doi: 10.1161/01.ATV.0000032153.19645.5C
© 2002 American Heart Association, Inc.
Letters to the Editor |
Acquired HDL Deficiency Associated With Apolipoprotein A-I Reactive Monoclonal Immunoglobulins
Department of Medicine, University of Miami School of Medicine, Florida
To the Editor:
Immunoglobulins (Igs) directed at components of lipoproteins to cause altered lipoprotein metabolism have been described in patients with multiple myeloma,1,2 xanthomatosis,3 benign gammopathies,4 rheumatoid arthritis,5 systemic lupus erythematosus (SLE), and primary antiphospholipid syndrome (APS).6,7 In most cases, hyperlipidemia results from Igs reactive with apolipoprotein (apo) B present on very low–density lipoproteins and LDLs. Less common have been associations of Igs with hypolipidemia or reactive with HDLs. Here we describe two patients who developed low HDL-cholesterol (HDL-C) levels (<5th percentile) associated with benign gammopathy and the presence of serum Igs reactive with apo A-I.
Patient 1 (P1) was a morbidly obese (body mass index, 48 kg/m2), 45-year-old woman with mild normocytic, normochromic anemia (hematocrit, 33 g/L; hemoglobin, 11.6 g/L) and low HDL-C (0.22 mmol/L [8 mg/dL]). Serum Ig levels were elevated. Antinuclear antibodies were detected but were nonreactive with dsDNA, Sm, RNP, SSA, SSB, SCL-70, and histone. Anticardiolipin and anti–ß2-glycoprotein I antibodies were negative. Immunofixation electrophoresis (IFE) identified monoclonal IgG
and IgG
bands. No Igs or light chains were detected in her urine.
Serum lipid levels showed that HDL-C was in the low-normal to normal range between 1992 and 1996 (1.0 to 1.4 mmol/L) but at the time of presentation (November 1999), HDL was markedly reduced (0.22 mmol/L). Concomitantly, there was an increase in serum triglyceride (from <1.3 to >2.5 mmol/L) and a decrease in LDL-C levels (from >3.8 to <2.2 mmol/L). Clinical features were fatigue and the development of asthma. In July 2000, a right perinephric mass was identified as a B-cell lymphoma. High-dose prednisone therapy was initiated and completed in January 2001. The anemia and asthma improved, the perinephric mass disappeared, IgA and IgM levels returned to normal, and IgG, IgG, and IgG were reduced to subnormal levels. Treatment increased HDL-C (1.14 mmol/L [44 mg/dL]), and the patient is currently well.
A second patient (P2) was later identified with an apparent acquired HDL deficiency. This healthy 61-year-old woman was receiving estrogen replacement but had a mild normocytic anemia (hematocrit 33 g/L). Serum lipid results dating to 1987 showed a gradual decline in HDL-C from 1.32 to 0.26 mmol/L (51 to 10 mg/dL), concomitant with increasing triglycerides (from 0.9 to 2.0 mmol). Ig levels were within the normal range, and serum was negative for antinuclear and anticardiolipin antibodies. IFE revealed a monoclonal IgG band. The patient remains well apart from the mild anemia and the recent development of peripheral neuropathy.
Neither patient was taking lipid-modifying medications, had metabolic abnormalities affecting HDL (such as diabetes, liver or renal disease), or had clinically defined SLE or APS.
We tested the hypothesis that the patients were producing antibodies reactive with HDL. Patient and normolipidemic control sera were incubated with goat anti–apo A-I to precipitate HDL, and the washed, solubilized immunoprecipitates were tested for the presence of human Igs by Ouchterlony immunodiffusion. For P1, precipitin bands formed with antibodies to IgG, , and light chains (Figure 1A), the same IgG subtypes identified by IFE. IgM and IgA were not detected in the immunoprecipitates (not shown). With P2, the solubilized immunoprecipitate reacted only with antibodies to IgG and chains (Figure 1B), also identifying the same Ig subtype observed by IFE. Control sera were negative. These data demonstrated the association of Ig with HDL in the serum of the two patients.
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Next, apo A-I was subjected to electrophoresis, and after transfer to nitrocellulose, individual lanes were incubated with purified P1 IgG or control goat anti–apo A-I (Figure 1C). P1 IgG, similar to goat anti–apo A-I, reacted specifically with apo A-I. Similar results were obtained with serum IgG isolated from P2 although the reaction was less intense (not shown).
The presence of apo A-I–reactive antibodies was associated with significant abnormalities of HDL composition in the patients’ serum reflected by the near absence of larger, mature HDL2, and lipid analysis revealed relatively lipid-deficient HDL. Apo A-I–reactive Igs might induce low HDL levels if antibodies diminished the ability of nascent HDL to become lipidated and form mature particles8 or if immune complexes containing apo A-I or HDL were rapidly cleared by the reticuloendothelial system. We found that immune complexes formed between apo A-I and both patients’ IgG in vitro induced apo A-I degradation by cultured macrophages. Thus, clearance of immune complexes in vivo could induce catabolism of apoA-I, potentially preventing HDL maturation and leading to reduced HDL levels.
Apo A-I can be autoimmunogenic in humans in vivo. Apo A-I–reactive antibodies have been described in subjects with SLE and APS, although a relationship between the antibodies and HDL levels was not directly reported.7 Neither patient had clinically defined SLE or APS. Levy et al9 reported low HDL-C in patients with benign monoclonal gammopathy, multiple myeloma and Waldenstrom’s macroglobulinemia. More than half of 49 patients showed an extra lipid band on lipoprotein electrophoresis, suggesting Ig-lipoprotein complexes, but apo A-I and apo B were not detectable in the extra lipid-staining band.
Additional mechanisms could account for low HDL. Acute inflammation causes lipoprotein abnormalities mediated by acute phase reactants and (or) cytokines (reviewed by Khovidhunkit et al10). Inflammatory mediators may have influenced HDL concentrations in our patients, particularly because raised CRP levels were identified in P1; however, the decrease in HDL was of significantly greater magnitude than seen in previous studies. Apo A-I autoantibodies present an additional mechanism for causing low HDL levels.
Until a better understanding of the origins of the acquired HDL deficiency is attained, these results suggest that an unexplained marked decrease in HDL may indicate a developing gammopathy. Additional studies are needed to understand and define the prevalence of antibodies recognizing apo A-I, the relationship to HDL-C levels, and importantly, to examine whether such a mechanism of HDL deficiency represents a potential for cardiovascular disease risk.
References
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