Fig. 1 , top panel). The restricted peak was eliminated when the patient’s serum was incubated with either his E. coli isolate (Fig. 1 , middle panel) or murine mAb (not shown) conjugated with Sepharose, whereas protein A-Sepharose did not eliminate the restricted peak (Fig. 1 , bottom panel). Incubation of the patient’s serum with the other two, irrelevant E. coli isolates also had no effect on the restricted peak (not shown). Thirty days after hospitalization, the restricted IgM {lambda} peak was no longer detectable by serum protein electrophoresis or immunofixation.



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  		Figure 1. Immunofixation electrophoresis of patient’s sample.

(top), untreated sample; (middle) sample after adsorption to formalin-fixed E. coli organisms; (bottom), sample after adsorption to protein A-Sepharose. IFE, immunoelectrophoresis; SPE, serum protein electrophoresis.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We describe here a 56-year-old male ambulatory, eating well, and asking to go home with simultaneous laboratory data that could be interpreted to suggest pregnancy (testicular carcinoma), myocardial infarction, hypothyroidism, and possible occult neoplasms. We have conclusively shown that these were falsely increased values that were the result of the IgM {lambda} antibody response the patient mounted to his E. coli infection. The patient’s antibody response to E. coli was very restricted as evidenced by the IgM {lambda} peak by serum protein electrophoresis and immunofixation. We suspect that that this antibody with HAMA activity is against the CHOs of the organism for several reasons: (a) It is well-known that the antibody repertoire to CHO antigens is very restricted in both humans and in mice (20)(21)(22). (b) There is considerable heterogeneity in the CHOs of different strains of gram-negative bacteria, and antibodies to bacterial CHO antigens often exhibit fine specificity that can differentiate subtle differences in CHO structure (19)(20). Thus, if these antibodies were against membrane proteins of E coli, it is likely that the IgM {lambda} restricted peak and the interferences present in the immunometric assays would also have been eliminated by the other two isolates of E. coli tested. (c) Antibodies to bacterial CHOs, such as E. coli K100 and Haemophilus influenzae type b, are known to frequently use the same V region genes that are present in human antibodies with autoimmune activity, including some rheumatoid factors (23)(24). (d) The mechanism of microorganism-induced anti-immunoglobulin antibodies is believed to be attributable to highly repetitive epitopes (25). Clearly, this patient’s anti-E. coli antibody also had anti-immunoglobulin activity as evidenced by the interference that was eliminated by adsorption to murine mAb-conjugated Sepharose. It is also possible that the heterophilic nature of this antibody allowed binding of other CHO epitopes on assay components in addition to the anti-immunoglobulin activity.

The restricted expression of a set of VH and VL genes in the response to bacterial CHO antigens in autoimmune antibodies and in the developing human antibody repertoire has led to the hypothesis that autoantibody-producing B cells may be stimulated by exposure to microorganisms (15)(25)(26). Early in the development of the antibody repertoire, a restricted set of V genes that have self-immunoglobulin reactivity are preferentially expressed (10)(12)(27), and these germline V genes often are expressed in murine and human antibacterial responses (22)(23). Although we do not have sufficient sample from this patient to sequence the VH gene of his anti-E. coli antibody with HAMA activity, we would predict that it would be the product of one of these dominant, early-expressed VH genes. Also of interest is that among some VH3 anti-CHO antibodies in humans, those expressing a {lambda} light chain have broader fine specificity than those containing a germline {kappa} L-chain product, which may explain the heterophilic nature of this patient’s antibody to E. coli (21).

The antibody from this patient clearly demonstrates that a restricted anti-E. coli antibody can have HAMA activity and also produce marked interference in several commercial immunometric assays. Aside from the obvious induction of HAMAs by administration of murine mAb products, this represents the first definitive etiology of an interfering heterophilic antibody that causes marked positive interference in diagnostic immunometric assays. Further studies will be necessary to determine whether other patients with antibacterial CHO responses express similar interfering activities and whether suspicion of interferences in immunometric assays should be heightened in patients with recent infections with gram-negative organisms. This case demonstrates the importance of both clinicians and laboratorians being aware of the possibility of falsely increased values from these types of assays despite the continuing efforts of manufacturers to add blocking reagents to overcome these interferences. It may also provide a clue for the best "recipe" for a blocking reagent because both manufacturers whose assays were affected by this antibody produce other assays that were not affected.


   Footnotes
 
1 Nonstandard abbreviations: HAMA, human anti-mouse antibody; mAb, monoclonal antibody; cTnI, cardiac troponin I; CK-MB, creatine kinase MB isoenzyme; PBS, phosphate-buffered saline; and CHO, carbohydrate.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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